Organochlorines, including polychlorinated biphenyls (PCBs) and *p*,*p*´-dichlorodiphenyl dichloroethylene (*p*,*p*´-DDE), although banned in the United States since the 1970s, are still of public health importance because of their persistence in the environment and in human tissue, and because of the continued use of DDT (dichlorodiphenyltrichloroethane) in malaria-endemic countries ([@r23]; [@r33]). These lipophilic contaminants cross the placenta and affect fetal development, including neurodevelopment ([@r18]; [@r25]).

Prenatal exposure to organochlorines, and to PCBs in particular, has been linked with behavioral impairments and functional deficits common to attention deficit/hyperactivity disorder (ADHD) ([@r7]), the most common neurobehavioral disorder of childhood, affecting 5--10% of children worldwide ([@r8]). PCBs have been reported to be associated with attention, response inhibition, and working memory, assessed primarily with neuropsychological tests ([@r9]; [@r13]; [@r29], [@r27], [@r28]; [@r35]). Animal data suggest sex differences in the effect of these exposures on neurodevelopment ([@r21]; [@r24]; [@r40]); there are limited data for such differences in epidemiologic studies ([@r10]; [@r36]).

We recently reported associations between prenatal PCB and *p*,*p*´-DDE levels and teacher-reported behaviors consistent with ADHD using a behavioral checklist (the Conners Rating Scale for Teachers) among 8-year-old children born to mothers residing adjacent to a PCB-contaminated harbor ([@r22]). We hypothesize an association between these persistent chemicals and standardized neuropsychological tests of attention and impulse control in this cohort.

Methods
=======

*Study population.* Children participating in this longitudinal cohort study were enrolled at birth. English- or Portuguese-speaking mothers ≥ 18 years of age residing in one of four towns (New Bedford, Acushnet, Fairhaven, Dartmouth) near a PCB-contaminated harbor in New Bedford, Massachusetts, for at least the duration of pregnancy were recruited from a local hospital with approximately 2,000 births per year. Approximately 10% of mothers met study eligibility criteria and were available for recruitment during times when a study examiner was on site. Infants too ill to undergo neonatal examination or born by cesarean section were excluded from the study. Of the 788 mother--infant pairs enrolled at birth, 607 were followed up for neurodevelopmental testing when the child was approximately 8 years of age (78% of those eligible). Multiple births (*n* = 3 children) were excluded from the present analysis.

*Exposure assessment.* Cord blood samples for organochlorine analyses were collected at the infant's birth; the serum fraction was removed after centrifugation and stored at --20°C. All sample analyses were performed by the Harvard School of Public Health Organic Chemistry Laboratory (Boston, MA). Laboratory personnel were blinded to health outcomes. Cord serum samples were analyzed for 51 individual PCB congeners and *p*,*p*´-DDE. Laboratory analytic methods and quality control procedures are described elsewhere ([@r17]). Briefly, liquid-liquid extraction and column chromatography cleanup were used, and the extracts were analyzed by gas chromatography with electron capture detection using an internal standard. Primary and confirmatory capillary columns were used, and where results differed, the lower value was reported.

PCB concentrations were reported as individual congeners in units of nanograms per gram serum after the amount of analyte in the procedural blank was subtracted. Lipid content could not be determined for study subjects because of insufficient sample volume (1.5--4 mL) and was therefore measured for 12 randomly selected cord bloods from discarded, anonymous samples collected at the study recruitment site; values were reproducible (1.7 g/L ± 0.3).

The method detection limits (MDLs) for individual PCBs ranged from 0.002 to 0.04 ng/g serum, with most MDLs \< 0.01 ng/g; the MDL for *p*,*p*´-DDE in serum was 0.07 ng/g ([@r17]). The frequency of values below the MDL for each congener for this study cohort was previously reported ([@r17]). We retained measured values below the detection limit to optimize statistical power and avoid biased exposure estimates associated with censoring at the MDL ([@r16]). Reproducibility of serum analyses was good; the within-batch coefficient of variation (CV) for the sum of four prevalent PCB congeners \[118, 138, 153, and 180 (ΣPCB~4~)\] was 3% and the between-batch CV was 20% over the 5 years of analysis, with similar performance for *p*,*p*´-DDE.

