United States
Environmental Protection
Agency
Office of Research and
Development
Washington, DC 20460
EPA, 600/8-89 049F
August 1990
c/EPA
Air Quality Criteria for
Lead:
Supplement to the 1986
Addendum
\
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EPA 600/8-89/049F
August 1990
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental Protection
Agency policy and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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CONTENTS
TABLES iv
FIGURES vi
PREFACE vii
ABSTRACT viii
AUTHORS ix
I. INTRODUCTION 1
H. RELATIONSHIP OF,BLOOD PRESSURE TO LEAD EXPOSURE .... 2
ffl. NEUROBEHAVIORAL AND GROWTH EFFECTS IN INFANTS
AND CHILDREN 24
IV. REFERENCES 65
111
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TABLES
Number
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 25
3 Change in McCarthy general cognitive index (GCI) and
subscale scores associated with each natural log unit increase
in blood lead level 27
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 . 29
5A The relationship of fetal (maternal and cord) blood lead
(PbB) levels with later developmental outcomes 34
5B The relationship of prior and current postnatal blood lead
(PbB) levels with later developmental outcomes 34
6 The relationship of prenatal and postnatal log blood lead
with IQ at age four years, ten months 35
7 Estimated coefficients of log blood lead concentration from
simple and multiple regression analyses of McCarthy scores
at the age of four years 38
8 Regression of developmental indices on maternal and cord
blood lead levels 40
9 Regression of developmental indices at 48 months on
current and prior blood levels 42
10 Unexplained correlations between log dentine lead levels
taking into account test reliability, confounding covariates,
sample selection factors, and reverse causality via
pica 46
IV
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TABLES (continued)
Number Page
11 Product moment correlations between maternal or teacher
behavior ratings and log dentine lead values 48
12 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 relationships in adult men 14
2 Normal distributions with means of 96 and 100 and standard
deviations of 16 64
VI
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PREFACE
*
This document updates the Addendum to the 1986 EPA Air Quality Criteria for Lead.
A draft of this Supplement was prepared in March 1989 and reviewed by the Clean Air
Scientific Advisory Committee (CASAC) at a public meeting on April 27, 1989. Comments
on the draft Supplement were received from the public until June 12, 1989. The CASAC
informed the EPA Administrator in a letter dated January 13, 1990 that the 1986 Lead
Criteria Document, Addendum, and Supplement afforded "a scientifically balanced and
defensible summary of our current knowledge of the effects of this pollutant, providing an
adequate scientific basis for EPA to retain or revise primary and secondary NAAQS [National
Ambient Air Quality Standards] for airborne lead." This draft final Supplement differs from
the 1989 draft only in minor corrections and additions.
Vll
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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 most pertinent scientific information concerning sources, routes,
and levels of lead exposure and associated health effects and potential risks. An Addendum,
issued as part of Volume 1, pages A1-A67, of the 1986 Criteria Document, focused on
additional emerging studies concerning the effects of lead on cardiovascular function and on
early physical and neurobehavioral development. This Supplement to the above materials
evaluates still newer information concerning (1) lead effects on blood pressure and other
cardiovascular endpoints, and (2) the effects of lead exposure prenatally and/or postnatally on
birth outcomes and early physical and neurobehavioral development of children. The
evaluations contained in this Supplement and the 1986 Criteria Document and Addendum are
to serve as scientific inputs to decision-making with regard to the review and revision, as
appropriate, of the National Ambient Air Quality Standards (NAAQS) for lead.
Vlll
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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 45276-0056
Dr. David J. Svendsgaard, Health Effects Research Laboratory (MD-55), OHR, ORD, U.S.
Environmental Protection Agency, Research Triangle Park, NC 27711
IX
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SUPPLEMENT TO'THE 1986 AIR QUALITY CRITERIA FOR LEAD; ADDENDUM
I. INTRODUCTION
In the mid-1980s, the 1977 EPA criteria document, Air Quality Criteria for Lead (U.S.
Environmental Protection Agency, 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. Environmental Protection Agency, 1986a), incorporating
revisions made in response to public comments and review of earlier drafts by the Clean Air
Scientific Advisory Committee (CASAC), was completed 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. Environmental Protection Agency, 1986b) to the revised
document, Air Quality Criteria for Lead (U.S. Environmental Protection Agency, 1986a), was
also completed in 1986 and evaluated newly published information 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 decision-making on potential revision of the
existing lead NAAQS.
The present update focuses primarily on key findings that have emerged in the 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 interpret
the critical effects of lead that have greatest significance for impending regulatory decisions
regarding this environmental pollutant, with discussion focussing on key newer papers
published since completion of the earlier 1986 Addendum.
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n. RELATIONSHIP OF BLOOD PRESSURE TO LEAD EXPOSURE
v*
The 1986 Addendum (U.S. Environmental Protection Agency, 19865) 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 quality of the evidence available 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 hypertension.
Also not fully resolved was the extent to which lead-induced hypertension 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 is being placed on updated
discussions 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. Environmental Protection Agency, 1986b) noted that several
then-recently-published studies provided generally consistent evidence for increased blood
pressure being associated with elevated lead body burdens in adults, especially as indexed by
blood lead 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 levels. It was
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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 n 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. Environmental Protection Agency, 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 disappearance 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 indicated
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
concentrations 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 mercury (Hg), revealed no significant overall trend; but
of those men with blood lead levels over 37 jig/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 /*g/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 /ig/dl, but not at lower concentrations typically
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found in British men. However, further analyses reported by Pocock et al. (1985) for the
same data indicated significantly higher statistical associations between both systolic
(p =0.003) and diastolic (p < 0.001) blood pressure and blood lead levels, when adjustments
were 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 site 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. Environmental Protection Agency, 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 n 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 examination, 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 atomic absorption spectrometry, were transformed to log values for 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
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(p < 0.005) higher PbB levels, body mass index values, and calcium foods than did
normotensive male subjects (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 subjects aged 56-74 years, 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) focused 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 n 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 /ig/dl. In fact, the dose-response relationships
characterized by Pirkle et al. (1985) indicate that large initial increments in blood pressure
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occur at relatively 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 mm Hg, 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. Ghanges 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 to: (1) 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) 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. Environmental Protection Agency, 1986b) also noted that
questions had been raised by Gartside (1985) and E. I. DuPoht de Nemours (1986) regarding
the robustness of the findings derived from the analyses of NHANES n data discussed above
and as to whether certain time trends in the NHANES n data set may have contributed to (or
account for) the reported blood-lead blood-pressure relationships. Gartside reported analyses
of NHANES n data, which found that the obtained size and level of coefficient statistical
significance 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, 22-41 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 n 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. DuPont de Nemours (1986) reported that multiple regression coefficients
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decreased in magnitude and some became non-significant (p >0.05) when adjusted for
geographic site in analyses of NHANES n data, including analyses for the male group (aged
12-74) reported by Harlan et al. (1985) and for males (aged 40-59) reported by Pirkle et al.
