Intellectual Impairment in Children with Blood Lead Concentrations Below 10 ?g per Deciliter Discussion 6 bullet points quickly summarizing the main points

Intellectual Impairment in Children with Blood Lead Concentrations Below 10 ?g per Deciliter Discussion 6 bullet points quickly summarizing the main points of the reading. Please not too much. new england
journal of medicine
The
established in 1812
april 17 , 2003
vol. 348
no. 16
Intellectual Impairment in Children with Blood Lead
Concentrations below 10 µg per Deciliter
Richard L. Canfield, Ph.D., Charles R. Henderson, Jr., M.A.,
Deborah A. Cory-Slechta, Ph.D., Christopher Cox, Ph.D., Todd A. Jusko, B.S.,
and Bruce P. Lanphear, M.D., M.P.H.
abstract
background
Despite dramatic declines in children’s blood lead concentrations and a lowering of
the Centers for Disease Control and Prevention’s level of concern to 10 µg per deciliter
(0.483 µmol per liter), little is known about children’s neurobehavioral functioning at
lead concentrations below this level.
methods
We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and
60 months of age and administered the Stanford–Binet Intelligence Scale at the ages of
3 and 5 years. The relation between IQ and blood lead concentration was estimated
with the use of linear and nonlinear mixed models, with adjustment for maternal IQ,
quality of the home environment, and other potential confounders.
results
The blood lead concentration was inversely and significantly associated with IQ. In the
linear model, each increase of 10 µg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the
subsample of 101 children whose maximal lead concentrations remained below 10 µg
per deciliter, the change in IQ associated with a given change in lead concentration was
greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4
points as lifetime average blood lead concentrations increased from 1 to 10 µg per
deciliter.
From the Division of Nutritional Sciences
(R.L.C.) and the Department of Human
Development (C.R.H.), College of Human
Ecology, Cornell University, Ithaca, N.Y.; the
Departments of Environmental Medicine
(D.A.C.-S.) and Biostatistics and Computational Biology (C.C.), University of Rochester School of Medicine, Rochester, N.Y.;
the Division of Epidemiology, Statistics,
and Prevention, National Institute of Child
Health and Human Development, National Institutes of Health, Department of
Health and Human Services, Bethesda,
Md. (C.C.); the Department of Epidemiology, School of Public Health and Community Medicine, University of Washington,
Seattle (T.A.J.); and Cincinnati Children’s
Environmental Health Center, Children’s
Hospital Medical Center, Cincinnati (B.P.L.).
Address reprint requests to Dr. Canfield at
the Division of Nutritional Sciences, College of Human Ecology, Cornell University,
Ithaca, NY 14853, or at rlc5@cornell.edu.
N Engl J Med 2003;348:1517-26.
Copyright © 2003 Massachusetts Medical Society.
conclusions
Blood lead concentrations, even those below 10 µg per deciliter, are inversely associated
with children’s IQ scores at three and five years of age, and associated declines in IQ are
greater at these concentrations than at higher concentrations. These findings suggest
that more U.S. children may be adversely affected by environmental lead than previously
estimated.
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l
ead is neurotoxic, and young
children are at particular risk for exposure.1
Numerous studies indicate that blood lead
concentrations above 10 µg per deciliter (0.483 µmol
per liter) are associated with adverse outcomes on
measures of intellectual functioning and social–
behavioral conduct.2-9 Such studies led to the identification of a blood lead concentration of 10 µg per
deciliter or higher as a “level of concern” by the
Centers for Disease Control and Prevention (CDC)
and the World Health Organization (WHO).1,10
It remains unclear whether lead-associated cognitive deficits occur at concentrations below 10 µg
per deciliter. The CDC and WHO recognized that
no evidence of a threshold existed for lead-associated deficits but noted an absence of research on the
possible effects of blood lead concentrations below
10 µg per deciliter. Although some studies in which
the average blood lead concentration was below
10 µg per deciliter have reported associations between the blood lead concentration and cognitive
deficits, the analyses did not focus specifically on
children whose concentrations remained below
10 µg per deciliter throughout life.6,11 Other evidence suggesting lead-related deficits at concentrations below 10 µg per deciliter relied on linear
extrapolation or on data unadjusted for important
potential confounders such as maternal intelligence
and the quality of caregiving.12-15 We examined associations between low-level exposure to lead and
children’s performance on intelligence tests at the
ages of three and five years in a population that included many children whose blood lead concentrations remained below 10 µg per deciliter.
