Blood lead levels and specific attention effects in young children

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Neurotoxicology and Teratology 29 (2007) 538 – 546 www.elsevier.com/locate/neutera

Blood lead levels and specific attention effects in young children Lisa M. Chiodo a,⁎, Chandice Covington f , Robert J. Sokol b , John H. Hannigan b,c , James Jannise, Joel Ager d , Mark Greenwald e , Virginia Delaney-Black a a

Carman & Ann Adams Department of Pediatrics, Wayne State University School of Medicine, University Health Center, Schoo-Be Research Study, 4201 St. Antoine, Suite 6D1, Detroit, MI 48201, United States b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, 48201, United States c Department of Psychology, Wayne State University School of Medicine, Detroit, Michigan, 48201, United States d Department of Family Medicine, Wayne State University School of Medicine, Detroit, Michigan, 48201, United States e Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, 48201, United States f College of Nursing, University of North Dakota, Grand Forks, North Dakota, 58202, United States Received 30 June 2006; received in revised form 9 March 2007; accepted 12 April 2007 Available online 21 April 2007

Abstract The detrimental effects of early exposure to lead are credible and persistent, but there is presently no agreement on a safe threshold for circulating lead levels. Although several research groups have found significantly poorer cognitive performance in children who have whole blood levels as low as 5 μg/dL, most government agencies, including the EPA and the CDC, continue to use 10 μg/dL as the criterion for concern in public health advisories. Prior research has consistently indicated a negative relation between lead levels and attention. Similarly, the results of the present study show a relation between blood lead level and neurobehavioral outcome in 7-year-old children (N = 506). Higher lead levels were associated significantly with decreased scores on measures of intelligence (i.e., overall, performance and verbal IQ), lengthened reaction time, hyperactivity, and social and delinquent behavior problems. Importantly, the present study documents a significant negative impact of blood lead levels on attention, but not impulsivity, in early elementary age children, further delineating the specific aspects of attention related to blood lead concentrations. Analyses were also conducted to identify a “safe” blood lead level threshold. Visual inspection of non-parametric regression plots suggested a gradual linear dose–response relationship for each endpoint. None of the neurobehavioral outcomes assessed showed evidence of a threshold under which lead levels appear to “safe”. In light of the consistency of these findings with those of several other groups, it is advisable to consider whether the threshold for an acceptable blood lead level should be reduced. © 2007 Elsevier Inc. All rights reserved. Keywords: Lead; Attention; Blood lead concentration; Threshold; Neurobehavioral development; Environmental contaminant

1. Introduction The detrimental effects of early exposure to lead are credible and persistent [43], however, no safe threshold for circulating lead levels has yet been identified. Through extensive efforts to reduce lead levels in the environment, mean blood lead levels in schoolage children across the U.S. have decreased from around 15 μg/ dL in the 1970s to 4 μg/dL in the 1990s [2]. Nevertheless, about 2.2% of all U.S. children continue to be exposed and register blood lead concentrations above the recommended “avoid” level of 10 μg/dL [32]. ⁎ Corresponding author. Tel.: +1 313 557 5396; fax: +1 313 557 5288. E-mail address: [email protected] (L.M. Chiodo). 0892-0362/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ntt.2007.04.001

Most governmental agencies, including the EPA and the CDC, continue to use the value of 10 μg/dL in whole blood samples as a criterion for concern in public health advisories. However, significantly poorer cognitive performance was identified in children with blood levels less than 10 μg/dL [4,9,31] and even as low as 5 μg/dL (e.g., Lanphear et al. [30]), and we have reported attention and reaction time deficits at blood lead levels as low as 3 μg/dL [11]. Although extensive research has identified specific lead-associated neurobehavioral deficits, a characteristic phenotype due to lead exposure has yet to be defined. Lanphear et al. [30] suggested four affected domains — attention, executive function, visual-motor integration and social behavior, and Dietrich et al. [18] suggested adding fine-motor coordination and balance to these behavioral signs. Several studies have