(1985). For example, E. I. DuPont de Nemours reported unpublished reanalyses of
NHANES II data confirming significant associations, for males aged 12-74 years as well as
40-59 years, between log blood lead 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. DuPont 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 variables having significant associations with blood pressure. Also,
other differences existed in regard to specific aspects of the modeling approaches employed,
making it extremely difficult to assess clearly the potential impact of variation 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 n data. Those analyses
confirmed 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 n. Using this approach, the coefficients for log
blood lead in relation to either diastolic or systolic blood pressure 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. DuPont 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 (logFibB) 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. DuPont
de Nemours (1986)
Schwartz (1986a,b)
E. I. DuPont
de Nemours (1986)
British Regional
Heart Study
White males aged 40-59
Systolic (n=7371)
Diastolic (n=7371)
NHANESn
Males aged 20-74
Systolic (n=2254)
Diastolic (n=2248)
NHANESH
Males aged 12-74
Systolic (n=2794)
Diastolic (n=2789)
NHANESn
White males aged 40-59
Systolic (n=543)
Diastolic (n=565)
NHANESn
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. Environmental Protection Agency, 1986b) concluded that,
overall, the analyses of data from the two large-scale general population studies (British
Regional Heart Study and U.S. NHANES n 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 appeared to exist for males aged 40-59 and for systolic somewhat more so than
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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
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. Environmental Protection Agency, 1986b) further concluded that
none of the observational studies in and of themselves can be stated as definitively
establishing causal linkages between lead exposure and increased blood pressure of
hypertension. However, the Addendum noted that the plausibility of the observed
associations reflecting causal relationships between lead exposure and blood pressure increases
was supported by: (1) the consistency of the significant associations found by numerous
independent investigators for a variety of study populations, and (2) extensive lexicological
data discussed in the 1986 Addendum which clearly demonstrated 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, appeared to be complex, and mathematical models describing the relationships
still remained to be more definitively characterized. At the time of the Addendum, log blood-
lead/blood pressure 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 characterizing these 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 blood lead versus systolic and
1.4 to 2.7 for log blood lead 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 n data
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analyses and some other study results) also indicating significant relationships between blood >•
pressure elevations and blood lead levels ranging down, possibly, to as low as 7 jtg/dl.
The earlier Addendum (U.S. Environmental Protection Agency, 1986b) further stated
that the quantification of likely consequent risks for serious cardiovascular outcomes, as
attempted by Pirkle et al. (1985), also remained to be more precisely characterized. The
specific magnitudes of risk obtained for serious cardiovascular 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 elevations in blood
pressure occur; and coefficients estimating relationships between blood pressure increases and
specific more serious cardiovascular outcomes. It was noted that uncertainty still exists
regarding the most appropriate model and blood-lead/blood-pressure coefficients, mading 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 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 cardiovascular outcomes as well.
The Addendum (U.S. Environmental Protection Agency, 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 relation 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 hereditary traits, nutritional factors, and environmental agents. The relative roles of
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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 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 discussions 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 (Harlan, 1988; Schwartz, 1988; Gartside, 1988; Landis and Flegal,
1988) and the British study (Pocock et al., 1988). Elwood et al. (1988a) 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
intercomparison of the results of the NHANES II, British, and Welsh studies. A number of
other relevant papers described studies of lead-blood pressure relationships in selected
populations of nonoccupationally 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 lexicological findings from in
vivo or in 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 1987 Symposium, a further alternative
analysis of the data from NHANES n (using a generalized Mantel-Haenzel test) was reported
by Landis and Flegal (1988). In order to more definitively assess the robustness of the earlier
NHANES H results (Harlan et al. 1985; Pirkle et al., 1985) and, also, to evaluate possible
time-trend effects confounded by variations in sampling sites, Landis and Flegal (1988)
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carried out further analyses for NHANES n males, aged 12-74, using a randomization mode.1-
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 blood lead and
diastolic blood pressure for all males (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 coefficients 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 comparison
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) nevertheless, even with
the severe adjustments by sampling sites, age, and Quetelet index, the diastolic blood
pressure/blood lead relationship remained statistically 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 considerably greater detail for the restricted group
of white men 40 to 59 years of age (as described in Pirkle et al., 1985).
Also reported at the 1987 Symposium were two surveys in Wales that 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 /xg/dl and for women 9.6 pg/dl. Blood lead increased with
age (1 jig/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
12
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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. Categorizing the
data by blood lead increments demonstrated no trend in the blood pressure levels.
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,
respectively, 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 a confounding factor,
because all other factors were 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 1987 Symposium, Pocock compared the results of the NHANES n 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 concentration, 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 jtg/dl), together with 95% confidence limits. Pocock concluded that an overview of
data from these large epidemiological surveys provides reasonably consistent evidence on lead
and blood pressure. That is, whereas the NHANES n data on 2,254 U.S. men indicate a
slightly stronger association between blood lead and systolic blood pressure than Pocock's
13
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BRHS (N = 7371)
NHANES II (N = 2254)
Caarphilly (N =1164)
Wales (N = 865)
-o-
-2
4
0
1
ESTIMATED CHANGE IN MEAN SYSTOLIC BLOOD PRESSURE
(mm Eg) FOR A DOUBLING OF BLOOD LEAD
Figure 1. Comparison of study results from four larger-scale epidemiology studies of
lead-blood pressure relationships in men. Depicted are each study's
estimated changes in mean systolic blood pressure (in mm Hg) for each
doubling of blood lead (e.g., from 8 to 16 /tg/dl) together with 95% confidence
limits. A = British Regional Heart Study (BRHS) analyses, described by
Pocock et al. (1988); B = National Health and Nutrition Evaluation Survey
(NHANES H) analyses described by Schwartz (1988); C and D = Caerphilly
and Wales'studies described by Elwood et al. (1988a,b).
Source: Pocock et al. (1988).
8/16/90
14
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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 overlapping
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.
