I
*
United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA/600/8-89/049A
March 1989
CASAC Review Draft
Research and Development
Supplement to the
1986 EPA Air Quality
Criteria for Lead -
Volume I Addendum
(pages A1-A67)
Review
Draft
(Do Not
Cite or Quote)
NOTICE
This document is a preliminary draft. It has not been formally released by EPA and
should not at this stage be construed to represent Agency policy. It is being
circulated for comment on its technical accuracy and policy implications.
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DRAFT EPA/600/8-89/049A
DO NOT QUOTE OR CITE March 1989
CAS AC Review Draft
Supplement to the 1986
EPA Air Quality Criteria for
Lead -Volume I Addendum
(pages A1-A67)
NOTICE
This document is a preliminary draft. It has not been formally released by the U.S.
Environmental Protection agency and Should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its technical accuracy
and policy implications.
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC 20460
Eiwfowmental Protection ***»
anf(Pt-l2£.
son Bou^aw
60604-3590
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DISCLAIMER
This document is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products does
not constitute endorsement or recommendation for use.
ii
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CONTENTS
TABLES iv
FIGURES vi
ABSTRACT vi i
AUTHORS vi i i
I. INTRODUCTION 1
II. RELATIONSHIP OF BLOOD PRESSURE TO LEAD EXPOSURE 2
III. NEUROBEHAVIORAL AND GROWTH EFFECTS IN INFANTS AND CHILDREN .. 23
IV. REFERENCES 63
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TABLES
Number Page
1 Coefficients for the natural log of blood lead
concentration (logPbB) vs. blood pressure (BP) in
men with and without adjustment for site variables 8
2 Infants' mental development index scores according
to cord blood lead group 24
3 Change in McCarthy general cognitive index (GCI) and
subscale scores associated with each natural log unit
increase in blood lead level 26
4 Results of multiple regression analyses examining
the relationship between blood lead level and
performance on the Bayley Mental Index at 3-24 months
of age 28
5A The relationship of fetal (maternal and cord) PbB with
later developmental outcomes 33
5B The relationship of prior and current postnatal PbB
with later developmental outcomes 33
6 The relationship of prenatal and postnatal log blood
lead with IQ at age four years, ten months 34
7 Estimated coefficients of log blood lead concentration
from simple and multiple regression analyses of McCarthy
scores at the age of four years 37
8 Regression of developmental indices on maternal and
cord blood 1 ead 1 eve! s 39
9 Regression of developmental indices at 48 months on
current and prior blood levels 41
10A Significant bivariate correlations of 30-day NBAS
trend and lead measures 43
10B Effect of addition of lead to the stepwise multiple
regression model using prior entry of all control
variables that have significant bivariate correlations
with 30-day trend of NBAS 43
11 Unexplained correlations between dentine lead levels
(log ug/g) taking into account test reliability,
confounding covariates, sample selection factors, and
reverse causality via pica 46
IV
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TABLES
Number Page
12 Product moment correlations between maternal, teacher
behaviour ratings and dentine lead values (log pg/g) 47
13 Strongest relationships between blood lead measures
at specified times and later neurobehavioral outcomes
as detected by prospective studies 60
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FIGURES
Number Page
1 Comparison of study results from four larger-scale
epidemiology studies of lead-blood pressure relation-
ships in adult men. BRHS = British Regional Heart
Study analyses, described by Pocock et al. (1988);
NHANES II = National Health and Nutrition Evaluation
Survey analyses described by Schwartz (1988);
Caerphilly and Wales = Welsh studies described by
Elwood et al. (1988a,b) 14
VI
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ABSTRACT
The 1986 U.S. EPA document Air Quality Criteria for Lead
(EPA-600/8-83/028 aF-dF) evaluated in detail the latest scientific
information concerning sources, routes, and levels of lead (Pb) exposure
and associated health effects and potential risks. An Addendum (1986)
to that document focuses on additional, newer studies concerning the
effects of lead on cardiovascular function and on early physical and
neurobehavioral development. The present Supplement to the above
materials evaluates further still newer information emerging in the
published literature concerning (1) lead effects on blood pressure and
other cardiovascular endpoints and (2) the effects of lead exposure
during pregnancy or early postnatally on birth outcomes and/or the
neonatal physical and neuropsychological development of affected
children. The evaluations contained in this Supplement and the 1986
Criteria Document and Addendum are to serve as scientific inputs to
decisionmaking with regard to review and revision, as appropriate, of
the National Ambient Air Quality Standards (NAAQS) for Lead.
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AUTHORS
Dr. J. Michael Davis, Environmental Criteria and Assessment Office
(MD-52), OHEA, ORD, U.S. Environmental Protection Agency,
Research Triangle Park, NC 27711
Dr. Lester D. Grant, Environmental Criteria and Assessment Office
(MD-52), OHEA, ORD, U.S. Environmental Protection Agency,
Research Triangle Park, NC 27711
Dr. Winona W. Victery, Environmental Criteria and Assessment Office
(MD-52), OHEA, ORD, U.S. Environmental Protection Agency,
Research Triangle Park, NC 27711
REVIEWERS
Dr. David Bellinger, Harvard Medical School, Children's Hospital,
Boston, MA 02115
Dr. Kim N. Dietrich, Institute of Environmental Health, University of
Cincinnati, College of Medicine, Cincinnati, OH 45267-0056
Dr. David J. Svendsgaard, Health Effects Research Laboratory (MD-55),
OHR, ORD, U.S. Environmental Protection Agency, Research Triangle
Park, NC 27711
vm
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SUPPLEMENT TO THE 1986 EPA LEAD CRITERIA DOCUMENT ADDENDUM
I. INTRODUCTION
In the mid-1980's, the 1977 EPA criteria document, Air Quality Criteria
for Lead (U.S. EPA, 1977) was updated and revised pursuant to Sections 108-109
of the Clean Air Act, as amended, 42 U.S.C. 7408 and 7409. The final version
of the updated criteria document (U.S. EPA, 1986a) incorporating revisions made
in response to public comments and CASAC review of earlier drafts, was com-
pleted in 1986 to be used as a basis for review and, as appropriate, revision
of the National Ambient Air Quality Standard (NAAQS) for lead. An Addendum
(U.S. EPA, 1986b) to the revised document, Air Quality. Criteria for Lead (U.S.
EPA, 1986a), was also completed in 1986 and evaluated newly published informa-
tion concerning two topics: (1) the relationship between blood lead levels and
cardiovascular effects; and (2) lead exposure effects on early development and
stature.
In the three years since the 1986 Addendum was prepared, information
pertaining to the health effects of lead has continued to emerge with regard to
the topics addressed in that Addendum. Although newer findings have been
generally consistent with the state of understanding that was articulated in
the 1986 Addendum, they still need to be evaluated as part of an updated
assessment of the latest scientific information that characterizes the health
effects of lead (Pb) with clear relevance for decisionmaking on potential
revision of the existing Lead NAAQS.
The present update focuses primarily on key findings that have emerged in
the lead literature since 1986 in the areas of lead effects on: (1) blood
pressure and related cardiovascular endpoints and (2) child development. It
does not attempt to be comprehensive in reviewing this literature, nor does it
attempt to address all the topics covered in the 1986 Air Quality Criteria
Document and Addendum. Rather, its explicit purpose is to describe and inter-
pret the critical effects of lead thft. have greatest significance for impending
regulatory decisions regarding this environmental pollutant.
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II. RELATIONSHIP OF BLOOD PRESSURE TO LEAD EXPOSURE
The 1986 Addendum (U.S. EPA, 1986b) addressed the issue of lead effects on
the cardiovascular system in a review of the findings with regard to overtly
lead-intoxicated individuals, epidemiologic studies of associations between
lead exposure and increased blood pressure, toxicologic data providing evidence
for lead-induced cardiovascular effects in animals, and information on the
possible mechanisms of action of lead on cardiovascular function. The amount
and sufficiency of the literature at that time were adequate to provide an
initial evaluation of the topic, but did not come to a fully definitive
consensus with regard to the contributory role of lead exposure to hyper-
tension. Also not fully resolved was the extent to which lead-induced hyper-
tension or other types of lead-induced pathogenic effects contribute to more
serious morbidity (heart attack, stroke) and mortality of the human population.
For the purposes of this supplement, primary emphasis will be placed here
on updated discussion of key human population-based studies which reflect
primarily non-occupational exposure to lead. The largest study populations
have been the second National Health and Nutrition Examination Survey (NHANES
II) for the U.S. population (performed during the years 1976-80) and the
British Regional Heart Study (BRHS), an ongoing evaluation of men aged 40 to 59
from 24 British towns. These studies were earlier described in detail in the
published literature (Harlan et al., 1985; Pocock et al., 1984; Pirkle et al.,
1985; Shaper et al., 1981); and further analyses of the subject data sets have
been presented and discussed extensively at a 1987 U.S. EPA co-sponsored
International Symposium on Lead-Blood Pressure Relationships and in other
recent publications. In addition, analyses of several other data sets have
been presented by other investigators at the 1987 Symposium or elsewhere in the
published literature since the 1986 Addendum was prepared.
The 1986 Addendum (U.S. EPA, 1986b) noted that several then recently
published studies provided generally consistent evidence for increased blood
pressure (BP) being associated with elevated lead body burdens in adults,
especially as indexed by blood lead (PbB) levels in various cohorts of adult
men. None of the individual studies, it was noted, provided definitive evidence
establishing causal relationships between lead exposure and increased blood
pressure, but they collectively provided considerable qualitative evidence
indicative of significant associations between blood lead and blood pressure
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levels. It was further emphasized that estimates of quantitative relationships
between blood lead levels and blood pressure increases derived from such study
results are subject to much uncertainty, given the relatively small sample
sizes and limited population groups typically studied. On the other hand, the
above-noted larger-scale studies (NHANES II and BRHS) of general population
groups, were singled out as providing reasonably good bases for estimation of
quantitative blood-lead blood-pressure relationships.
As reviewed in the 1986 Addendum (U.S. EPA, 1986b), in the BRHS, Pocock
et al. (1984) evaluated relationships between blood lead concentrations,
hypertension, and renal function indicators in a clinical survey of 7,735
middle-aged men (aged 40-49) from 24 British towns. Each man's blood pressure,
while seated, was measured twice in succession by means of a London School of
Hygiene sphygmomanometer. Diastolic pressure was recorded at phase V disap-
pearance of sounds. The mean of the two readings of blood pressure was
adjusted for observed variation within each town to correct for any differences
among three observers. Results for 7,371 men included in data analyses indi-
cated correlation coefficients of r = +0.03 and r = +0.01 for associations
between systolic and diastolic blood pressure, respectively, and blood lead
levels. The systolic blood pressure correlation, though small in magnitude,
was nevertheless statistically significant at p <0.01. However, analyses of
covariance using data for men categorized according to blood lead concentra-
tions only suggested increases in blood pressure at lower blood lead levels; no
further significant increments in blood pressure were observed at higher blood
lead levels either before or after adjustment for factors such as age, town,
body mass index, alcohol consumption, social class, and observer. Evaluation
of prevalence of hypertension defined as systolic blood pressure over 160 mm Hg
revealed no significant overall trend; but of those men with blood lead levels
over 37 ug/dl, a larger proportion (30 percent) had hypertension when compared
with the proportion (21 percent) for all other men combined (p =0.08). Similar
results were obtained for diastolic hypertension defined as >100 mm Hg, i.e., a
greater proportion (15 percent) of men with blood lead levels over 37 ug/dl had
diastolic hypertension in comparison with the proportion (9 percent) for all
other men (p =0.07).
Pocock et al. (1984) interpreted their findings as being suggestive of
increased hypertension at blood lead levels over 37 ug/dl, but not at lower
concentrations typically found in British men. However, further analyses
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reported by Pocock et al. (1985) for the same data indicated highly statisti-
cally significant associations between both systolic (p =0.003) and diastolic
(p <0.001) blood pressure and blood lead levels, when adjustments are made for
variation due to site (town) in multiple regression analyses. The regression
coefficients for log blood lead versus systolic and diastolic pressure were
+2.089 and +1.809, respectively, when adjusted for town as well as body mass,
age, alcohol, smoking, social class and observer. Noting the small magnitude
of the association observed and the difficulty in adjusting for all potentially
relevant confounders, Pocock et al (1985) cautioned at that time against
prematurely concluding that elevated body lead burden has a causal influence on
blood pressure.
The 1986 Addendum (U.S. EPA, 1986b) also noted that relationships between
blood lead and blood pressure among American adults had begun to be evaluated
in another large-scale study, as reported by Harlan et al. (1985), Pirkle
et al. (1985), and Schwartz (1985a,b; 1986a,b). These analyses were based on
evaluation of NHANES II data, which provide careful blood lead and blood
pressure measurements on a large-scale sample representative of the U.S.
population and considerable information on a wide variety of potentially
confounding variables as well. As such, these analyses avoided the problem of
selection bias, the healthy-worker effect, workplace exposures to other toxic
agents, and problems with appropriate choice of control groups that often
confounded or complicated earlier, occupational studies of blood-lead blood-
pressure relationships. Three blood pressure readings were recorded for each
subject: while seated early in the examination, supine midway in the examina-
tion, and seated near the end. First and fifth phase sounds were taken as
systolic and diastolic pressures, respectively. The second seated blood
pressure was used in statistical analyses, but analyses using the first seated
pressure or a mean of the first and second seated pressure yielded similar
results. Blood lead values, determined by AA spectrometry, were transformed to
log values used in statistical analyses.
Relationships between blood pressure and other variables were evaluated in
two ways. First, men and women were stratified into normotensive and
hypertensive categories and mean values for relevant variables contrasted
across the categories. For ages 21-55 yr, diastolic high blood pressure (>90
mm Hg) male subjects (N = 475) had significantly (p <0.005) higher PbB levels,
body mass index values, and calcium foods than did normotensive male subjects
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(N = 1,043). Similar results were obtained for aged 21-55 yr diastolic high
blood pressure females (N = 263) in comparison to normotensive females
(N = 1,316). For ages 56-74 yr subjects, significantly (p <0.05) higher PbB
levels were found for female subjects (but not males) defined as having
isolated systolic high blood pressure (i.e., systolic >160 and diastolic <90 mm
Hg). Simple correlation analyses and step-wise multiple regression analyses
were carried out as a second statistical evaluation approach; PbB values were
entered into predictive models for systolic and diastolic pressure as well as
several other pertinent variables (such as age, body mass index, etc.) entered
sequentially according to greatest magnitude of variance explained for the
dependent variable. The simple correlation analyses reported by Harlan et al.
(1985) demonstrated statistically significant linear associations (p <0.001)
between blood lead concentrations and blood pressure (both systolic and
diastolic) among males and females, aged 12 to 74 years. Using multiple
regression analyses controlling for a number of other potentially confounding
factors, however, the blood-lead blood-pressure associations remained
significant for males but not for women after adjusting for the effects of
other pertinent variables.
Additional analyses of NHANES II data reported by Pirkle et al. (1985)
focussed on white males (aged 40 to 59 years) in order to avoid the effects of
collinearity between blood pressure and blood lead concentrations evident at
earlier ages and because of less extensive NHANES II data being available for
non-whites. In the subgroup studied, Pirkle et al. (1985) found significant
associations between blood lead and blood pressure even after including in
multiple regression analyses all known factors previously established as being
correlated with blood pressure. The relationship also held when tested against
every dietary and serologic variable measured in the NHANES II study.
Inclusion of both curvilinear transformations and interaction terms altered
little the coefficients for blood pressure associations with lead (the
strongest relationship was observed between the natural log of blood lead and
the blood pressure measures). The regression coefficients for log blood lead
versus systolic and diastolic blood pressure were 8.436 and 3.954,
respectively. No evident threshold was found below which blood lead level was
not significantly related to blood pressure across a range of 7 to 34 ug/dl.
