THE
LONG-TERM EFFECTS OF EXPOSURE TO LOW DOSES OF LEAD IN CHILDHOOD
An
11-Year Follow-up Report
Herbert
L. Needleman, M.D., Alan Shell, M.A. , David Bellinger, Ph.D., Alan
Leviton, M.D., and Elizabeth N. Allred, M.S.
Abstract
To determine whether
the effects of low-level lead exposure persist, we reexamined 132 of
270 young adults who had initially been studied as primary schoolchildren
in 1975 through 1978. In the earlier study, neurobehavioral functioning
was found to be inversely related to dentin lead levels. As compared
with those we restudied, the other 138 subjects had had somewhat higher
lead levels on earlier analysis, as well as significantly lower IQ scores
and poorer teachers' ratings of classroom behavior.
When the 132 subjects
were reexamined in 1988, impairment in neurobehavioral function was
still found to be related to the lead content of teeth shed at the ages
of six and seven. The young people with dentin lead levels >20 ppm
had a markedly higher risk of dropping out of high school (adjusted
odds ratio, 7.4; 95 percent confidence interval, 1.4 to 40.7) and of
having a reading disability (odds ratio, 5.8; 95 percent confidence
interval, 1.7 to 19.7) as compared with those with dentin lead levels
<10 ppm. Higher lead levels in childhood were also significantly
associated with lower class standing in high school, increased absenteeism,
lower vocabulary and grammatical-reasoning scores, poorer hand-eye coordination,
longer reaction times, and slower finger tapping. No significant associations
were found with the results of 10 other tests of neurobehavioral functioning.
Lead levels were inversely related to self-reports of minor delinquent
activity.
We conclude that
exposure to lead in childhood is associated with deficits in central
nervous system functioning that persist into young adulthood. (N Engl
J Med 1990; 322:83-8.).
Within the past
three years, the Environmental Protection Agency and the Agency for
Toxic Substances and Disease Registry have concluded in policy statements
that lead at low doses is a serious threat to the central nervous systems
of infants and children.1, 2 These policy statements have
been based on a growing convergence of results from both epidemiologic
and experimental studies of lead toxicity in the United States, Europe,
and Australia.3-8 Whether the effects on the central nervous
system of exposure to low doses of lead that have been observed in infants
and children persist has received limited attention. Only three follow-up
studies have been published to date, and the longest follow-up has been
five years.9-11 No data have yet been reported on whether
early disturbances influence functional abilities in later life.
In 1979 we reported
that first- and second-grade children without symptoms of plumbism,
but with elevated dentin lead levels, had deficits in psychometric intelligence
scores, speech and language processing, attention, and classroom performance.3
When they were studied in the fifth grade, the children with high dentin
lead levels had lower IQ scores, needed more special academic services,
and had a significantly higher rate of failure in school than other
children.9 We have now evaluated the neuropsychological and
academic performance in young adulthood of 132 of the original sample
of 270 subjects, and we report the relation of their recent performance
to their exposure to lead, as measured 11 years earlier.
Methods
The initial sample
was chosen from the population of 3329 children enrolled in the first
and second grades in the Chelsea and Somerville, Massachusetts, school
systems between 1975 and 1978. Of this population, 70 percent provided
at least one of their shed primary teeth for lead analysis. From this
sample of 2335 children, 97 percent of whom were white, we identified
270 from English-speaking homes whose initial dentin lead levels were
either >24 ppm or <6 ppm. These children (mean age, 7.3 years)
underwent an extensive neurobehavioral examination. More teeth were
subsequently collected and analyzed, and the subjects whose teeth were
discordant with respect to lead level according to a priori criteria
were excluded from the data analysis. Also excluded from the analysis
were children who had not been discharged from the hospital after birth
at the same time as their mothers, who had a noteworthy head injury,
or who were reported to have had plumbism.3
In a later reanalysis,
conducted in response to suggestions from the Environmental Protection
Agency,12 the tooth lead level was treated as a continuous
variable. A mean dentin lead level was computed for each subject from
all the teeth collected. The exclusionary factors previously used were
found not to be related to outcome scores. The subjects initially excluded
were therefore not excluded from this follow-up sample.
The 270 subjects
tested from 1975 to 1978 constitute the base population for this report.