of
medicine
assessed at the age of five years because they missed
appointments, relocated, declined to participate, or
died. Children were tested at three and five years of
age. The institutional review board of the University
of Rochester Medical Center (Rochester, N.Y.) approved the study protocol, and parents or guardians
of all children provided written informed consent.
analysis and quality control
of blood samples
Blood lead concentrations were determined by electrothermal atomic absorption spectrometry (Wadsworth Laboratories). Lead values were calculated
as the means of six analyses of each sample (SD,
0.03 µg per deciliter [0.001 µmol per liter]). The results of repeated analyses, separated by five days,
were highly consistent (SD, 0.40 µg per deciliter
[0.019 µmol per liter]) for blood lead concentrations below 20 µg per deciliter (0.966 µmol per liter). The limit of detection was 1.0 µg per deciliter
(0.048 µmol per liter), and values below this limit
were set to 1.0 µg per deciliter.17
assessment of intelligence
Children were assessed with the Stanford–Binet Intelligence Scale, fourth edition, which tests vocabulary, spatial pattern analysis, quantitative ability,
and memory. We used the composite score (mean
[±SD], 100±16) to represent IQ, because it is similar to the IQ score of other intelligence tests.18,19
A different examiner administered an abbreviated
Stanford–Binet Scale at each age. Examiners were
unaware of children’s lead status. Scores from the
abbreviated batteries are highly correlated with
the Stanford–Binet full composite score (0.94 at the
age of three years and 0.99 at the age of five years).20
methods
Because of the limited diagnostic value of Stanford–
study cohort
Binet subscales at these ages, the composite score
Participants had been enrolled at five to seven was the dependent variable.19
months of age for a prior study of dust-control efficacy.16 The children had been born between July lead exposure variables
1994 and January 1995. Families were invited to Venous blood samples were obtained at 6, 12, 18,
participate in the current study when the children 24, 36, 48, and 60 months of age. Four exposure inwere 24 to 30 months of age. Thirty-six of the 276 dexes were analyzed: lifetime average, peak, concurchildren in the original study were excluded from rent, and average blood lead concentration in inthe current study because of premature birth (less fancy. The lifetime average blood lead concentration
than 37 weeks’ gestation), low birth weight (less was estimated at 3 and 5 years of age by computing
than 2500 g), Down’s syndrome, speech and hear- the area under the blood lead curve (AUC) from
ing abnormalities, or death or because their parents 6 through 36 months of age and from 6 through
were short-term custodians or lacked English profi- 60 months of age, respectively. Dividing the AUC by
ciency. Of the 240 eligible participants, 54 were not the corresponding age span yields an average conassessed at the age of three years and 65 were not centration expressed in micrograms per deciliter.
1518
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intellectual impairment in lead-exposed children
The peak blood lead concentration is the child’s
highest measured lead concentration through the
age of three or five years. The concurrent blood lead
concentration is that measured on the day of cognitive testing. The average blood lead concentration
in infancy is the AUC for values measured between
6 and 24 months of age.
The lifetime average blood lead concentration
best reflects chronic exposure and was used as the
primary exposure variable. The blood lead concentration was specified as an untransformed continuous variable. To compute the AUC, conditional
means regression21 was used to impute values for
72 of the 1168 age-specific lead values (6.2 percent).
covariates
All analyses used the same set of prespecified
covariates, which were based on established predictors of children’s intellectual outcomes and
those widely used in studies of pediatric lead exposure.2-4,8,22,23 The following variables were used:
the child’s sex, birth weight, and iron status (defined by the serum transferrin saturation at three
and five years of age) and the mother’s IQ (determined with use of the abbreviated Stanford–Binet
Intelligence Scale), years of education, race (selfassigned as white or nonwhite), tobacco use during
pregnancy (user or nonuser), yearly household income, and the total score for the Home Observation
for Measurement of the Environment Inventory.24
statistical analysis
the same for all children, and covariances between
children were assumed to be negligible. All significance tests were two-tailed.
For a given lead variable, regressions were specified separately according to age, and the homogeneity of these estimates was tested (i.e., the interaction of age with lead concentration). In the absence
of a difference between the age-specific estimates,
their unweighted average (based on all available
data) is the best estimate of the association between the blood lead concentration and IQ and is
referred to as the overall estimate.