In fact, the dose-response relationships characterized by Pirkle et al. (1985)
indicate that large initial increments in blood pressure occur at relatively
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low blood lead levels, followed by leveling off of blood pressure increments at
higher blood lead levels. Pirkle et al. (1985) also found lead to be a
significant predictor of diastolic blood pressure greater than or equal to
90 mmHg, the criterion blood pressure level now standardly employed in the
United States to define hypertension. Additional analyses were performed by
Pirkle et al. (1985) to estimate the likely public health implications of their
findings concerning blood-lead, blood-pressure relationships. Changes in blood
pressure that might result from a specified change in blood lead levels were
first estimated. Then coefficients from the Pooling Project and Framingham
studies (Pooling Project Research Group, 1978 and McGee and Gordon, 1976,
respectively) of cardiovascular disease were used as bases: (1) to estimate
the risk for incidence of serious cardiovascular events (myocardial infarction,
stroke, or death) as a consequence of lead-induced blood pressure increases and
(2) to predict the change in the number of serious outcomes as the result of a
37 percent decrease in blood lead levels for adult white males (aged 40-59
years) observed during the course of the NHANES II survey (1976-1980).
The earlier Addendum (U.S. EPA, 1986b) also noted that questions had been
raised by Gartside (1985) and E.I. Du Pont de Nemours (1986) regarding the
robustness of the findings derived from the analyses of NHANES II data
discussed above and as to whether certain time trends in the NHANES II data set
may have contributed to (or account for) the reported blood-lead blood-pressure
relationships. Gartside reported analyses of HNANES II data which found that
the size and level of statistical significance of coefficients obtained varied
depending upon specific data aggregations used in analyzing the data. The
largest and most significant coefficients for blood lead versus blood pressure
were obtained by Gartside for data aggregated by age groups that approximated
that of the 40-59 yr male aggregation described by Pirkle et al. (1985), with
coefficients for most younger cohort groups aggregated by varying 20 yr age
intervals (e.g., 21-40, 22-42 yrs, etc.) or older groups not always being
significant at p <0.05. As for the time trend issue, both blood lead and blood
pressure declined substantially during the 4-yr NHANES II study and different
geographic sites were sampled without revisitation of the same site over the
survey period. Thus, variations in the sampling sites over time, coincident
with changes in blood lead and/or blood pressure, might contribute to any
observed associations between blood lead and blood pressure. E.I. Du Pont de
Nemours (1986) reported that multiple regression coefficients decreased in
magnitude and some became non-significant at p <0.05 when geographic site was
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adjusted for in analyses of NHANES II data, including analyses for the male
group (aged 12-74) reported on by Harlan et al. (1985) and for males (aged
40-59) reported on by Pirkle et al. (1985). For example, E.I. Du Pont de
Nemours reported unpublished reanalyses of NHANES II data confirming signifi-
cant associations for both aged 12-74 yrs males and 40-59 yr males between log
PbB and systolic or diastolic blood pressure unadjusted for geographic site,
but smaller coefficients (nonsignificant for diastolic) when geographic site
was included in the analysis. However, neither the Gartside nor E.I. Du Pont
de Nemours analyses adjusted for all of the variables that were selected for
stepwise inclusion in the Harlan et al. (1985) and Pirkle et al. (1985)
published analyses by means of a priori decision rules for inclusion of vari-
ables having significant associations with blood pressure. Also, other differ-
ences existed in regard to specific aspects of the modeling approaches employed,
making it extremely difficult to assess clearly the potential impact of varia-
tion in selection of age groups and geographic site adjustment on NHANES II
analyses results.
In order to address the "site" issue more definitively, Schwartz (1985a,b;
1986a,b) carried out a series of additional reanalyses of the NHANES II data.
Those analyses confirm that the regression coefficients remain significant for
both systolic and diastolic blood pressure when site is included as a variable
in multiple regression analyses. Of several different approaches used by
Schwartz, the most direct was holding all aspects of the original Pirkle et al.
(1985) analyses the same except for the addition of a variable controlling for
the 64 geographic sites sampled in NHANES II. Using this approach, the coffi-
cients for log PbB in relation to either diastolic or systolic BP dropped
somewhat from those of the original analyses when site was controlled for
(i.e., from 8.44 to 5.09 for systolic and from 3.95 to 2.74 for diastolic blood
pressure), but the coefficients for each still remained significant at p <0.05.
When still other approaches were used to control for site along with variations
in other variables included in the analyses, statistically significant results
were still consistently obtained both for males aged 40-59 and for males aged
20-74. The results obtained by Schwartz (1985a,b; 1986a,b) via reanalysis of
NHANES II data (unadjusted versus adjusted for geographic site) are presented
in Table 1 in comparison to results reported by E.I. Du Pont de Nemours (1986)
and in relation to the findings presented by Pocock et al. (1984, 1985) for
British men (also unadjusted versus adjusted for site).
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TABLE 1. COEFFICIENTS FOR THE NATURAL LOG OF BLOOD LEAD CONCENTRATION
(logPbB) VS. BLOOD PRESSURE (BP) IN MEN WITH AND WITHOUT
ADJUSTMENT FOR SITE VARIABLES
Analysis
Performed by
Study
Group
Coefficient of
log PbB vs. BP
Unadjusted
for Site
Adjusted
for Site
Pocock et al.
(1984, 1985)
Schwartz (1985a,b)
E.I. Du Pont
de Nemours(1986)
Schwartz (1986a,b)
E.I. Du Pont
de Nemours (1986)
British Regiona]
Heart Study
White males aged 40-59
Systolic (n=7371)
Diastolic (n=7371)
NHANES II
Males aged 20-74
Systolic (n=2254)
Diastolic (n=2248)
NHANES II
Males aged 12-74
Systolic (n=2794)
Diastolic (n=2789)
NHANES II
White males aged 40-59
Systolic (n=543)
Diastolic (n=565)
NHANES II
White males aged 40-59
Systolic (n=553)
Diastolic (n=575)
1.68**
0.30
5.23***
2.96***
3.43***
2.02***
8.44**
3.95**
6.27**
4.01**
2.09**
1.81***
3.23**
1.39*
1.95*
0.36
5.01*
2.74*
3.46*
1.93*
*p < 0.05
**p < 0.01
***p < 0.001
The 1986 Addendum (U.S. EPA, 1986b) concluded that, overall, the analyses
of data from the two large-scale general population studies (British Regional
Heart Study and U.S. NHANES II Study) discussed above collectively provide
highly convincing evidence demonstrating small but statistically significant
associations between blood lead levels and increased blood pressure in adult
men. The strongest associations appear to exist for males aged 40-59 and for
systolic somewhat more so than for diastolic pressure. Virtually all of the
analyses revealed positive associations for the 40-59 aged group, which remain
or become significant (at p <0.05) when adjustments are made for geographic
site. Furthermore, the results of these large-scale studies were noted to be
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consistent with similar findings of statistically significant associations
between blood lead levels and blood pressure increases as derived from other
smaller-scale studies discussed in the Addendum, which also mainly found
stronger associations for systolic pressure than for diastolic.
The Addendum (U.S. EPA, 1986b) further concluded that none of the observa-
tional studies in and of themselves can be stated as definitively establishing
causal linkages between lead exposure and increased blood pressure of hyper-
tension. However, the Addendum noted that the plausibility of the observed
associations reflecting causal relationships between lead exposure and blood
pressure increases is supported by: (1) the consistency of the significant
associations found by numerous independent investigators for a variety of study
populations; and (2) by extensive toxicological data discussed in the 1986
Addendum which clearly demonstrate increases in blood pressure for animal
models under well-controlled experimental conditions. The precise mechanisms
underlying relationships between lead exposure and increased blood pressure,
the Addendum further stated, appear to be complex and mathematical models
describing the relationships still remained to be more definitively charac-
terized. At the time of the Addendum log PbB-BP models appeared to fit best
the available data, but linear relationships between blood lead and blood
pressure could not be ruled out. The most appropriate coefficients character-
izing PbB-BP relationships also remained to be more precisely determined,
although those listed in Table 1 obtained by analyses adjusting for site
appeared to be the currently best available and most reasonable estimates of
the likely strength of the association for adult men (i.e., generally in the
range of 2.0-5.0 for log PbB versus systolic and 1.4 to 2.7 for log PbB versus
diastolic blood pressure). The 1986 Addendum went on to note that the full
range of blood lead levels that may be associated with increased blood pressure
also remained to be more clearly defined. However, the collective evidence
from the above studies points toward low or moderately elevated blood lead
levels as being associated with blood pressure increases, with certain evidence
(e.g., the NHANES II data analyses and some other study results) also indicat-
ing significant relationships between blood pressure elevations and blood lead
levels ranging down, possibly, to as low as 7 (jg/dl.,
The earlier Addendum (U.S. EPA, 1986b) further stated that the quantifica-
tion of likely consequent risks for serious cardiovascular outcomes, as
attempted by Pirkle et al. (1985), also remained to be more precisely
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characterized. The specific magnitudes of risk obtained for serious cardio-
vascular outcomes in relation to lead exposure, estimated on the basis of
lead-induced blood pressure increases, depend crucially upon: the form of the
underlying relationship and size of the coefficients estimated for blood-lead
blood-pressure associations; lead exposure levels at which significant eleva-
tions in blood pressure occur; and coefficients estimating relationships
between blood pressure increases and specific more serious cardiovascular
outcomes. It was noted that uncertainty still existed regarding the most
appropriate model and blood-lead blood-pressure coefficients, which made it
difficult to resolve which specific coefficients should be used in attempting
to project more serious cardiovascular outcomes. Similarly, it was indicated
that it is difficult to determine appropriate blood lead levels at which any
selected coefficients might be appropriately applied in models predicting more
serious cardiovascular outcomes. Lastly, it was noted that the selection of
appropriate models and coefficients relating blood pressure increases to more
serious outcomes is also fraught with uncertainty. Questions exist regarding
the general applicability of coefficients derived from the Pooling Projects and
Framingham Study to the men aged 40-59 in the general U.S. population. Further
analyses of additional large scale epidemiologic data sets, it was stated in
the Addendum, would be necessary to determine more precisely quantitative
relationships between blood-lead and blood-pressure, and more serious cardio-
vascular outcomes as well.
The Addendum (U.S. EPA, 1986b) went on to note further that the above
findings, while pointing toward a likely causal effect of lead in contributing
to increased blood pressure need to be placed in broader perspective in rela-
tion to other factors involved in the etiology of hypertension. The underlying
causes of increased blood pressure or "hypertension" (diastolic blood pressure
above 90 mm Hg), which occurs in as many as 25 percent of Americans, are not
yet fully delineated (Frohlich, 1983; Kaplan, 1983). However, it is very clear
that many factors contribute to development of this disease, including heredi-
tary traits, nutritional factors and environmental agents. The relative roles
of various dietary and environmental factors in influencing blood pressure and
the mechanisms by which they do so are a matter of intense investigative effort
and debate (see proceedings of conference "Nutrition and Blood Pressure:
Current Status of Dietary Factors and Hypertension," McCarron and Kotchen,
1983). The contribution of lead, compared to many other factors evaluated in
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various analyses discussed above, appears to be relatively small, usually not
accounting for more than 1-2 percent of the variation explained by the models
employed when other significant factors are controlled for in the analyses.
Many of the above issues and questions have been further addressed since
the 1986 Addendum was completed, in part at the 1987 Lead-Blood Pressure
Symposium and in other recent publications as well. Presentations and dis-
cussions at the 1987 Symposium (see Victery, 1988a) were contributed by (1)
many of the key scientists who have carried out important investigations of the
relationship of lead exposure and hypertension (including observational,
epidemiologic, and experimental reports), as well as (2) other experts in
hypertension and cardiovascular disease in general. Several speakers reviewed
their analyses of the NHANES II data (Marian, 1988; Schwartz, 1988; Gartside,
1988; Landis and Flegal, 1988) and the British study (Pocock et al., 1988).
Elwood et al. (1988) also summarized the results of two new large-scale Welsh
studies. Pocock further provided a new comparison of the relative magnitude of
the contribution of lead exposure to blood pressure changes based on inter-
comparison of the results of the NHANES II, British, and Welsh studies. A
number of other relevant papers were also presented which described studies
of lead-blood pressure relationships in selected populations of nonoccupation-
ally exposed individuals, as well as workers (Kromhout, 1988; Moreau et al.,
1988; Weiss et al., 1988; Wedeen, 1988; Cooper, 1988; Selevan et al., 1988; de
Kort and Zwennis, 1988; Elwood et al. , 1988; Neri et al. , 1988; Staessen
et al., 1988; Sharp et al., 1988). Other presentations addressed pertinent
toxicological findings from HI vivo or J_n vitro animal studies (Vander, 1988;
Chai and Webb, 1988; Kopp et al., 1988; Boscolo and Carmignani, 1988; Weiler
et al., 1988; Victery, 1988b).
With regard to new findings reported at the Symposium, a further alterna-
tive analysis of the data from NHANES II (use of a generalized Mantel-Haenzel
test) was reported by Landis and Flegal (1988). In order to more definitively
assess the robustness of the earlier NHANES II results (Harlan et al. 1985;
Pirkle et al., 1985; etc) and, also, to evaluate possible time-trend effects
confounded by variations in sampling sites, Landis and Flegal (1988) carried
out further analyses for NHANES II males, aged 12-74, using a randomization
model-based approach to test the statistical significance of the partial
correlation between blood lead and diastolic blood pressure, adjusting for age,
body mass index, and the 64 NHANES II sampling sites. Simple linear and
multiple regression coefficients between log PbB and diastolic BP for all males
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(aged 12-74) were 0.15 and 4.90, respectively; for various groups broken out by
age (<20, 21-39, >40 yrs) and body mass index levels, the respective coeffi-
cients ranged from 0.04 to 0.12 and from 1.29 to 3.55 (predominantly between
2.3 and 3.6), displaying considerable consistency across age-body mass compari-
son groups. Also, the most stringent or "conservative" approach used to
calculate a randomized model statistic controlling for effects due to 64
sampling sites yielded a test statistic of 4.62 (still significant at p <0.05).
The authors noted that: (1) the association must be sufficiently robust to
persist across 478 subgroups formed on the basis of factors also having an
association with the levels of blood lead and blood pressure; and (2) neverthe-
less, even with the severe adjustments by sampling sites, age, and Quetelet
index, the diastolic blood pressure/blood lead relationship remained statisti-
cally significant at the p <0.05 level. In summary, their analyses indicate
that the significant linear association between blood-lead levels and diastolic
blood pressure readings cannot be dismissed as due to concurrent secular trends
in the two variables across the 4-year survey period. Finally, the authors
noted that, even though these partial correlations are not large, the magnitude
of the regression coefficients suggests that elevated blood lead levels may be
an important risk factor for elevated blood pressures, as developed in con-
siderably greater detail for the restricted group of white men 40 to 59 years
of age (as described in Pirkle et al., 1985).
Also reported on at the 1988 Symposium were two surveys in Wales which
evaluated possible relationships between blood lead and blood pressure (Elwood
et al., 1988a,b). The Welsh Heart Programme was carried out in 1985 throughout
Wales, using a stratified cluster random sample of 21,000 households, with
2,010 male and female adult subjects being included in the survey population
for whom blood lead determinations were made. Complete blood lead, blood
pressure, and other key data were available for 865 men and 856 women. Mean
blood lead values for men were 12.4 |jg/dl and for women 9.6 ug/dl. Blood lead
increased with age (1 |jg/dl every 15.6 years in men and every 13.1 years in
women). The partial regression coefficients with standard error were reported
after the effect of age had been removed by cubic regression. In males, the
coefficients for systolic and diastolic pressure were 0.82 + 1.49 and 1.29 +
0.95, respectively. For females, these coefficients were 0.19 + 1.46 and 0.54
+ 1.00. In neither sex was the relationship statistically significant. Cate-
gorizing the data by blood lead increments demonstrated no trend in the blood
pressure levels.
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The second group studied was about half of the planned subjects in the
Caerphilly Collaborative Heart Disease study; this study on ischemic heart
disease was based on a cohort of men aged 45-59, living in Caerphilly, a small
town in Wales. Several risk factors for ischemic heart disease were considered.
Blood pressure was measured with a random-zero muddler sphygmomanometer after a
5-minute rest and during a cold pressor test. The correlation coefficients
for resting systolic and diastolic pressure were 0.0183 and 0.0230, respec-
tively, and for the rise in pressure with the cold pressor test, 0.0342 and
0.0078 respectively. None were significant at p <0.05. Ranking the blood
pressure readings according to blood lead groups did not reveal any trend in
the percentage of subjects with systolic blood pressure greater than 160 mm Hg.
The authors (Elwood et al., 1988a,b) only corrected for age as the single
confounding factor controlled for, because all other factors are positively
correlated with both blood pressure and blood lead. They concluded that, in
the event these other factors (e.g., cigarette use and alcohol consumption)
were controlled for, they would probably reduce the already trivial (and
nonsignificant) relationships found by them for blood lead and blood pressure
measurements in the two Welsh studies.
