Lead exposure and the cognitive development of urban preschool children: The cincinnati lead study cohort at age 4 years

Neurotoxicologyand Teratology,Vol. 13, pp. 203-211. ©Pergamon Press plc, 1991. Printed in the U.S.A.

0892-0362/91 $3.00 + .00

Lead Exposure and the Cognitive Development of Urban Preschool Children: The Cincinnati Lead Study Cohort at Age 4 Years K I M N. D I E T R I C H , .1 P A U L A. S U C C O P , * O M E R G. B E R G E R , t P A U L B. H A M M O N D * A N D R O B E R T L. B O R N S C H E I N *

*University of Cincinnati College of Medicine, Department of Environmental Health tUniversity of Cincinnati College of Medicine, Department of Pediatrics and the Children's Hospital Medical Center, Cincinnati, OH R e c e i v e d 12 July 1990

DIETRICH, K. N., P. A. SUCCOP, O. G. BERGER, P. B. HAMMOND AND R. L. BORNSCHEIN. Lead exposure and the cognitive developmentof urban preschool children: The CincinnatiLead Study cohort at age 4 years. NEUROTOXICOL TERATOL 13(2) 203-211, 1991.--The purpose of this analysis was to determine if significant associations could be observed between prenatal/postnatal blood lead (PbB) levels and the cognitive development of 258 urban, inner-city children at 4 years of age. These children have been followed since birth with frequent assessments of general health, PbB, and neuropsychological status. The Kaufman Assessment Battery for Children (K-ABC) was administered at approximately 4 years of age. Higher neonatal PbB levels were associated with poorer performance on all K-ABC subscales. However, this inverse association was limited to children from the poorest families. Maternal PbB levels were unrelated to 4-year cognitive status. Few statistically significant associations between postnatal PbB levels and K-ABC scales could be found. However, the results did suggest a weak inverse relationship between postnatal PbB levels and performance on a K-ABC subscale which assesses visual-spatial and visual-motor integration skills. In these results we note both contradiction and accord with previously published prospective studies. Lead

Cognition

Preschool children

LEAD (Pb) exposure in the general population of children in the United States has been substantially reduced by measures taken during the past two decades to lower the concentration of the metal in the atmosphere and diet (2). However, children who reside in the interiors of our major urban centers and elsewhere remain at risk of undue Pb exposure. This is primarily owing to the fact that, in older dwellings, the exterior and interior surfaces often contained Pb-based paint which over the years has weathered and become a constituent of soils and dusts (7). Elevations in blood Pb (PbB), the most frequently used biomarker of exposure, begin to occur in such children as soon as they are able to crawl and bring their contaminated hands or toys to their mouths (11). Therefore, Pb toxicity can occur quite early in life as a result of the normal development of prewalking progression and hand-tomouth behavior. As PbB levels have dropped over the last decade, so has the level at which many researchers and clinicians believe there is an adverse developmental impact to fetuses and young children.

Thus, while during the 1960's a "level of concern" for PbB of 60 p,g/dL was cited by federal agencies and medical committees, now the level at which close observation is recommended is 25 p.g/dL (9), and it is quite probable that this will be reduced to 10-15 p,g/dL in the near future (1). The most frequently studied critical effects of prenatal/postnatal Pb exposure have been cognition, learning, and behavior. Much of the current concern in the regulatory and pediatric communities has been generated by findings from several well-designed prospective and cross-sectional studies which have reported behavioral and/or cognitive effects at levels which were thought to be innocuous only a few years ago (18). Although not all of these studies have reported positive findings, the majority of them have found some effect of low to moderate Pb exposure on cognition and behavior (30). Collectively, these studies suggest that Pb exposures which are capable of producing an early PbB level of 10-15 Ixg/dL will likely result in measurable delays or deficits in sensorimotor or cognitive development. For example, Boston

1Requests for reprints should be addressed to Kim N. Dietrich, Ph.D., University of Cincinnati, College of Medicine, Department of Environmental Health, Cincinnati, OH 45267-0056.

203

204

DIETRICH ET AL.

investigators have reported a statistically significant effect of early low-level postnatal Pb exposure on the Perceptual-Performance I.Q. of 5 year olds. The group mean PbB level in this prospective cohort study never exceeded 8 IJ,g/dL (5,6). Our objective in this analysis was to examine the relationship between prenatal/postnatal Pb exposure and the cognitive performance of a sample of 258 inner-city children who have been followed prospectively with repeated assessments of PbB and neuropsychological development. We have previously reported significant associations between prenatal and early postnatal Pb exposure and indices of early sensorimotor development in this cohort (12-14). However, such relationships were not observed when these subjects were examined in late infancy (15). Therefore, the question arose as to whether the apparent disappearance of the early Pb effects on sensorimotor development represented true recovery or a recovery which was limited to infant sensorimotor functions. METHOD