From old research records, telephone directories, town records, and
driver's-license rolls, we located 177 subjects. Of these, 132 agreed
to participate, and the remaining 45 declined. The subjects were paid
$35 each and received travel expenses. Ten subjects tested in 1988 had
been excluded from the analysis reported in 1979 because their parents
stated at the time of testing that the children had elevated blood lead
levels or had undergone chelation for lead poisoning. This group is
discussed separately in this report. The mean age of the 132 subjects
at the 1988 reexamination was 18.4 years; the mean length of time between
the two examinations was 11.1 years. All but four subjects in the current
follow-up study were white. No clinical manifestations of lead exposure
were recorded in the earlier interviews for the 122 subjects who were
not treated with chelating agents.
The research protocol
and informed-consent procedures were approved by the institutional review
boards of the Children's Hospital of Pittsburgh and the Children's Hospital,
Boston. Informed consent was given by all the subjects or their parents.
Classification
of Lead Exposure
All the dentin lead
levels measured from 1975 through 1977 were used to compute an arithmetic
mean lead concentration for each subject. The lead burden was treated
in two ways: as an interval variable in linear regressions and as a
categorical variable - i.e., high (>20 ppm), medium (10 to 19.9 ppm),
and low (<10 ppm)--in the logistic regressions described below. Lead
levels in venous blood were measured at the time of the reexamination
to estimate current exposure. This practice was discontinued after the
first 48 subjects were tested, because none had a lead level exceeding
034 m mol per liter (7m g per deciliter), well below the Centers for
Disease Control's definition of undue lead exposure of 1.25 m mol per
liter (25/m g per deciliter).
Behavioral Evaluation
The subjects were
evaluated individually by a single examiner, who remained blinded to
their lead-exposure status until all the data had been coded and entered
into a computer database. All assessments were carried out in a fixed
order; the duration of the testing was about two hours.
Neurobehavioral
Evaluation System
The subjects completed
an automated assessment battery in which they used a personal computer,
joystick, and response key.13 We selected the following items
from the battery for evaluation:
Symbol-digit
substitution, an adaptation of the Wechsler item for computer administration.
Hand-eye coordination.
Using a joystick to move the cursor, the subject traced over a large
sine wave generated on the monitor screen; deviations from the line
(root mean square error) were recorded.
Simple visual-reaction
time. Subjects pressed the response key when an O appeared on the
screen; the interval before the stimulus was varied randomly.
Finger tapping.
The subject pressed a response button as many times as possible
during a 10-second period; both hands were tested.
Pattern memory.
The subject was presented with a computer-generated pattern formed
by a 10-by-10 array of dark and bright elements. After a brief exposure,
the subject was presented with three patterns, only one of which was
identical to the original pattern. The number of correct responses and
the length of time to the correct choice were recorded.
Pattern comparison.
The subject was presented with three computer-generated patterns
on the 10-by-10 array. Two were identical, and one differed slightly
from the other two. The subject was required to select the non-matching
pattern.
Serial-digit
learning. The subject was presented with a string of 10 digits,
then asked to enter the string into the computer. After an error, the
same stimulus was presented, and the second trial began.
Vocabulary.
For each of 25 words, the subject chose the word most nearly synonymous
from a list of four choices.
Grammatical
reasoning. The subject was presented with a pair of letters, A and
B, whose relative position varied. Then the screen cleared, and the
letters were replaced by a sentence that described the order of the
letters. The sentence might be active or passive, affirmative or negative,
true or false (examples are "A follows B" and "B is not
followed by A'). The subject had to choose the correct sentences, and
the number of errors was recorded.
Switching attention.
The subject was required to choose which key to press in response
to three different
instructions. In the '"side" trials, the subject had to press
the key on the same side as the stimulus. In the "direction"
trials, the correct choice was the direction in which an arrow pointed.
Before each trial in the third set, the subject was told whether to
choose the side the arrow was on or the direction in which it pointed.
Mood scales.
This test was derived from the Profile of Mood States. 15 Five scores
were computed for tension, anger, depression, fatigue, and confusion.
The following tests
were also used to evaluate neurobehavioral functioning:
California Verbal
Learning Test
The California Verbal
Learning Test16 was used to assess multiple Strategies and
processes involved in verbal learning and memory. Scores for immediate
and delayed recall were also obtained.