At the 1988 Symposium, Pocock compared the results of the NHANES II data
analyses as discussed by Schwartz (1988), his analyses of the British study
(Pocock et al., 1988), and the two Welsh studies (Elwood et al., 1988a,b).
Figure 1 shows the magnitudes of effects obtained for adult men in these four
large-scale studies, relating systolic blood pressure to blood lead concentra-
tion, as depicted by Pocock et al. (1988). The graph shows each study's
estimated change in mean systolic blood pressure for each doubling of blood
lead (e.g., from 8 to 16 ug/dl), together with 95% confidence limits. Pocock
concluded that an overview of data from these large epidemiological surveys
provide reasonably consistent evidence on lead and blood pressure. That is,
whereas the NHANES II data on 2,254 U.S. men indicate a slightly stronger
association between blood lead and systolic blood pressure than Pocock1s
British study, the data from the two Welsh studies on over 2,000 men also
showed a small positive, (but not statistically significant) association.
Pocock noted that the overlaping confidence limits for all these studies
suggest that there may be a weak positive statistical association whereby
systolic blood pressure in adult men is increased by about 1 mm Hg for every
doubling of blood lead concentration.
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BRHS(N=7371)
NHANE S II (N=2254)
Caerphilly (N=1164)
Wales (N=865)
-2-101 234
Estimated change in mean systolic blood pressure
(mm Hg) for a doubling of blood lead
Figure 1. Comparison of study results from four larger-scale epidemiology
studies of lead-blood pressure relationships in audit men. BRHS =
British Regional Heart Study analyses, described by Pocock et al.
(1988); NHANES II = National Health and Nutrition Evaluation Survey
analyses described by Schwartz (1988); Caerphilly and Wales = Welsh
studies described by Elwood et al. (1988a,b).
Source: Pocock et al. (1988).
There was an additional report of an analysis of cross-sectional data from
Canada (Neri et al., 1988) presented at the 1988 Lead-Blood Pressure Symposium.
This study was performed on data collected during 10 months of 1978-1979 for
2,193 subjects aged 25 to 64. The zero-order correlation between diastolic
blood pressure and blood lead level was found to be 0.115. The authors con-
cluded that, although this association is a weak one (as was also the case in
the NHANES II data), its statistical significance is not in doubt (p <0.001).
They further concluded that (1) the Canadian data were at least weakly support-
ive of the inference drawn from NHANES II, in that elevation of blood lead did
seem to entail some risk of blood pressure elevation, but (2) it would be
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premature, in the absence of longitudinal data, to infer that this is a cause-
and-effect relationship. Neri et al., 1988 then reported the findings for a
group of subjects studied longitudinally for blood lead levels and blood
pressure. That is, in a study of lead foundry workers, an association was
found between short-term changes in an individual's blood lead level and
contemporary changes in diastolic pressure, which remained significant after
allowance for age (or time) trends and for effects attributable to changes in
body weight. The authors also noted that short-term changes in urinary cadmium
were similarly predictive of diastolic blood pressure levels.
There were several other reports presented at the 1988 Symposium with
regard to smaller-scale observational studies of blood lead and blood pressure
in two types of occupationally lead-exposed groups: bus drivers (Sharp et al.,
1988) and policemen (Weiss et al., 1988 and Moreau et al., 1988). These
studies all yielded findings that are also indicative of lead-induced increases
in blood pressure.
In other recent reports besides those presented at the 1988 Symposium,
three new studies (with generally small study cohorts) of occupationally
exposed workers have yielded further results with regard to lead effects on
blood pressure or other cardiovascular outcomes. For example, Parkinson et al.
(1987) reported findings on data collected in 1982 from 270 lead workers and
158 nonexposed workers in Pennsylvania. Four measures of lead exposure were
used: (a) employment at lead exposure vs. control plants; (b) current blood
lead values at time of examination (exposed group mean = 39.9 ug/dl vs.
7.4 pg/dl for controls); (c) zinc protoporphyrin values at time of examination:
(d) time weighted average (TWA) blood lead values for lead-exposed workers
since date of hire. Other risk factors (age, years of education, etc.) were
also included in the regression analysis. Of the three lead measures, only
TWA blood lead was significantly, although modestly, correlated with blood
pressure. After controlling for other predictive risk factors, including age,
the effect of TWA on blood pressure was no longer significant and the authors
did not find evidence of renal disease.
Also, in 1987, de Kort and colleagues reported finding a statistically
significant increase in systolic and diastolic pressure in 53 exposed males
compared with 52 controls (de Kort et al, 1987). Blood lead averaged 47.4
ug/dl vs. 8.1 for controls. Blood and urine cadmium were also higher than in
controls; there were no adverse effects on kidney function. The prevalence of
clinically-defined hypertension (systolic greater than 160 mm Hg and/or
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diastolic greater than 95 mm Hg and/or under treatment for hypertension) was
higher in the exposed group, but the observed relative risk was not different.
In addition to the above study results which focussed primarily on lead-
blood pressure effects in adult males, some additional analyses of such rela-
tionships in females have become available since the 1986 Addendum and the 1987
Lead-Blood Pressure Symposium. For example, Schwartz (1989) has recently
reported the results of still further analyses of the NHANES II data set.
These latest analyses used variables identified as being important in earlier
NHANES II analyses and examined the relationship between blood lead and blood
pressure in both males and females, aged 20-74 years. The analyses were
carried out in stages, with separate regressions first being performed for
males and females. Diastolic blood pressure was regressed on age, age2,
Quetelet's body mass index, and the natural log of blood lead. If, in this
first step, lead was significant, then a stepwise regression was carried out
taking into account a number of covariates or potentially confounding cofactors
(e.g., dietary sodium, smoking, etc.); and final models were then ultimately
estimated using SURREGR (a program correcting for study design effects as
well). Statistically significant relationships were found between blood lead
and blood pressure in both males (p <0.01) and females (p <0.01) in the first
stage regressions, correcting for the above-noted covariates. Lead also
continued to be significantly related to blood pressure in the separate step-
wise regressions for males and females. The final models yielded a smaller,
but statistically significant (p <0.03) blood lead coefficient (1.640) for
females than the coefficient for males (2.928; p <0.006). These results
therefore (1) further confirm the earlier findings of Schwartz and other
investigators demonstrating significant associations between blood lead and
blood pressure increases in adult males in the NHANES II study population and
(2) demonstrate analogous, although somewhat smaller effects in women from the
same study population.
In another study, Grandjean et al. (1989) evaluated lead-hypertension
relationships in a cohort of 504 men and 548 women born in the same year and
residing in the Glostrup area of Denmark. Both blood lead concentrations and
blood pressure determinations were first obtained at age 40 and then, again,
five years later for 451 men and 410 of the women. The average blood lead
levels for men at age 40 and 45 years were 13 and 9 (jg/dl, respectively; for
women they were 9 and 6 ug/dl, respectively, at age 40 and 45 years. At age
40, women with systolic blood pressure above 140 mm Hg and/or diastolic above
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90 mm Hg had slightly elevated blood leads compared to non-hypertensive women;
but no differences were found for blood lead levels in men with increased
versus normal (i.e., 140 or 90 mm Hg, respectively, for systolic and diastolic)
blood pressure. Significant correlations were found between log blood lead and
systolic blood pressure in both men and women and diastolic blood pressure in
women only at age 40, but not at age 45. The relationship at aged 40 indi-
cated a doubling of blood lead being associated with a <3 mm Hg increase in
blood pressure. When blood hemoglobin and alcohol intake (the only two of nine
potential confounders assessed that were significantly related to both blood
lead and blood pressure) were entered into multiple regression analyses, then
all blood-lead blood-pressure associations become non-significant. Grandjean
et al. (1989) noted that the initial association found between blood lead and
blood pressure was similar or slightly weaker than those earlier reported for
the BRHS (Pocock et al., 1985) or the NHANES II (Pirkle et al., 1985) data
analyses. The impact of alcohol and blood hemoglobin on the subsequent mul-
tiple regression outcomes indicate clear confounding with blood lead and an
inability in this study to separate out relative contributions due to those
factors versus lead (with blood lead increasing with number of units of alcohol
consumed as documented in the study cohort at age 40, for example). The
authors (Grandjean et al.) further noted that non-response and loss to follow-
up, the very low range of blood lead values, and the limited statistical power
of the study (with fewer than 1,000 subjects) to detect small effects may
help to account for their observed pattern of results.
The issue of lead effects on more serious cardiovascular disease outcomes,
possibly mediated by lead effects in blood pressure or via other lead-induced
pathogenic processes has been further addressed since the 1986 Addendum to the
EPA Lead Criteria Document was prepared. Some of the newer evidence has been
derived from studies of occupationally exposed workers and other new results
have emerged from still further analyses of the two larger-scale BRHS and
NHANES II data sets.
The causes of mortality of lead workers in the United Kingdom between 1926
and 1985, for example, have recently been updated in a case-control study
written by Fanning (1988). There were 867 deaths in men with relatively high
occupational exposure to lead during these years, and 1206 deaths during the
same period in men whose exposure had been low or absent. During the period
between 1946 and 1965 there was a significant excess of deaths from cardiovas-
cular disease; but there was no difference between the two groups over the past
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20 years. Also, no statistically significant excess in the number of deaths
from malignant neoplasms was evident. Fanning concluded that the previous
evidence of an increased risk of death from cerebrovascular disease (in lead
workers) was therefore confirmed, but it would seem that with the introduction
of stricter standards of lead control this increased risk has now disappeared,
as has any marginal risk of death from malignant disease.
Another occupational exposure study, an analysis of causes of death in
U.S. battery and lead production workers during the years 1947 to 1980 was
carried out, was presented at the 1987 Lead-Blood Pressure Symposium by Cooper
(1988). Mortality causes were coded according to the seventh (1955) revision
of the International Classification of Diseases. Data were from deaths of
4,519 battery plant workers and 2,300 lead production or smelter workers during
this time period. Cooper reported that there were significant excess deaths
for "other hypertensive disease" (444-447) and "chronic nphritis" (592-594);
but deaths from other hypertension-related diseases did not show comparable
excesses and renal cancer deaths were fewer than expected. Also, Selevan
et al. (1988) reported at the 1987 Symposium that an analysis of causes of
mortality in 1,281 lead smelter workers employed at an Idaho smelter between
1940 and 1965 did not suggest an association between occupational lead exposure
and mortality from hypertension. On the other hand, the data do suggest an
association between lead and renal disease and, possibly, renal cancer.
The 1988 Symposium report by Pocock et al. (1988) not only reviewed
relationships between blood lead concentration and blood pressure as determined
in the British Regional Heart Survey, but also looked at relationships between
lead and more serious cardiovascular outcomes. The results of these further
analyses of the BRHS data set were reported by Pocock et al. (1988) to show
that, by 6 years of follow-up, 316 of the men had major ischemic heart disease
and 66 had a stroke. After controlling for the confounding effects of ciga-
rette smoking and town of residence, statistical analyses did not yield sta-
tistically significant associations between blood lead levels and such cardio-
vascular events. However, as the blood lead-blood pressure association is so
weak, Pocock et al. (1988) noted, it is unlikely that any consequent associa-
tion between lead and cardiovascular disease could be demonstrated from pros-
pective epidemiological studies.
On the other hand, Schwartz (1989) has recently reported results derived
from new NHANES II data analyses, which provide evidence for significant
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associations between blood lead levels and electrocardiogram (ECG) abnormal-
ities indicative of left ventricular hypertrophy (LVH). Such ECG abnormalities
represent an early indicator of cardiovascular disease that is much more common
than frank myocardial infarctions. The logistic regression analyses employed
by Schwartz (1989) yielded a small (0.028) but statistically significant (p
<0.01) coefficient for an association between blood lead levels and increased
prevalence of LVH, taking into account age, race and sex (all of which were
significantly related to LVH at p< 0.01, <0.0001, and <0.0001, respectively).
The interaction terms for sex or race differences, however, were non-
significant (p> 0.20) with regard to the cardiovascular effects of lead.
The Schwartz (1989) results are consistent with previous reports of
cardiovascular effects being associated with high levels of lead exposure,
e.g., Kirkby and Gyntelberg's 1985 report of a 20% increase (p <0.01) in
ischemic changes as coded on the Minnesota Codes in lead workers as compared
to controls matched on age, race, and several other pertinent factors. The
new findings by Schwartz, however, point toward small but not inconsequential
increased risks for serious cardiovascular outcomes being associated with the
relatively low range of blood lead levels encountered in the general U.S.
adult population. It remains to be determined to what extent the observed
lead effects on left ventricular hypertrophy or other cardiovascular functions
are due to a lead-induced increase in blood pressure or to some other lead-
related pathogenic mechanism.
At the 1988 Symposium, there was extensive discussion concerning contro-
versy in the published epidemiology literature about the nature of a relation-
ship between blood lead and blood pressure. As summarized by Tyroler (1988),
the general population studies discussed above were seen as pointing toward a
causal relationship between increases in blood-lead levels and significant and
increases in blood pressure, extending to below values below those currently
considered to be clinically significant as hypertensive. Tyroler further
noted that the association has not been found in all studies and, when present,
has been such that the increase in blood pressure with increase in blood lead
levels has been of small absolute magnitude and not constant across age, sex,
and race subgroups. Nevertheless, despite the seemingly small elevations in
blood pressure when viewed from the clinical perspective of each individual,
Tyroler further noted that the potential public health importance of a blood-
lead blood-pressure relationship is considerable due to the strong association
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of blood pressure with cardiovascular morbidity and mortality, the leading
cause(s) of death in our society, and the large number of individuals exposed.
Importantly for substantiating the plausibility of blood-lead blood-
pressusre associations observed in human populations, the physiological and
pharmacological regulation of blood pressure has been studied extensively by
experimental investigators. Much of the then available information on the
subject was discussed in the 1986 Addendum (U.S. EPA 1986b). It is now under-
stood that various hormonal regulatory systems, vascular smooth muscle, and
heart contractility all contribute to the development of blood pressure changes
Several of the speakers at the 1988 Symposium (Victery, 1988a) also reviewed
findings of changes in the cardiovascular system in animals exposed to lead.
For example, Victery (1988b) reviewed the experimental studies that have been
conducted over 40 years on the effects of lead on blood pressure. Differences
in animals species, age at beginning of exposure, level of lead exposure, and
the effects of lead on blood pressure were described. It was noted that in
several of the high-dose experiments, hypertension was observed, but nephro-
toxicity of lead may have contributed to its development. In one experiment,
high lead exposure may have reduced an elevated blood pressure. In contrast,
lower dose experiments consistently demonstrated a hypertensive effect. The
data suggest that a biphasic dose-response relationship may exist. Future
research should be able to characterize in animals dose-response relationships
for blood pressure effects across low-level lead exposure ranges most applica-
ble to the general human population.
With regard to mechanisms potentially underlying lead-blood pressure
relationships, Vander (1988) reviewed the chronic effects of lead on the renin-
angiotensin system (one of the primary regulatory hormones for blood pressure).
The changes observed in both animals and humans are highly variable and are
deoendent on the lead exposure level, the time of exposure, and other stimuli
of the renin-angiotensin system. The human data are consistent with the
tentative hypothesis that lead-exposed persons may have higher plasma renin
activity (PRA) than normal during periods of modest exposure but normal or
depressed PRA following more chronic severe exposures.
In another 1988 Symposium paper, the effects of lead on vascular reactivity
were described by Chai and Webb (1988). There is convincing evidence that lead
alters vascular reactivity in lead-exposed animals, which demonstrated a 15 to
20 mm Hg increase in systolic blood pressure. Increased pressor responsiveness
to catecholamines has been demonstrated in an enhanced contraction of isolated
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vascular smooth muscle to adrenergic agonists. Further experimental evidence
suggests that there are alterations in the mechanisms that regulate intra-
cellular calcium concentration and that this may contribute to the abnormal
vascular function in lead-induced hypertension. There were further reports of
morphological, biochemical, and functional alterations in cardiovascular tissue
in the reports by Kopp et al. (1988) and Boscolo and Carmignani (1988). The
paper by Kopp et al. (1988) in the Symposium volume reviews the cardiovascular
actions of lead, including evidence that lead exposure (at least at high
levels) leads to morphological, biochemical, and functional derangements of the
heart. The experimental literature also confirmed findings of cardiovascular
complications in experimental animals. Findings include myocarditis, electro-
cardiographic disturbances, heightened catecholamine arrhymogenicity, altered
myocardial contractile responsiveness to inotropic stimulation, dengerative
structural and biochemical changes affecting the musculature of the heart and
vasculature, hypertension, hyperchloesterolemia, atherosclerosis, and increased
vascular reactivity to alpha-adrengergic agonists. The precise nature of the
exposure-response relationships that apply are still poorly characterized, as
well as the exact pathogenic mechanisms for the effects of lead on the cardio-
vascular system; but importantly, the experimental results provide clear
evidence for lead causally affecting cardiovascular function.