Subjects Details of the procedures for subject recruitment and eligibility criteria can be found in an earlier report (12). Between 1979 and 1984, women who resided in an area of Cincinnati where pediatric Pb toxicity has been common in the past were recruited at their first prenatal medical appointment. Women who were known to be behaviorally disturbed, alcoholic or addicted to drugs were not recruited. Infants were recruited at birth if they met certain perinatal medical criteria (e.g., birth weight->1500 g, gestational age-->35 weeks, without serious medical conditions, or congenital anomalies). For this analysis, 263 of the 302 children who were originally evaluated during early infancy were available. Subjects were missing from these analyses for various reasons, including attrition, uncooperative behavior which necessitated early termination of testing, and missed appointments. Five subjects who were evaluated at 4 years were excluded for a medical reason (i.e., early head trauma, visual handicap, sickle cell anemia, and documented and severe psychosocial mental retardation). This cohort included 5 sets of twins. Data analyses were performed excluding all twins to determine the impact of their presence in the sample on the findings. Results did not significantly differ as a function of their presence in the sample. Subjects who were evaluated at 3 and 6 months, but not at 4 years, were compared with those in the current analysis on a variety of biomedical, social, and Pb exposure variables. No statistically significant or near significant (e.g,, p<0.25) differences were found. This protocol has been reviewed and approved by the Committee on Human Research of the University of Cincinnati College of Medicine.

Exposure Assessment Blood lead was measured in the mother at her first prenatal visit, and in the neOnate at 10 days corrected for gestational age. Postnatal PbB levels were assessed quarterly in the child from 3 months to 4 years of age. Most samples were obtained by venipuncture, although sometimes it was only practical to sample via heel or finger stick. Contamination of blood samples drawn by a method other than venipuncture was not a problem because of thorough presampling cleansing procedures and the controlled clinical conditions under which phlebotomy took place. Blood samples were analyzed by anodic stripping voltammetry. A detailed description of the analytical procedures and proficiency of the microanalytical laboratory in our department has been pub-

TABLE 1 NUMBER OF OBSERVED PbB DETERMINATIONS FROM BIRTH TO 4 YEARS OF AGE

PbB Variable

N

Percentage of Total Sample (N = 258)

10 Day PbB 3 Month PbB 6 Month PbB 9 Month PbB 12 Month PbB 15 Month PbB 18 Month PbB 21 Month PbB 24 Month PbB 27 Month PbB 30 Month PbB 33 Month PbB 36 Month PbB 39 Month PbB 42 Month PbB 45 Month PbB 48 Month PbB

218 220 230 221 222 232 234 237 233 236 237 234 234 233 236 226 236

84.5 85.3 89.2 85.7 86.0 89.9 90.7 91.9 90.3 91.5 91.9 90.7 90.7 90.3 91.5 87.5 91.5

lished elsewhere (31). All PbB values were corrected to an average hematocrit for developmental age, because the concentration of erythrocytes will affect the concentration of Pb measured in whole blood. Duplicate data analyses were performed with both logged and untransformed data to determine whether this transformation affected the final regression models or statistical significance of the PbB variables. Since the results of these comparisons were negative, we only report results of untransformed PbB in Ixg/dL. In utero exposure to Pb was indirectly assessed by prenatal (maternal) PbB (PrePbB) and neonatal PbB (NeoPbB). We chose to express postnatal Pb exposures as the mean of the 1st, 2nd, 3rd, and 4th year PbB levels (MPbB1-4) and mean lifetime PbB (MPbBLife) for each subject, as well as the peak PbB level during years 1--4 and over the child's lifetime. Our findings did not significantly differ as a function of postnatal PbB expression (i.e., mean versus peak). Therefore, we only report results for mean PbB in this paper. The number of subjects available for any given analysis differed as a function of which PbB variables were being considered. Thus, 224 subjects had data for both PrePbB and 4-year neurobehavioral indices. Table 1 presents the proportion of observed PbB values for each postnatal sampling period. The highest proportion of missing data occurred in the neonatal period where it was sometimes difficult or medically inadvisable to obtain a sample. Seventy-seven percent of the sample had complete PhB data from the neonatal period to 4 years of age. Missing postnatal PbB levels were imputed from a weighted average of a within subject regression of PbB on age and the cohort mean at each age. The effect of this imputation is likely to be minimal for MPbB levels. This imputation was done to avoid the folly of simply excluding those subjects who may have one or only a few missing PbB's in the context of an otherwise data-rich exposure history. Analyses were conducted with data sets which contained both imputed and observed PbB values, and also with data sets which contained only observed PbB values. This was done to determine if there were differences in the regression coefficients obtained

LEAD EXPOSURE AND COGNITIVE DEVELOPMENT

for PbB in these two overlapping data sets. No significant differences in magnitude, direction or statistical significance of PbB regression coefficients were found in these analyses. Therefore, we only report results obtained from the larger data set which contained both observed and imputed PbB's.