There was an additional report of an analysis of cross-sectional data from Canada (Neri
et al., 1988) presented at the 1987 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 concluded 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 supportive 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 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. In this 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 1987 Symposium with regard to
smaller-scale observational studies of blood lead and blood pressure in two types of
occupationally lead-exposed groups: bus drivers (Shaip et al., 1988) and policemen (Weiss
et al., 1988; 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 1987 Symposium, several new
studies (with generally small 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
15
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used: (a) employment at lead exposure vs. control plants; (b) current blood lead values at
time of examination (exposed group mean = 39.9 /xg/dl vs. 7.4 /xg/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 /xg/dl for the exposed workers 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 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.
On the other hand, Sharp et al. (1989) did find a statistically significant (p <0.036)
relationship between blood lead levels and blood pressure (diastolic but not systolic) levels
among a subsample of bus drivers evaluated in their earlier study (Sharp et al., 1988) who
were under beta-blocker treatment for hypertension. The association between diastolic blood
lead and blood pressure was significant at the stated level even after controlling for other
relevant risk factors, and none of the blood lead levels at the time of blood pressure testing
exceeded 18 /tg/dl.
In addition to the above study results which focused primarily on lead-blood pressure
effects in adult males, some additional analyses of such relationships 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 n data set. These latest analyses used variables identified as being important in
earlier NHANES n 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, age squared, Quetelet's body mass index, and the natural log
16
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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), 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 stepwise
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) tend to 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. However, the strength of the relationship (blood lead coefficient) for women
remains to be more precisely defined in terms of adjustments for geographic site effects
analogous to those described above for earlier analyses for NHANES n and BRHS male
subjects.
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 i*g/dl, respectively;
for women they were 9 and 6 /ig/dl, respectively, at age 40 and 45 years. At age 40, women
with systolic blood pressure above 140 mm Hg and/or diastolic above 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 age 40 indicated 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
17
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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 E (Pirkle et al., 1985) data analyses. The impact of alcohol
and blood hemoglobin on the subsequent multiple regression outcomes indicated 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., 1989) 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 H 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 reported by Fanning (1988).
There were 867 deaths in men with relatively nigh 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 cardiovascular disease; but there was no difference between the two groups over the past
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.
18
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' 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 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 nephritis" (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 1987 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
cigarette smoking and town of residence, statistical analyses did not yield statistically
significant associations between blood lead levels and such cardiovascular events. However,
as the blood lead-blood pressure association is so weak, Pocock et al. (1988) noted, it is
unlikely that any consequent association between lead and cardiovascular disease could be
demonstrated from prospective epidemiological studies.
On the other hand, Schwartz (1989) has recently reported results derived from new
NHANES II data analyses, which provide evidence for significant associations between blood
lead levels and electrocardiogram (ECG) abnormalities 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
19
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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 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 1987 Symposium, there was extensive discussion concerning controversy in the
published epidemiology literature about the nature of a relationship 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 increases in blood pressure, extending to values below those currently
considered to be clinically significant hypertension. 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 of blood pressure with
cardiovascular morbidity and mortality, the leading cause(s) of death in our society, and the
large number of individuals exposed.
Of importance for substantiating the plausibility of the blood-lead/blood-pressure
associations observed in human populations representing causal relationships, the
physiological and pharmacological regulation of blood pressure has been studied extensively
20
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by, experimental investigators. Much of the then available information on the subject was
discussed in the 1986 Addendum (U.S. Environmental Protection Agency, 1986b). It is now
understood 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 1987 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 for 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 nephrotoxicity 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
applicable 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 dependent 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
than normal during periods of modest exposure but normal or depressed plasma renin activity
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 15-20 mm Hg increase in systolic
blood pressure. Increased pressor responsiveness to catecholamines has been demonstrated in
chronically lead exposed animals and an enhanced contraction of isolated vascular smooth
muscle to adrenergic agonists occurs in rats with lead-induced hypertension. Further
experimental evidence suggests that there are alterations in the mechanisms that regulate
21
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intracellular 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,
electrocardiographic disturbances, heightened catecholamine arrhythmogenicity, altered
myocardial contractile responsiveness to inotropic stimulation, degenerative structural and
biochemical changes affecting the musculature of the heart and vasculature, hypertension,
hypercholesterolemia, 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
cardiovascular 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 n, BRHS, and the two Welsh studies) and
22
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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 /ig/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 potentially 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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fflo MEUMOBEMAVIORAL AND GROWTH EFFECTS IN INFANTS AND
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. Environmental Protection Agency, 19865). 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 Pine, 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 /*g/dl and possibly even lower, as indexed by
maternal or cord blood lead concentrations" (U.S. Environmental Protection Agency, 1986b).
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.
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 performance deficit in infants with cord blood lead levels of 10-25 jxg/dl is
0.25-0.5 standard deviations, or approximately 4-8 points on the MDI (Table 2). Moreover,
24
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TABLE 2, INFANTS' MENTAL BEVELOFMENT INDEX SCORES
ACCORDING TO CORD BLOOD LEAD GROUP
Cord Blood Mental Development Index Score
Lead Group 6 Months 12 Months 18 Months 24 Months
Mean ± Standard Deviation
Unadjusted score
Low 109.2 ± 12.9 113.1 ± 12.5 113.4 ± 15.5 115.9 ± 17.2
Medium 108.6 ± 12.0 115.4 ± 12.9 116.6 ± 16.7 119.9 ± 14.4
High 106.1 ± 11.1 108.7 ± 12.8 109.5 ± 17.5 110.6 ± 16.5
Mean ± Standard Error
Controlled for potential
Low
Medium
High
p value**
No. of infants
confounders*
110.2 ± 1
108.0 ± 1
105.9 ± 1
0.095
201
.3
.3
.4
114.7 ±
114.4 ±
108.9 ±
0.020
199
1.6
1.5
1.6
116.2 ±
114.8 ±
109.5 ±
0.049
187
1.
1.
2.
9
9
0
118.9 ±
117.8 ±
111.1 ±
0.006
182
1
1
1
.8
.7
.8
*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).
Bellinger et al. (1989a) found that this association 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 /ig/dl) was not due to a disproportionate influence of results from infants
at higher (e.g., > 15 /ig/dl) blood lead levels. That is, the MDI effect was evident across the
entire range of blood lead levels starting at 10 /ig/dl, which reinforces the previous selection
of 10-15 /ig/dl as a blood lead level of concern for early developmental deficits (U.S.
Environmental Protection Agency, 1986b).
25
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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, infants from less 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 /*g/dl scored significantly
worse on the Bayley MDI than infants with low cord blood lead levels of <3 /*g/dl.