In the 1987 Symposium discussion session (Victery et al., 1988), one of
the invited discussants, Dr. Anthony 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 the angiotensin-converting enzyme (now used as antihypertensive
therapeutic agents) could be tried to determine if this can prevent the blood
pressure increase during lead exposure. The levels of intracellular calcium
should be measured in vascular tissue and the pharmacologic agents that block
calcium or potassium channels in cell membranes should be examined to determine
if they might reduce the effects of lead.
CONCLUSIONS
With regard to the effects of lead on blood pressure, the new information
emerging since preparation of the 1986 Addendum, overall, substantiates further
the main conclusions stated in that Addendum. Sufficient evidence exists from
both the four large-scale general population studies discussed above (NHANES II,
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BRHS, and the two Welsh studies) and numerous other smaller-scale studies to
conclude that a small but positive association exists between blood lead levels
and increases in blood pressure. Quantitatively, the relationship appears to
hold across a wide range of blood-lead values, extending possibly down to as
low as 7 ug/dl for middle-aged men and, furthermore, an estimated mean increase
of about 1.5-3.0 mm Hg in systolic blood pressure appears to occur for every
doubling of blood lead concentration in adult males and something less than
1.0-2.0 mm Hg for adult females. The plausibility of these relationships
observed in epidemiologic studies of human populations being of a causal nature
is supported by controlled experimental animal studies demonstrating increased
blood pressure effects clearly attributable to lead, with an apparent biphasic
dose-response relationship being involved (i.e. blood pressure elevations at
low lead dose levels and possible blood pressure reductions at very high lead
exposure levels).
The implications of lead-induced blood-pressure increases with regard to
potential increased risk for other, more serious cardiovascular outcomes still
remain to be more clearly delineated. As noted by Tyroler and other
discussants at the 1988 Symposium mentioned above, essentially any increase in
blood pressure carries with it likely increased risk (albeit however small)
for stroke, heart attack, and/or associated mortality. As such, projections
of potential lead effects on such outcomes, as were modeled by Pirkle et al.
(1985) and discussed in the 1986 Addendum, are not unreasonable in view of
the potential very large public health impacts; however, much caution must be
exercised in accepting the validity of any specific quantitative estimates
derived from such projections in view of the uncertainties associated with
selection of the specific coefficients used for (1) blood-lead blood-pressure
relationships and (2) relationships between blood pressure increases and more
serious cardiovascular outcomes. The difficulty in directly demonstrating
associations between lead exposure and stroke, heart attacks, etc. lies in the
very large study cohorts (many thousands of subjects) that would be necessary
to have sufficient statistical power to detect the relatively small increased
risk levels expected for the more serious cardiovascular outcomes. Some
newly available results (i.e. those of Schwartz, 1989) from at least one large
scale study help to illustrate the possibility of detecting indications of
such small increased risks in the general population.
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III. NEUROBEHAVIORAL AND GROWTH EFFECTS IN INFANTS AND CHILDREN
A major advance in the epidemiological investigation of the health effects
of lead occurred with the advent of independent but somewhat coordinated
prospective studies of child development. Some of the results of four such
studies were discussed in the 1986 Addendum (U.S. EPA, 1986b). Much of the
same information, with updating, was also presented in a critical review and
interpretation by Davis and Svendsgaard (1987). The four prospective studies
in question were conducted in Boston, Cincinnati, Cleveland, and Port Pirie,
Australia.
Based on an assessment of these studies, the 1986 Addendum concluded
that fetal lead exposure could have undesirable effects on infant mental
development, length of gestation, and possibly other aspects of fetal
development, with the most consistent evidence pertaining to neurobehavioral
function. In particular, "All of these studies taken together suggest that
neurobehavioral deficits, including declines in Bayley Mental Development Index
scores and other assessments of neurobehavioral function, are associated with
prenatal blood lead exposure levels on the order of 10 to 15 pg/dl and possibly
even lower, as indexed by maternal or cord blood lead concentrations" (U.S.
EPA, 1986b, p. A-48).
This update summarizes and assesses the evidence from these and other,
more recent studies, both individually and collectively, and draws conclusions
regarding their implications for regulatory decision-making.
Boston
As noted in the 1986 Addendum, a series of reports by Bellinger, Needleman,
and their colleagues (Bellinger et al. , 1984a, 1985, 1986a,b) described the
results of a longitudinal study of early neurobehavioral development through
the first two years of life in a cohort of Boston children. More recent
updates on this work have since been published by Bellinger et al. (1987a,
1989a), covering the same period of development. The latter reports confirm
that performance on the Bayley Mental Development Index (MDI) at 6, 12, 18, and
24 months postnatally is inversely related to cord blood lead levels at birth
and that the amount of deficit in infants with cord blood lead levels of
10-25 (jg/dl is 0.25-0.5 standard deviations, or approximately 4-8 points on the
MDI (Table 2). Moreover, Bellinger et al. (1989a) found that this association
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TABLE 2. INFANTS' MENTAL DEVELOPMENT INDEX SCORES
ACCORDING TO CORD BLOOD LEAD GROUP
Cord Blood
Lead Group
Unadjusted score
Low
Medi urn
High
6 Months
109.
108.
106.
2 ±
6 ±
1 ±
Mean ±
12.9
12.0
11.1
Mental Development Index Score
12 Months 18 Months
24 Months
Standard Deviation
113.
115.
108.
1 ±
4 ±
7 ±
12.5
12.9
12.8
113.4
116.6
109.5
± 15.
± 16.
± 17.
5
7
5
115.9
119.9
110.6
± 17.2
± 14.4
± 16.5
Mean ± Standard Error
Controlled for
Low
Medi urn
High
p value**
No. of infants
potential confounders*
110.2 ±1.3 114.7 ±1.6
108.0 ±1.3 114.4 ±1.5
105.9 ±1.4 108.9 ±1.6
0.095
201
0.020
199
116.2 ±1.9
114.8 ±1.9
109.5 ±2.0
0.049
187
118.9 ±1.8
117.8 ± 1.7
111.1 ±1.8
0.006
182
*Least-squares mean ± standard error, derived from regression equations that
included 12 potential confounders and cord blood lead group coded as two
indicator variables.
**Indicates p value associated with the F ratio that evaluates whether the
mean Mental Development Index for any cord blood lead group differed
significantly from the common mean after potential confounders were
controlled for.
Source: Bellinger et al. (1987a).
was evident in several different regression models and was not an artifact of
the approach they used in analyzing the data. In addition, more detailed
analyses showed that the average MDI deficit in high cord lead infants (blood
lead levels of 10-25 ng/dl) was not due to a disproportionate influence of
results from infants at higher (e.g., >15 (JQ/dl) blood lead levels. That is,
the MDI effect was evident across the entire range of blood lead levels
starting at 10 ug/dl, which reinforces the previous selection of 10-15 ug/dl as
a blood lead level of concern for early developmental deficits (U.S. EPA,
1986b).
Other recent analyses by Bellinger et al. (1988) have focused on the
interaction of lead-related Bayley MDI deficits with socioeconomic status
(SES). Even in the relatively advantaged cohort of the Boston study,
3/27/89 24
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
infants from other than the highest SES grouping tended to have lower covariate-
adjusted scores on the MDI. Moreover, the second-year MDI performance of these
"lower" SES children was adversely affected at lower blood lead levels than was
the performance of the higher SES children. Specifically, within the lower SES
grouping, infants with mid-range cord blood lead levels of 6-7 ug/dl scored
significantly worse on the Bayley MDI than infants with low cord blood lead
levels of <3 |jg/dl.
Bellinger et al. (1987b, 1989b) have also recently reported preliminary
results of later testing of 170 children of the Boston cohort at about 5 years
(57 months) of age on the McCarthy Scales of Children's Abilities. They found
that the association between cord blood lead and cognitive performance, as
measured by the General Cognitive Index (GCI) of the McCarthy Scales, was no
longer statistically significant at 57 months. However, the relationship
between blood lead level at 24 months postnatally and GCI scores was statis-
tically significant, even after adjusting for covariates and confounders
(Table 3). The mean 24-month blood lead level was 6.8 ug/dl (SD = 6.3). Other
postnatal blood lead measurements at 18 and 57 months were consistent with this
association but failed to achieve statistical significance. The size of the
deficit amounted to approximately 3 GCI points for every natural log unit
increment in blood lead level.
Bellinger et al. (1989b) examined the change in cognitive performance of
children from 24 to 57 months of age in relation to pre- and postnatal lead
exposure levels and various sociodemographic variables. Improvement in rela-
tive performance was associated with lower blood lead levels at 57 months,
higher SES, higher HOME scores, higher maternal IQ, and female gender. Con-
versely, the risk of an early deficit persisting to 5 years of age was
increased in children with higher prenatal lead exposure (10-25 ug/dl) and
either high postnatal exposure or less favorable sociodemographic factors. For
example, "if two children with high cord blood lead achieved the same MDI score
at 24 months, but one had a low blood lead level [<3 ug/dl] at 57 months while
the other had a high [>10 ug/dl] level, the child with lower exposure would be
expected to have a GCI score that is 0.61 standard normal deviate units
higher..., [which] corresponds to a difference of 9.8 points" (Bellinger
et al., 1989b). Similar comparisons of males and females with high cord blood
lead levels indicated that boys scored 7.7 points lower than girls on the GCI,
and children in the lower SES grouping scored 13.3 points lower than those in
the higher SES grouping.
3/27/89 25
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OO
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PRELIMINARY DRAFT: 00 NOT QUOTE OR CITE
Bellinger et al. (1987b) also evaluated the degree of disparity in
McCarthy subscale performance, since learning disabilities are often highly
specific to certain cognitive functions. A greater number of subscale
discrepancies was associated with higher (>10 ug/dl) concurrent (57 month)
blood lead levels.
Cincinnati
Interim results of a longitudinal study of inner-city children born in
Cincinnati, Ohio were reported by Dietrich et al. (1986, 1987a) and summarized
in the 1986 Addendum. Structural equation modeling, a statistical method of
examining relationships among factors that may be both independent and
dependent variables or mediators of effects, indicated that prenatal lead
exposure had an indirect effect on 6-month MDI and PDI (Psychomotor Development
Index) scores through its effects on gestational age and/or birth weight.
Higher prenatal (maternal) blood lead levels were associated with reduced
gestational age and reduced birth weight, which in turn were significantly
associated with reduced MDI and PDI performance.
Although the Cincinnati subjects were not grouped by blood lead levels for
these analyses, separate analyses of birth weight effects by Bornschein et al.
(1989) investigated the dose-response relationship by grouping into five
6-|jg/dl intervals. An increase in the percentage of low birthweight newborns
between the 7-12 (jg/dl grouping and the S13 pg/dl grouping implied the possi-
bility of a threshold for low birthweight effects (categorically defined as
less than 2750 g) in the vicinity of 12-13 ug/dl, although a precise deter-
mination is not possible and could extend as low as 7 ug/dl or perhaps as high
as 18 ug/dl. To the extent that low birthweight mediated the effect of lead on
Bayley scores in the Cincinnati study, the inferred information is consistent
with the conclusion (U.S. EPA, 1986b) that a blood lead level of 10-15 ug/dl, and
possibly lower, constitutes a level of concern for impaired performance on the
Bayley MDI.
Dietrich et al. (1987b, 1989a,b) later reported more complete results for
neurobehavioral developmental outcomes in approximately 300 infants from the
Cincinnati study (Table 4). The children were tested on the Bayley Scales at
3, 6, 12, and 24 months of age. After adjusting for covariates, deficits in
3- and 6-month Bayley MDI scores were significantly associated with prenatal
(maternal) and cord blood lead levels, confirming the earlier, preliminary
3/27/89 27
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
TABLE 4. RESULTS OF MULTIPLE REGRESSION ANALYSES EXAMINING
THE RELATIONSHIP BETWEEN BLOOD LEAD LEVEL
AND PERFORMANCE ON THE BAYLEY MENTAL INDEX AT 3-24 MONTHS OF AGE*
Blood
Lead
Measure (|jg/dl)
Prenatal
Umbilical cord
10 day
3 month
Prenatal
Prenatal by
Child Sex
10 day
10 day by SES
Prenatal
Umbilical cord
10 day
Prenatal
10 day
3 month
Maximum 1st Year
Maximum 2nd Year
24 months
N
228
80
261
n. r.
249
283
258
98
257
237
270
270
270
270
270
Standard
Beta Error
3-month MDI
-.34
-.60
.06
-.23
6-month MDI
-0.89
1.53
-3.15
0.16
12-month MDI
0.09
-0.17
-0.62
24-month MDI
0.51
-0.02
0.24
0.24
0.10
0.13
0.17
0.26
0.22
0.18
0.34
0.51
1.30
0.08
0.26
0.36
0.31
0.22
0.25
0.21
0.10
0.07
0.09
t
Value
-1.96
-2.30
0.26
-1.30
-2.60
2.98
-2.43
2.13
n. r.
n. r.
n. r.
2.31
-0.07
1.12
1.39
1.39
1.45
P
Value**
.05
.02
.79
.20
0.009
0.003
0.016
0.034
N.S.
N.S.
<0.04
0.022
0.948
0.262
0.166
0.166
0.149
*Betas adjusted for different sets of covariates for each age of MDI testing.
**Two-tailed values.
Sources: Dietrich et al. (1987b, 1988, 1989b).
3/27/89 28
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
analyses of Dietrich et al. (1987a). The magnitude of the deficit in the
3-month MDI amounted to 6 points for every 10-pg/dl increment in cord blood
lead; the corresponding 6-month MDI deficit was nearly 7 points. Also, a
conservative reanalysis (Dietrich et al., 1989b) of the 6-month data using all
potential covariates and confounders confirmed earlier findings, although
interactive effects with gender and SES were evident (see below). However,
neither prenatal nor cord blood lead measures were significantly related to
12-month MDI scores, although the association between neonatal (10-day) blood
lead levels and 12-month (as well as 6-month) MDI scores remained statisti-
cally significant (Dietrich et al. , 1989a). It should be noted that analyses
of the 12-month data are not yet final.
By 24 months, no statistically significant negative relationships were
detectable between lead exposure variables (either pre- or postnatal) and MDI
scores (Dietrich et al. , 1989b). Only one parameter estimate (for prenatal
blood lead) achieved statistical significance (p = 0.0217), and it was positive
rather than negative.
In addition, the Bayley Infant Behavior Record (IBR) was administered at
12 and 24 months to assess the infants' social and emotional development
(Dietrich et al., 1989a,b). Factor analysis of the 30 IBR items at 24 months
yielded principal factors of Sustained Attention, Activity Level, and Positive
Mood, which were used in regression analyses to assess the effect of lead
exposure. Lower scores on Sustained Attention and Positive Mood factors were
both significantly associated with increased neonatal (10-day) blood lead
levels, consistent with the 12-month MDI relationship to neonatal blood lead
(Dietrich et al. , 1989a). However, none of the 24-month IBR results achieved
statistical significance. Bayley PDI results were incomplete.
Dietrich et al. (1987b, 1989b) also found that gender and SES interacted
with the lead exposure-MDI relationship. Male infants and children from the
lower half of the SES distribution for this cohort were more sensitive to the
effects of early lead exposure on neurobehavioral development. For example,
male infants showed an 8.67-point deficit on the 6-month MDI for every 10-ug/dl
increment in prenatal blood lead, and infants below the sample median SES score
had a 7.57-point deficit for every 10-ug/dl increment in neonatal blood lead
(Dietrich et al. , 1989b).