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reported lead-related behavior problems consistent with this pattern, such as delinquency, antisocial behavior, and aggression [3,19,35], while others have identified early childhood lead-related deficits in attention and executive function [20,39,40,46]. Lead-related attention problems have been examined in detail [5,6,11,22,30,39,47]. Independently, Bellinger et al. [5], Needleman et al. [35] and Chiodo et al. [11] each examined the specific aspects of lead's effects on attention by administering Mirsky's attention battery, which assesses sustained attention, focused attention, shift (executive function), and encoding or working memory [33]. In a middle-class sample with low mean blood lead levels (i.e., 79% of the sample was below 5 μg/dL), Bellinger et al. [5] reported significant associations between lead exposure and deficits on the focus and executive function domains of attention. Needleman et al. [35] also identified executive dysfunction and poor sustained attention, but no alterations in focused attention, associated with lead levels. Chiodo et al. [11] confirmed the findings of Needleman et al. [35] implicating lead exposure in sustained attention deficits, and partially confirmed the findings of Bellinger et al. [5], suggesting that lead impairs executive function. Like Needleman et al. [35], Chiodo et al. [11] also reported no significant impact of lead on focused attention. Walkowiak et al. [41] identified a significant relation between low blood lead levels and both errors of commission (false negatives) and omission (false positives) in an attention task. Increased commission errors are taken to indicate increased impulsivity and increased omission errors to reflect poorer attention [41,44]. One would expect a negative correlation between errors of commission and omission in this model, but this was not found and the authors hypothesized that this was due to a few extremely long response latencies attributable to lead-related lapses in attention. In their procedure, very long response times were recorded as both misses and false alarms, thus a single response could be coded as both an error of commission and an error of omission. The present study furthers the examination of blood lead levels and attention, including both commission and omission errors, as well as several additional neurobehavioral outcomes, in a sample of children with low concurrent blood lead levels (mean = 5.0 μg/dL). Although this cohort has not been previously reported, they are demographically similar to those reported in Chiodo et al. [11]. In the current research, we examined the various domains of attention in 7-year-old children for their specific sensitivity to lead exposure.

use using a structured interview at each prenatal visit. Maternal and infant drug testing were also performed as indicated below. Inclusion criteria for this study were: singleton gestation, birth between September 1, 1989 and August 31, 1991, and continued residence within the Detroit area. Exclusion criteria included children born to women known to be HIV positive, those with multiple congenital malformations, and non-African American race. Because African American women constituted more than 90% of the prenatal clinic population, participation was limited to this single group. Offspring from repeat pregnancies to the same participating mother were also excluded. At follow-up at age 7 years, six of these children were deceased and four additional children had major congenital malformations — one was microcephalic, two had neural tube defects, and one had a heart defect. Families were not geographically stable, although movement was largely within the Detroit area. The average number of home address changes was three over the 7 years since birth. After an exhaustive search, 656 eligible children were located in the Detroit area at age 7 years, 94% of the 656 contacted families agreed to participate, and 85% completed laboratory testing (N = 556). For the present analyses, data are presented for 506 children. Some of the outcomes assessed were obtained via the local school system, including teachers (achievement scores and behavioral assessment). All data could not be obtained from 50 of these children so the final sample size for the current analyses was N = 506.

2. Methods

2.1. Sample

Children and their mothers were transported by private car or, if needed, by taxi to our laboratory for the 7-year assessment. Examiners were blind to lead and prenatal drug exposures, including alcohol, cocaine and marijuana. Since this was a sample derived for aims other than examining the impact of blood lead level of child development, this sample contains children who were exposed prenatally to several drugs, including alcohol. All prenatal exposures were controlled for statistically in all analyses.

Participants were children born to women who received prenatal care and were extensively screened by research staff during pregnancy for tobacco, alcohol, cocaine, and other drug

2.3.1. Outcome variables Children were individually administered the Wechsler Primary and Preschool Scale of Intelligence-Revised (WPPSI-R, [42]) and

This study had prior approval by the Institutional Review Board at Wayne State University. Parents or guardians provided informed consent for all participants and a Certificate of Confidentiality was obtained prior to study initiation.