Bellinger et al. (19875, 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 /xg/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 relative performance was associated with lower
blood lead levels at 57 months, higher SES, higher HOME scores, higher maternal IQ, and
female gender. Conversely, the risk of an early deficit persisting to 5 years of age was
increased in children with higher prenatal lead exposure (10-25 /*g/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 /*g/dl] at 57 months while the other had a high [> 10 /*g/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
26
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TABLE 3. CHANGE IN McCARTHY GENERAL COGNITIVE INDEX (GO)
AND SUBSCALE SCORES ASSOCIATED WITH EACH
NATURAL LOG UNIT INCREASE IN BLOOD LEAB LEVEL
Age at
Measurement
of Blood
Lead Level
(months) GCI
6 0.28 + 1.29*
.83**
12 -1.43 + 1.25
.25
18 -1.62 ± 1.39
.25
24 -2.95 + 1.42
.040
57 -2.28 ±1.88
.23
Verbal
0.75 ± 0.93
.42
-0.98 ± 0.89
.27
-0.19 ± 1.01
.85
-0.41 + 1.04
.69
-1.06 ± 1.38
.44
Perceptual-
Performance
-0.72 ± 0.77
.35
-0.64 + 0.79
.42
-0.72 ± 0.87
.41
-2.58 ± 0.88
.004
-2.33 ±1.13
.042
Quantitative
0.00 + 0.76
.99
-0.09 ± 0.74
.90
-1.20 ± 0.82
.15
-1.45 ± 0.85
.088
0.13 ± 1.13
.91
Memory
0.82 ± 0.83
.33
-0.09 ± 0.81
.91
-0.52 ± 0.91
.57
-0.66 ± 0.94
.49
0.49 ± 1.25
.70
Motor
0.02 + 0.81
.98
-0.82 ± 0.80
.31
0.30 + 0.89
.74
-0.90 ± 0.92
.33
-1.89 ± 1.15
.10
*Parameter estimate ± standard error.
**p-value associated with the null hypothesis that the parameter estimate is zero.
Source: Bellinger et al. (1987b).
-------
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.
Bellinger et al. (19875) 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 jtg/dl)
concurrent (57 month) blood lead levels.
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-jtg/dl intervals. An increase in the
percentage of low birthweight newborns between the 7-12 jtg/dl grouping and the £13 jtg/dl
grouping implied the possibility of a threshold for low birthweight effects (categorically
defined as less than 2750 g) in the vicinity of 12-13 Mg/dl, although a precise determination is
not possible and could extend as low as 7 jtg/dl or perhaps as high as 18 jtg/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. Environmental Protection
Agency, 1986b) that a blood lead level of 10-15 Atg/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 various
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
28
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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 (/ig/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
Beta
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
Standard
Error
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).
29
-------
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 analyses of Dietrich et al. (1987a). The magnitude of the deficit in the
3-month MDI amounted to 6 points for every 10-/xg/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 statistically 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 =
0.022), 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-/xg/dl increment in prenatal blood lead, and infants below the
sample median SES score had a 7.57-point deficit for every 10-/*g/dl increment in neonatal
blood lead (Dietrich et al., 1989b).
30
-------
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 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 ng/& (range: 1-26 ng/d\). 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
31
-------
covariate-adjusted birth weight (Bornschein 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.
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,
1989). Splitting prenatal blood lead levels and the average increase in postnatal blood lead
levels at the median (7.7 /xg/dl for prenatal, 3.4 /*g/dl for the postnatal increase) provided a
matrix of lowAow, 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 /xg/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 /xg/dl.
Other neurobehavioral test results 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 /xg/dl (range: 9.3-49.4 /xg/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 dysfunction during
early childhood exposure to lead.
Cleveland
As noted in the 1986 Addendum (U.S. Environmental Protection Agency, 1986b), the
prospective study conducted by Emhart 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
32
-------
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). 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 5.84 jig/dl and the maximum was only 14.7 jig/dl, any effect of prenatal
lead exposure necessarily occurred at blood lead levels below 15 ^ig/dl.
Later reports by Ernhart and her colleagues (Ernhart et al., 1987, 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 ^g/dl, with a maximum of 11.8 ^g/dl; 6-month blood lead levels averaged
10.05 fjig/dl, with a maximum of 24.00 Atg/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 and
Morrow-Tlucak (1987). 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).
33
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TABLE 5A<, THE RELATIONSHIP OF FETAL (MA
(PfoB) LEVELS WITH LATER BEVELO
ANB CORD) BLOOD LEAD
AL OUTCOMES
Incremental Regression Model
PbB With Race by PbB
Covariate Control Interactions
Blood
Lead
Measure
Maternal
Cord
Developmental
Measure
6 Month MDI
6 Month PDI
6 Month KID
1 Year MDI
2 Year MDI
3 Year S-B IQ
6 Month MDI
6 Month PDI
6 Month KID
1 Year MDI
2 Year MDI
3 Year S-B IQ
N
127
127
119
145
142
138
113
113
109
127
125
120
r
,24**
,21*
,28**
-.14
-.14
-.10
-.14
,11
,10
-.24**
,15
,21*
Covariate
Variance
0.2460
0.2485
0.1464
0.1887
0.3664
0.3894
0.2394
0.1891
0.1418
0.2327
0.3746
0.4393
Variance
0.0302
0.0295
0.0779
0.0002
0.0020
0.0059
0.0046
0.0006
0.0107
0.0146
0.0003
0.0125
t
-2.12*
-2.12*
-3.22***
-0.16
+0.48
+ 1.09
-0.76
-0.26
-1.07
-1.47
-0.21
-1.54
Variance
0.0161
0.0093
0.0182
0.0026
0.0000
0.0020
0.0056
0.0249
0.0051
0.0143
0.0002
0.0086
t
-1.57
-1.19
-1.56
-0.64
-0.01
-0.63
-0.74
+ 1.73
+0.74
-1.46
-0.13
-1.28
*p <0.05, **p <0.01, ***p = 0.002, two-tailed tests.
TABLE SB, THE RELATIONSHIP OF PRIOR AND CURRENT POSTNATAL BLOOD LEAD
(PbB) LEVELS WITH LATER DEVELOPMENTAL OUTCOMES
Incremental Regression Model
Blood
Lead
Measure
Simple PbB with
Developmental Correlation Covariate
Measure N r p Covariates p Control p Interaction p
6 month
6 month MDI
6 month PDI
1 year MDI
2 year MDI
3 year S-B IQ
146
146
131
126
126
.09
.06
.08
.03
.04
.29
.49
.40
.74
.65
.18
.19
.14
.30
.29
.000
.000
.02
.000
.000
.01
.01
.01
.00
.00
.31
.32
.25
.95
.49
.01
.00
.00
.00
.00
.34
.48
.51
.63
.87
2 year
3 year
2 year MDI
3 year S-B IQ
3 year S-B IQ
165
153
167
,25
,31
-.27
.000
.000
.000
.32
.31
.36
.000
.000
.000
.00
.01
.00
.95
.29
.98
.01
.00
.01
.07
.32
.08
*Two-tailed statistical test.