Boston Naming
Test
In the Boston Naming
Test,17 the subject was presented with 60 pictures in order
of increasing difficulty and asked to name the objects shown.
Rey-Osterreith
Complex Figure Test
The Rey-Osterreith
Complex Figure Test18 was used to evaluate visual-motor and
visual-spatial skills. The subject was asked to copy an abstract geometric
figure and then to draw it from memory both immediately and after 30
minutes. Accuracy and organization scores were calculated.
Word-identification
Test
Form B from the
Woodcock Reading Mastery Test was used to evaluate reading skill. Grade-equivalency
scores were calculated from raw scores. Reading disability was defined
as indicated by scores two grade levels below the score expected on
the basis of the highest grade completed.
Self-Reports
of Delinquency
The subjects completed
a structured questionnaire from the National Youth Survey19
that included scales for minor antisocial behavior and for violent crimes.
Review of School
Records
High-school records
were obtained for all but two of the subjects tested. Class size and
rank, the highest grade completed, and the number of days absent and
tardy in the last full semester were recorded. Students who were still
in the 11th grade at the time of testing were not included in analyses
of the highest grade completed. Class rank was computed as 1 - (class
rank/Class size).
Statistical Analysis
To evaluate whether
the participants in this follow-up evaluation were representative of
the original cohort, subjects who were tested and not tested in 1988
were compared in terms of variables reported in 1979, including dentin
lead levels, covariates not related to lead exposure, teachers' ratings
of classroom behavior, and IQ scores. In addition, we carried out separate
regressions of dentin lead level against IQ score as measured between
1976 and 1978 for subjects tested and not tested in 1988. We then performed
a regression on both groups taken together, entering both a dummy term
for participation in the current follow-up (yes or no) and a lead-level-by-participation
status term.
To evaluate the
relation between early exposure to lead and each of the continuously
distributed outcome variables, subjects were classified according to
dentin lead-level quartiles, and mean scores, adjusted for covariates,
were computed. Ordinary least-squares linear regression, with the mean
or log-mean dentin lead level as the main effect, was used to estimate
the significance of the relation. Outcomes that were significantly associated
with lead exposure in these bivariate analyses were further evaluated
by multiple regression analysis. Ten covariates were included in the
model. They were the mother's age at the time of the subject's birth,
the mother's educational level, the mother's IQ, family size, socioeconomic
status (a two-factor Hoilingshead index), sex, age at the time of testing,
birth order, alcohol use, and whether the subject and the mother left
the hospital together after the subject's birth. The lead measure (the
mean or the log of the mean) that produced the best-fitted model (highest
R2) is reported. Five of these covariates were employed in
the first study of these subjects and shown to be influential. Five
others (sex, age at testing, prolonged hospitalization as a neonate,
birth order, and current alcohol use) were added to the model on the
basis of prior knowledge of their effects on psychometric function.
Logistic-regression analysis was used to model the association of lead
level and two outcomes treated categorically (failure to graduate from
high school and reading disability). In this analysis, we controlled
for the covariates listed above. Two indicator variables were used to
represent the three exposure groups. Odds ratios and 95 percent confidence
intervals, adjusted for covariates, were computed for the high-lead-level
group, with the low-lead-level group used as the reference group.
Results
Selection
Bias
The 132 subjects
who were retested in 1988 (Table 1) were not representative of the group
of 270 subjects tested in 1979. The subjects we retested tended to have
slightly lower dentin lead levels, more highly educated families of
higher socioeconomic status, and mothers with higher IQs and better
obstetrical histories; a higher proportion of the retested subjects
were girls.
In addition, they
had had fewer head injuries and had significantly higher IQ scores and
better teachers' ratings as reported in 1979. The slope of the regression
of childhood IQ on dentin lead level was steeper in the group not tested
in the follow-up study, although the difference from the slope in the
group we retested was not statistically significant (F=1.82, 1,196 df;
P= 0.18)
Academic
and Neurobehavioral Outcome
Table 2 shows
the covariate-adjusted scores of the 122 subjects who did not have
clinical
plumbism, according
to their dentin lead concentrations. Table 3 summarizes the results
of
modeling the relation
between early exposure to lead and outcome by multiple regression.
Earlier exposure
to lead was significantly associated with diminished academic success.