Neurobehavioral Assessment The Kaufman Assessment Battery for Children (21) was administered to study subjects at approximately 4 years of age. The mean age at the time of assessment was 48.2---0.6 months. The Kaufman Assessment Battery for Children (K-ABC) is a neurobehavioral survey of general intelligence, information processing, and achievement for children between the ages of 2.5 to 12.5 years. It was normed on a large national sample and yields a Mental Processing Composite standard score (MPC), Sequential Processing standard score (SEQ), Simultaneous Processing standard score (SIM), Nonverbal standard score (NONVB), and an Achievement standard score (ACHIV). All standard scores have a national standardized mean and standard deviation of 100 ___15. The MPC is a composite of SEQ and SIM subscales and is interpretable as an intelligence quotient or full-scale " I . Q . " The SEQ and SIM subscales contain subtests that call for somewhat different strategies to solve problems. For example, SEQ subtests require the child to solve problems by arranging stimuli mentally in a step by step manner, while the SIM subtests challenge the child to assimilate information all at once and to solve problems by integrating separate but related stimuli into a cohesive pattern. There is empirical support in the neuropsychological literature for the proposition that these two different methods of information processing reflect the dominant functional specializations of the left (SEQ) and fight (SIM) cerebral hemispheres (10). The NONVB subscale assesses both sequential and simultaneous information processing skills, but it is limited to K-ABC subtests which require only gestural responses. The ACHIV subscale measures what the child has learned from his home and academic environments. Vocabulary, knowledge of places and people, computational skills, and the ability to solve a series of fiddles are assessed in the 4 year old. Children were tested at a pediatric clinic located in the heart of the geographical area where subjects and their families were recruited. Medical examinations and phlebotomy immediately followed neuropsychological testing. Care was taken to insure that the child was in good health and not receiving medication that could affect test performance. All children were tested by one of 2 female research assistants or the first author. Both research assistants were trained by the first author to administer the K-ABC. Data analyses could detect no significant or near significant examiner effects on K-ABC subscales. All three examiners were blind to the previous and current PbB levels of the children. After testing, each examiner evaluated the degree to which the examination results reflected an acceptably accurate estimate of the child's current abilities. This K-ABC test rating was done on a standardized 5 point scale, with a score of 1 indicating little or no validity, and a score of 5 indicating a completely untroubled protocol. The reality of neuropsychological testing in the clinic or field is that many things can and do go wrong. Thus, the child may have been ill and an examination could not be rescheduled within a reasonable time-frame, the clinic environment may not have been conducive to testing on a given day (e.g., failure of the heating or cooling systems, excessive noise), or for any number of unknown reasons the child may have refused a few or many of the test items.

Assessment of Covariables Lead exposure is known to covary with other pediatric social

205

and biomedical factors that are believed to have a potentially adverse impact on development. Thus, there is the potential for confounding in studies examining the "independent" relationship between PbB and cognition. Figure 1 presents a listing of covariates which were quantitatively assessed in this study. Most of the perinatal data were obtained from the obstetrical and neonatal medical records. Assessments of social class were conducted on an approximately yearly basis. The H.O.M.E. (Home Observation for Measurement of the Environment), which is a measure of the caretaking and physical qualities of the home environment, was administered in the subject's homes at 6, 12, 24, and 36--48 months of age. Each H.O.M.E. was administered by one of three teams of female research assistants or by the first author. Each home visitor underwent an intensive period of training and interobserver reliability was monitored throughout the study. As an integrated index of environmental quality over the first four years of life, the mean of the total H.O.M.E. score at each age was calculated and used in data analyses. Since the 3-year H.O.M.E. contains more items than the infant H.O.M.E. scale, each total H.O.M.E. score was Z-transformed prior to calculating a mean Z-score for each family.

Data Analyses We have previously presented our data analytic strategy in detail (13). Briefly, covafiates were pretested for their confounding potential by examining their bivariate relationship with both PbB and K-ABC subscales. Following both backward and forward step-wise multiple regression analyses, those covariates which were independently related to one or more K-ABC subscales at p-<0.10 were included in all subsequent multiple regression analyses. For substantive reasons, certain variables were included in each regression analysis regardless of the statistical significance of their relationship to the K-ABC or PbB. Thus, cigarette consumption, alcohol use, and marijuana use during pregnancy were retained in all analyses. Each K-ABC subscale was examined independently for its relationship to PrePbB, NeoPbB, MPbB1, MPbB2, MPbB3, MPbB4 and MPbBLife after adjustment for the qualified covariates. Data analyses employing bivariate and multiple regression procedures [GLM procedure, SAS (32)] were executed in several steps. First, the relationship between PbB variables and K-ABC subscales was assessed with all available subjects (maximum N = 258). A separate series of regression analyses were performed with subjects who received a K-ABC test rating (see above) of greater than or equal to 3 (maximum N = 195). This was done to determine if the perceived quality of the behavioral data had any impact on the regression coefficients (i.e., by limiting the amount of measurement error in the K-ABC scales). Finally, regression analyses were performed with two significant predictors of 4-year cognitive performance and childhood PbB level pruned from the multiple regression model--maternal intelligence and mean H.O.M.E. score. This last series of analyses were executed to assess the effect of removing these two factors on the PbB coefficients. It has been argued that the introduction of these covariables may represent a case of statistical overcontrol in studies of pediatric Pb exposure (29). For example, the lower H.O.M.E. scores and maternal I.Q. may be manifestations of previous or concurrent Pb toxicity in the mother. This is a possibility because the mother is currently living in the same potentially hazardous environment as her child, and indeed may also have experienced undue Pb exposure as a child. This could conceivably result in lowered adult intelligence and impaired caretaking abilities. We also examined two potential effect modifiers, child sex and social class. Such interactions have been observed in previ-

206

DIETRICH ET AL.