Dietrich et al. (1989b) interpreted their failure to detect a persistent
effect of fetal lead exposure on the 24-month Bayley Scales as probably due
3/27/89 29
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
to a neurobehavioral catch-up response, similar to that observed in infant
twins (Wilson, 1986) or other infants compromised during prenatal development
(Tanner, 1981). Exploratory analyses indicated that the greatest percentage
increase in MDI raw scores (number of items passed) from age 3 months to
24 months was inversely related to prenatal lead exposure, birth weight,
gestation, and head circumference (Dietrich et al. , 1989b). Thus, those
infants with the highest prenatal blood lead levels, lowest birth weight,
shortest gestation, or smallest head circumference showed the greatest degree
of catch-up in postnatal neurobehavioral development.
As previously noted, the Cincinnati study has also produced evidence
of direct effects of prenatal lead exposure on infant physical development at
birth. Bornschein et al. (1989) reported that initial results from 202 infants
showed an inverse relationship between maternal blood lead levels and both
birth weight and length. Maternal blood lead samples were obtained at the
first prenatal visit (between 6 and 28 weeks of gestation; mean = 16 wks). The
mean maternal blood lead level was 7.6 ug/dl (range: 1-26 |jg/dl). Exclusion
criteria included birth weight less than 1500 g, less than 35 weeks gestational
age at birth, twin birth, and serious medical conditions. Regression analyses
considered 21 potential confounders and covariates. The final regression model
for birth weight showed that log maternal blood lead was significantly related
to birth weight, but interacted with maternal age to produce a significant
(p <0.007) reduction in covariate-adjusted birth weight. Thus, the effect of
each natural log increment in blood lead varied from a birthweight reduction of
58.1 g for 18-year-old mothers to a reduction of 600.1 g for 30-year-old
mothers. Maternal blood lead and race interacted to produce a significant
reduction in birth length in white infants (p <0.025). Thus, the birth length
of white infants decreased ~2.5 cm for each natural log increment in maternal
blood lead. Maternal blood lead showed no significant relationship to
covariate-adjusted head circumference or gestation length. Obstetrical
complications and Apgar scores also showed no relationship with lower birth
weight or lead exposure.
Separate analyses of 861 women (including the 202 subjects just described)
from the Cincinnati cohort, but including pregnancies of not less than 20 weeks
duration, also showed a highly significant (p <0.0006) negative relationship
between maternal blood lead level and covariate-adjusted birth weight (Born-
schein et al., 1989). Overall, this cohort had a decrease of approximately
114 g in birth weight for each natural log increment in maternal blood lead.
3/27/89 30
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
Analyses of postnatal growth rates in a cohort of 260 children from the
Cincinnati study suggested an interactive effect of prenatal and postnatal lead
exposure (Shukla et al. , 1987). Splitting prenatal blood lead levels and the
average increase in postnatal blood lead levels at the median (7.7 ug/dl for
prenatal, 3.4 ug/dl for the postnatal increase) provided a matrix of low/low,
low/high, high/low, and high/high exposure conditions. Analysis of data for
129 subjects in the high prenatal exposure classification indicated that
covariate-adjusted growth rates for stature over 3-15 months of age were
significantly (p = 0.006) and negatively related to the postnatal increase in
blood lead level. No effect was seen for the low prenatal exposure group.
Thus, for infants whose prenatal blood lead levels were greater than 7.7 ug/dl,
there would be, on average, a 2-cm difference in height at 15 months of age
between those infants who experienced no increase in postnatal blood lead and
those who experienced an increase of ~10 ug/dl.
Other recent results of a neurobehavioral nature from the Cincinnati
study have also been reported by Bhattacharya et al. (1988, 1989). Postural
sway was assessed by an automated apparatus in 33 children at 6 years of age
(Bhattacharya et al., 1988). Initial results indicated that maximum blood lead
level during the second year of life was significantly related to degree of
postural sway or imbalance at 6 years. Blood lead levels in this sample peaked
during the second year, averaging 25.6 ug/dl (range: 9.3-49.4 ug/dl), measured
quarterly. The later report by Bhattacharya et al. (1989) covers 63 children
and confirms the earlier results showing a significant relationship between
sway and second year maximum blood lead (r = 0.34, p = 0.02). Although more
test results are needed to fully explore these effects, these preliminary
findings provide additional indications of neurobehavioral disruption during
early childhood exposure to lead.
Cleveland
As noted in the 1986 Addendum (U.S. EPA, 1986b), the prospective study
conducted by Ernhart and her colleagues has provided some direct as well as
indirect evidence of an effect of prenatal lead exposure on neurobehavioral
development. Ernhart et al. (1985a, 1986) reported significant associations
between cord blood lead levels and measures of Abnormal Reflexes (on the
Brazelton Neonatal Behavioral Assessment Scale: NBAS) and Neurological Soft
Signs (on the Graham-Rosenblith Behavioral Examination for Newborns: G-R).
3/27/89 31
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
Also, the G-R Muscle Tonus measure was significantly related to maternal blood
lead levels at delivery. However, restricting the analyses to only 132 pairs
of mother-infant data, Ernhart et al. found only the G-R Neurological Soft
Signs to be significantly related to cord blood lead. A brief report on later
outcomes in this same cohort mentioned a significant association between
performance on the G-R Neurological Soft Signs scale and 12-month MDI scores
(Wolf et al., 1985). Thus, it is possible to infer a relationship between
cord blood lead levels and 12-month MDI performance in the Cincinnati study,
although Ernhart et al. (1985a, 1986) did not conclude that such an association
exists. Since the mean cord blood lead was 5.89 ug/dl and the maximum was only
14.7 ug/dl, any effect of prenatal lead exposure necessarily occurred at blood
lead levels below 15 ug/dl.
Later reports by Ernhart and her colleagues (Ernhart et al., 1987a, 1988;
Ernhart and Morrow-Tlucak, 1989) presented more complete results from their
continuing longitudinal study (Table 5). The Bayley MDI was administered at 6,
12, and 24 months; the Bayley PDI and the Kent Infant Development Scale (KID)
at 6 months; and the Stanford-Binet IQ test at 36 months. Postnatal blood lead
levels were measured at 6, 24, and 36 months. A total of 285 children from the
original cohort of 389 were sampled for blood lead levels; N's for individual
analyses ranged from 109 to 165. After control for covariates, maternal blood
lead accounted for a significant amount of the variance in 6-month MDI, PDI,
and KID scores. Although these three relationships were all negative (higher
PbB associated with lower developmental scores), concurrent blood lead was
positively related to the 6-month KID and accounted for nearly as much variance
as did maternal blood lead. Maternal blood lead levels averaged 6.50 ug/dl,
with a maximum of 11.8 |jg/dl; 6-month blood lead levels averaged 10.05 ug/dl,
with a maximum of 24.00 ug/dl.
More recent results from testing these children at age 4 years, 10 months
on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) were
reported by Ernhart et al. (1987b). Analyses were based on N's ranging from
117 to 211. Although bivariate correlations were statistically significant for
all PbB-WPPSI relationships except 6-month PbB, in no case did PbB account for
a significant amount of the variance (by two-tailed t test) after control for
13 covariates (Table 6).
3/27/89 32
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Two-tailed statist
Source: Ernhart et
33
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
TABLE 6. THE RELATIONSHIP OF PRENATAL AND POSTNATAL LOG BLOOD LEAD
WITH IQ AT AGE FOUR YEARS, TEN MONTHS
Blood
Lead
Measure
Prenatal
Maternal
Cord
Postnatal
6 Months
2 Years
3 Years
Mean
N
134
117
121
149
154
211
Full Scale
rB t
-.23**
-.21*
-.06
-.38**
-.32**
-.26**
-0.27
-0.54
-0.08
-0.69
+0.30
+0.48
iQa
Verbal Scale
r t
-.25**
-.22*
-.07
-.36**
-.39**
-.30**
-0.49
-0.78
-0.26
-1.41
-1.58
-1.00
Performance Scale
r t
-.23**
-.20*
-.08
-.34**
-.30**
-.26**
-0.48
-0.78
+0.10
+0.22
+0.96
+0.56
aWPPSI scores except for two S-B IQ scores; latter two cases were necessarily
excluded from the tests of the Verbal and Performance Scales.
r describes the unadjusted relationship of the PbB and IQ measures; t is
the test of the increment in variance associated with the addition of PbB to
the covariate variance in the IQ model.
*p <.05, **p <.01, two-tailed tests.
Source: Ernhart et al. (1987b).
Language development in the Cleveland cohort was also assessed at age 1,
2, and 3 years (Morrow-Tlucak and Ernhart, 1987). The Sequenced Inventory of
Communication Development (SICD) was administered to assess expressive and
receptive language development. In addition, productive speech (quantity,
length of utterance, vocabulary, communicative intent, and intelligibility) was
assessed at about 2 years. The number of subjects for each of the analyses was
not reported, but the number of blood lead measurements over the period from
delivery to 3 years ranged from 146 to 169. Alpha was set at 0.01. Several
bivariate correlations achieved statistical significance, but no relationship
achieved significance in multivariate F tests, although the regression analysis
for cord PbB and mean length of utterance was significant at p = 0.03. By
backward elimination, lead (cord PbB) remained in the model (at p ^0.05) for
two measures of language development: mean length of utterance and one aspect
of communicative intent ("expanded repetitions"). However, concurrent (2-year)
blood lead was positively related to one aspect of intelligibility (a decrease
in "unintelligible utterances").
3/27/89 34
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
Preliminary analyses of physical growth in the preschool period (up to
4 years, 10 months) revealed no significant negative relationship between
either cord blood lead or integrated postnatal blood lead and height or weight
in an unspecified number of children from the Cleveland study (Marler and
Ernhart, 1987). Earlier analyses (Ernhart et al. , 1986) of birth weight,
length, and head circumference had shown no significant effect of either
maternal blood lead (N = 185) or cord blood lead (N = 162).
Port Pirie
Vimpani et al. (1985) reported preliminary neurobehavioral results for the
prospective study conducted in Port Pirie, South Australia. The Bayley MDI and
PDI were administered to 592 children at age 24 months. Initial results
indicated that a decline in 24-month MDI performance was significantly associ-
ated with postnatal blood lead levels at 6 months or integrated over the
24 months after birth. Although several covariates were taken into account in
these partial linear regression analyses, maternal IQ had been measured for
only part of the cohort and HOME scores had not yet been included in the
analyses. Nevertheless, as noted in the 1986 Addendum, the available informa-
tion suggested that results from the Port Pirie study were consistent with the
other prospective studies in pointing to deficits on the Bayley MDI as a
function of perinatal lead exposure.
Although postnatal rather than prenatal lead exposure appeared to play a
greater role in the MDI deficits of the Port Pirie cohort, it has been noted
that blood lead levels increased considerably after birth, particularly from 6
to 15 months of age, and that earlier testing on the Bayley Scales (e.g., at
6 months) might have revealed a more significant relationship with a measure of
prenatal lead exposure (U.S. EPA, 1986b; Davis and Svendsgaard, 1987). Indeed,
the Port Pirie investigators have since stated that "the likely greater impact
of the much higher levels of PbB encountered postnatally" may have accounted in
part for the difference in their results versus the other prospective studies
(Wigg et al., 1988).
Later reports from the Port Pirie study have noted that the effect of
postnatal blood lead levels on the 2-year MDI was attenuated as more complete
control for maternal IQ and HOME scores was incorporated into the analysis,
although all regression coefficients for postnatal blood lead measures remained
negative (Vimpani et al., 1989; Wigg et al. , 1988; Baghurst et al. , 1987).
3/27/89 35
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
Elevations in 6-month blood lead continued to have the greatest measurable
impact on 2-year MDI scores, although the regression coefficient for 6-month
blood lead was only -0.16, with p = 0.07, after controlling for at least
15 covariates. The results indicated that "with other factors remaining
constant, a child's MDI at 24 months will be 1.6 points (equivalent to 1.5%)
lower for every 10 ug/dl rise in PbB at 6 months of age Moreover, in
view of the fit of a linear model in multiple regression analysis, these
findings provide no evidence of a threshold effect" (Wigg et al., 1988).
Continuing study of the Port Pirie cohort has yielded results for neuro-
behavioral development at age four years (McMichael et al. , 1988). The
McCarthy Scales of Children's Abilities were administered to 537 children
within 6 months of their fourth birthday; N's for individual analyses ranged
from 463 to 534. Multiple regression analyses incorporating 18 covariates
indicated that scores on the McCarthy GCI were significantly related to
log-transformed postnatal blood lead levels at 6, 24, and 36 months as well as
an integrated average for the four-year postnatal period (Table 7). Similar
effects were also evident for the McCarthy Perceptual-Performance and Memory
Scales.
The largest single coefficient (-15.0; p = 0.04) was for the GCI and
integrated postnatal average blood lead relationship, which indicates that GCI
scores decreased by 15 points for every 10-fold increment in blood lead.
Alternatively stated, GCI scores declined approximately 7.2 points as blood
lead levels increased from 10 to 30 pg/dl. Further analyses indicated that the
relationship between lead exposure and GCI was as strong or even stronger at
blood lead levels below 25 ug/dl than it was overall (geometric mean blood lead
level peaked at 2 years: 21.2 ug/dl; integrated postnatal average: 19 (jg/dl).
Other analyses revealed no indication that GCI performance at four years was
especially influenced by more recent blood lead levels; rather, the effect of
lead on the GCI appeared to be cumulative across the entire postnatal period.
Pregnancy outcomes were also evaluated in the Port Pirie cohort (McMichael
et al., 1986). A significantly elevated risk of preterm (<37 weeks) delivery
was associated with maternal blood lead levels above 14 ug/dl. Neither birth
weight nor spontaneous abortions (<20 weeks) showed a signficant association
with blood lead levels. However, blood lead levels of mothers who had still-
births were significantly lower than those who had live births (7.9 vs.
10.4 ug/dl). As discussed in the 1986 Addendum and by Davis and Svendsgaard
3/27/89 36
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37
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
(1987), this seemingly paradoxical relationship might reflect increased
transfer of lead from the mother to the fetus, resulting in greater fetal
toxicity and stillbirth. Vimpani et al. (1989) reported preliminary results of
an analysis of tissue lead concentrations in cord and placental membrane and
body that are consistent with this hypothesis. Placental membrane and body
concentrations of lead were higher in cases of late fetal deaths and preterm
births than for normal births. However, the number of cases analyzed was
limited (e.g., 6 stillbirths, 23 preterm births) and statistical analyses have
not been completed.
Sydney
Reports have recently started to emerge from a longitudinal study of
children in Sydney, Australia (Cooney et al. , 1989a, 1989b; McBride et al.,
1989). Of an original cohort of 318, 298 mothers and infants were sampled for
blood lead levels at birth. After 3 years, 215 children remained in the study.
A second cohort of 123 children was also recruited because of "concern over the
possible contamination of some of the early capillary blood samples" (Cooney
et al., 1989b). However, the results reported by Cooney et al. (1989a)
apparently pertain to the original cohort only. Geometric mean blood lead
levels for mothers and infants at birth were 9.1 and 8.1 ug/dl, respectively
(overall range: 0-29 ug/dl). Although blood lead measures were also taken at
6, 12, 18, 24, 30, and 36 months (McBride et al., 1989), the postnatal values
were not considered in the analysis of neurobehavioral outcomes during the
first three years. The Bayley MDI and PDI were administered at 6, 12, and
24 months, and the McCarthy GCI and Motor Scales were administered at
36 months. Other outcomes were also evaluated but the results have not yet
been reported.
Unadjusted bivariate correlations between blood lead levels (either
maternal or cord) and cognitive and psychomotor outcomes (either Bayley or
McCarthy Scales) were generally small, positive, and nonsignificant (Table 8).
The only statistically significant simple correlations were for the relation-
ship between cord blood lead and the 12-month Bayley MDI (r = 0.153, p <0.05,
two-tailed) and PDI (r = 0.167, p <0.05, two-tailed). However, the direction
of the relationship was positive, i.e., as blood lead increased, Bayley scores
increased. After adjustment for covariates, the contribution of blood lead to
the variance in the regression model approached significance only for the
3/27/89 38
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
TABLE 8. REGRESSION OF
AND CORD
DEVELOPMENTAL INDICES ON MATERNAL
BLOOD LEAD LEVELS
Simple Correlations
6
12
24
36
Age
Months
Cognitive
Psychomotor
Months
Cognitive
Psychomotor
Months
Cognitive
Psychomotor
Months
Cognitive
Psychomotor
Maternal
-.044
.035
.015
.081
.006
.021
.040
.015
Cord
-.061
.025
.153*
.167*
.053
-.060
.045
.010
Effect of
Rz
.136
.153
.177
.106
.219
.081
.165
.081
F
3.