Abbreviations: MDI = Bayley Mental Development Index; PDI = Bayley Psychomotor Development Index; KID = Kent Infant
Development Scale; S-B IQ = Stanford-Binet Intelligence Quotient
Source: Emhart et al. (1987, 1988).
34
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TABLE 6. THE RELATIONSEniF OF PRENATAL ANB POSTNATAL LOG
BLOOB LEAB WITH IQ AT AGE FOUR YEARS, TEN MONTHS
Blood
Lead
Measure
Prenatal
Maternal
Cord
Postnatal
6 Months
2 Years
3 Years
Mean
IQ"
N
134
117
121
149
154
211
Full
^
-.23**
-.21*
-.06
-.38**
-.32**
-.26**
Scale
t
-0.27
4X54
-0.08
-0.69
+0.30
+0.48
Verbal
T
-.25**
-.22*
-.07
-.36**
-.39**
-.30**
Scale
t
-0.49
-0.78
-0.26
-1.41
-1.58
-1.00
Performance Scale
r
-.23**
-.20*
-.08
-.34**
-.30**
-.26**
t
-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: Emhart and Morrow-Tlucak (1987).
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").
35
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However, concurrent (2-year) blood lead was positively related to one aspect of intelligibility
(a decrease in "unintelligible utterances").
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 Emhart, 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).
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 associated with postnatal blood lead levels both at 6 months and
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 information 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. Environmental Protection Agency, 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 controls for maternal IQ and
36
-------
, HOME scores were incorporated into the analysis, although all regression coefficients for
postnatal blood lead measures remained negative (Vimpani et al., 1989; Wigg et al.9 1988;
Baghurst et al., 1987). 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 /xg/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 neurobehavioral
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 /xg/dl. Further analyses
indicated that the relationship between lead exposure and GCI was as strong or even stronger
at blood lead levels below 25 /xg/dl than it was overall (geometric mean blood lead level
peaked at 2 years: 21.2 /xg/dl; integrated postnatal average: 19 /xg/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 /xg/dl. Neither birth weight nor spontaneous abortions
(<20 weeks) showed a significant association with blood lead levels. However, blood lead
37
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TABLE 7. ESTIMATED COEFFICIENTS OF LOG BLOOD LEAD CONCENTRATION FROM SIMPLE
AND MULTIPLE REGRESSION ANALYSES OF MCCARTHY SCORES AT THE AGE OF FOUR YEARS°
00
Blood Sample
Prenatal average
Delivery
Cord
6 Month
15 Month
24 Month
36 Month
48 Month
Integrated postnatal
average
General Cognitive Index
Simple Partial
-15.1 ± 4.7
(0.001)
-10.4 ± 3.9
(0.008)
-6.1 ± 3.4
(0.08)
-15.1 ± 3.8
(<0.001)
-14.3 ± 3.8
(<0.001)
-25.8 ± 4.3
(<0.001)
-25.1 ± 4.3
(<0.001)
-20.1 ± 4.1
(<0.001)
-28.9 ± 5.5
(<0.001)
-1.8 ± 5.7
(0.75)
-0.4 ± 4.5
(0.93)
3.3 ± 4.1
(0.42)
-8.5 ± 4.4
(0.05)
-3.5 ± 4.8
(0.46)
-11.1 ± 5.4
(0.04)
-13.1 ± 5.6
(0.02)
-5.5 ± 5.1
(0.29)
-15.0 ± 7.3
(0.04)
Perceptual-Performance Scale
Simple Partial
-9.5 ± 2.7
(<0.001)
-5.1 ± 2.3
(0.03)
-3.0 ± 2.0
(0.13)
-7.8 ± 2.2
(< 0.001)
-8.2 ± 2.2
(<0.001)
-13.5 ± 2.5
(<0.001)
-13.6 ± 2.5
(<0.001)
-11.2 ± 2.4
(<0.001)
-15.1 ± 3.2
(<0.001)
-4.1 ± 3.3
(0.22)
0.2 ± 2.7
(0.95)
1.6 ± 2.4
(0.50)
-4.8 ± 2.5
(0.06)
-3.2 ± 2.8
(0.26)
-6.2 ± 3.2
(0.05)
-7.7 ± 3.3
(0.02)
-4.0 ± 3.0
(0.18)
-8.3 ± 4.1
(0.05)
Memory
Simple
-4.8 ± 2.7
(0.07)
-4.9 ± 2.2
(0.03)
-3.0 ± 2.0
(0.12)
-4.9 ± 2.2
(0.03)
-5.3 ± 2.2
(0.01)
-13.4 ± 2.4
(< 0.001)
-12.7 ± 2.4
(<0.001)
-10.3 ± 2.3
(<0.001)
-13.3 ± 3.1
(<0.001)
Scale
Partial
2.0 ± 3.3
(0.54)
-0.4 ± 2.6
(0.89)
2.6 ± 2.5
(0.27)
-2.4 ± 2.5
(0.34)
-0.5 ± 2.7
(0.87)
-7.3 ± 3.1
(0.02)
-7.2 ± 3.2
(0.27)
-4.1 ± 3.0
(0.17)
-7.9 ± 4.2
(0.06)
The partial regression coefficients are from analyses incorporating 18 covariates. The p values are for assessments of the two-sided hypothesis that the estimates
are not zero.
Source: McMichael et al. (1988).
-------
levels of mothers who had stillbirths were significantly lower than those who had live births
(7.9 vs. 10.4 jig/dl). As discussed in the 1986 Addendum and by Davis and Svendsgaard
(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 j*g/dl, respectively (overall range: 0-29 jtg/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 relationship 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
39
-------
TABLE 8. REGRESSION OF DEVELOPMENTAL INDICES ON MATERNAL <
AND CORD BLOOD LEAD LEVELS
Simle Correlations
ffect of Covariates
Incremental Effect
of Lead
Age
6 Months
Cognitive
Psychomotor
12 Months
Cognitive
Psychomotor
24 Months
Cognitive
Psychomotor
36 Months
Cognitive
Psychomotor
Maternal
-.044
.035
.015
.081
.006
.021
.040
.015
Cord
-.061
.025
.153*
.167*
.053
-.060
.045
.010
1?-
.136
.153
.177
.106
.219
.081
.165
.081
F p
3.16 <.001
3.63 <.001
df = 13,261
4.08 <.001
2.23 <.01
df = 13,245
4.79 <.001
1.49 >.10
df = 13,222
3.11 <.001
1.39 >.10
df = 13,204
R"
.008
.003
df
.008
.019
df
.001
.013
df
.001
.001
df
F
1.22
0.46
= 2,259
1.17
2.60
= 2,243
.19
1.54
= 2,220
.13
.10
= 2,202
P
>.25
>.60
>.30
.08
>.70
>.20
>.70
>.90
*p < .05, two-tailed test.