Among children with dentin lead levels > 20 ppm, as compared with
those whose dentin lead levels were < 10 ppm, the unadjusted odds
ratio for failure to graduate from high school was 4.6 (95 percent confidence
interval, 1.2 to 17.4).
Adjustment for covariates
increased the odds ratio to 7.4 (95 percent confidence interval, 1.4
to 40.8). Higher dentin lead levels were also associated with lower
class rank, increased absenteeism, lower scores on vocabulary and grammatical-reasoning
tests, significantly slower finger-tapping speed, longer reaction times,
poorer hand-eye coordination, and lower reading scores. In subjects
with dentin lead levels >20 ppm, the unadjusted odds ratio for having
a reading disability, defined by a score two grades below that expected
for the highest grade completed, was 3.9 (95 percent confidence interval,
1.5 to 10.5). Adjustment for covariates increased the odds ratio to
5.8 (95 percent confidence interval, 1.7 to 19.7). For most outcomes,
neither the size of the lead regression coefficients nor their standard
errors were substantially changed by adjustment for covariates.
Table 2. Outcomes
in Young Adulthood According to Dentin Lead Concentration In Childhood*
Of
the 10 children with clinical plumbism (who either underwent chelation
or were reported to have had elevated blood lead levels), 3 of 7 (43
percent) dropped out before graduating from high school (3 others are
still in school), and 5 of 10 (50 percent) have reading disabilities.
When the children with plumbism were grouped with the other subjects
according to quartiles for dentin lead levels, a dose-response relation
was evident for both outcomes (Fig. 1 and 2).
Early exposure to
lead was not significantly associated with performance on the symbol-digit
or serial-digit tests, the continuous-performance test, pattern memory
or pattern comparison, switching attention, the California Verbal Learning
Test, the Rey-Osterreith figures, the Boston Naming Test, or mood scores.
The lead level was inversely related to the summed score on the self-report
of delinquency questionnaire, which consisted primarily of reports of
minor antisocial behavior. When subjects were divided into two groups
according to their dentin lead levels (<10 ppm vs. ³ 10 ppm), high
dentin lead levels predicted future failure to graduate from high school
with a sensitivity (+SE) of 0.71 -+0.12 and a specificity of0.61±0.05(Table4).
Discussion
In this extended
follow-up study, in which the mean length of follow-up was 11.1 years,
we found that the associations reported earlier between lead and children's
academic progress and cognitive functioning persisted into young adulthood.
The persistent toxicity of lead was seen to result in significant and
serious impairment of academic success, specifically a sevenfold increase
in failure to graduate from high school, lower class standing, greater
absenteeism, impairment of reading skills sufficiently extensive to
be labeled reading disability (indicated by scores two grades below
the expected scores), and deficits in vocabulary, fine motor skills,
reaction time, and hand-eye coordination.
A number of issues
require consideration when one is interpreting the data reported here.
The first is the influence of selection bias on the associations we
observed. The subjects retested in 1988 had more favorable characteristics
than those who could not be located or who declined to participate.
The subjects who were not retested tended to have had higher lead levels,
lower socioeconomic status, and lower IQ scores and teachers' ratings
of classroom behavior. The inverse relation between dentin lead levels
and IQ reported in 1979 was stronger for the subjects who were not retested
in 1988 than for those we retested, although the difference did not
reach statistical significance. This finding is in agreement with the
observation, made by us and others, that children from families in lower
socioeconomic groups are more vulnerable to the effects of lead than
children from more favored economic backgrounds?0 We infer that the
estimates made on the basis of the data on the 132 subjects we restudied
are likely to be conservative. Indeed, had all the original subjects
been located and retested, the magnitude of the effect of lead exposure
might have been even greater.
