Lead exposure and behavior in India of lead above and below 10 µg/dL or effect modification by sex. Discussion Lead levels in this population were higher than currently seen in many countries (CDC 1997, 2005a), and higher blood lead levels among young children were associated with deficits across a wide range of behavioral outcomes. Our study is among the first to note that lead exposure is associated with increased specific childhood internalizing behaviors such as anxi- ety and social problems. We also observed that children with higher blood lead levels presented Quartiles of blood lead (µg/dL) Q4 18.71 ± 4.80 1.85 ± 0.65 1.51 ± 0.68 13.71 ± 8.67 10.29 ± 7.26 10.3 ± 6.60 129.83 ± 33.03 51.05 ± 12.66 78.77 ± 21.19 p-Value 0.017 0.027 0.053 0.012c 0.126 0.001d Q1 6.13 ± 1.16 1.65 ± 0.57 1.40 ± 0.65 11.57 ± 8.2 7.88 ± 6.14 8.96 ± 6.4 112.55 ± 29.14 44.69 ± 11.65 67.86 ± 18.18 Q2 9.06 ± 0.78 1.74 ± 0.64 1.49 ± 0.68 11.59 ± 8.56 8.4 ± 6.96 9.35 ± 6.60 118.15 ± 31.63 46.73 ± 12.72 71.43 ± 19.60 Q3 12.10 ± 1.10 1.76 ± 0.60 1.44 ± 0.64 11.49 ± 9.08 8.39 ± 6.84 8.89 ± 6.56 120.15 ± 28.77 48.28 ± 11.67 71.87 ± 18.21 Raw scores β (95% CI) 0.17 (0.03 to 0.31) 0.14 (0.02 to 0.26) 1.45 (–0.10 to 3.01) 1.67 (0.38 to 2.98) 0.87 (–0.26 to 1.99) 12.96 (5.46 to 20.45) p-Value 0.020 0.025 0.066 0.012 0.129 0.001 Z-scoresb β (95% CI) 0.27 (0.05 to 0.51) 0.20 (0.02 to 0.38) 0.17 (–0.00 to 0.36) 0.24 (0.05 to 0.43) 0.13 (–0.04 to 0.30) 0.42 (0.18 to 0.65) Environmental Health Perspectives • volume 117 | number 10 | October 2009 1609 the behavioral domains of ADHD, a one-unit change in log blood lead was associated with an increase of 0.24 Z-score of attention compared with 0.13 points of Z-score of hyperactivity and was significantly different (p < 0.05). There were no significant differences between the effects of lead within the different domains of executive function (Figure 1). The dose–response relationships for lead and all behavioral outcomes, assessed by cubic penalized splines, were linear. No inflection points, indicating particular threshold levels, were noted in any of the associations (Figure 2). There was no significant difference in the effect Table 2. Behavioral raw scores by quartiles of blood lead (mean ± SD). subscales of executive functions and between the CADS-T ADHD index score, DSM-IV inattentive and hyperactivity subscales. We explored dose–response relationships using generalized additive models within mixed models, accounting for clustering, using R statistical software (Free Software Foundation Inc., Boston, MA, USA). When nonlinearity was present, the penalized spline model was compared with the linear model using Akaike’s information criterion and generalized cross-validation. Results Mean (± SD) blood lead was 11.4 ± 5.3 µg/ dL (range, 2.6–40.5) and 54.5% of the chil- dren had blood lead levels > 10 µg/dL. Blood lead was associated with markers of socioeco- nomic status, with higher blood lead observed among those who had lower average family monthly income [compared with those who made > 13,000 rupees/month (US$518)] and greater number of children in the family. Significantly lower blood lead levels were noted among children whose parents had finished college (Table 1). Bivariate analyses indicated a trend of higher (i.e., worse) behavioral scores with increasing blood lead concentrations (Table 2). The variance in neurobehavioral outcomes, assessed using a random effects model, was sig- nificantly associated within schools and class- rooms, indicating correlation. Multivariate GEE analyses, accounting for clustering at the class and school level and controlling for child’s age (months), sex, hemoglobin level, family average monthly income, maternal and paternal education, and number of children in the family, showed that higher blood lead level was associated with higher behavioral raw and Z-scores (indicating worse behavior). The use of Z-scores versus raw scores did not change the overall direction or significance of the associations (Table 3). Nevertheless, the use of Z-scores allowed for standardization by age and sex, and for direct comparison of beta coefficients for different test scores. On the CTRS-39, a one-unit increase in log blood lead was associated with 0.27 higher anxiety Z-score (p = 0.017) and 0.20 higher sociability Z-score (p = 0.027). On the CADS-T, blood lead was associated with higher ADHD index Z-scores and DSM-IV inattentive, (β = 0.17, p = 0.05 and β = 0.24, p = 0.01, respectively) but not hyperactive. On the BRIEF, the global executive composite score was strongly associated with higher blood lead level (p < 0.001). In comparing the response of the behaviors, we found that change in executive function with blood lead was significantly higher than that of ADHD index, anxiety, or sociability (p < 0.001), with a change of 0.42 Z-scores per increase in one unit of log blood lead. Within Behavioral scales CTRS Anxiety–shy Social problems CADS-T ADHD index DSM-IV inattentive DSM-IV hyperactivity BRIEF Global executive Behavioral regulation Metacognition Behavioral scales CTRS-39 Anxiety–shy Social problems CADS-T ADHD index DSM-IV inattentive DSM-IV hyperactive BRIEF Global executive function d 0.6 a e l do 0.5 o l gb 0.4 o l / reo 0.3 c -sZ 0.2 n i ge 0.1 n a hC 0 Composite Global executive function Table 3. Comparison of multivariatea GEE analysis of log blood lead and behavior (raw scores and Z-scores). CI, confidence interval. aAdjusting for age, sex, hemoglobin, average monthly income, maternal and paternal education, number of other children and accounting for clustering at school and classroom level. bCreated by standardizing raw scores by age (3–5/6–7 years) and sex-stratified mean and SD. cThe effect of lead on attention is significantly larger that the effect on hyperactivity (p < 0.05). dGlobal executive function (BRIEF) is significantly (p < 0.001) more sensitive to the effect of lead compared with ADHD, anxiety, and social problems. Composite Inhibit Shift Emotional control Behavioral regulation Composite Initiate Working Planning Organization Monitoring memory Metacognition Figure 1. Differing sensitivity (change in Z-score/unit log blood lead) of executive function subscales (BRIEF) to lead exposure. Error bars indicate SE.