2.2. Blood lead levels The 7-year-old venous blood samples were obtained at the Children's Hospital of Michigan out-patient laboratory. Blood lead concentration was measured by graphite furnace atomic absorption spectrometry by Varian AA-400. Both internal and external quality control programs were utilized. In the internal quality control program, three samples of whole blood with different, known concentrations of lead were included in each batch of specimens. If the results of the control samples were not within the specified range, the analyses were repeated. In addition, every month, a three-level precision study was performed to assure the accuracy of the instrumentation. Multiple external quality control programs were also utilized, including monthly participation in the Quebec Interlaboratory Comparison Program. 2.3. Procedures

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the Test of Early Reading Ability, 2nd Ed. (TERA-2) in our laboratory. The TERA-2 is a brief measure that has been validated with large national samples, has an internal consistency coefficient of 0.93, and a demonstrated two-week test–retest reliability of r = 0.89 [37]. Total reading and math scores from the groupadministered Metropolitan Achievement Test (MAT) given by the school district were also used to measure achievement. Originally developed in 1933 and revised frequently since, the MAT is a nationally standardized measure of academic achievement [36]. Sustained attention was measured using a Conners’ Continuous Performance Test (CPT; [12]). In this 15-min task, a series of letters is presented sequentially to the child. The child presses the keyboard spacebar for every letter presented with the exception of “X”. When the letter “X” is presented the child is instructed not to press the spacebar. Commission errors (pressing the bar when an “X” appeared) were considered a measure of impulsivity and omission errors (failing to press the bar when an “X” appeared) were considered a measure of inattention. Teachers completed the 39-item Conners’ Teacher Rating Scale (CTRS-39; [13]) and the Achenbach Teacher Report Form (TRF; [1]). The CTRS-39 includes an ADHD index and provides 4 other subscales sensitive to oppositional behavior, cognitive problems, and hyperactivity– impulsivity. In the TRF, the teacher is asked to rate 112 behaviors as “0” not like the child, “1” somewhat like the child, or “2” very much like the child. Eight behavior problem scales were constructed from these behavior ratings: Withdrawn, Somatic, Anxious/Depressed, Delinquency, Aggression, Social, Thought, and Attention. Three summary scores were also computed: Externalizing, comprised of Delinquency and Aggression; Internalizing, comprised of Withdrawn, Anxious/Depressed and Somatic; and an overall Total problem behavior score. T-scores of 70 or more are considered in the clinical range while scores between 67 and 69 are considered “borderline”. Teachers also rated behavior using the PROBS-14 [15]. This validated instrument is comprised of 14 visual analogue scale items assessing behaviors identified previously by a teacher consensus group as those believed to be associated with prenatal cocaine exposure. When completing the PROBS-14, teachers rate each behavior on a scale from 0 to 10, with points ranging from 0 to 2.5 denoting “not at all like”, 2.5 to 5.0 “just a little like”, 5.0 to 7.5 “pretty much like”, and 7.5 to 10 “very much like.” The 14 items generate a total score and items can be individually analyzed. In addition, factor analysis has consistently revealed two factors, hyperactivity-conduct and central processing subscales [14,15]. The PROBS-14 was designed for use with first and second grade students who have had a full academic year of kindergarten and/or first grade. The measure is administered in the second half of the school year to reduce error due to the student's unfamiliarity with the classroom setting or teacher unfamiliarity with the student. 2.3.2. Control variables Prenatal alcohol and drug use were determined from maternal interviews conducted at each prenatal clinic visit. At each visit, the mother was asked about her alcohol and drug consumption during the previous 2 weeks on a day-by-day basis. For alcohol, drinking volume was calculated for each day, converted to oz.