3.
df =
4.
2.
df =
4.
1.
df =
3.
1.
df =
Covariates
16
63
13
08
23
13
79
49
13
11
39
13
P
<.001
>.001
,261
<.001
<.01
,245
>.001
>.10
,222
<.001
>.10
,204
Incremental Effect
of Lead
Rz
.008
.003
.008
.019
.001
.013
.001
.001
F
1.22 >.
0.46 >.
df = 2,259
1.17 >.
2.60
df = 2,243
.19 >.
1.54 >.
df = 2,220
.13 >.
.10 >.
df = 2,202
P
25
60
30
08
70
20
70
90
*p <.05, two-tailed test.
Source: Cooney et al. (1989a).
3/27/89
39
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
positive relationship between cord blood lead and 12-month Bayley PDI
(p = 0.08, two-tailed).
Regression analyses and path models indicated that the greatest influences
on MDI and PDI scores at 6 and 12 months were gestational age and HOME scores,
while at later ages HOME and parental characteristics (maternal IQ and educa-
tion) were the more important influences on cognitive measures. The fact that
Bayley scores accounted for a significant amount of the variance in regressing
HOME scores on prior HOME scores in two instances (12-month PDI for the 12-
versus 6-month HOME and 36-month MDI for the 36- versus 24-month HOME) raises
the question of whether lead exposure (e.g., maternal blood lead) might have
covaried with HOME scores. This particular relationship was apparently not
examined by the investigators. However, the authors did examine the relation-
ships between maternal/cord blood lead and gestational age, which were shown to
be statistically nonsignificant (as were also birth weight, obstetrical
complication, and postnatal risk factors).
Cooney et al. (1989b) reported the results of testing the Sydney cohort at
4 years of age on the McCarthy GCI and Motor Scales. At 4 years, 207 children
of the original cohort remained in the study. In addition to maternal and cord
blood lead samples at delivery, postnatal blood lead samples were taken every
6 months. Geometric means for capillary and venous blood samples combined rose
from 15 ug/dl at 6 months to a peak average of 16.4 ug/dl at 18 months and then
declined to 10.1 |jg/dl at 48 months.
Bivariate and partial (correcting for venous versus capillary collection)
correlations between 48-month McCarthy Scales and blood lead levels at differ-
ent ages were generally quite small, mixed in sign, and uniformly nonsignifi-
cant. Analyses using composite blood lead measurements (averaged over 12-month
periods) produced only one significant relationship, a positive correlation
(r = 0.160; p <0.05, two-tailed) between first year blood lead and GCI perfor-
mance (Table 9). However, after allowing for covariates, regression analysis
showed the relationship to be only marginally significant (p <0.07). Analysis
of covariance did not indicate that change in developmental outcome from 36 to
48 months was significantly related to either current (48 month) or cumulative
(current and prior) past lead exposure, although cumulative lead was a better
predictor (p = 0.14) than current lead exposure alone (p = 0.36) for GCI
scores. HOME score was stated to be the most important covariate for the GCI,
apart from the 36-month GCI.
3/27/89 40
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
TABLE 9. REGRESSION OF DEVELOPMENTAL INDICES AT 48 MONTHS
ON CURRENT AND PRIOR BLOOD LEVELS
Age
Prenatal :
Cognitive
Motor
First Year:
Cognitive
Motor
Second Year:
Cognitive
Motor
Third Year:
Cognitive
Motor
Fourth Year:
Cognitive
Motor
All Prior and Current:
Cognitive
Motor
Unadjusted
AR2 df
.004
.001
.023
.003
.001
.001
.001
.008
.001
.005
.044
.022
2,204
2,204
1,205
1,205
1,205
1,205
1,205
1,205
1,205
1,205
6,200
6,200
P
.36
.91
.03
.46
.82
.60
.70
.20
.88
.32
.17
.72
AR2
.009
.002
.013
.001
.002
.004
.003
.006
.001
.001
.028
.018
Adjusted
df
2,199
2,199
1,199
1,199
1,199
1,199
1,199
1,199
1,199
1,199
6,193
6,193
P
.14
.55
.07
.67
.60
.33
.76
.26
.76
.96
.14
.56
Source: Cooney et al. (1989b).
Mexico City
Preliminary results of a pilot study in Mexico City for a longitudinal
investigation of developmental outcomes related to lead exposure and other
factors have been reported by Rothenberg et al. (1989). Approximately
50 mothers were sampled for blood lead levels at 36 weeks (M36) of pregnancy
and delivery (MD); umbilical cord blood lead (UC) was also sampled at delivery.
Mean blood lead levels were: M36, 15.0 MQ/dl; MD, 15.4 ug/dl; and UC,
13.8 ug/dl. The Brazelton Neonatal Behavioral Assessment Scale (NBAS) was
administered to the infants at 48 hours and 15 and 30 days after birth.
The data were analyzed by calculating the trend of the NBAS subscale
scores over the first 30 days by linear regression analysis and by computing
the difference in M36 and MD values or M36 and UC values. The relationships
among the various primary and secondary measures were then examined through
3/27/89 41
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
bivariate correlations and multivariate regression analyses (Table 10).
Significant bivariate correlations were found between UC blood lead and the
30-day trend in NBAS Abnormal Reflexes (r = 0.299, p <0.05), between the M36-MD
blood lead difference and Regulation of States (r = 0.378, p <0.05), and
between the MD-UC blood lead difference and Abnormal Reflexes (r = -0.451,
p <0.01). The signs of all the correlations reflected impairment of function.
Stepwise multiple regression modeling with all covariates entered before the
lead variable revealed that the blood lead differentials for M36-MD and for
MD-UC accounted for a significant amount of the variance in the Abnormal
Reflexes trend (p ~ 0.03 for each). Similarly, M36-MD accounted for a signifi-
cant amount of the variance in Regulation of States (p = 0.025). However, UC
alone was no longer significantly associated with Abnormal Reflexes.
Alternatively stated, these results reflect impaired neurobehavioral
outcomes in infants as the mothers' blood lead levels increased from 36 weeks
to delivery or as the infants' blood lead levels approached or exceeded the
mothers' at delivery. Davis and Svendsgaard (1987) commented on the possible
significance of such disequilibria in the normal maternal-fetal blood lead
relationship and the possibility that the fetus/infant could act as a sink for
the mother's lead burden. However, Rothenberg et al. (1989) speculated that
some fetal stress factor may be responsible for both the disparity in fetal/
infant lead burden and the unfavorable neurobehavioral outcomes in the neonate
(cf. Ernhart et al., 1986).
Rothenberg et al. (1989) also evaluated physical development outcomes at
birth in their cohort. After controlling for covariates, multiple regression
analyses indicated that M36-MD and M36-UC each accounted for a significant
amount of the variance in birthweight (p <0.05); M36-UC accounted for a
significant amount of the variance in chest circumference (p = 0.054); and UC
and M36-UC accounted for a significant amount of the variance in trunk length
(p s 0.06).
Yugoslavia
A longitudinal study involving two communities in Yugoslavia, Titova
Mitrovica and Pristina, has been undertaken by Graziano et al. (1989a,b).
T. Mitrovica is a major lead smelter and industrial site, whereas Pristina,
40 km to the south, serves as a relatively non-exposed control community. The
analyses completed thus far have been retrospective as well as prospective.
Only reproductive outcomes have been assessed.
3/27/89 42
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PRELIMINARY DRAFT: DO NOT QUOTE OR CITE
TABLE 10A. SIGNIFICANT BIVARIATE CORRELATIONS OF 30-DAY NBAS* TREND
AND LEAD MEASURES
Maternal lead at 36 weeks (M36)
Maternal lead at delivery (MD)
Umbilical cord lead (UC)
M36 - MD
M36 - UC
MD - UC
reflexes, 0.299**
regulation of states, 0.378**
reflexes, -0.451
***
*NBAS = Neonatal Behavioral Assessment Scale.
**p <0.05.
***
TABLE 10B. EFFECT OF ADDITION OF LEAD TO THE STEPWISE MULTIPLE
REGRESSION MODEL USING PRIOR ENTRY OF ALL CONTROL VARIABLES THAT HAVE
SIGNIFICANT BIVARIATE CORRELATIONS WITH 30-DAY TREND OF NBAS*
NBAS Scale
Reflex
Regulation
of States
Lead
Measure
M36 - MD
MD - UC
M36 - MD
N
44
44
44
F
Value
4.87
5.08
5.54
Additional
Percent
of Variance
Explained
by Lead
6.0
6.2
8.5
P
Value
0.034
0.030
0.025
*NBAS habituation scale not tested because of low number of subjects with
complete data. All other variables not shown were not significant.
Source: Rothenberg et al. (1989).
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Of the first 1032 women enrolled in the study, 639 (304 in T. Mitrovica;
335 in Pristina) had had at least one pregnancy (only first pregnancies were
considered in the analysis) and had lived at their current address at least
since their first pregnancy. Geometric mean blood lead levels at the time of
initial interview were 15.9 ug/dl in T. Mitrovica and 5.1 ug/dl in Pristina.
The rate of spontaneous abortions (fetal loss prior to 7th month) was not
significantly different in the two communities: 16.4% of T. Mitrovica women
versus 14.0% of Pristina women reporting such loss. Graziano et al. (1989b)
noted that they had systematically attempted to demonstrate an association
between lead exposure and spontaneous abortion and that their failure to detect
such an association suggested that it did not exist at the levels of exposure
encountered in their samples.
A preliminary analysis of prospective data from 907 births (401 in T.
Mitrovica; 506 in Pristina) indicated that mean birthweights did not differ
significantly between the two communities: 3308 g (SD = 566) in T. Mitrovica
versus 3361 g (SD = 525) in Pristina. Geometric mean blood lead levels were
17.1 ug/dl in the former and 5.1 ug/dl in the latter mothers. Regression
analysis controlling for several covariates also failed to show any significant
relationship between mid-pregnancy blood lead levels and birthweight.
Glasgow
Following a cross-sectional duplicate diet study that showed, among other
things, an inverse relationship between gestational age and lead exposure
during pregnancy (Moore et al. , 1982a), Moore et al. (1982b) initiated a
prospective study of the neurobehavioral effects of lead in children born in
Glasgow, Scotland. A major source of lead exposure for this population was its
plumbosolvent drinking water. However, subsequent to a successful program to
control the plumbsolvency of the water supply for Glasgow, average blood lead
levels declined substantially (Richards and Moore, 1984). Notwithstanding this
complication in the design of their prospective investigation, Moore et al.
(1989) undertook to assess whether prenatal or perinatal lead exposure was
associated with birth outcomes or postnatal neurobehavioral development.
Their study sample consisted of 151 subjects drawn from an initial pool of
885 families. Based on maternal blood lead levels during pregnancy, three
groups, matched for social class, were created: high (£30 ug/dl, mean =
33.05), medium (15-25 ug/dl, mean = 17.73), and low (S10 ug/dl, mean = 7.02).
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Infant blood lead levels were measured at 1 and 2 years of age, but were not
included in the reported analyses because of incomplete records.
Although birth weight appeared to be inversely related to maternal blood
lead (a reduction of nearly 100 g for each increment in blood lead grouping),
no statistical analysis of the data was reported. Birth length showed a slight
trend in the oppposite direction, and other pediatric measures (head circum-
ference, Apgar scores, obstetric complications) showed no evident trend in
either direction.
Unadjusted Bayley scores (MDI, PDI, and mean) at 1 and 2 years generally
decreased with increasing maternal blood lead grouping. However, stepwise
linear regression anlayses indicated that birth weight, social class, and HOME
scores accounted for Bayley Scales performance better than lead exposure (as
represented by maternal blood lead, water lead concentration, or reported
history of pica). Since birth weight was significantly related inversely to
lead exposure, it was removed from the model to see if the explanatory power of
one of the lead variables could be improved. Only second year pica showed a
notable improvement, although HOME score alone still had less predictive
ability for 2-year Bayley scores than pica coupled with HOME score. An
analysis of the Bayley IBR revealed no consistent direction of association
between lead exposure and IBR factors. Moore et al. (1989) concluded that
their dataset provided "no firm evidence for either a direct or an indirect
contribution of lead to decrements in cognitive development."
Christchurch
Fergusson and his colleagues (Fergusson and Purchase, 1987; Fergusson
et al., 1988a,b,c) collected shed deciduous teeth from more than 1000 children
in Christchurch, New Zealand to assess their long-term lead exposure and the
relationship of such exposure to neurobehavioral outcomes. Blood lead levels
were not measured.
As reported by Fergusson et al. (1988b), IQ, reading ability, and school
performance were assessed in relation to dentine lead levels in samples of
664-886 children from an original cohort of 1265 drawn from the Christchurch
Child Development Study. The subjects were evaluated at ages 8 and 9 years on
the WISC-R, the Burt Reading Test, and by teachers' ratings of reading, written
expression, spelling, mathematics, and handwriting. All bivariate correlations
between these outcomes and dentine lead levels were in the predicted direction
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(negative), and all but one (out of 18) were statistically significant at
p <0.05 (one-tailed). After correcting for test unreliability, dentine lead
measurement error, sample selection factors, and several covariates, the
coefficients for the reading test and all five teacher ratings at both ages 8
and 9 years remained significant. Further correction for pica (to test for the
reverse causality hypothesis that reduced cognitive ability results in more
pica, which in turn results in greater lead exposure) reduced the size of the
correlations even more (ranging from -0.07 to -0.14), but 7/12 of the correla-
tions remained statistically significant at p <0.05 (Table 11).
TABLE 11. UNEXPLAINED CORRELATIONS BETWEEN DENTINE LEAD LEVELS (log
TAKING INTO ACCOUNT TEST RELIABILITY, CONFOUNDING COVARIATES,
SAMPLE SELECTION FACTORS, AND REVERSE CAUSALITY VIA PICA
Measure
Verbal IQ
Performance IQ
Total IQ
Burt reading test
Teacher ratings
Reading
Written expression
Spelling
Mathematics
Handwriting
8 years
r
-0.03
-0.02
-0.04
-0.07
-0.13
-0.13
-0.14
-0.08
-0.12
P*
N.S.
N.S.
N.S.
<0.05
<0.001
<0.001
<0.001
<0.10
<0.05
9 years
r
-0.02
-0.02
-0.03
-0.08
-0.08
-0.08
-0.09
-0.10
-0.08
P*
N.S.
N.S.
N.S.
<0.05
<0.10
N.S.
<0.10
<0.05
<0.10
*0ne-tailed test.
Source: Fergusson et al. (1988b).
Fergusson et al. (1988c) also investigated the hypothesis that the
demonstrated relationship between lead exposure and school performance was due
to lead-related deficits in attentional processes. Mothers' and teachers'
ratings of signs of restless activity and inattention at ages 8 and 9 years
were correlated with dentine lead levels of 888 children (Table 12). Several
aspects of the ratings were significantly correlated with dentine lead, with
bivariate correlations for total rating scores ranging between 0.08 (p <0.05)
and 0.14 (p <0.01, one-tailed). Teachers' ratings were more highly correlated
with lead and were also judged to be a more accurate measure of the children's
behavior than were maternal ratings. After correcting for measurement errors,
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TABLE 12. PRODUCT MOMENT CORRELATIONS BETWEEN MATERNAL, TEACHER
BEHAVIOUR RATINGS AND DENTINE LEAD VALUES (log M9/g)
8 years 9 years
Measure r p* r p*
Maternal ratings
Activity
Restless, overactive 0.07 <0.05 0.05 <0.10
Excitable, impulsive 0.07 <0.05 0.05 <0.10
Constantly fidgeting 0.03 N.S. 0.04 N.S.
Always climbing 0.07 <0.05 0.04 N.S.
Squirmy, fidgety 0.03 N.S. 0.06 <0.05
Attention
Short attention span 0.09 <0.01 0.08 <0.01
Inattentive, easily distracted 0.09 <0.01 0.05 <0.10
Can't settle to tasks 0.06 <0.05 0.04 N.S.