Source: Cooney et al. (1989a).
the regression model approached significance only for the 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 education) 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 apparently was not
40
-------
examined by the investigators. However, the authors did examine the relationships 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 /*g/dl at 6 months to a peak average of
16.4 /xg/dl at 18 months and then declined to 10.1 /xg/dl at 48 months.
Bivariate and partial (correcting for venous versus capillary collection) correlations
between 48-month McCarthy Scales and blood lead levels at different ages were generally
quite small, mixed in sign, and uniformly nonsignificant. 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 performance (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.
Mexico Citv
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. (1989a,b). 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 jtg/dl; MD, 15.4 /*g/dl; and
UC, 13.8 /ig/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
41
-------
TABLE 9. REGRESSION OF DEVELOPMENTAL INDICES AT 48 MO:
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
AR2
.004
.001
.023
.003
.001
.001
.001
.008
,001
.005
.044
.022
Unadjusted
df
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).
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 bivariate correlations and multivariate regression analyses.
Based on preliminary data analyses reported at a 1986 conference, Rothenberg et al.
(1989a) initially reported that statistically significant bivariate correlations were found:
between UC blood lead and the 30-day trend in NBAS Abnormal Reflexes (p <0.05);
between the M36-MD blood lead difference and Regulation of States (p <0.05); and between
42
-------
the MD-UC blood lead difference and Abnormal Reflexes (p <0.01) — all reflecting
impairment of function. Also, stepwise regression modeling with all covariates entered before
lead was reported to show that: blood lead differentials (M36-MD; MD-UC) accounted for a
significant portion of the variance in the Abnormal Reflexes trend; the M36-MD differential
accounted for a significant amount of variance in Regulation of States; but UC alone was no
longer significantly related to Abnormal Reflexes. Rothenberg et al. (1989a) also reported
that evaluations of physical development outcomes at birth in their cohort indicated that:
M36-MD and M36-UC each accounted for a significant amount of variance in birthweight
(p <0.05); M36-UC accounted for significant amount of variance in chest circumference
(p < 0.054); and UC and M36-UC accounted for a significant amount of the variance in trunk
length (p - 0.06)
Upon further analysis of their dataset, however, Rothenberg et al. (1989b) reported that
Abnormal Reflexes were not significantly associated with any of the lead measures and no
simple lead measure yielded significant effects on any of the perinatal outcomes in multiple
regression analyses. On the other hand, several outcome variables (Regulation of States,
Autonomic Regulation, and Gestation Age) were statistically significantly related to composite
lead measures (i.e., M36-MB, MB-UC, M36-UC). Generally, increases in the blood lead of
the mother during the last month of pregnancy (indexed by the M36-MB and M36-UC
differentials) or an umbilical cord lead higher than the mother's blood lead (MB-UC
differential) were associated with deleterious changes in the last-noted outcome variables.
Rothenberg et al. (1989b) interpreted their findings as indicating that either (1) the deleterious
effects were related to increases in blood lead levels of the mother and fetus during the last
several weeks of pregnancy or during delivery (regardless of initial maternal blood lead values
before the increase) or (2) the negative outcomes were related to increased stress factors
during late pregnancy or delivery that also raised maternal and fetal blood lead levels.
A longitudinal study involving two communities in Yugoslavia, Titova Mitrovica and
Pristina, has been undertaken by Graziano et al. (1989a,b; Murphy et al., 1990).
T. Mitrovica is a major lead smelter and industrial site, whereas Pristina, 40 km to the south,
43
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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 reported.
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 ^tg/dl in T. Mitrovica and
5.1 jig/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 reported 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 ^tg/dl in the former and 5.1 ^tg/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.
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 plumbosolvency 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.
44
-------
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 fe30 jig/dl, mean = 33.05), medium (15-25 ng/dl, mean = 17.73), and
low (^10 jig/dl, mean = 7.02). 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 opposite direction, and other
pediatric measures (head circumference, 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 analyses
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 greater 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."
Christchmrch
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
45
-------
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
(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 correlations remained statistically significant at p <0.05
(Table 10).
TABLE 10. UNEXPLAMHJ) CORRELATIONS BETWEEN LOG DENTINE
LEAD LEVELS TAKING INTO ACCOUNT TEST RELIABILITY,
CONFOUNDING COVARIATES, SAMPLE SELECTION FACTORS,
AND REVERSE CAUSALITY VIA PICA
8 years 9 years
Measure r p* r p*
Verbal IQ
Performance IQ
Total IQ
Burt reading test
Teacher ratings
Reading
Written expression
Spelling
Mathematics
Handwriting
-0.03
-0.02
-0.04
-0.07
-0.13
-0.13
-0.14
-0.08
-0.12
N.S.
N.S.
N.S.
<0.05
< 0.001
<0.001
<0.001
<0.10
<0.05
-0.02
-0.02
-0.03
-0.08
-0.08
-0.08
-0.09
-0.10
-0.08
N.S.
N.S.
N.S.
<0.05
<0.10
N.S.
<0.10
<0.05
<0.10
•"One-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
46
-------
attentional processes. Mothers1 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 11). 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, 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 intelligence, 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 /*g/g, which may be compared to a mean dentine lead level of ~ 14.5 /*g/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 /*g/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 /*g/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.
Norderibflim - StoHberg :.
As noted in the 1986 Addendum, Winneke et al. (1985a,b) enrolled 114 children in
1982 from a population of 383 children bom 6-7 years previously in Nordenhairi, Federal
47
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TABLE 11. PRODUCT MOMENT CORRELATIONS BETWEEN MATERNAL
OR TEACHER BEHAVIOR RATINGS AND LOG DENTINE LEAD VALUES
Measure
8 years
p*
9 years
Maternal ratings
Activity
Restless, overactive
Excitable, impulsive
Constantly fidgeting
Always climbing
Squirmy, fidgety
Attention
Short attention span
Inattentive, easily distracted
Can't settle to tasks
Total Score
Teacher ratings
Activity
Restless, overactive
Excitable, impulsive
Squirmy, fidgety
Very restless
Attention
Inattentive, easily distracted
Short attention span
Poor concentration
Total Score
0.07
0.07
0.03
0.07
0.03
0.09
0.09
0.06
0.11
0.09
0.03
0.11
0.10
0.16
0.11
0.13
0.13
<0.05
<0.05
N.S.