*Outcome assessment.* We analyzed components of a continuous performance test (CPT) and a psychometric test of intelligence that reflect attention and impulse control; both tests were administered at the 8-year exam. The Neurobehavioral Examination System 2 (NES2) CPT is a computer-assisted examination that measures response to visual cues in a continuous performance task ([@r19]). A random series of animal silhouettes are displayed on the screen, and the child is instructed to press a button on a joystick only upon the appearance of a cat, to respond as quickly as possible, and to refrain from pressing the button for any other animal. The computer records response time (recorded only for correct responses), the number of nonresponses or errors of omission (button not pressed when cat appeared; the maximum time given was 1,200 msec), and the number of false-positive errors or errors of commission (button pressed for an animal other than the cat). Four blocks of trials were completed, with the first block designated as a practice block that was not scored. We analyzed four components of the CPT: *a*) mean response time, *b*) response time variability (standard deviation of mean response time), *c*) total errors of omission, and *d*) total errors of commission. Outcomes were summed across the last three test blocks. Inattention was interpreted as a higher number of errors of omission and longer reaction time, and poor response inhibition was interpreted as a higher number of errors of commission. Higher reaction time variability or performance inconsistency is also thought to indicate fluctuations or lapses in attention ([@r32]).

The Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), is a test that evaluates intellectual abilities ([@r38]). We focused on the two specific age-standardized subscales for which children with ADHD are found to score lowest: Processing Speed (includes coding and symbol search)and Freedom from Distractibility (includes digit span and arithmetic) ([@r38]).

*Statistical analysis.* We analyzed associations between attention and impulse control and two PCB congener groups: *a*) ΣPCB~4~, the sum of four prevalent PCB congeners with relatively high levels that were measured with less error, and *b*) the computed toxic equivalent (TEQ) for the sum of the five dioxin-like mono-*ortho* PCB congeners measured (105, 118, 156, 167, and 189), computed on a lipid basis (1.7 g/L) and weighted with toxic equivalency factors ([@r34]). The TEQ group was included to investigate the potential for an aryl hydrocarbon receptor--mediated mechanism for the effect of dioxin-like congeners on neurodevelopment. We also investigated associations with *p*,*p*´-DDE.

CPT mean reaction time and reaction time variability and WISC-III outcomes were approximately normally distributed, met regression model assumptions, and were modeled with linear regression. Processing Speed and Freedom from Distractibility scores were standardized (mean ± SD = 100 ± 15). CPT errors of omission and commission were considered count data and initially modeled as Poisson distributed variables with log risk models; to correct for overdispersion (variance exceeded the mean), our final models were fitted using negative binomial regression.

Covariate data came from multiple sources, including maternal and pediatric medical records (including lead screening) and questionnaires administered 2 weeks after birth and at the 8-year follow-up examiantion. The 8-year exam included an assessment of maternal intelligence and depression using the Kaufman Brief Intelligence Test ([@r15]) and the Beck Depression Inventory ([@r1]), respectively, and family and home characteristics using the Home Observation for Measurement of the Environment (HOME) ([@r4]). Potential confounders considered were characteristics of the mother \[age at child's birth, prenatal smoking and alcohol consumption, prenatal diet (local and overall fish consumption), illicit drug use in the year before the child's birth, breast-feeding, parity, and, at the 8-year examination, education, marital status, IQ, and depression\] and the child (age at exam, birth year, sex, race/ethnicity, ADHD medication use, and peak and mean 12- to 36-month blood lead levels). Examiner (there were two possible examiners), household income, and quality of the home environment (HOME score) assessed at the time of the 8-year examination were also considered.

Inclusion of covariates in multivariable models was based on *a priori* considerations of covariate associations with exposure and outcome, model fit (statistically significant partial *F*-test at α \< 0.10), and whether covariate inclusion materially affected the organochlorine exposure effect estimate. To check the sensitivity of our estimates to covariates that were not included in the model, we added each back to the final model to make sure they did not substantially change our final effect estimates. We also assessed differences in exposure--outcome associations across sex using stratified analyses and by including an interaction term between sex and exposure in the model.

Based on recent literature suggesting that performance on the CPT may vary over the course of the test session ([@r14]) (scores averaged over the entire testing period could mask these differences), block-specific effect estimates were also investigated. The [@r14] paradigm divides performance over a 10-min testing period into three sequential stages: *a*) orientation, learning, and habituation (first 2 min), *b*) processing speed and selective focused attention (next 4 min), and *c*) sustained attention (last 4 min). Because our children were younger than those in the [@r14] study, we used a 4-min CPT, where block 1 is omitted as a training block and blocks 2--4 (1 min each) correspond to Julvez's three sequential stages. We investigated block-specific results for all four CPT outcomes.