Total Score 0.11 <0.01 0.08 <0.05
Teacher ratings
Activity
Restless, overactive 0.09 <0.01 0.11 <0.001
Excitable, impulsive 0.03 N.S. 0.10 <0.001
Squirmy, fidgety 0.11 <0.001 0.13 <0.001
Very restless 0.10 <0.001 0.13 <0.001
Attention
Inattentive, easily distracted 0.16 <0.001 0.14 <0.001
Short attention span 0.11 <0.001 0.12 <0.001
Poor concentration 0.13 <0.001 0.12 <0.001
Total Score 0.13 <0.001 0.14 <0.001
"'One-tailed test.
Source: Fergusson et al. (1988c).
sample selection factors, covariates, and pica, the correlation between dentine
lead and inattention/restless behavior was 0.08 (p <0.01) at both 8 and 9 years
of age.
Although small, the corrected correlations between dentine lead and
various outcomes reflecting school behavior and performance were consistent and
stable over a one-year interval in the Christchurch study. The uniformity and
stability of these results across time provide compelling reason to judge the
effects as real. However, this same study provided no evidence that intelli-
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gence, as measured by the WISC-R at 8 or 9 years of age, was related to dentine
lead levels.
The lack of blood lead measurements makes it difficult to interpret the
Christchurch study for dose-response information. However, the mean dentine
lead value in this study was 6 ug/g, which may be compared to a mean dentine
lead level of ~14.5 ug/g found by Needleman et al. (1979; see also Bellinger
et al., 1984b) for a sample of 2335 Boston children. Given the comparability
of the methods employed by Fergusson (Fergusson and Purchase, 1987; Fergusson
et al., 1988a,b,c) and by Needleman et al. (1979), and an estimated mean blood
lead level on the order of 30 ug/dl at age 2-3 years in the study by Needleman
et al. (1979), it is possible to infer that the average blood lead level of the
Christchurch cohort could have been roughly on the order of $15 ug/dl at age
2-3 years. Although this estimate is rather imprecise and based on several
assumptions, it suggests that the level of lead exposure in the Christchurch
study population was roughly comparable to populations in some of the other
studies under consideration here.
Nordenham
As noted in the 1986 Addendum, Winneke et al. (1985a,b) enrolled 114 chil-
dren in 1982 from a population of 383 children born 6-7 years previously in
Nordenham, Federal Republic of Germany. An ongoing federal screening program
of the Nordenham residents had taken blood samples from mothers and cords at
delivery. The maternal geometric mean blood lead level was 9.3 |jg/dl (range:
4-31); for umbilical cord, it was 8.2 ug/dl (range: 4-30). When tested at
age 6-7, the children's average blood lead level was again 8.2 ug/dl, but
distributed differently (range: 4-23). In terms of accounting for a signifi-
cant amount of variance in various measures of reaction time performance,
maternal blood lead was better than cord; the combination of maternal and cord
blood lead was better than either alone; and the combination was about as good
as concurrent blood lead. These relative standings are probably only rough
comparisons, since differences in the quality of the samples from different
sources and at different times could have affected these results (Winneke
et al., 1985a).
Retesting of 76 of the Nordenham children at age 9, with blood lead levels
then averaging 7.8 ug/dl (range: 4-21), indicated some persisting deficits in
reaction time test performance related to blood lead levels 3 years earlier
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(Winneke et al., 1989a,b). WISC-R performance was also significantly related
to the preceding blood lead levels after correction for confounding.
Concurrent blood lead did not significantly account for either reaction time or
WISC-R performance at age 9, although it had (for reaction time errors) at age
6-7. No results were reported for the relationship of 9-year outcomes to
perinatal blood lead measures.
Buffalo
A prospective study was recently initiated in the Buffalo, NY area by
Shucard et al. (1988a,b). Cord blood levels averaged ~4.4 ug/dl for 802 new-
borns. Outcomes have not yet been reported.
Other Recent Studies
In addition to the longitudinal studies discussed above, several other
studies of neurobehavioral function in lead-exposed children have been reported
since the 1986 Addendum. Although most appear to be well conducted, many of
these studies are of somewhat limited relevance, either because of their
cross-sectional design, their relatively high blood lead levels, or their
primary reliance on tooth lead as an exposure indicator. Despite its limita-
tions, blood lead is currently the bioindicator of greatest utility for
regulatory decision-making purposes. Consequently, the following studies will
be discussed in less detail than the prospective longitudinal studies described
above.
A cross-sectional study of cognitive abilities and educational attainment
in a population of school-age children from central Edinburgh, Scotland has
been reported by Fulton et al. (1987) and Raab et al. (1989). The geometric
mean blood lead level for the 501 children in the study sample was 11.5 ug/dl
(range: 3.3-34.0). Multiple regression analyses indicated significant
relationships between log-transformed blood lead levels and composite scores on
the British Ability Scales (p = 0.003) and between blood lead levels and
attainment test scores for quantitative (p = 0.04) and reading (p = 0.001)
skills, even after allowing for 33 covariates. Grouping the subjects by blood
lead levels showed a clear dose-response relationship without any evident
threshold down to the lowest subgroup mean blood lead level of 5.6 ug/dl.
Hatzakis et al. (1987, 1989) conducted neuropsychological testing on
509 children living near a lead smelter in Lavrion, Greece, and found impair-
ments in WISC-R IQ scores and reaction time performance scores. These effects
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were significantly associated with blood lead levels after controlling for as
many as 23 covariates in multiple regression models. Blood lead concentrations
ranged from 7.4 to 63.9 ug/dl and averaged 23.7 ug/dl. Depending on the number
of covariates included in the model, full scale IQ decreased by 2.4-2.7 points
for every 10-ug/dl increase in blood lead concentration. Subjects were grouped
by blood lead levels (10-|jg/dl increments) to analyze dose-response relation-
ships for IQ as well as reaction performance scores. A nonlinearity in the
dose-response pattern for IQ makes it difficult to interpret these data for a
threshold. However, reaction time performance showed no evident threshold.
Wolf et al. (1987) used structural equation modeling to evaluate the
variables related to low-level lead exposure and infant mental development in
an urban population in Costa Rica. Blood lead levels averaged 10.8 ug/dl
(range: 5.4-21.5 ug/dl) in 182 subjects whose average age was 16.6 months
(range: 12-23 months). Blood lead had neither direct nor indirect effects on
the Bayley MDI. However, blood lead did have a significant negative relation-
ship with birth weight (p = 0.05) and mother's height (p = 0.001), as well as a
positive relationship with mother's age (p = 0.01), after adjustment for
covariates. Birth weight, iron deficiency anemia, and child's age had signifi-
cant direct effects on MDI.
Vivoli et al. (1989) measured lead concentrations in blood, teeth, and
hair, as well as ALA-D activity, in 237 children from Sassuolo, Italy. At the
time of the study, blood lead levels averaged ~11.5 |jg/dl. Although concurrent
blood lead measures showed no significant relationship to covariate-adjusted
scores on any of six neurobehavioral tests, tooth lead was significantly
related to full scale and verbal WISC-R scores. Moreover, ALA-D was signifi-
cantly associated with one verbal subtest of the WISC-R and with delayed
reaction time performance.
Tooth lead also accounted for a significant amount of the variance in
WISC-R full scale and verbal IQ as well as Bender Gestalt visual motor test
performance in 156 children from Aarhus, Denmark (Hansen et al., 1989).
Circumpupal tooth lead levels averaged 10.7 ug/g. A study of children in
Brussels (Cluydts and Steenhout, 1989) showed marginally significant (p <0.10)
covariate-adjusted regression coefficients for tooth lead and neurobehavioral
outcomes (WISC-R, reaction time and attentional performance), despite the small
(N = 41) number of children evaluated.
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In separate but similar studies conducted in Rhode Island and Lavrion,
Greece, Faust and Brown (1987) and Benetou-Marantidou et al. (1988), respec-
tively, administered neurobehavioral test batteries to small groups (N's of
15-30) of children whose blood lead levels had been measured at ~30-60 ug/dl.
Significantly impaired performance was evident by comparison to matched con-
trols, even after blood lead levels had been below 30 ug/dl for at least one
year (Faust and Brown, 1987) or after a 4-year intervening period before
follow-up testing (Benetou-Marantidou et al., 1988).
In analyses of data from the second National Health and Nutrition Examina-
tion Survey, Schwartz and Otto (1987) have also found evidence of retarded
neurobehavioral development and impaired neurosensory capability in relation to
low-level lead exposure. The ages at which a child first sat up, walked, and
spoke were significantly associated with blood lead levels, as was also hearing
threshold. The decline in hearing ability is qualitatively consistent with
other evidence linking low-level lead exposure to electrophysiological changes
in the auditory system (reviewed in U.S. EPA, 1986a).
With regard to fetal growth effects, a recent report by Ward et al.
(1987) indicated that placental lead concentrations were highly significantly
correlated with reductions in birth weight, head circumference, and placental
weight in 100 obstretically normal births in England. Gestational age was
correlated at borderline statistical significance (p <0.10). Dividing the
data into two birthweight groups, low (<3000 g) and high (>4000 g), revealed
a highly significant difference in mean placental lead concentrations:
2.349 ug/9 (S.D. = 0.883) versus 1.122 pg/g (S.D. = 0.361) for low and high
weight groups, respectively. Of the 37 elements analyzed, lead and cadmium
showed the most consistent negative relationships with these fetal outcomes.
Other factors, such as parity, sex of neonate, social class, and history of
miscarriage, did not appear to the authors to significantly confound their
results.
Conclusions
As noted in the 1986 Addendum (U.S. EPA, 1986b), prospective studies offer
a major advantage over cross-sectional and even many retrospective studies in
that they provide a better history of lead exposure. This key difference is
the reason why more weight is placed on findings from prospective studies.
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However, notwithstanding this advantage, prospective studies may have various
types of shortcomings in common with other epidemiological studies. One
problem of particular importance is statistical power, especially in longi-
tudinal studies that typically experience attrition and declining sample sizes
over the course of the study.
The studies reviewed here differ considerably in population size and, even
within some studies, in the number of subjects included in individual analyses.
To illustrate, the first results from the Boston prospective study were based
on analyses involving 201 infants out of a cohort of 249 (Bellinger et al.,
1987a). By 5 years, the analyses were based on 170 children (Bellinger et al.,
1989b). While this rate of attrition is certainly not high, it does neverthe-
less make it increasingly difficult to detect an effect of low-level lead
exposure. According to Cohen (1977), an N of over 400 subjects would be
required to detect an effect size of 0.01 with a power of 0.80 at an alpha of
0.05, one-sided. This calculation assumes that the analysis includes 13
covariates having an R2 of 0.30. If the covariate R2 is overestimated in the
analysis for some reason, e.g., because of spurious sample correlations between
covariates and blood lead or because the covariates are involved in causal
pathways linking lead exposure to development, then regression methods may fail
to detect a truly significant association between lead and developmental
outcomes.
Another factor that can affect the power to detect a signficant relation-
ship in these studies is the amount of variance in the sample blood lead
measures. A small standard deviation in the independent variable (e.g., blood
lead) will necessarily reduce any correlation between it and a dependent
variable (e.g., MDI scores). Also, the presence of a significant effect of
another variable on the outcomes under consideration will make it more diffi-
cult to detect the effect of lead exposure by regression analysis. For exam-
ple, over 50 percent of the mothers enrolled in the Cleveland study were
determined to be alcoholic, and significant early developmental effects were
shown to be alcohol-related in the Cleveland study population (Ernhart et al.,
1985b).
Perhaps the most surprising outcome of the prospective studies as a whole,
then, is that so many of them are able to detect any effect of lead at all.
Given the limitations of sample size and power of most of the studies under
consideration, one's confidence in the reality of any detected effects that
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achieve statistical significance is enhanced. Conversely, it is difficult to
interpret a failure to detect a lead effect as suggesting the absence of
effect, if the analyses in question were based on fewer than 400 subjects, as
was generally the case.
Despite these limitations, some important conclusions emerge from the
findings reported above. Various lines of evidence still relate neuro-
behavioral effects to blood lead levels of "10-15 ug/dl, and possibly lower,"
as was previously concluded in the 1986 Addendum (U.S. EPA, 1986b). Further
analyses from the Boston study, which has provided the most direct information
bearing on dose-response relationships for neurobehavioral effects, not only
supported the 10-15 |jg/dl level of concern but indicated that MDI deficits can
be detected in relation to cord blood lead levels of 6-7 (jg/dl in lower SES
children (Bellinger et al., 1988). Since the Boston cohort was mostly middle
to upper-middle class, "lower" SES merely refers to less than the highest SES
levels and is probably in fact much closer to the median of the U.S. popula-
tion than the term suggests. Although the postnatal lead exposure levels were
somewhat higher in the Port Pirie study, analyses of the relationship between
postnatal blood lead levels and covariate-adjusted MDI scores provided "no
evidence of a threshold effect" (Wigg et al., 1988). Indeed, restricting the
analysis to children with blood lead levels below 25 ug/dl in the Port Pirie
study yielded an even stronger association between covariate-adjusted McCarthy
GCI scores and integrated postnatal blood lead measures (McMichael et al.,
1988).
Supporting evidence for the stated level of concern may also be derived
from other studies. Although McCarthy Scale results from the Boston study have
not been analyzed in a manner to allow direct extraction of dose-response
information, the average blood lead level significantly associated with
covariate-adjusted performance on the McCarthy Scales (GCI and Perceptual-
Performance subscale) was 6.8 ug/dl (SD = 6.3) (Bellinger et al., 1987b).
Similarly, analyses relating cord blood lead levels to the G-R Neurological
Soft Signs and, indirectly, to 12-month MDI scores were previously reported for
the Cleveland study (Ernhart et al., 1986; Wolf et al., 1985), along with more
recent significant results, by more than one analysis, relating cord blood lead
to Length of Utterance, a measure of language development in 24-month-old
infants (Morrow-Tlucak and Ernhart, 1987). Significant relationships were also
indicated for maternal blood lead and deficits in 6-month MDI, PDI, and KID
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scores in the Cleveland cohort, but results of other analyses were mixed
(Ernhart et al., 1987a). Any significant neurobehavioral effects associated
with cord blood lead in the Cleveland study necessarily occurred at levels
below 15 ug/dl since the maximum single cord blood lead level measured was only
14.7 ng/dl (mean: 5.99 pg/dl). Moreover, the fact that significant evidence of
lead-associated impairments was found in a relatively small cohort (N's <200)
suggests that the work was carefully conducted and that the results are
credible.
Preliminary evidence from the Mexico City study is not inconsistent with a
level of concern of 10-15 ug/dl, and possibly lower. Rothenberg et al. (1989)
found that two measures of neonatal neurobehavioral function during the first
30 days of life were significantly accounted for by differentials in maternal
blood lead levels during the last month of pregnancy and/or maternal and cord
blood lead levels. The nature of the reported analyses does not provide direct
dose-response information, but the mean cord blood lead level in the Mexico
City cohort was 13.8 ug/dl and the mean maternal delivery blood lead was
15.4 pg/dl, levels that approximate the stated level of concern. However,
little weight can be placed on these findings until more complete results are
obtained from a larger number of subjects.
Some evidence from recent cross-sectional studies is also consistent
with the identified level of concern. The Edinburgh study (e.g., Fulton
et al., 1987) shows a significant relationship between blood lead levels
averaging as low as 5.6 ug/dl and covariate-adjusted scores of cognitive
ability and educational attainment. As noted by Grant and Davis (1989), this
finding appears to closely parallel the results of Schroeder and Hawk (1987),
whose North Carolina cross-sectional study population showed IQ deficits in
relation to blood lead extending to levels as below 10 ug/dl. The latter study
was described in detail and evaluated in the 1986 Air Quality Criteria for
Lead (U.S. EPA, 1986a). In addition, the reaction time performance results of
Hatzakis et al. (1989) showed no evident threshold over a blood lead range of
7.4 to 63.9 ug/dl.
Based on all of the above considerations, a blood lead concentration
of 10-15 ug/dl, and possibly lower, remains the level of concern for impaired
neurobehavioral development in infants and children. Given the fact that such
effects have been associated with blood lead measures in pregnant women,
umbilical cords, and infants up to at least 2 years of age, there is no
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apparent distinction at present as to whether this level of concern applies to
only fetuses or infants or preschool-age children. Thus, a blood lead level of
10-15 ug/dl, and possibly lower, ought to be avoided in pregnant women,
fetuses, infants, and young children, although it is recognized that pregnant
women per se are not necessarily a population at risk.