absolute alcohol (AA)/day, and then averaged across all clinic visits to create an average alcohol per day (AAD) measure. Mothers were also asked about their drug use and smoking at each prenatal visit. Cocaine was an ordinal exposure variable — none, some, and/or heavy/persistent exposure. Heavy exposure was considered if the mother reported use two times or more per week during pregnancy; exposure was considered as persistent if there was a positive maternal and/or infant urine test at delivery. Marijuana was dichotomized as “use/no use”; smoking was defined as number of cigarettes smoked per day. 2.3.3. Other control variables Additional data were also collected to allow for control for potentially confounding variables in analyses. Neonatal and maternal information were obtained from medical records at birth. At the 7-year follow-up, caregivers were queried about drug, alcohol and cigarette use in the home, and they provided demographic information including a measure of socioeconomic status (SES). A measure of psychopathology (Symptom Checklist-90), an index of the quality of home environment (based on the HOME), and an assessment of maternal IQ (WAIS) were administered in the laboratory. 2.4. Data analyses Prior to analyses addressing study aims, checks were performed for missing and out-of-range data, and for normality. Initial analyses also included data reduction on the items from the hyperactivity scale of the CTRS-39 to examine the presence of both an inattention and impulsivity component. The relation of child blood lead level to each of the neurobehavioral outcomes was examined by multiple regression analysis, controlling for potential confounding variables listed above. Because a control variable cannot be a confounder unless it is related to both exposure and outcome, association with either exposure or outcome can be used as the criterion for statistical adjustment [38]. In this study, control variables were selected for inclusion in the regression analyses based on their relation to the outcome, which has the additional advantage of increasing precision by also including covariates unrelated to exposure [27]. Pearson correlations were used to examine the relation of each control variable to each outcome. All control variables that were even modestly related to each outcome (at p b 0.10) were adjusted statistically by regressing the outcome on child lead level and the control variables related to that outcome. Table 1 provides the covariates included ( p N 0.10) for each neurobehavioral outcome. The associations of the specific neurobehavioral outcomes with lead were considered significant only when p b 0.05, after controlling for the potential confounders. In the tables presenting the results of the regression analyses, the bivariate correlation of blood lead level with the endpoint is shown as Pearson's ‘r’; the relation of lead to the endpoint after adjustment for confounders is shown as ‘β,’ the standardized regression coefficient. Non-parametric regression analyses were then performed to examine the relation between blood lead concentration and fifteen neurodevelopmental endpoints to identify the presence of a threshold below which lead exposure has no apparent

L.M. Chiodo et al. / Neurotoxicology and Teratology 29 (2007) 538–546 Table 1 Neurodevelopmental outcomes and covariates PROBS-14 Central processing Hyperactivity Teacher Report Form Attention problems Social problems Delinquent behavior Total behavior problems Reading performance Math performance Appropriate behavior Hard working CPT % Commission errors % Omission errors Mean reaction time Conner's Teacher Rating Scale Attention factor Impulsivity factor Test of Early Reading Ability Metropolitan aptitude test Math Reading WPPSI Arithmetic Comprehension Geometric design Information Mazes Object assembly Picture completion Performance IQ Verbal IQ Full IQ

3. Results

1,2,4,5,7,9,10,13,18 7,8,10, 2,5,10,13,18 5,9,10,18 1,2,4,5,8,9,10,11,13 1,2,4,5,8,9,13 1,5,6,9,10,18 1,2,4,5,7,9,10,13

3.1. Sample characteristics

1,2,5,7,9,10,13,18 4,8,10, 2,4,5,8,9,10,13 2,4,5,6,9,10,17 1,2,4,5,9,10,11,17 1,2,4,5,6,9,10,15,17 1,2,3,4,5,8–11,13,17 2,4,5,6,9,11 2,4,5,8,9,10,13,15,17 1,2,4,5,6,9 2,4,9, 2,4,5,7,9,10 1,2,4,5,6,9, 2,4,5,8,9,10,13,15,17 2,4,5,6,8,9,10,15,17

Numbers in the right column are the corresponding covariates used for each outcome. Covariate 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

these short lines to identify the shape of the distribution, which allowed for visual inspection for the presence of a threshold.