Sensitivity of our results to ADHD medication use was explored by excluding children with parent-reported medication use and recomputing organochlorine exposure--outcome associations. In addition, we investigated the influence of missing covariate data on our results by comparing unadjusted exposure--outcome associations for all children (regardless of whether covariate data was missing) with unadjusted exposure--outcome associations in the subset of children with nonmissing covariate data.

The study protocol was reviewed and approved by the Human Subjects Committees of Harvard School of Public Health and Brigham and Women's Hospital (Boston, MA) and Southcoast Hospitals Group (New Bedford, MA). Written informed consent was obtained from all participating families before study evaluations.

Results
=======

Exposure and outcome summary statistics are displayed in [Table 1](#t1){ref-type="table"} for children administered the CPT and WISC-III exam who also had exposure data. An observation with an extremely high PCB value (ΣPCB~4~ \> 4 ng/g) that disproportionately influenced exposure--outcome associations was excluded from all analyses. Approximately half of the total PCB concentration (sum of 51 congeners, mean ± SD = 0.53 ± 0.55 ng/g serum) was attributable to ΣPCB~4~ (mean ± SD = 0.25 ± 0.26 ng/g serum). PCBs and *p*,*p*´-DDE were positively correlated, with Spearman correlation coefficients ranging from 0.56 (mono-*ortho* PCB TEQ and *p*,*p*´-DDE) to 0.88 (mono-*ortho* PCB TEQ and ΣPCB~4~).

###### 

Summary statistics for cord serum organochlorines and CPT and WISC-III outcomes for children with both exposure and outcome measures born in New Bedford, 1993--1998.

  Exposure or outcome measure                   n   Mean ± SD   Median (range)   IQR                                         
  --------------------------------------------- --- ----------- ---------------- -------------- -- ---------------------- -- ------
  Exposure statistics                                                                                                        
  ΣPCB4 (ng/g)                                      584                          0.25 ± 0.26       0.19 (0.01--2.59)         0.19
  PCB TEQ (pg/g lipid)                              584                          1.41 ± 1.97       0.89 (0.00--26.56)        1.00
  p,p´-DDE (ng/g)                                   584                          0.50 ± 1.03       0.31 (0.00--14.93)        0.27
  Outcome statistics                                                                                                         
  CPT (n = 578)                                                                                                              
  Mean reaction time (msec)                         578                          646.7 ± 65.0      645.4 (487.8--861.7)      
  Reaction time variability (msec)                  578                          127.7 ± 31.7      125.9 (53.2--393.9)       
  Total errors of omission                          578                          2.3 ± 2.7         1.0 (0.0--17.0)           
  Total errors of commission                        578                          2.4 ± 2.2         2.0 (0.0--14.0)           
  WISC-III, age-standardized scores (n = 584)                                                                                
  Processing Speed                                  584                          104.5 ± 14.8      104.0 (58.0--146.0)       
  Freedom from Distractibility                      583                          98.1 ± 13.1       98.0 (50.0--134.0)        

Supplemental Material, [Tables 1](#ehp-1104372-s001){ref-type="supplementary-material"} and [2](#ehp-1104372-s001){ref-type="supplementary-material"} (<http://dx.doi.org/10.1289/ehp.1104372>), presents the distribution of background characteristics and their unadjusted associations with the CPT and WISC-III outcomes. Briefly, 11% and 24% of mothers and fathers, respectively, did not complete high school; 20% had an annual household income \< \$20,000/year, and 41% were unmarried at the child's 8-year examination, representing a socioeconomically diverse population. In addition, 31% of children were of nonwhite race/ethnicity, with 11% of Cape Verdean ethnicity, which is representative of the New Bedford population.

###### 

Associations between ΣPCB4, PCB TEQ, and p,p´-DDE and CPT and WISC-III outcomes for all children and by sex for 8-year-old children born in New Bedford, 1993--1998 \[IQRa (95% CI)\].