Perinatal and Child Health Factors

Sociohereditar7

Birth Weight

Social Class Score

Birth Length

H.O.M.E.

Scores

Neonatal Head Circumference

Maternal

Intelligence

Gestational Age by Physical Exam (3)

Highest Grade Attained by

Gestational Age by Dates

Factors (19)

(8) (34)

Primary Caregiver

Apgar at One Minute

Family on Public Assistance

Apgar at Five Minutes

Number of Adults at Home

Obstetrical

Complications

Postnatal Complications Cigarette Consumption Alcohol Consumption

Scale Score

Scale Score

Child Attends Preschool

(1/2 packs per day)

(Yes/No)

During Pregnancy

Narcotics Use During Pregnancy

Number of Children at Home

(24)

During Pregnancy

During Pregnancy

Marijuana Consumption

(24)

(Yes/No)

(Yes/No)

N-mher of Previous Abortions N,,mher of Previous Stillbirths Gravidity Parity Chi]~'~ H a m ~ l o b i n .

HAmatocrit.

and ~otal Iron Bindina Canacitv at i. 2. 3. and

4

Years

FIG. 1. Candidate covariates and confounders. ous studies (4), and in this cohort during early infancy. For example, children from the lower social classes may express more severe Pb-related intellectual deficits than more advantaged children, or they may express such deficits at lower levels of exposure. Furthermore, males may be more vulnerable developmentally to early Pb exposure owing to genetic factors which have previously been shown to result in somewhat higher rates of perinatal mortality and morbidity in males (12).

TABLE 2 DESCRIPTIVE STATISTICS ON SOCIOHEREDITARY FACTORS ASSESSED DURING THE FIRST FOUR YEARS OF LIFE*

Variable

Mean

Standard Deviation

Lowest

Highest

Socioeconomic status 3-Year H.O.M.E. score Maternal intelligence Maternal years of education Number of people in household Total Adults Children % Black children % Male children % of Families on public assistance % of Mothers unmarried

17.9 32.4 75.4 11.3

6.0 4.5 9.5 1.5

8 17 55 2

53 39 110 16

4.2 1.4 2.8 90.3 50.8 87.6

1.7 0.9 1.4

2 1 1

12 10 8

RESULTS

Sample Characteristics Table 2 presents selected demographic statistics on the study cohort. The sample of 258 subjects and their families was predominantly black, lower social class, unmarried, and on public assistance. Means for the 3--4-year H.O.M.E. score and maternal I.Q. were low by national standards, although there was a considerable degree of variability in both variables. Table 3 presents descriptive statistics on the perinatal status and lead-related medical management of study subjects. On average, the cohort was healthy when born, a result of predesignated study design criteria which precluded the recruitment of high-risk neonates. A total of 22 children were hospitalized for a diagnostic or therapeutic chelation.

PbB Profiles Figure 2 presents the mean and average peak PbB level by

84.5

*See Fig. 1 for references to specific instruments and measurements.

LEAD EXPOSURE AND COGNITIVE DEVELOPMENT

207

TABLE 3 DESCRIPTIVESTATISTICSON PERINATALSTATUSAND LEAD-RELATEDMEDICALMANAGEMENTOF STUDYSUBJECTS*

Variable

Mean

Birth weight (g) 3143.3 Gestational age in weeks (Ballard) 39.6 Gestational age in weeks (Dates) 39.8 Head circ. (cm) 33.8 Length (cm) 49.3 Obstetrical complications score 82.6 Postnatal complications score 94.1 Apgar (1 minute) 7.9 Apgar (5 minute) 8.9 Gravidity 1.8 Maternal age at birth of child 22.8 Cigarette use during pregnancy 6.4 (average number smoked per day) % Consuming during pregnancy Alcohol 15.5 Marijuana 11.6 Narcotics 1.2 % of Children chelated one or more times Challenge 8.5 Therapeutic 5.0

Standard Deviation Lowest Highest 474.0 1.7 1.9 1.4 2.5 5.8 9.9 1.2 0.4 1.6 4.4 7.9

1814 35 35 30 41 68 30 1 6 0 15 0

4400 43 45 39 56 95 100 9 9 7 37 40

*See Fig. 1 for references to specific instruments and measurements.

year for study subjects. Blood Pb levels tended to peak in the latter part of the second year and slowly decline thereafter. Approximately 34% of the subjects had at least one postnatal PbB level equal to or in excess of the current Centers for Disease