Is the nature of
the relation between lead and later outcome causal, or does it result
from confounding by other variables? The association between lead and
outcome reported here meets six criteria for valid causal inference:
proper temporal sequence, strength of association, presence of a biologic
gradient, non-spuriousness, consistency, and biologic plausibility.21
In this study, the
exposure to lead preceded the school failure and the reading disabilities
measured. The strength of the association, as measured by adjusted odds
ratios of 7.4 and 5.8, was substantial. A dose-response relation has
been demonstrated between exposure and numerous outcome variables (Table
2, Fig. 1 and 2). "Nonspuriousness" indicates that the association
observed is not due to confounding. In this analysis, we controlled
for both the covariates that were identified in 1979 as potential confounders
and others we suspected were important. The magnitude of the effect
of lead was reduced only slightly, if at all, by this procedure. The
zero-order correlation between socioeconomic status and dentin lead
levels
in this sample was
not great (r = 0.04). Many covariates that were important contributors
to performance in the early grades (e.g., the mother's IQ and the mother's
educational level) had less effect on the subject's performance in young
adulthood. The results, moreover, are consistent with those of several
other studies by workers who have reported lead-associated deficits
in reading4,22,23 and early classroom behavior.25
The lead-related deficits in IQ, speech and language processing, and
attention reported in 1979 provide plausible mechanisms by which lead
could impair performance in Class and produce eventual failure. Similar
effects on learning have been demonstrated in the experimental studies
by Gilbert and Rice of subhuman primates.7 In these investigations,
rhesus monkeys, administered lead only in the first 100 days of life,
had impairments in learning as adolescents. In adolescence, the mean
blood lead level of these monkeys was 0.73/m mol per liter (15/m g per
deciliter).
The value accepted
as the threshold for lead-engendered neurotoxicity in children has declined
steadily over the past decade as more sophisticated population studies,
with larger samples, better designs, and better analyses, have been
conducted.4,5,11,22,24,26-29 When this study was begun in
1975, the toxic level of lead in the blood was defined by the Centers
for Disease Control as 2.0/m mol per liter (40/.m g per deciliter).
In 1973, the mean blood lead level in a subsample of 23 children chosen
from among those with the highest
*Of the 122 asymptomatic
subjects studied, 7 subjects who were still attending school at the
time of this analysis were excluded.
One subject's school
records were not found. Of the 132 subjects retested in 1988, the 10
with clinical plumbism have been excluded.
dentin lead levels
in an earlier study was 1.7 m mol per liter (34 m g per deciliter).3
None of our subjects were symptomatic. That these subjects were exposed
to high doses of lead after the original study was completed is unlikely.
Lead exposure, the incidence of pica, and hand-to-mouth behavior diminish
after the fifth year of life. The low blood lead levels found in these
subjects in young adulthood (all < 0.034 m mol per liter) provide
convincing evidence that their later exposure to lead was not excessive.
The consensus on
what level of lead is toxic has changed in recent years. After reviewing
the studies published up to 1987, the Agency for Toxic Substances and
Disease Registry defined the threshold for neurobehavioral toxicity
as 0.5 to 0.7 m mol per liter (10 to 15 m g per deciliter).1
The agency estimated that 3 to 4 million American children have blood
lead levels in excess of 0.7 m mol per liter. The mean blood level among
our subjects with high tooth lead levels, estimated in 1979 from a limited
lead-screening program, was 1.6 m mol per liter (34 m g per deciliter)
(range, 0.87 to 2.6 m mol per liter [18 to 54 m g per deciliter]). For
subjects with low tooth lead levels, it was 1.2 m mol per liter (24
m g per deciliter) (range, 0.58 to 1.7 m mol per liter [ 12 to 36 m
g per deciliter]). Thus, the lead levels in the reference sample used
in the calculation of the odds ratios for one high-lead-level group
were relatively high by contemporary standards.
The data presented
here indicate that exposure to lead, even in children who remain asymptomatic,
may have an important and enduring effect on the success in life of
such children and that early indicators of lead burden and behavioral
deficit are strong predictors of poor school outcome. For the small
group of 10 subjects who were diagnosed earlier as having plumbism,
the outcome was especially dire; half of these young people have reading
disabilities, and almost half left high school before graduation. Given
the federal estimates that 16 percent of children in the United States
have elevated blood lead levels (> 0.7m mol per liter [15m g per
deciliter]), the implications of these findings for attempts to prevent
school failure are intriguing. The practical importance of early detection
and abatement of lead in the environment, before it enters the bodies
of children, is borne out by these long-term findings in young adults.
We are indebted
to Drs. Richard Frank, Constantine Gatsonis, Alan Mirsky, and Rolf Loeber
for their careful review and critiques of the manuscript and to Ms.
Pat Hadidian for her careful work in finding subjects and reviewing
records.
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Printed with
permission from New England Journal of Medicine, 322:83-88 (January
11, 1990)