1,2,5,7,9,10,11,13 1,10

10,17 2,5,9,12,13 7,9,10,12,13,15

Age of child at 6 year visit Caretaker education Caretaker marital status SES Home total score SCL Global Severity Index Mother's age at prenatal screen # of children in child’s home Maternal IQ Child gender Maternal custody Ordinal cocaine Alcohol across pregnancy Current alcohol consumption/week Prenatal # cigs/day Current # cigs/day Prenatal marijuana use (yes/no) Current marijuana use (yes/no)

effect. The domains represented in this analysis include IQ, attention, hyperactivity, central processing ability, and achievement. In the non-parametric regression analyses, regression lines were fitted locally to each region of the data. Then, a smoothing spline was used to produce a smooth curve from

541

Caregivers were generally low SES and unmarried. The majority of caregivers were the biological mothers (81.6%) and had completed high school by the time they gave birth to the child in this study (55.2%). Prospective report of alcohol and drug use indicated that about 38% of children were cocaine exposed in utero, whereas about 35% were prenatally exposed to marijuana. Average prenatal alcohol exposure levels were low in this sample (mean oz. absolute alcohol per day = 0.15, SD = 0.4). Only 6.5% of the children were exposed to levels greater than 0.5 average oz. alcohol per day across pregnancy (AAD), a level of maternal drinking determined in previous research to put fetuses “at risk” for alterations in neurobehavioral function [24,25]. Child mean age at the 7-year follow-up was 6.9 years (SD = 0.3); 49% were female. Mean blood lead level was 5.0 (SD = 3.0) and only 8.9% of the children (N = 45) had blood lead levels at or above 10 μg/ dL; 47% had blood lead level at or above 5 μg/dL; and 81% had blood lead levels at or above 3 μg/dL. Teacher-reported attention behavior problem scores (Achenbach Teacher Report Form-TRF) were at or above the clinical range (t-scores N 70) for 12.2% of the sample. In addition, child IQ scores were lower than national norms (Table 2). 3.2. Factor analysis of the Conner’s Teacher Rating Scale Items from the hyperactivity scale of the CTRS-39 were factor analyzed to further define attention/hyperactivity problems. Two factors were revealed: an inattention factor and an Table 2 Sample characteristics N Maternal Education a Marital status (% married) WAIS Performance IQ SES b Age at 7-year visit Primary caregiver (% mother) AA/day across pregnancy Define AA/day in footnote Cocaine (% users) Marijuana (% users) Child Age at the 7-year visit Gender (% male) Lead (μg/dL) WISC-III Verbal IQ Performance IQ Full Scale IQ TRF % clinical/borderline a b

Mean or %

SD

Range

502 503 503 505 506 506 506

4.6 27.5 84.3 29.1 32.6 81.6 0.2

1.4 – 10.1 10.1 6.4 – 0.4

1–7 – 53–117 8–66 19.5–52.0 – 0.0–5.1

506 506

38.3 34.8

– –

506 506 506

6.9 50.8 5.0

0.2 – 3.0

5.9–7.9

505 505 507 463

80.7 83.7 80.4 20.5

14.1 12.2 12.3 –

46–137 45–124 41–130 ––

Based on a 7-point scale. Based on Hollingshead Four Factor Index of Social Status, 1975.

– –

1–20.0

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Table 3 Conner's Teacher Rating Scale attention factors

with higher lead values, again, like the CPT, the CTRS-39 impulsivity factor also yielded a non-significant result. Factor Loadings

Inattention – Inattentive, easily distracted – Fails to finish things s/he starts/short attention span – Constantly fidgeting – Restless or overactive – Disturbs other children Impulsive – Temper outbursts, explosive and unpredictable behavior – Mood changes quickly and drastically – Cries often and easily – Demands must be met immediately/easily frustrated – Excitable, impulsive

1

2

0.890 0.834 0.769 0.748 0.666

0.203 0.053 0.410 0.476 0.548

0.280 0.348 0.018 0.486 0.597

0.826 0.805 0.752 0.736 0.657

impulsivity factor. Items loading on the inattention factor include “inattentive, easily distracted” and “fails to finish things s/he starts — short attention span." Items loading on the impulsivity factor include “excitable, impulsive” and “demands must be met immediately — easily frustrated” (Table 3). 3.3. Relation between lead and child outcome