  Unadjusted model (all children)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Adjusted modelb   Sex interaction p-valuec                                                                                   
  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------- -------------------------- -- -------------------- -- ----------------------- -- ---------------------- -- ------
  CPT                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  n = 578                       n = 512                 n = 254                    n = 258                   
  Reaction time (β)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
  ΣPCB4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                --3.2 (--7.0, 0.6)            --3.1 (--7.3, 1.0)      --5.8 (--10.5, --1.0)      3.5 (--3.6, 10.5)         0.02
  PCB TEQ                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              --2.8 (--5.4, --0.1)          --2.1 (--4.9, 0.7)      --3.4 (--6.5, --0.4)       3.0 (--2.6, 8.6)          0.04
  p,p´-DDE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             --0.7 (--2.0, 0.7)            --0.6 (--1.9, 0.8)      --1.5 (--3.0, 0.1)         1.8 (--0.7, 4.2)          0.03
  Reaction time variability (β)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
  ΣPCB4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                --0.5 (--2.3, 1.4)            0.3 (--1.6, 2.2)        --0.7 (--2.9, 1.4)         2.9 (--0.3, 6.2)          0.05
  PCB TEQ                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              --0.4 (--1.7, 0.9)            0.4 (--0.9, 1.7)        --0.4 (--1.8, 1.0)         3.3 (0.7, 5.8)            0.01
  p,p´-DDE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             --0.2 (--0.9, 0.4)            --0.1 (--0.7, 0.6)      --0.4 (--1.1, 0.3)         0.8 (--0.4, 1.9)          0.09
  Errors of omission (rate ratio)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
  ΣPCB4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                1.00 (0.93, 1.07)             1.01 (0.93, 1.10)       0.95 (0.86, 1.05)          1.11 (0.98, 1.27)         0.04
  PCB TEQ                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              1.00 (0.95, 1.06)             1.02 (0.97, 1.08)       0.98 (0.92, 1.05)          1.12 (1.01, 1.25)         0.03
  p,p´-DDE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             1.00 (0.97, 1.03)             1.00 (0.97, 1.03)       0.97 (0.94, 1.01)          1.05 (0.99, 1.10)         0.02
  Errors of commission (rate ratio)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
  ΣPCB4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                1.00 (0.95, 1.06)             1.01 (0.95, 1.07)       1.00 (0.93, 1.08)          1.03 (0.93, 1.13)         0.68
  PCB TEQ                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              1.00 (0.97, 1.04)             1.02 (0.98, 1.06)       1.01 (0.97, 1.06)          1.04 (0.96, 1.12)         0.63
  p,p´-DDE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             1.00 (0.98, 1.02)             1.01 (0.99, 1.03)       1.00 (0.98, 1.02)          1.02 (0.99, 1.06)         0.23
  WISC-III                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             n = 584                       n = 535                 n = 264                    n = 271                   
  Processing Speed (β)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
  ΣPCB4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                0.3 (--0.6, 1.2)              --0.5 (--1.5, 0.4)      0.0 (--1.0, 1.1)           --2.0 (--3.5, --0.4)      0.03
  PCB TEQ                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              0.3 (--0.3, 0.9)              --0.1 (--0.7, 0.5)      0.2 (--0.4, 0.9)           --1.4 (--2.7, --0.2)      0.02
  p,p´-DDE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             0.0 (--0.4, 0.3)              --0.2 (--0.5, 0.1)      0.0 (--0.4, 0.3)           --0.4 (--1.0, 0.1)        0.22
  Freedom from Distractibility (β)d                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
  ΣPCB4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                0.2 (--0.6, 0.9)              --0.1 (--0.9, 0.7)      --0.1 (--1.0, 0.8)         --0.2 (--1.6, 1.2)        0.91
  PCB TEQ                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              0.0 (--0.5, 0.6)              0.0 (--0.6, 0.5)        0.0 (--0.6, 0.6)           --0.2 (--1.4, 0.9)        0.68
  p,p´-DDE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             --0.1 (--0.4, 0.2)            --0.1 (--0.3, 0.2)      --0.2 (--0.5, 0.2)         0.1 (--0.4, 0.6)          0.40
  Sex-specific estimates are from a single model (total n = x). aBeta (linear regression model) or rate ratio (negative binomial regression model) for an IQR (ΣPCB4 = 0.19 ng/g, PCB TEQ = 1.00 pg/g lipid, p,p´-DDE = 0.27 ng/g) increase in exposure. bCPT models were adjusted for child's age at examination, sex, and birth year; maternal age at birth and prenatal smoking; and maternal and paternal education. WISC-III models were adjusted for child's age at examination and sex and maternal age at birth, prenatal smoking, intelligence, and education; a higher WISC-III score indicates better performance. cSex interaction p-value is based on a likelihood ratio test. dFor Freedom from Distractibility, unadjusted n = 583.                                                                                                                                