Regression diagnostics were carried out for the
mixed models.27 Only one value had a standardized residual of more than 3.0 (a child who had a
low IQ and a low lead concentration). It did not pass
a discordancy test27 and was retained in all analyses.
The linear relations of IQ scores to lifetime average, concurrent, peak, and infancy average blood
lead concentrations were estimated in the full sample. A second, parallel set of analyses estimated the
relation between IQ and the lead concentration for
children whose peak lead concentration was below
10 µg per deciliter. Observations for children who
were three years of age were included in these calculations only when their maximal blood lead concentration through that age was below 10 µg per
deciliter and were included at the age of five years
only when their maximal concentration was below
10 µg per deciliter during the entire five-year span.
Nonlinearity in the relation between IQ and the
blood lead concentration across the full range of
lead values was examined with the use of the mixed
models described above in two types of analyses:
quadratic, cubic, and higher-degree polynomials
were estimated for each lead variable; and semiparametric models were estimated with the use of
parametric adjustment for covariates and penalized
spline smoothing for the nonparametric relation
between IQ and the blood concentration.28 The
semiparametric models estimate the regression locally and, unlike the polynomial models, do not require the restrictive assumption that the true relation
between IQ and the blood lead concentration conforms to a particular parametric function. Inference
is less well developed in the mixed semiparametric
model, and confidence intervals are not reported.
Mixed-model methods25,26 were used to estimate
and test parameters in linear, polynomial, and semiparametric models that always included the child’s
sex and the mother’s race and prenatal smoking
status as fixed classification effects, and a lead
measure, the child’s iron status, and the mother’s
income, level of education, IQ, and Home Observation for Measurement of the Environment score as
covariates. The child’s IQ (the composite score on
the Stanford–Binet Intelligence Scale) was the dependent variable. The longitudinal study design provides repeated measures of the IQ variable at the
ages of three and five years, and the models also include a fixed classification factor for age and a random factor for individual children. The mother’s
income and level of education, the child’s iron status, and all lead measures (except the infancy averresults
age) were measured at both time points and are
time-varying covariates. The error structure for each A total of 198 children completed at least one assesschild assumes different variances at each age and a ment. Of these, 172 (86.9 percent) had complete
covariance between ages; these were assumed to be data for all variables included in the model (305 obn engl j med 348;16
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1519
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Table 1. Characteristics of the Children at the Age of Five Years
and of Their Mothers.*
Characteristic
Children with Children with
Children
Complete
Incomplete Who Did Not
Data
Data
Participate
(N=154)
(N=21)
(N=65)
of
medicine
servations; 151 at the age of three years and 154 at
the age of five years). There were no significant differences in the background characteristics among
children with complete data, those with incomplete
data, and those who did not participate (Table 1).
blood lead concentrations
The mean blood lead concentration was lowest at
the age of six months (3.4 µg per deciliter [0.164
µmol per liter]), was maximal at two years (9.7 µg
per deciliter [0.483 µmol per liter]), and then decreased to 6.0 µg per deciliter (0.290 µmol per liter)
at five years (Fig. 1). The lifetime average blood lead
concentration was 7.7 µg per deciliter (0.372 µmol
per liter) at the age of three years and 7.4 µg per deciliter (0.368 µmol per liter) at the age of five years. At
three years of age, 86 children (57.0 percent) had a
peak blood lead concentration below 10 µg per deciliter, as did 86 (55.8 percent) at the age of five years
(71 of these children had such a concentration at
both ages, and the remaining 30 had data at either
three or five years).
Children
Age at testing (mo)
60.6±1.0
60.6±0.9
—
52.6
45.5
53.9
Weeks of gestation
39.5±1.2
39.8±1.0
39.4±1.2
Birth weight (g)
3295±405
3400±496
3304±473
Transferrin saturation (%)
22.5±9.4
23.5±6.6
—
Blood lead concentration
(µg/dl)†
Lifetime average
Peak
Concurrent
Average in infancy
7.4±4.3
11.1±7.1
5.8±4.1
7.0±3.8
7.3±3.6
12.6±8.2
6.4±7.5
7.4±3.4
—
—
—
7.2±4.1
IQ‡
89.8±11.4
85.6±12.2
—
11.1±4.1
10.2±5.0
10.4±3.7
intelligence test results
The mean IQ was approximately 90 at both three
and five years of age (Table 1), a value consistent
with the sample demographics.20,29 Children’s IQ
scores at three and five years of age were strongly
correlated (r=0.67, P
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