3.4. Identification of threshold Non-parametric regression analyses were performed on the relations between blood lead concentration and fifteen endpoints to identify the presence of a threshold below which lead exposure has no apparent effect. Graphic representation of a subset of these analyses is shown in Fig. 1. Similar to the analyses performed on a different 7.5-year-old sample from the same inner-city population reported in Chiodo et al. [11], non-parametric regression analyses were completed on the associations between blood lead levels and eight of the neurobehavioral endpoints to identify the presence of a threshold below which lead exposure has no apparent effect, and to examine if a non-linear relation exists for any of these relations. Examination of these non-parametric regression lines indicated linear relationships between lead and each of the neurobehavioral endpoints examined. Upon visual inspection, for most outcomes, there is no evidence of a flattened regression line at lower levels of exposure where the associations were no longer Table 4 Relations between child outcome and lead N

Regression analyses, controlling for all prenatal drug exposures (cocaine, alcohol, marijuana and cigarettes) and potential confounds (p b 0.10), of postnatal lead level and child outcome identified significant relations between lead level and the following neurodevelopmental endpoints: poorer achievement, lower IQ scores, and increased behavior problems, including increased inattention (see Table 4). Achievement deficits in both reading and math were identified using both the Test of Early Reading Ability — 2 (TERA-2) and the Metropolitan Achievement Test (MAT). Blood lead levels were significantly related to lower Full-scale, Verbal, and Performance IQ scores. All subscales, with the exception of arithmetic, were also negatively related to blood lead levels. Lead levels were related to central processing problems and hyperactivity as measured by the teacher-rated PROBS-14 and the TRF. Both instruments revealed significant relations between blood lead levels and increased problems in attention and delinquent behavior. Increases in social behavior problems and total behavior problems were also related to blood lead levels (see Table 4). To further examine attention problems, regression analyses assessed the relations between blood lead levels and inattention and impulsivity. Analyses of omission errors and longer response times on the CPT, together indicating poorer attention [12,13,41,44], revealed significant negative relations between blood lead levels and these inattention outcomes. However, there were no significant relations between lead and a measure of impulsivity, that is, commission errors on the CPT (Table 3). Analyses using the CTRS-39 identified the same results. The CTRS-39 inattention factor was significantly and positively related to blood lead levels, indicating more inattentive behavior

PROBS-14 Central processing Hyperactivity Teacher Report Form Attention problems Social problems Delinquent behavior Total behavior problems Appropriate behavior Hard working Math performance Reading performance Continuous performance task Errors of commission (%) Errors of omission (%) Reaction time Conner's Teacher Rating Scale Attention factor Impulsivity factor Test of early reading ability Metropolitan aptitude test Math Reading WPPSI Arithmetic Comprehension Geometric design Information Mazes Object assembly Picture completion Similarities Verbal IQ Performance IQ Full IQ

β

456 464

0.20⁎⁎⁎ 0.13⁎⁎

451 460 452 455 451 451 443 420

0.16⁎⁎⁎ 0.08† 0.10⁎ 0.10⁎ − 0.13⁎⁎ − 0.13⁎⁎ − 0.18⁎⁎⁎ − 0.19⁎⁎⁎

0.13⁎⁎ 0.10⁎ 0.09⁎ 0.09⁎ −0.09⁎ −0.10⁎ −0.12⁎⁎ −0.10⁎

466 464 467

− 0.07† 0.26⁎⁎⁎ 0.17⁎⁎⁎

−0.08 0.18⁎⁎ 0.15⁎⁎⁎

458 457 495

0.17⁎⁎ − 0.02 − 0.22⁎⁎⁎

0.12⁎ 0.04 −0.14⁎⁎⁎

331 330

− 0.19⁎⁎⁎ − 0.08†

−0.17⁎⁎⁎ −0.06

497 495 497 495 497 499 486 497 495 497 495

− 0.12⁎⁎ − 0.26⁎⁎⁎ − 0.16⁎⁎⁎ − 0.19⁎⁎⁎ − 0.14⁎⁎⁎ − 0.17⁎⁎⁎ − 0.16⁎⁎⁎ − 0.15⁎⁎⁎ − 0.23⁎⁎⁎ − 0.21⁎⁎⁎ − 0.26⁎⁎⁎

−0.07 −0.22⁎⁎⁎ −0.13⁎⁎ −0.14⁎⁎⁎ −0.11⁎⁎ −0.13⁎⁎ −0.11⁎⁎ −0.12⁎⁎ −0.17⁎⁎⁎ −0.16⁎⁎⁎ −0.19⁎⁎⁎

p b 0.10. ⁎p b 0.05. ⁎⁎p b 0.01. ⁎⁎⁎p b 0.001.