Unadjusted and adjusted associations between CPT and WISC-III outcomes and organochlorines, including the ΣPCB~4~, mono-*ortho* PCB TEQ, and *p*,*p*´-DDE, for all children (males and females combined) were very weak or null ([Table 2](#t2){ref-type="table"}). Furthermore, CPT mean reaction time was slightly shorter with greater exposure, in contrast to the hypothesized direction for this association.

Results were notably different by sex ([Table 2](#t2){ref-type="table"}). Although females had considerably shorter CPT mean reaction time with increasing exposure, particularly for the ΣPCB~4~ \[for an interquartile range (IQR) increase in ΣPCB~4~: β = --5.8; 95% confidence interval (CI): --10.5, --1.0\], the opposite association was observed for males, with longer mean reaction time with increasing exposure (for an IQR increase in ΣPCB~4~: β = 3.5; 95% CI: --3.6, 10.5); the ΣPCB~4~ × sex interaction was statistically significant using a likelihood ratio test (*p* = 0.02). Reaction time variability also differed by sex with lower variability among females and higher variability in males with increasing exposure to ΣPCB~4~, mono-*ortho* PCB TEQ, and *p*,*p*´-DDE. PCB-associated omission error rate was also higher among males than among females, with an 11% increase in the rate of an error of omission per IQR increase in ΣPCB~4~ among males and no association among females (*p*-value for interaction = 0.04). This pattern is illustrated in [Figure 1](#f1){ref-type="fig"}, where a higher rate of errors of omission was observed with higher ΣPCB~4~ levels among males and the opposite association was observed for females. Errors of commission were not associated with organochlorines in males or females ([Table 2](#t2){ref-type="table"}). In general, associations with *p*,*p*´-DDE were weaker than those with ΣPCB~4~ or mono-*ortho* PCB TEQ.

![Unadjusted scatterplots and adjusted negative binomial regression lines of the association between cord serum levels of ΣPCB~4~and errors of omission on the CPT by sex for 8-year-old children born in New Bedford, 1993--1998, adjusted for child's age at examination, sex, and birth year; maternal age at birth and prenatal smoking; and maternal and paternal education. Adjusted rate ratios: females, 0.95 (95% CI: 0.86, 1.05); males, 1.11 (95% CI: 0.98, 1.27).](ehp.1104372.g001){#f1}

ΣPCB~4~--CPT associations were further explored by block period ([Table 3](#t3){ref-type="table"}). Associations among males were stronger for the third and fourth block periods than for the second block period for most CPT outcomes. Block-specific trends among females were less consistent. Results were similar for PCB TEQ (data not shown).

###### 

Association between ΣPCB4 (ng/g) and CPT measures of attention and impulse control by block period for all children and by sex for 8-year-old children born in New Bedford, 1993--1998: adjusted modela \[IQRb (95% CI)\].