<0.05
N.S.
<0.01
<0.01
<0.05
<0.01
<0.01
N.S.
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.05
0.05
0.04
0.04
0.06
0.08
0.05
0.04
0.08
0.11
0.10
0.13
0.13
0.14
0.12
0.12
0.14
<0.10
<0.10
N.S.
N.S.
<0.05
<0.01
<0.10
N.S.
<0.05
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
"•One-tailed test.
Source: Fergusson et al. (1988c).
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 /tg/dl (range: 4-31); for umbilical cord, it was 8.2 /tg/dl (range:
4-30). When tested at age 6-7, the children's average blood lead level was again 8.2 /tg/dl,
48
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but distributed differently (range: 4-23). In terms of accounting for a significant 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 /*g/dl (range: 4-21), indicated some persisting deficits in reaction time test
performance related to blood lead levels 3 years earlier (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.
Analogous results as for the Nordenham children have recently been reported by
Winneke et al. (1989) for another cohort of 6 to 9 yr old children (N = 109) from Stolberg,
West Germany whose blood lead levels averaged 7.4 /*g/dl (range 4.2-18.0 /ig/dl).
Performance deficits on a serial choice reaction task were found to be significantly related to
lead exposure after correction for confounders. The authors noted that certain features of the
performance deficit resembled clinical observations for children with attention deficit
disorder.
Buffalo.
A prospective study was recently initiated in the Buffalo, NY area by Shucard et al.
(1988a,b). Cord blood levels averaged ~4.4 /*g/dl for 802 newborns. 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
49
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high blood lead levels, or their primary reliance on tooth lead as an exposure indicator.
Despite its limitations, 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 jtg/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 ftg/dl. More recently, Thomson et al. (1989) reported that significant associations
were found for the Fulton Edinborough study cohort between log blood lead levels and
teacher's ratings on the Rutter scale of aggressive/anti-social hyperactive, and overall deviate
behavior.
Hatzakis et al. (1987, 1989) conducted neuropsychological testing on 509 children living
near a lead smelter in Lavrion, Greece, and found impairments in WISC-RIQ scores and
reaction time performance scores. These effects 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 jtg/dl and averaged 23.7 jtg/dl. Depending on
the number of .covariates included in the model, full scale IQ decreased by 2.4-2.7 points for
every 10-pig/dl increase in blood lead concentration. Subjects were grouped by blood lead
levels (10-jtg/dl increments) to analyze dose-response relationships 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 jtg/dl (range: 5.4-21.5 jtg/dl) in 182 subjects whose average
50
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Blood lead levels averaged 10.8 jtg/dl (range: 5.4-21.5 A*g/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 relationship
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 significant direct effects on MDI.
Vivoli et al. (1989) and Bergomi 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 /tg/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 significantly 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 /ig/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.
In separate but similar studies conducted in Rhode Island and Lavrion, Greece, Faust
and Brown (1987) and Benetou-Marantidou et al. (1988), respectively, administered
neurobehavioral test batteries to small groups (N's of 15-30) of children whose blood lead
levels had been measured at ~ 30-60 /tg/dl. Significantly impaired performance was evident
by comparison to matched controls, even after blood lead levels had been below 30 j*g/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 Examination 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
51
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with other evidence linking low-level lead exposure to electrophysiological changes in the
auditory system (reviewed in U.S. Environmental Protection Agency, 1986a).
With regard to fetal growth effects, a recent report by Ward et al. (1987) indicated that
placenta! lead concentrations were highly significantly correlated with reductions in birth
weight, head circumference, and placenta! weight in 100 obstetrically 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 placenta! lead concentrations: 2.349 /tg/g (S.D. =
0.883) versus 1.122 /tg/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. Environmental Protection Agency, 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. 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 longitudinal 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
nevertheless 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 (AR2) of 0.01 with a power of 0.80 at an alpha of 0.05, one-sided. This calculation
52
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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 significant relationship 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 mate it more difficult to
detect the effect of lead exposure by regression analysis. For example, 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
(Ernhartetal., 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 achieve statistical significance is enhanced. Conversely, it is difficult
to interpret a failure to detect a lead effect as suggesting the absence of an 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 neurobehavioral effects to blood lead levels of
"10-15 M8/dl> and possibly lower," as was previously concluded in the 1986 Addendum (U.S.
Environmental Protection Agency, 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 Mg/dl level of concern but indicated that
MDI deficits can be detected in relation to cord blood lead levels of 6-7 jig/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. population than the term suggests. Although the
postnatal lead exposure levels were somewhat higher in the Port Pirie study, analyses of the
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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 /*g/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 /*g/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 scores in
the Cleveland cohort, but results of other analyses were mixed (Ernhart et al., 1987). Any
significant neurobehavioral effects associated with cord blood lead in the Cleveland study
necessarily occurred at levels below 15 /*g/dl since the maximum single cord blood lead level
measured was only 14.7 /*g/dl (mean: 5.84 /*g/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.
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 /*g/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 /*g/dl. The latter study was described in detail and evaluated
in the 1986 Air Quality Criteria for Lead (U.S. Environmental Protection Agency, 1986a). In
54
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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 jxg/dl.
Based on all of the above considerations, a blood lead concentration of 10-15 pg/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 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 ng/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 may be additional
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). However, McMichael et al. (1988) found that the blood lead-GCI
regression coefficient was slightly higher for girls than for boys, although stratification by
gender did not significantly improve their model in repeated analyses.
The evidence regarding pregnancy outcomes and physical growth effects related to
prenatal lead exposure is less consistent than that for neurobehavioral outcomes. Such was
the case at the time of the 1986 Addendum (U.S. Environmental Protection Agency, 1986b)
and is still the case simply because relatively little additional information pertaining to
pregnancy outcomes and growth has appeared since the 1986 assessment.
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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 growth rates (over 3-15 months)
have also been associated with lead exposure pre- and postnatally in the Cincinnati study
(Shukla et al., 1987, 1989). (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 study and, possibly, the Glasgow study. Although birth weightier se showed no
relationship to cord blood lead in the 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 Glasgow, the high maternal blood lead infants (mean: 33.05
fig/dl) weighed 3.32 kg, on average, at birth, whereas the medium blood lead group (mean:
17.73 jtg/dl) weighed 3.43 kg and the low group (mean: 7.02 jtg/dl) weighed 3.51 kg (Moore
et al., 1989). However, these data were not adjusted for covariates and were not tested for
statistical significance.