†

r

0.18⁎⁎⁎ 0.13⁎⁎

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Fig. 1. Scatterplots of blood lead level and several neurodevelopmental endpoints.

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apparent. This linear relation was clear for all outcomes with the exception of the CPT Reaction Time and Percent Omission Errors. For both of these outcomes the dose–response relation appeared to have a non-linear component at blood lead levels higher than ∼ 8 μg/dL; for Percent Omission Errors there is also a non-linear component below 3 μg/dL. For the CPT, there is no blood lead level below which a linear dose–response effect is not evident. 4. Discussion Similar to the results of other researchers, the results of this study show consistent neurobehavioral deficits in relation to lower levels of lead exposure (5 μg/dL or less) in a low SES, urban sample of children. These deficits were found in the domains of intelligence (i.e., Full Performance and Verbal IQ), reaction time, and attention, but not in impulsivity. Mean blood lead levels were related to poorer IQ scores, slower reaction times and more inattentive behavior. In addition, increased hyperactivity, poorer central processing, and increased social and delinquent behavior problems were identified in relation to higher blood lead levels. The most important current finding is that none of these neurobehavioral outcomes showed evidence of a threshold below which blood lead levels appear to be “safe.” Simple visual inspection of the non-parametric regression plots shows a gradual linear dose–response relationship for each endpoint. This conclusion is consistent with those reached by Needleman [34], Fulton et al. [21], Bellinger and Dietrich [3], Lanphear et al. [30], Bellinger and Needleman [4], and Chiodo et al. [11], that there is no apparent threshold for the effects of lead on many neurobehavioral outcomes. As detailed previously, attention is one domain that has been examined extensively [5,6,11,22,30,39,47]. Bellinger [5] found significant associations between lead exposure and focused attention and executive function, whereas Needleman et al. [35] identified lead-related executive dysfunction and deficits in sustained attention. Chiodo et al. [11] confirmed the findings of Needleman et al. [35] implicating lead exposure in deficits in sustained attention, and partially confirmed the findings of Bellinger et al. [5], that lead impairs executive function but not focused attention. Walkowiak et al. [41] identified positive relations between blood lead concentration and errors of both commission and omission. However, the relation with reaction time was only borderline. The positive correlation between errors of commission and omission in their data was hypothesized as due to a few extremely long response latencies in their data attributable to lead-related lapses in attention. However, they did not have a significant relation between response time and blood lead level. The present data identified significant relations between blood lead level and lengthened reaction time and increased errors of omission, indicating inattention, yet did not identify a relation between errors of commission, an indicator of impulsivity, as did Walkowiak et al. [41]. In addition, the relation between errors of commission and omission in this data set is negative (r = − 0.28, p b 0.001), as it should be, and unlike the relation found by Walkowiak et al. [41]. The current data