  Outcome measure                                                                                                                                                                                                                                                                                                                    All children (n = 512)   Females (n = 254)    Males (n = 258)   Sex interaction p-valuec                             
  ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------ -------------------- ----------------- -------------------------- -- ------------------- -- ------
  Reaction time (β)                                                                                                                                                                                                                                                                                                                                                                                                                                       
  Block 2                                                                                                                                                                                                                                                                                                                                                     --4.1 (--8.8, 0.7)                     --6.5 (--11.9, --1.1)         2.0 (--6.0, 10.1)      0.07
  Block 3                                                                                                                                                                                                                                                                                                                                                     --2.5 (--7.2, 2.2)                     --5.4 (--10.7, 0.0)           4.5 (--3.5, 12.4)      0.03
  Block 4                                                                                                                                                                                                                                                                                                                                                     --2.7 (--7.3, 2.0)                     --5.3 (--10.7, 0.0)           3.9 (--4.0, 11.8)      0.05
  Reaction time variability (β)                                                                                                                                                                                                                                                                                                                                                                                                                           
  Block 2                                                                                                                                                                                                                                                                                                                                                     --0.3 (--3.0, 2.3)                     --1.3 (--4.3, 1.7)            2.0 (--2.5, 6.5)       0.21
  Block 3                                                                                                                                                                                                                                                                                                                                                     1.1 (--1.7, 3.8)                       0.3 (--2.8, 3.5)              2.9 (--1.8, 7.5)       0.36
  Block 4                                                                                                                                                                                                                                                                                                                                                     0.0 (--2.8, 2.8)                       --1.4 (--4.7, 1.8)            3.6 (--1.2, 8.4)       0.07
  Errors of omission (rate ratio)                                                                                                                                                                                                                                                                                                                                                                                                                         
  Block 2                                                                                                                                                                                                                                                                                                                                                     1.00 (0.90, 1.12)                      0.95 (0.82, 1.10)             1.08 (0.91, 1.27)      0.23
  Block 3                                                                                                                                                                                                                                                                                                                                                     1.04 (0.94, 1.14)                      0.98 (0.87, 1.10)             1.15 (0.99, 1.33)      0.07
  Block 4                                                                                                                                                                                                                                                                                                                                                     0.98 (0.88, 1.09)                      0.90 (0.78, 1.05)             1.08 (0.93, 1.26)      0.07
  Errors of commission (rate ratio)                                                                                                                                                                                                                                                                                                                                                                                                                       
  Block 2                                                                                                                                                                                                                                                                                                                                                     1.00 (0.92, 1.07)                      1.03 (0.94, 1.12)             0.94 (0.83, 1.06)      0.21
  Block 3                                                                                                                                                                                                                                                                                                                                                     0.97 (0.87, 1.08)                      0.85 (0.72, 1.01)             1.10 (0.95, 1.27)      0.01
  Block 4                                                                                                                                                                                                                                                                                                                                                     1.05 (0.96, 1.14)                      1.05 (0.94, 1.16)             1.05 (0.91, 1.20)      0.98
  Sex-specific estimates are from a single model (total n = x). aAdjusted for child's age at examination, sex, and birth year; maternal age at birth and prenatal smoking; and maternal and paternal education. bBeta or rate ratio for an IQR increase in exposure. cSex interaction p-value is based on a likelihood ratio test.                                                                                                                        

Sex-specific effects were also detected between organochlorines and WISC-III Processing Speed ([Table 2](#t2){ref-type="table"}). Males had lower scores, indicating slower Processing Speed, with higher exposure (for an IQR increase in ΣPCB~4~: β = --2.0; 95% CI: --3.5, --0.4), whereas associations for females were null (*p*-value for interaction = 0.03), as illustrated in [Figure 2](#f2){ref-type="fig"}. A similar pattern of associations was observed for PCB TEQ ([Table 2](#t2){ref-type="table"}). All associations were null for Freedom from Distractibility, and all *p*,*p*´-DDE--WISC-III associations were null.

![Unadjusted scatterplots and adjusted linear regression lines of the association between cord serum levels of ΣPCB~4~and processing speed on the WISC-III by sex for 8-year-old children born in New Bedford, 1993--1998, adjusted for child's age at examination and sex, maternal age at birth and prenatal smoking, and maternal intelligence and maternal education. Adjusted β-values: females, 0.0 (95% CI: --1.0, 1.1); males, --2.0 (95% CI: --3.5, --0.4).](ehp.1104372.g002){#f2}

Sensitivity analysis (data not shown) excluding children with a history of ADHD medication use (*n* = 45) did not change exposure--outcome associations. In addition, lead was not a confounder of the association between organochlorines and CPT or WISC-III measures reported here, which is consistent with the absence of an association between lead and organochlorines in our study (e.g., 2-year blood lead Spearman correlation coefficients with ΣPCB~4~, mono-*ortho* PCB TEQ, and *p*,*p*´-DDE were --0.08, --0.07, and --0.05, respectively). Finally, the unadjusted exposure effects were essentially unchanged when restricted to children with nonmissing covariate data (CPT, *n* = 512; WISC-III, *n* = 535), suggesting that excluding data from subjects with missing covariates data did not bias our estimates.