Control "level of concern" of 25 Ixg/dL during the study period. The highest single observed PbB level in the sample was 83 p,g/ dL. Perinatal PbB levels are also presented in the figure. Both PrePbB and NeoPbB levels were low. The highest PrePbB was 27 ~g/dL. Seventy-five percent of the women presented with PrePbB levels of 10 ixg/dL or below. The highest NeoPbB was 22 p,g/dL. Seventy-five percent of the newborns presented with NeoPbB levels of 7 tJ,g/dL or below. Correlations between postnatal PbB levels suggested that there was a considerable degree of intraindividual tracking. For example, the Pearson correlation between mean PbB levels in the first two years of life and mean PbB levels for the third and fourth years was 0.82 (p = 0.0001). This indicates that, for most children in the cohort, the relative magnitude of the PbB concentration remained constant with increasing age. Such consistency in the rank order of PbB levels has been observed in a previous prospective study of children who were also exposed to high levels of environmental Pb (26). Naturally, this constancy severely limits the exploration of the effect of age-specific PbB concentrations on neuropsychological development, and therefore the determination of the critical or sensitive periods postnatally. Correlations between indices of prenatal exposure (PrePbB and NeoPbB) and postnatal PbB ranged from 0.25 to 0.41. This correlation may reflect a small contribution of maternal PbB to postnatal PbB level, and/or the fact that mother and child shared a similar physical environment. Not surprisingly, there were a number of key developmental cofactors which were significantly associated with prenatal and postnatal PbB levels. Higher PrePbB levels were significantly associated with lower maternal I.Q. scores, while higher postnatal PbB levels were significantly associated with lower social class, lower H.O.M.E. scores and lower maternal I.Q. However, regardless of sociohereditary standing, most subjects achieved peak postnatal PbB levels in the latter part of the second year, and displayed a similar rate of decline as a percentage of peak PbB thereafter. A significantly higher percentage of children who were admitted for chelation came from the economically most stressed families and from families with the lowest H.O.M.E. scores.

35

i ~

Perinatal

i ~

Mean

Neurobehavioral Status at 4 Years

30

25

Table 4 presents descriptive statistics on study subjects' performance on the Kaufman Assessment Battery for Children at four years of age. On the MPC and all subscales, this socioeconomically underprivileged sample averaged well below the national mean of 100. Indeed, approximately 25% of the sample had MPC scores equal to or below 70, which is indicative of a significant delay or deficit in intellectual development. There also appeared to be a somewhat severe restriction in range of performance on the K-ABC ACHIV subscale which assesses the amount of factual information the child has learned from home, community, and preschool academic environments.

---~Ir- Average Peak

"~ 2O

15 ~o o

_'--4 0

I

PbB and K-ABC Performance at 4 Years

j

Prenatal Neonatal

I

I

I

I

YRI

YR2

YR3

YR4

Developmental Period

FIG. 2. Arithmetic mean perinatal and postnatal PbB levels. One-way bars represent standard deviations.

Results of regression analyses did not differ as a function of the examiner's rating of test adequacy. Therefore, we only report results for the full cohort. Table 5 presents the unadjusted and adjusted PbB regression coefficients for K-ABC subscales. Adjusted regression coefficients are statistically corrected for birth weight, child race, maternal intelligence, H.O.M.E. score, preschool attendance, and maternal cigarette, alcohol, and marijuana consumption during pregnancy. PrePbB and NeoPbB regression coefficients are adjusted for postnatal Pb exposure (MPbBLife).

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DIETRICH ET AL.

TABLE 4

TABLE 5

DESCRIPTIVE STATISTICS ON STUDY SUBJECTS' PERFORMANCE ON THE KAUFMAN ASSESSMENT BAIq'ERY FOR CHILDREN AT AGE FOUR YEARS*

COVARIATE-ADJUSTED* AND UNADJUSTED REGRESSION COEFFICIENTS FOR BLOOD LEAD INDICES AND K-ABC MENTAL PROCESSING SUBSCALES AND ACHIEVEMENT

K-ABC Subscale Mental processing composite (MPC) Sequential processing scale (SEQ) Simultaneous processing scale (SIM) Nonverbal scale (NONVB) Achievement scale (ACHIV) Vocabulary Faces/places Arithmetic Riddles

N

Mean

Standard Deviation

Lowest

Highest

247

80.3

10.4

60

116

247

83.1

10.4

64

115

258

81.7

11.6

55

119

250

83.5

10.4

66

113

242

79.4

6.8

67

104

251 251 247 241

83.8 80.3 82.1 81.7

8.8 6.3 9.7 8.1

69 69 71 74

111 101 121 111

*N's vary for subtests due to the presence of incomplete protocols for some subjects. Protocols could not be completed for every child mainly as a result of fatigue or other state or situational factors which made it impossible to administer all subtests. The Achievement subscale is administered last, thus resulting in a greater amount of missing data for the Achievement standard score.