suggest that previous research identifying both impulsivity- and attention-related CPT effects may be due to data collection methodology as an extremely long response latencies would be recorded as both misses and false alarms. We argue that coding long response latencies as false alarms erroneously inflated errors of commission, indicating impulsivity, when long response latency, together with omission errors, is taken to indicate poorer attention [12,13,41,44]. Further, this pattern of leadrelated inattention without impulsivity was also seen in performance on a second measure, the CTRS-39, so that multiple assessment methods obtained the same conclusion. Blood lead levels are related to inattention but not impulsivity. Decades of research have concluded that attention deficits are related to postnatal lead levels, however, many of the “attention” measures include items or procedures such as errors of both omission and commission on the CPT have been labeled as inattention. Identifying omission errors as inattention and commission errors as impulsive allows for a more detailed understanding of lead's specific effects. Results from this present research show a clear relation between postnatal lead exposure and inattention problems, yet show no significant relation between lead and impulsivity. Although lead has been shown to have adverse effects on a range of central nervous system (CNS) processes, including synaptogenesis, myelination, catecholamine metabolism, and capillary integrity, it is not clear how these processes mediate the effects on the neurobehavioral endpoints identified in children [17]. Understanding the specific impact of lead exposure on attention is an important step in delineating lead's neurobehavioral signature. The present results with lead exposure need to be evaluated relative to the different behavioral profiles associated with different CNS toxins (cf., Jacobson, [23]). Domain-sensitive result patterns among different neurotoxins add to the understanding of behavioral signatures, and to the understanding of the specific affected brain regions. Domain specificity has been examined extensively among the teratogens alcohol and cocaine during prenatal exposure. For example, among the IQ factors on the WISC-III subscales, all subscales, with the exception of arithmetic, were negatively related to current lead levels. In contrast, prenatal alcohol exposure has been found to be negatively and specifically associated with the WISC Arithmetic subscale [26]. Other research on prenatal cocaine exposure has found deficits related to errors of commission, an indicator of impulsivity, but not errors of omission, an indicator of inattention [16]. One limitation of this study is that only one blood lead measure was available and it was not obtained until the children were 7 years old, several years after the point of peak exposure, which usually occurs at 2 years of age. Many neurocognitive processes are undergoing rapid growth during the first 2 years of life. It is, therefore, not clear to what degree deficits at 7 years of age are due to current lead exposure compared to the influence of exposure during the first 2 years of life. However recent research has suggested that the impact of concurrent exposure may actually be greater than that of peak exposure [10]. This limitation is not specific to this study (see Ref. [22]). It is also important to note that although our cohort was recruited to over-

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represent children exposed prenatally to alcohol and cocaine, the effects observed here cannot be attributed to alcohol. Wherever prenatal alcohol and/or other prenatal drugs (i.e., cocaine) were correlated with a neurobehavioral outcome at p b 0.10, alcohol and drug exposure was controlled statistically in the analyses. Although this study controlled for several covariates not controlled for in other studies (e.g., maternal IQ & HOME; see for example, Walkowiak et al. [41]; Kordas et al. [28]), this study did not control for iron status. This omission is important as research has identified a relation between increased lead absorption and iron deficiency [8,45] and Kordas et al. [29] reports a relation between iron status and cognitive performance [29]. Unfortunately, data on maternal and child nutritional status, including iron deficiency, are not available, so we cannot control for their possible influence on the association between blood lead level and neurodevelopmental outcomes reported here. It should also be noted that the effect sizes reported here are small (CPT effects = 4%; CTRS-39, full IQ, Verbal IQ, and MAT Math effect = 3%; Performance IQ = 2%). The magnitude of the associations between blood lead levels and neurobehavioral outcomes is reduced when socioenvironmental and other control variables are included in the analyses, in part because lead exposure co-occurs with socioenvironmental variables making it difficult to isolate the full impact of lead exposure. In conclusion, the present study documents a significant negative impact of blood lead level on specific attention components in early elementary age children. The most important current finding is that none of these neurobehavioral outcomes showed evidence of a threshold below which blood lead levels appear to be “safe”. In light of these findings which are consistent with the research of several other groups, it is advisable to consider whether the threshold for an “acceptable” blood lead level ought to be reduced. Acknowledgements This research was supported by the National Institute of Drug Abuse (R01-DA08524; Dr. Delaney-Black), the March of Dimes Birth Defects Foundation (research grant no. 12-FY970047), and the Helppie Institute for Urban Pediatric Health Research, the Children's Research Center of Michigan, and the Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan. The authors thank the children, families, and research staff who made this research possible. References [1] T.M. Achenbach, Manual for the Teacher's Report Form and 1991 Profile, University of Vermont Department of Psychiatry, Burlington, VT, 1991. [2] D. Bellinger, Interpreting the literature on lead and child development: the neglected role of the “experimental system”, Neurotoxicol. Teratol. 17 (1995) 201–212. [3] D. Bellinger, K.N. Dietrich, Low-level lead exposure and cognitive function in children, Pediatr. Ann. 23 (1994) 600–605. [4] D.C. Bellinger, H.L. Needleman, Intellectual impairment and blood lead levels, N. Engl. J. Med. 349 (2003) 500–502.

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