No other prospective study has shown a significant association between reduced birth
weight and lead exposure. The Yugoslavian study (Graziano et al., 1989b; Murphy et al.,
1990), 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 study by Ward et
al. (1987) did indicate highly significant simple relationships 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 significant 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
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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 significant negative associations between
gestational age and maternal as well as cord blood lead after allowing for a number of
covariates. A reduction in gestational age was associated with an increase in maternal blood
lead level between the 36th week of pregnancy and delivery in the Mexico City pilot study
(Rothenberg et al., 1989b). 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; Murphy et al., 1990) 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 pregnancies 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 of lead on gestation. Also, there were interactions
involving mother's age and race evident in the Cincinnati 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 (past as well as current), 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. Environmental Protection Agency, 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 neurobehavioral 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 jig/dl. The average maternal blood lead levels
in the studies where the pre-term delivery effect was clearest (Port Pirie and Glasgow) were
in the 10-15 jig/dl range, in contrast to somewhat mixed findings in the Cincinnati, Boston,
and Cleveland studies where the maternal or cord blood lead levels averaged below 10 pg/dl.
57
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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 jtg/dl, but possibly extending from 7 to
18 /ig/dl. However, other prospective studies provide no support for this conclusion, and so
it must be considered an open issue awaiting more definitive resolution.
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 jtg/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
development 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
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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 analysis. 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 previously (U.S.
Environmental Protection Agency, 1986b; Davis and Svendsgaard, 1987) and supported by
preliminary results from the Mexico City study (Rothenberg et al., 1989a,b), 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 adjustment, 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 strongest relationship to postnatal neurobehavioral
effects. Such a lagged effect has been suggested by several findings, as shown in Table 12.
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
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TABLE 12. STRONGEST RELATIONSHIPS BETWEEN BLOOD LEAD MEASURES'
AT SPECIFIED TIMES AND LATER NEUROBEMAVIORAL OUTCOMES
AS DETECTED BY PROSPECTIVE STUDIES
Study
Time/Type
of Blood Lead Measure
Outcome
Boston
(Bellinger
etal., 1987a,b)
Cincinnati
(Dietrich
etal., 19875,
1988; Bhatta-
charyaetal.,
1988, 1989)
Cleveland
(Emhart
etal., 1986,
1987; Wolf et
al., 1985;
Morrow-Tlucak
& Ernhart, 1987)
Pt. Pirie
(Wigg et al.,
1988; McMichael
etal., 1988)
Sydney
(Cooney etal.,
1989b)
Delivery/cord
2yr
Prenatal (x: 16 wk)/maternal
10 day
2yr
Delivery/cord
Delivery/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)
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
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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. 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 /xg/dl) contributed
to a persistence of neurobehavioral 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.
By this line of reasoning, one would perhaps expect that increased postnatal blood lead
measures should then show a significant relationship to later neurobehavioral 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 measures, but they do not fully represent all aspects of a child's cognitive,
social, and emotional development. Thus, considerable caution must be exercised in drawing
conclusions from findings of "no effect." Not only are there many facets to a child's
development 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. Findings of lead-related aggressive/antisocial behavior in the
Edinburgh cohort (Thomson et al., 1989) support this view.
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
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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, its secondary effects on language development in young children may be much
longer lived. As noted by Jenkins (1986), "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."
Important new evidence for the long-term persistence of lead-induced intellectual and
behavioral deficits has recently been reported by Needleman et al. (1990). In an 11-year
follow-up of children studied earlier at age 6-7 years, those children originally having high
dentin lead levels (>20 ppm) had markedly higher rates of having a reading disability and of
dropping out of high school than lower lead children (dentin lead < 10 ppm). Also, higher
lead levels in earlier childhood were significantly related to lower class standing, increased
absenteeism, lower verbal scores, and poorer sensory-motor performance. These persisting
effects were detected a decade later when blood lead levels had declined to 7 /xg/dl or lower
(in contrast to the high-lead dentin group with blood lead levels averaging approximately
34 /xg/dl at the time of the original study).
It is also important to note the convergence of animal findings, particularly 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 /xg/dl. Although it is
difficult to precisely equate blood lead leads in different species, the parallels between humans
and animals in the developmental neurotoxicity of lead are striking in many respects (Davis
et al., 1990). Indeed, the similarity of the animal findings in the absence of socioeconomic
and other complex variables that sometimes complicate interpretation of the human data
provide compelling support for concluding that low level lead exposure and developmental
neurotoxicity in children are causally related and not merely associated artifactually.
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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 neurobehavioral 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-/tg/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 /tg/dl) and low (mean:
1.8 /tg/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-^ig/dl increment in maternal blood lead.
Also, the Port Pine study demonstrated a 1.6-point decrease in the 24-month MDI per
10 /tg/dl of blood lead at 6 months, and a ~ 3.5-point decrease in GCI scores for every
10 /tg/dl in average postnatal blood lead.
The implications of such deficits are more apparent when considered in population rather
than individual terms (Needleman, 1983; Davis, 1990). Figure 2 illustrates the effect of
shifting a normal distribution of MDI scores downward by 4 points. The lighter shaded area
is 50% of the darker area, which represents the children in a population who score 80 or
lower. Thus, even a 4-point shift in average performance results in a considerable increase in
subnormal scores. Since the MDI has a standard deviation of 16, a score of 80 is one
standard deviation below a mean of 96 and provides a convenient reference point for
illustration purposes. However, the impact of such a shift applies across the entire
distribution of scores, reducing the number of children scoring above the norm as well as
increasing the number scoring below the norm (Weiss, 1988).
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7
©
x
2(0)
HOO
12©
•140
Figure 2. Normal distributions with means of 96 and 100 and standard deviations of 16.
Source: Davis (1990).
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IV. REFERENCES
Baghurst, P. A.; Robertson, E. P.; McMichael, A. J.; Vimpani, G. V.; Wigg, N. R.; Roberts, R. R. (1987) The
Port Pine cohort study: lead effects on pregnancy outcome and early childhood development.
Neurotoxicology 8: 395-402.
Bellinger, D. C.; Needleman, H. L.; Leviton, A.; Watemaux, C.; Rabinowitz, M. B.; Nichols, M. L. (1984a)
Early sensory-motor development and prenatal exposure to lead. Neurobehav. Toxicol. Teratol.
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