Scale

PbB

Unadjusted

Adjusted

MPC

PrePbB NeoPbB MPbB 1 MPbB2 MPbB3 MPbB4 MPbBLife

- . 10 - .46 b - . 17 - .09 - .22 ¢ - .26 c -.22 b

.11 - .63t c - .03 - .02 - .08 - . 10 - .07

SEQ

PrePbB NeoPbB MPbB 1 MPbB2 MPbB3 MPbB4 MPbBLife

.03 - .41 b - .06 - .02 - . 13 - . 17a - . 12

.20 - .68t c .06 .04 - .02 - .04 .00

SIM

PrePbB NeoPbB MPbB1 MPbB2 MPbB3 MPbB4 MPbBLife

- . 19 - .41 a - .23 ~ - . 13 - .26 c - .31 c -.27 c

.01 - .50t b - .08 - .05 - . 11 - .15 - . 12

NONVB

PrePbB NeoPbB MPbB 1 MPbB2 MPbB3 MPbB4 MPbBLife

- . 19 - .42 b - .06 - .03 - . 15a - .20 b - . 14

- .08 - .63t ¢ .05 .03 - .02 - .04 - .00

ACHIV

PrePbB NeoPbB MPbB1 MPbB2 MPbB3 MPbB4 MPbBLife

- .06 - . 13 .01 - .01 - .07 - . 12b -.06

.04 -.28t b .15 .06 .04 .01 .07

T h e s e coefficients are " u n s t a n d a r d i z e d " and represent the average linear c h a n g e in a K - A B C subscale score for each Ixg/dL inc r e m e n t in PbB. All p - v a l u e s are two-tailed.

Fetal Pb Exposure N e o P b B , but not P r e P b B , w a s significantly and inversely related to the M P C , SIM, a n d N O N V B s u b s c a l e s o f the K - A B C in regression a n a l y s e s u n a d j u s t e d for covariates. Following covariate a d j u s t m e n t , N e o P b B w a s significantly related to all K - A B C subscales. However, there w a s also a statistically significant NeoPbB × Social C l a s s interaction w h i c h w a s retained in the final model. T o determine the nature o f this interaction, separate r e g r e s s i o n analyses were u n d e r t a k e n for t h o s e subjects above and b e l o w the sample m e d i a n s o c i o e c o n o m i c status score o f 17. For subjects b e l o w the m e d i a n s o c i o e c o n o m i c status score, N e o P b B w a s significantly a n d inversely related to all K - A B C subscales. T h u s , for the M P C , the covariate-adjusted r e g r e s s i o n coefficient for N e o P b B w a s - .91 (p = 0 . 0 0 3 ) for children f r o m the poorer families, while for children o f families o f relatively h i g h e r s o c i o e c o n o m i c standing the adjusted N e o P b B regression coefficient w a s .06 (p = 0.81). W h i l e these results s u g g e s t a c o n t i n u i n g adverse effect o f fetal Pb e x p o s u r e on cognitive d e v e l o p m e n t , this c o n c l u s i o n is t e m p e r e d by the lack o f significant findings for P r e P b B , e v e n in u n a d j u s t e d regression analyses. H o w e v e r , it can also be pointed o u t that the Pearson correlation b e t w e e n these two indirect m e a s u r e s o f fetal Pb e x p o s u r e s w a s low ( r = .28, p = 0 . 0 0 1 ) , s u g g e s t i n g that they m a y represent two different aspects o f e x p o s u r e (see the D i s c u s sion section). T h e low correlation b e t w e e n PrePbB and N e o P b B w a s also possibly due to the length o f time b e t w e e n blood s a m piing occasions, on average about 6 m o n t h s .

Postnatal Pb Exposure In unadjusted regression analyses, the m o s t consistently sig-

*Adjusted for birth weight, maternal cigarette use during pregnancy, maternal alcohol use during pregnancy, maternal marijuana use during pregnancy, child race, H.O.M.E. score, maternal intelligence, and preschool attendance, p-Values are two-tailed and rounded. Prenatal Pb exposure variables (PrePbB and NeoPbB) regression coefficients are adjusted for postnatal Pb exposure (MPbBLife). tNeoPbB level by social class interaction in the model. ~p-
bp_<0.05. ~p
nificant negative associations b e t w e e n PbB a n d K - A B C s u b s c a l e s were f o u n d for later m e a s u r e s o f e x p o s u r e (MPbB3--4 and M P b B Life). S o m e w h a t surprisingly, the earlier postnatal e x p o s u r e indices ( M P b B 1-2) were u s u a l l y unrelated to K - A B C p e r f o r m a n c e . After covariate a d j u s t m e n t , no statistically significant PbB effects were f o u n d for a n y o f the K - A B C subscales. Table 6 presents PbB regression coefficients for K - A B C subscales after p r u n i n g maternal I.Q. a n d m e a n H . O . M . E . scores f r o m the r e g r e s s i o n m o d e l s . S o m e small impact on the size and

LEAD EXPOSURE AND COGNITIVE DEVELOPMENT

209

TABLE 6 REGRF~SION COEFFICIENTS FOR BLOOD LEAD INDICES AND K-ABC SUBSCALES UNADJUSTED* FOR MATERNAL I.Q. OR H.O.M.E. SCORES Scale