Various lines of evidence suggest that lower SES and male gender are addi-
tional risk factors for the developmental effects of low-level lead exposure.
Increased vulnerability in lower SES children has been indicated in analyses
of MDI scores (Bellinger et al., 1988) and MDI-GCI change scores in the Boston
study (Bellinger et al., 1989b) and in the MDI results from Cincinnati
(Dietrich et al., 1987b, 1989b). Also, some IQ results from cross-sectional
investigations are consistent with the view that lower SES children are more
vulnerable to lead-induced cognitive impairment (Harvey et al., 1984; Lansdown
et al., 1986; Schroeder and Hawk, 1987). Greater susceptibility of male
infants to lead developmental toxicity has been evident in analyses of MDI-GCI
change scores in the Boston study (Bellinger et al., 1989b), in MDI results
from the Cincinnati study (Dietrich et al., 1987b, 1989b), in reanalyses of IQ
data from the Southampton cross-sectional study (Pocock et al., 1987), and in
some early data on sex ratios of stillbirths in Port Pirie and other locations
(Scragg et al., 1977).
The evidence regarding pregnancy outcomes and physical growth effects
related to prenatal lead exposure is less consistent than that for neurobehav-
ioral outcomes. Such was the case at the time of the 1986 Addendum (U.S. EPA,
1986b) and is still the case simply because little additional information
pertaining to pregnancy outcomes and growth has appeared since the 1986 assess-
ment.
As far as growth effects are concerned, the Cincinnati study has shown a
significant covariate-adjusted reduction in birth weight associated with
prenatal (maternal) blood lead levels (Bornschein et al., 1989). In addition,
early postnatal (3-15 months) growth rates have also been associated with lead
exposure pre- and postnatally in the Cincinnati study (Shukla et al., 1987).
(Interactions with other variables were evident in both of these cases, which
will be discussed further below.)
Some supporting evidence of lead-related reductions in birth weight also
comes from the Boston and Mexico City studies and, possibly, the Glasgow study.
Although birth weight per ^e showed no relationship to cord blood lead in the
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Boston study, there was an exposure-related trend in the percentage of small-
for-gestational age infants that approached statistical significance (Bellinger
et al., 1984a). In Mexico City, the difference in the blood lead level of the
mother at 36 weeks versus either her level at delivery (M36-MD) or the blood
lead level of the cord (M36-UC) accounted for a significant amount of the
variance in birth weight (Rothenberg et al., 1989). Similar findings
(p = 0.06) were noted for chest circumference and trunk length. In Glasgow,
the high maternal blood lead group (mean: 33.05 ug/dl) weighed 3.32 kg, on
average, at birth, whereas the medium blood lead group (mean: 17.73 ug/dl)
weighed 3.43 kg and the low group (mean: 7.02 ug/dl) weighed 3.51 kg (Moore et
al., 1989). However, these data were not adjusted for covariates and were not
tested for statistical significance.
Otherwise, no other prospective study has shown a significant association
between reduced birth weight and lead exposure. The Yugoslavian study
(Graziano et al., 1989b), in particular, has failed thus far to yield any
evidence of lead-related birthweight reductions in more than 900 births, even
at relatively high blood lead levels. Also, analyses by Ernhart et al. (1986)
showed no significant effect of lead on birth weight, birth length, or head
circumference; nor, according to preliminary analyses, was any effect evident
on postnatal growth (Marler and Ernhart, 1987). However, the cross-sectional
analysis by Ward et al. (1987) did indicate highly significant simple relation-
ships between placenta! lead concentrations and reduced birth weight and head
circumference.
The Port Pirie study provided strong evidence relating prenatal lead
exposure to increased risk of preterm delivery (<37 weeks gestation) in a
sample of 749 pregnancies (McMichael et al., 1986). Also, a small but signifi-
cant relationship between prenatal lead and gestational maturity was observed
in the structural analyses of the Cincinnati study (e.g., Dietrich et al.,
1987b). However, regression analyses of a different sample from the Cincinnati
study did not reveal a significant association between prenatal lead and
preterm (<35 weeks) deliveries (Bornschein et al., 1989). Also, as previously
discussed in the 1986 Addendum, the Boston prospective study showed a positive
but nonsignificant relationship between cord blood lead and gestation length
(Bellinger et al., 1984a), whereas the cross-sectional study of Moore et al.
(1982a) found signficant negative associations between gestational age and
maternal as well as cord blood lead after allowing for a number of covariates.
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Placental lead concentrations appeared to be inversely related to gestation
length in the analyses of Vimpani et al. (1989) and Ward et al. (1987), but
were of uncertain statistical significance.
There are many possible explanations for these apparent inconsistencies
among studies. The lack of a significant difference in pregnancy outcomes
between the high exposure and reference communities in Yugoslavia (Graziano
et al., 1989a,b) could reflect the difficulty of assessing fetal lead exposure
by means of maternal blood lead levels. With regard to gestation length,
Bornschein et al. (1989) noted that their analysis was restricted to pregnan-
cies of at least 35 weeks. A similar cutoff of 34 weeks was used in the Boston
prospective study (Bellinger et al., 1984a). Constraining the data in this
fashion could make it more difficult to detect an effect on gestation. Also,
there were interactions involving mother's age and race evident in the Cincin-
nati study (Bornschein et al., 1989). Thus, differences in the age of the
mothers, racial make-up, other population characteristics, sample sizes, level
of lead exposure (current as well as past), and approaches to analyzing data
could underlie the varying results of different studies.
Based on the evidence reviewed here and in the 1986 Air Quality Criteria
for Lead (U.S. EPA, 1986a), it seems likely that prenatal lead exposure poses a
potential hazard to the developing fetus in terms of reduced gestational length
and possibly other aspects of fetal growth (in addition to postnatal neuro-
behavioral development, as already noted above). It is difficult, however, to
derive a definitive dose-response relationship for fetal outcomes from the
available data, although some indications point to a level of concern starting
in the region of 10-15 |jg/dl. The average maternal blood lead levels in the
studies where the pre-term delivery effect was clearest (Port Pirie and
Glasgow) was in the 10-15 yg/dl range, with somewhat mixed findings in the
Cincinnati, Boston, and Cleveland studies where the maternal or cord blood lead
levels averaged below 10 pg/dl. A similar pattern seems to hold for birth
weight as well. The strongest evidence of a birthweight effect comes from the
Cincinnati study, with some of their analyses suggesting that such an effect
could start in the region of 12-13 (jg/dl, but possibly extending from 7 to 18
ug/dl. However, other prospective studies provide no support for this conclu-
sion, and so it must, be considered an open issue for more definitive resolu-
tion.
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The issue of the persistence of the neurobehavioral effects needs to be
considered in an assessment of the risk of low-level lead exposure. If
decreased scores on the Bayley Scales reflected merely a transient delay in
children's neurobehavioral development -- a minor perturbation that children
could quickly "grow out of" — then the public health significance of lead
exposure at blood lead levels of 10-15 ug/dl would perhaps be diminished. Some
recent results from two of the studies that had convincingly demonstrated a
link between prenatal lead exposure (either maternal or cord blood lead levels)
and early deficits on the Bayley Mental Development Index now suggest that the
association between prenatal lead exposure and cognitive development may not
hold up at later ages. The Cincinnati study found a declining influence of
prenatal exposure indicators on MDI scores at 12 months and 24 months: only
10-day blood lead measures were significantly associated with MDI scores at
12 months, and no significant negative PbB-MDI relationships were evident at 24
months (Dietrich et al., 1989b). Although the Boston study did continue to
find a significant relationship between prenatal lead exposure (cord blood
lead) and MDI performance at 24 months, no relationship could be shown for
prenatal lead exposure and cognitive abilities at 57 months on the McCarthy
Scales (Bellinger et al., 1987b). Thus, one implication of these 'findings
might be that the effects of prenatal lead exposure on neurobehavioral develop-
ment are not permanent.
Such a conclusion could be valid, but the evidence available to support it
is not adequate. The inability to detect a continuing significant association
between prenatal lead exposure and neurobehavioral function at age 2 in the
Cincinnati study or age 5 in the Boston study could result from, among other
things, a lack of adequate statistical power, as noted above. Other factors
could also interfere with detecting such a relationship and possibly account
for differing results in separate studies. For example, it is not clear which
measure of blood lead provides the best indicator of exposure during critical
periods of organogenesis. The Cincinnati study primarily used maternal blood
samples obtained during the first or second trimester of pregnancy to indicate
prenatal lead exposure. Prenatal exposure was also reflected in samples taken
from the Cincinnati infants 10 days after birth (gestationally corrected), but
comparatively few cord blood samples were available for data analyses. The
Boston study relied exclusively on cord blood samples while other studies have
also sampled the mother's blood around the time of delivery. As suggested
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previously (U.S. EPA, 1986b; Davis and Svendsgaard, 1987) and supported by
preliminary results from the Mexico City study (Rothenberg et al., 1989), there
may be differences in these measures, particularly during the last month or so
of pregnancy, that reflect important biokinetic transfers of lead between
compartments, both within the mother and infant individually and between them.
In addition to the nature and extent of such biokinetic transfers, their
timing (and the point at which blood lead is sampled) could make an important
difference in the ontogenesis of neural structures and, consequently, later
neurobehavioral function. It is interesting to note, for example, that almost
no significant negative associations have been found, after covariate adjust-
ment, between concurrent blood lead levels and postnatal outcomes in any of the
prospective studies reviewed here. Rather, cumulative past exposure (e.g.,
average postnatal blood lead levels) or, in several instances, blood lead
levels several months or years prior to a given outcome have shown the strong-
est relationship to postnatal neurobehavioral effects. Such a lagged effect
has been suggested by several findings, as shown in Table 13. When significant
positive (unpredicted) relationships between a measure of blood lead and some
outcome have occasionally been found, they generally involved concurrent blood
lead levels.
Thus, it may well be that the ability to detect a significant relationship
between low-level lead exposure and neurobehavioral outcomes depends, at least
in part, on where and when the measure of blood lead is obtained. Since the
fetus and infant constitute the population at greatest risk, it would be
preferable to measure a direct indicator of their exposure. However, that
approach has not been as feasible as measuring a related indicator, such as
maternal or cord blood lead. (Even cord blood is sampled from the placenta!
rather than the fetal side and may therefore not fully reflect fetal exposure.)
Consequently, measures such as maternal and cord blood lead levels, while
reasonably good indicators of prenatal lead exposure, may not afford the most
accurate predictors of later neurobehavioral outcomes.
Another factor that could obscure a relationship between prenatal lead
exposure and postnatal neurobehavioral function and that could account for some
differences in results among studies is the rather precipitous increase in lead
exposure observed in most of the prospective studies during the first 2-3 years
of life. Sizeable rises in postnatal blood lead levels were noted in the
Cincinnati, Cleveland, and Port Pirie studies, but not in the Boston study.
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TABLE 13. STRONGEST RELATIONSHIPS BETWEEN BLOOD LEAD MEASURES
AT SPECIFIED TIMES AND LATER NEUROBEHAVIORAL OUTCOMES
AS DETECTED BY PROSPECTIVE STUDIES
Study
Time/Type
of Blood Lead Measure
Outcome
Boston
(Bellinger
et al., 1987a,b)
Cincinnati
(Dietrich
et al., 1987b,
1988; Bhatta-
charya et al.,
1988, 1989)
Cleveland
(Ernhart
et al., 1986,
1987a; Wolf et
al., 1985;
Morrow-Tlucak
& Ernhart, 1987)
Pt. Pi He
(Wigg et al. ,
1988; McMichael
et al., 1988)
Sydney
(Cooney et al.,
1989b)
Delivery/cord
2 yr
Prenatal (X: 16 wk)/maternal
10 day
2 yr
Delivery/cord
Deli very/maternal
Delivery/cord
6 month
6, 24, 36 month and
integrated postnatal
Cumulative (prior plus
current)
6- , 12-, 18-, and
24-month MDI
5-yr McCarthy
3- and 6-month MDI
12-month MDI
6-yr postural sway
12-month MDI (via 30-day
G-R soft signs)
6-month MDI, PDI, KID
2-yr language acquisition
(2 measures)
2-yr MDI
4-yr McCarthy
36 to 48 month change in
cognitive development (p
0.14, two-tailed)
None of the first three studies showed a significant association between
prenatal lead exposure indicators and 2-year MDI scores, but the Boston study
did. While analyses from the Boston study also indicated that continuing
"high" lead exposure (>10 ug/dl) contributed to a persistence of neurobehav-
ioral deficits at later ages, a high postnatal blood lead in the Boston cohort
was not as high as the average for any of the other prospective studies at age
2 years. Thus, the relationship between lead exposure at a critical stage of
early development and subsequent neurobehavioral function could be obscured by
differential lead exposure (most often, but not always, increased exposure) in
the intervening period.
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By this line of reasoning, one would perhaps expect that increased post-
natal PbB measures should then show a significant relationship to later neuro-
behavioral outcomes. This was in fact the case in the Port Pirie study, where
sample size was more clearly large enough to afford relatively good statistical
power. (This also points up, as discussed above, why it is not possible at
present to discriminate between prenatal and postnatal lead exposure in stating
a blood lead level of concern for developmental neurobehavioral effects.)
It should also be kept in mind that scores on tests such as the Bayley or
McCarthy Scales are only indicators or reflections of neurobehavioral function.
Such variables may be valid and reliable mesures, but they do not fully repre-
sent all aspects of a child's cognitive, social, and emotional development.
Thus, considerable caution must be exercised in drawing conclusions from find-
ings of "no effect." Not only are there many facets to a child's develop-
ment that need to be assessed, but these facets may interact in complex ways
that may be quite difficult to detect or evaluate. For example, a child's
emotional and social adaptation (including such notions as "self-esteem") may
be influenced in subtle as well as obvious ways by his or her cognitive
abilities.
Such complexities make it difficult to presume that a failure to detect a
continuing association between an indicator of prenatal lead exposure and, for
example, scores on the McCarthy Scales at 5 years is evidence of no permanent
effect. It is well known that the nervous system is capable of adapting to and
even compensating for various insults during early development. But it is also
true that the full realization of developmental potential can very much depend
on events during critical stages of ontogeny. A parallel may be drawn with
impaired language acquisition in children whose hearing has been affected by
chronic otitis media (e.g., Kavanagh, 1986). Although otitis media itself may
be transient and fully reversible, it secondary effects on language development
in young children may be much longer lived. As noted by Jenkins (1986, p. 216),
"With a fluctuating hearing loss, such children may receive inconsistent and
inadequate information, or may have to devote so much attention to the decoding
process itself that there is little capacity left over for higher-order
cognitive operations. If children are, in fact, doing something different or
expending more resources on lower levels of speech perception, we may see
deficits in other processes at a later period."
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It is also important to note the convergence of animal findings, particu-
larly those showing impairments in higher-level behavioral processes such as
discrimination reversal learning in primates as well as rodents at blood lead
levels below 20 ug/dl. A number of such studies, conducted in at least three
independent laboratories, provide evidence free of the socioeconomic and other
complex variables that sometimes complicate the interpretation of the human
literature. These studies were summarized and reviewed in Air Quality
Criteria for Lead (U.S. EPA, 1986a).
A remaining issue is whether the effects discussed here are large enough
to constitute a significant risk to public health. Valuable information has
been provided by various prospective studies on the magnitude of neuro-
behavioral deficits relative to increments in blood lead levels. Despite
different approaches to treating their data, three of the prospective studies
provide results suggesting that Bayley MDI scores decline by 2-8 points for
approximately every 10-ug/dl increase in blood lead level. The Boston study
found 4-8 point differences in 6- to 24-month MDI scores between high (mean:
14.6 ug/dl) and low (mean: 1.8 ug/dl) cord blood lead groups. The Cincinnati
study showed as much as an 8.4-point decline in boys 6-month MDI scores for
every 10-ug/dl increment in maternal blood lead. Also, the Port Pirie study
demonstrated a 1.6-point decrease in the 24-month MDI per 10 ug/dl of blood
lead at 6 months, and a ~3.5-point decrease in GCI scores for every 10 ug/dl in
average postnatal blood lead. As noted by Davis and Svendsgaard (1987), an
overall 4-point downward shift in a normal distribution of scores such as the
MDI or GCI would result in 50 percent more children scoring below 80 on these
exams (cf. Needleman, 1983; McMichael et al., 1988).
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