Discussion
==========

Cord serum PCB levels were low for this cohort relative to other population-based studies ([@r17]; [@r20]), given maternal residence adjacent to the PCB-contaminated New Bedford Harbor. Despite low exposure levels, among males we found evidence for an association between organochlorines, especially PCBs, and neuropsychological end points, measured with the NES2 CPT and WISC-III. Associations, albeit modest, were strongest for CPT errors of omission and reaction time variability, indicators of inattention, and WISC-III Processing Speed, also related to attentional skills. Organochlorines were also associated with longer reaction time among males, but CIs were wide. Among females, associations were generally null, except for mean reaction time, which was shorter with higher organochlorine exposure, the opposite of the hypothesized direction of effect. This unexpected finding among girls could have been attributable to chance or residual confounding.

We previously reported moderate associations of cord serum PCB and *p*,*p*´-DDE levels with inattentive and hyperactive-impulsive behaviors assessed with the Conners Rating Scale for Teachers at approximately 8 years of age in the same cohort ([@r22]). Although not reported in that article, we did not detect sex differences in the association between organochlorines and teacher-rated behavior.

Several other studies report associations between PCBs and attention/impulse control using CPTs. Slower reaction time was observed in three studies in relation to prenatal PCB exposure ([@r9]; [@r13]; [@r35]). A prospective birth cohort in Michigan found associations between cord serum PCBs and slower reaction time on a visual discrimination task at 4 years of age; however, associations with reaction time were null for a CPT administered at 11 years of age in the same study population ([@r12]; [@r13]). Associations between late pregnancy maternal serum PCBs and slower reaction time on the Simple Reaction Time Test at 9 years of age were also observed in a cohort in the Netherlands ([@r35]). A study conducted in the Faroe Islands found associations between cord tissue PCB levels and longer reaction time on the NES2 CPT at 7 years of age (the same test used in the present study), although only in the presence of high cord blood mercury ([@r9]).

Two studies have reported associations between PCBs and errors of commission, an indicator of response inhibition, on the CPT ([@r12]; [@r13]; [@r27], [@r28]). The Michigan cohort detected more frequent errors of commission on the Sternberg visual and recognition memory test at 4 years of age and on the Catch-the-Cat CPT at 11 years of age in relation to prenatal PCB exposure ([@r12]; [@r13]). Participants in the Oswego Children's Study with higher cord serum PCB levels also made more errors of commission on the Michigan Catch-the-Cat CPT at 4 years of age ([@r27]), the NES2 CPT at 8 years of age, and an extended CPT, which was designed specifically to differentiate between response inhibition and sustained attention by varying the target presentation rate, at 9 years of age ([@r28]). An association between PCBs and impaired response inhibition in this cohort was further supported using a delayed reinforcement paradigm at 9 years of age ([@r30]).

In contrast to the Michigan and Oswego study findings, associations between ΣPCB~4~, PCB TEQ, and *p*,*p*´-DDE and errors of commission were null in the present study. Instead, we found associations between PCBs/*p*,*p*´-DDE and CPT errors of omission, an indicator of inattention, among males. One possible explanation for different sensitivity to errors of commission versus omission is the low target presentation rate in the NES2 CPT; that is, the target is presented infrequently. Results from [@r28] based on the Extended CPT suggest that PCB associations with response inhibition are stronger using a test with a high target presentation rate. The NES2 CPT used in our study has a low target presentation rate and is therefore more suited for detecting inattention, demonstrated by more frequent errors of omission which could explain our ability to detect this behavior, compared with response inhibition.

Stronger effects of PCBs on CPT outcomes were detected for later blocks (third and fourth blocks, compared with second block) primarily for males. These findings were consistent with a previous study of methylmercury and NES2 CPT reaction time ([@r14]), which attributed this trend to higher neurotoxicant sensitivity of sustained attention (and, for this study, perhaps focused attention) represented by these later block periods.

Our study also found associations between PCBs and Processing Speed, a subscale of the WISC-III, among males only. Although associations between PCBs and Processing Speed have not been previously reported, associations were found with Freedom from Distractibility, another WISC-III subscale, in the Michigan study ([@r11]), with suggestive associations for Digit Span, a subtest of Freedom from Distractibility ([@r12]). Null associations were found between PCBs and Digit Span in the Faroes cohort ([@r9]) and the present study (data not shown).