PbB

Regression Coefficient

MPC

PrePbB NeoPbB MPbB1 MPbB2 MPbB3 MPbB4 MPbBLife

.06 - .65t c -.15 - .07 - . 17b - .21 b - . 17a

SEQ

PrePbB NeoPbB MPbB 1 MPbB2 MPbB3 MPbB4 MPbBLife

.17 - .68f c - .02 - .00 - .08 - . 12 - .07

SIM

PrePbB NeoPbB MPbB1 MPbB2 MPbB3 MPbB4 MPbBLife

- .03 - .52I b - . 19 - . 10 - .20 b - .26¢ - .22 b

PrePbB NeoPbB MPbB 1 MPbB2 MPbB3 MPbB4 MPbBLife

- . 13 - .66t c - .06 - .02 - . 11 - . 15a - . 11

PrePbB NeoPbB MPbB 1 MPbB2 MPbB3 MPbB4 MPbBLife

.01 - .30t"b -.03 .00 - .05 - .09 - .04

NONVB

ACHIV

*Adjusted for birth weight, maternal cigarette use during pregnancy, maternal marijuana use during pregnancy, child race, and preschool attendance, p-Values are two-tailed and rounded. Prenatal Pb exposure variables (PrePbB and NeoPbB) regression coefficients are adjusted for postnatal Pb exposure (MPbBLife). tPbB level by social class interaction in the model. ~p-
statistical significance o f the regression coefficients can be noted. As in regression analyses with full covariate control, NeoPbB continued to be inversely associated with K - A B C performance. H o w e v e r , PrePbB remained unrelated to cognitive functioning at 4 years. Regression coefficients for measures o f later and lifetime Pb exposure were now statistically significant for the M P C and SIM subscales in most analyses. H o w e v e r , it is apparent that any inverse relationship b e t w e e n postnatal M P b B variables and M P C was largely a function o f their negative relationships to the SIM subscale. It is equally clear that statistical adjustment for maternal I.Q. and H . O . M . E . reduces both the unadjusted and partially

90 F ~

Lox

i 5-9ug/dL Loil-)lod t------10-I

I~

Moderate

14-17ug/dL

High

18-3gug/dL

BO

75

tlnlJdjust:ed P e r t : t a l l y Ad|ueted

Fully Adlustea

Type of Date Anelyte FIG. 3. Dose-effect relationship between mean lifetime PbB level and the Simultaneous Processing standard score (SIM) of the Kaufman Assessment Battery for Children (K-ABC). One-way bars represent standard errors. Unadjusted, partially adjusted, and fully adjusted associations are presented.

adjusted postnatal PbB regression coefficients to statistical nonsignificance. Figure 3 presents the dose-effect relationship between M P b B Life and SIM subscale performance. M P b B L i f e is subdivided into quartiles. The mean M P b B L i f e levels in quartiles 1 to 4 were 7.9, 11.4, 15.2, and 23.7 p,g/dL, respectively. Unadjusted, partially adjusted, and fully adjusted SIM means are presented. W e do not propose that any one o f these three models is " c o r r e c t " in the absolute sense. Results o f these three modeling procedures are presented in the interest o f providing as complete a presentation o f the data as possible. Other longitudinal studies o f childhood lead exposure in low socioeconomic status populations have also found parental I.Q. and quality o f caregiving to be potent confounders, and the handling o f these interweaving sociohereditary factors is never a simple matter [see (33)]. The unadjusted relationship between M P b B L i f e category and the SIM was statistically significant w h e n examined with an analysis o f variance procedure (p = 0.03). Least-square means were calculated from an analysis o f covariance procedure to examine the dose-effect relationship between M P b B L i f e category and the SIM subscale with both partial and full covariate adjustment. With partial covariate adjustment (i.e., pruning maternal I.Q. and H . O . M . E . from the regression model), the effect o f lifetime Pb exposure w h e n treated categorically was only marginally significant (p = 0.08). With full covariate adjustment, this relationship was reduced to statistical nonsignificance ( p = 0 . 3 3 ) . The difference between the lowest and highest lifetime Pb exposure groups on the SIM subscale was never greater than 5.6 points in any o f the analyses. DISCUSSION In an analysis o f the relationship b e t w e e n prenatal and postnatal Pb exposure and the cognitive status o f 4 year olds, few

210

statistically significant associations were found after adjustment for all qualified developmental covariates. A significant relationship between fetal Pb exposure as indexed by NeoPbB was found, but this relationship was limited to children from the poorer families in the sample. The finding of a significant interaction with social class is consistent with our own previous findings in young infants (12), as well as others in infants, preschoolers, and schoolage children (4,18). These studies suggest that children from less advantaged environments express cognitive deficits at lower PbB levels than do children from families of relatively higher socioeconomic status. However, we did not observe similar inverse relationships between K-ABC subscales and PrePbB. Two factors may be responsible for this. First, NeoPbB may be a more appropriate index of later Pb exposure, and therefore a more sensitive indicator of the potential for prenatal developmental insult to higher cortical centers. Second, NeoPbB may also be a better measure of the actual amount of Pb that was crossing the placenta and absorbed by the fetus. Nevertheless, the inconsistency in these findings should be acknowledged, and temper any over-interpretation of the NeoPbB " e f f e c t " on preschool intellectual attainment. Consistently significant unadjusted relationships between measures of postnatal Pb exposure and the K-ABC were found only for later postnatal PbB levels. No significant relationships between postnatal PbB levels and K-ABC subscale scores were found after full covariate-adjustment which included maternal I.Q. and H.O.M.E. scores. With partial covariate adjustment, statistically significant inverse relationships were observed for later PbB measures and mean PbB level over the lifetime of the child. However, it was clear that the strongest associations between postnatal Pb exposure variables and K-ABC performance were observed for the SIM subscale. In these findings it is possible to note both contradiction and accord with some previously reported studies. In many ways the overall findings of our study do not agree with those of at least two major prospective studies. Boston investigators (5,6) have reported a statistically significant, covariate-adjusted relationship between PbB level at 24 months and children's Full-Scale and Perceptual-Performance I.Q.'s on the McCarthy Scales of Children's Abilities (a measure of preschool intelligence). No direct effects of fetal Pb exposure were found, although children with higher cord PbB levels were reported to be more adversely affected by higher postnatal Pb exposure than children with lower cord PbB levels. These findings were reported for a cohort of 170 middle to upper class children with considerably lower levels of postnatal exposure than those encountered in the Cincinnati sample. For example, in the Boston cohort the mean PbB at 24 months was 6.8-+ 6.3 Ixg/dL while in the Cincinnati cohort the mean PbB at 24 months was 1 7 . 5 - 8.9 ~g/dL. The Boston findings were also very similar to those reported by a group of investigators in South Australia (26). The Australian children presented exposure histories which were quite like those of the Cincinnati cohort. In this cohort of 537 children living near a longstanding Pb smelter in Port Pirie, Australia, McCarthy Full-Scale and Perceptual-Performance I.Q. scores at 4 years of age were significantly and inversely related to integrated average postnatal PbB levels following covariate adjustment. In the Port Pirie study, a change in integrated mean postnatal PbB from 10 to about 30 Ixg/dL was associated with a drop of 7.2 points in full scale I.Q. In both of these studies, the relationship between Pb exposure and I.Q. was strongest for the Perceptual-Performance subscale. Our finding of few significant inverse relationships between most measures of prenatal and postnatal Pb exposure and preschool cognitive performance is consistent with a study reported out of Cleveland (17). However, any comparative analysis of our

DIETRICH ET AL.

results with the Cleveland findings is complicated by the high prevalence (50%) of maternal alcoholism in the Cleveland cohort. In certain respects, our findings bear some similarity to the results of the Boston and Port Pirie studies. For example, when significant unadjusted or adjusted effects of PbB on K-ABC performance were found, they were most frequently observed on the SIM subscale. Among the K-ABC subscales, it could be argued (20) that the SIM subscale is similar psychometrically to the Perceptual-Performance subscale of the McCarthy Scales of Children's Abilities, which was the subscale which appeared to be most affected by postnatal Pb exposure in the Boston and Port Pirie studies. In both of the K-ABC SIM and McCarthy Perceptual-Performance subscales, most items assess visual-spatial and visual-motor integration skills. The most apparent procedural difference between the Cincinnati and Boston/Port Pirie studies is the use of the Kaufman Battery for cognitive assessment. Studies comparing the performance of preschoolers and young school-age children on the Kaufman Assessment Battery and the McCarthy Scales find the two tests to be quite comparable (25,27). Furthermore, the K-ABC has been shown to be as effective as more traditional tests in differentiating mentally retarded, learning disabled, and normal functioning children, at least in the late elementary school years (28). Thus, the construct validity of the K-ABC for the assessment of children seems well established by these and other studies (23). However, some have questioned whether the K-ABC is measuring different aspects of intellectual functioning in the preschool child as compared to the older elementary school student (22). This issue is not indigenous to the Kanfman Battery. It would be remarkable indeed if this were not the case for other test batteries that span such a wide developmental age range. For a small subsample of the children in this study (N = 44), the McCarthy Scales of Children's Abilities were administered at a second clinic visit which occurred about 2 weeks after the KABC assessment. The correlation between the McCarthy General Cognitive Index and the corresponding Kaufman Mental Processing Composite was 0.78 (p<0.0001), thus suggesting that both tests were tapping similar cognitive abilities. Therefore, we are reluctant to conclude that the distinctive results of our study were due to procedural differences alone. Many urban children continue to exhibit PbB levels that, according to some studies, pose a threat to central nervous system development (18). After review of the existing scientific data, the Environmental Protection Agency (16) concluded that prenatal and/or postnatal PbB levels of 10-15 ixg/dL or higher can significantly affect neurobehavioral development. While the results of this study provide only weak support for this position, two caveats are required. First, the effects of earlier Pb exposure may become more apparent and detectable over time. As the child matures, tests of intellectual attainment will become more challenging as well as more reliable, and assess a wider and more differentiated range of cognitive skills. Therefore, we continue to follow these children with assessments of exposure and neuropsychological development into the elementary school years. Second, environmental regulations and public health policies must be based on all of the available data, not on the results of one or only a few studies. ACKNOWLEDGEMENTS This research was supported by a grant from the National Institute of Environmental Health Sciences POLES01566. We gratefully acknowledge the invaluable assistance of Dr. Kathleen Krafft, Mariana Bier, Susan Naraine, Jill Edwards, Holly Jason, Sandra Roda, Joyce Frondorf, Robert Greenland, Joanne Grote, and Veronica Ratliffe. We also wish to thank the staff of Findlay Street Clinic and the Babies' Milk Fund.

LEAD EXPOSURE AND COGNITIVE DEVELOPMENT

211

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