Sex differences in estimated PCB effects were not found for CPT outcomes in the Oswego study ([@r28]) and were not reported for the Michigan CPT study ([@r12]). However, sex differences in organochlorine associations with neurodevelopment have been observed in other studies. Among the Yu-Cheng cohort, a Taiwanese population heavily exposed prenatally (or via lactation) to cooking oil contaminated with PCBs and polychlorinated dibenzofurans, decreased cognitive function was observed among exposed males but not females ([@r10]). Sex differences in prenatal PCB exposure effects are also supported by a study of Dutch school children, where changes in play behavior among males and females in relation to PCBs were observed, with less masculine play behaviors among boys and more masculine play behaviors among girls ([@r36]). Sex differences have also been reported in relation to other prenatal exposures, including lead, bisphenol A, and phthalates ([@r3]; [@r6]; [@r37]), supporting a growing belief that the neurodevelopmental impact of early-life exposure to environmental neurotoxicants on neurodevelopment is different for males and females ([@r39]).

Sexual dimorphism of effect has also been observed in animal studies in relation to PCB exposure, but results are inconsistent ([@r21]; [@r24]; [@r40]). Although the biological basis for these sex-specific effects is not fully understood, prenatal PCB and dioxin exposure has been linked with gonadal hormone levels, including reduced cord serum testosterone levels in females and reduced estradiol levels in males ([@r5]). In addition, sex differences in prenatal gonadal hormones levels could explain differences in susceptibility to neurotoxicants, including PCBs ([@r26]; [@r31]).

Neuropsychological indicators of behavior, assessed in this study with the CPT and WISC-III, do not represent clinical diagnosis of ADHD but are neuropsychological correlates of ADHD that are measured on a continuum. Continuous outcomes are preferable for the purposes of research for three reasons: *a*) minimization of bias due to outcome misclassification, where categorization is often made at an arbitrary cutoff point that may change over time; *b*) detection of early or milder manifestations of a disorder that a clinical diagnosis could miss; and *c*) enhancement of power to detect an effect of an exposure ([@r2]). In addition, these tests could be viewed as a more objective measure of functional limitations than parent or teacher report of observed behaviors.

However, a limitation of using the CPT and WISC-III outcomes as markers for inattentive and hyperactive/impulsive behaviors is that these outcomes may also reflect other skills that could compromise or enhance resulting scores for these neuropsychological tests. For example, longer mean reaction time could be a function of slower information processing skills, rather than, or in addition to, inattention---the confluence of which may be impossible to disentangle using a mean reaction time score.

A more conservative analytic approach may contribute to differences in our findings compared with other studies ([@r9]; [@r13]; [@r29], [@r27], [@r28]). For example, CPT errors were modeled as count variables in this analysis, in contrast to previous studies that were not specific about how these errors were modeled but presumably used linear regression to model these outcomes ([@r12]; [@r13]; [@r27], [@r28]). Given that count of errors (and their respective residuals) in this study did not follow a normal distribution and were overdispersed, the negative binomial distribution was a good fit for these data; this distribution is a conservative choice, however, as demonstrated by the wide CIs reported for CPT error outcomes. In previous studies using CPT error measures, model misspecification for count data may have led to underestimated variability of exposure effect estimates. We also omitted data for a child with an extremely high cord serum PCB level (ΣPCB~4~ \> 4 ng/g); this data point disproportionately influenced the association between ΣPCB~4~ and errors of omission. After omitting data for this child, the association between ΣPCB~4~ and errors of omission was null for males and females combined, although it did persist for males (the child with omitted data is female).

Conclusions
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In summary, our results support an association between organochlorines, particularly PCBs, and neuropsychological measures of inattention. Our observation of an association among boys only has not been consistently explored in previous studies and warrants further exploration of sex-specific effects of organochlorines on these outcomes. These findings contribute to a growing literature showing associations between PCBs and ADHD-related behavior.

Supplemental Material
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Click here for additional data file.

We thank C. Kehoe and W. Atkinson for data collection; D. Sredl, C. Chen, C. Crociani, and E. Wood for database management and programming; and D. Raposo and the labor and delivery staff at St. Luke's Hospital (New Bedford, MA), for support on data collection.

This work was supported by grants P42 ES05947 and R01 ES014864 from the National Institute of Environmental Health Sciences, National Institutes of Health (NIH). S.K.S. was additionally supported by grant T32 MH073122 from the National Institute of Mental Health, NIH. L.M.A. is employed by Environmental Health and Engineering, Inc. (Needham, MA).

The authors declare they have no actual or potential competing financial interests.
