Roy et al. with more ADHD-type behaviors, especially the inattention component, which builds upon the nascent literature in this area (Braun et al. 2006; Wang et al. 2008). Of particular interest is the finding of a larger effect of lead on execu- tive function and attention compared with the other behaviors assessed. The dose response in this population failed to identify a threshold level for the association between lead and the behaviors. Specifically, we found no evidence that the associations departed from linearity. The association of blood lead level with anxiety and poor sociability among children is important. The children with higher anxiety and sociability scores in the CTRS-39 were those who had low self-esteem and little self- confidence; were withdrawn, shy, emotionally distant, and detached from their peers; and also tended to worry and to be emotional and sensi- tive to criticism as well as being particularly anxious in new or unfamiliar situations. Such behaviors may lead to functional isolation, which is hypothesized to decrease exploration of the environment and may make children less likely to seek and/or receive attention and nurturing stimulation, such as developmentally facilitating care from their caregivers (teach- ers/parents) through responsiveness and verbal stimulation (Lozoff 1998; Walter 1989). There are very few studies that describe a statistically significant effect of lead on anxi- ety in children. A few studies have reported increased internalizing behaviors among chil- dren exposed to lead, but except for the study by Burns et al. (1999), most did not find signifi- cant associations with different types of internal- izing behaviors (Sciarillo et al. 1992; Wasserman et al. 2001). A study by Bellinger et al. (1994) reported increased internalizing behavior and noted higher anxiety among children. Evidence 0.6 0.4 re0.2 o c s - Z 0.0 –0.2 –0.4 Global executive function DSM-IV inattentive Anxiety–shy DSM-IV hyperactive ADHD index Social problems 5 10 15 20 Blood lead (µg/dL) 25 30 Figure 2. Dose–response relationship between blood lead and behavior. Smooth functional term relating behavior Z-scores to blood lead in an adjusted generalized additive mixed model, adjust- ing for age, sex, hemoglobin, average monthly income, maternal and paternal education, and number of other children and accounting for clus- tering at school and classroom level. Social prob- lems were not significantly nonlinear (effective degrees of freedom = 1.56). 1610 from animal research indicates that early lead exposure causes permanent changes in the hypo- thalamic–pituitary axis, glucocorticoid dysregula- tion, and altered dopaminergic and GABA-ergic (γ-aminobutyric acid–containing) systems, which are associated with increased anxiety and decreased socializing behavior (Nieto-Fernandez et al. 2006). These pathways are also potentiated by stress (Cory-Slechta et al. 2008; White et al. 2007), which may be more prevalent among lower socioeconomic populations. ADHD refers to a constellation of symp- toms including difficulty in delaying gratifi- cation, overactivity or motor restlessness, distractibility, impulsivity, aggression, and short attention span (Spreen et al. 1995). In the cur- rent study, children with higher lead exposures had higher prevalence of ADHD-like behaviors (marginally significant). This is consistent with a recent analysis of the National Health and Nutrition Examination Survey by Braun et al. (2006), which showed that the odds of diag- nosed ADHD were 4.1 times higher among children within the highest quintile of concur- rent blood lead level than among those in the lowest quintile of lead exposure. These results were corroborated by results from other stud- ies among children (Millichap 2008; Tuthill 1996; Wang et al. 2008). However, other stud- ies have not differentiated between inattention and hyperactive-type ADHD. In this study we found that blood lead was strongly associ- ated with behaviors reflecting predominantly inattention rather than hyperactivity. In fact, lead was not significantly associated with the latter in this population. Previous studies have shown the impact of lead on attention, and that among older children and adolescents, processes regulating attention may be the underlying cause (Bellinger et al. 1994; Burns et al. 1999; Davis et al. 2004). Animal studies also indicate that lead affects processes regulat- ing attention such as impulsivity (Brockel and Cory-Slechta 1998). During the last decade there has been increasing interest in executive function in childhood. Executive function is an umbrella term that incorporates a collection of inter- related processes responsible for purposeful, goal-directed behavior (Anderson 2002). This construct includes cognitive control processes such as planning, regulation of attention (resistance to distraction), decision making, working memory, problem solv- ing, and behavioral control (impulse control, initiation and monitoring of action, includ- ing self-monitoring, and shifting from task to task) (Arnsten and Li 2005; Mitchell and Phillips 2007). The association between lead exposure and executive function—such as metacognitive functioning involving working memory, plan- ning, and organization—confirms the finding of poorer functioning in task clusters among schoolchildren with higher prenatal blood lead, which suggests these deficits (Leviton et al. 1993). Studies using the digit span test as a measure of working memory have suggested a detrimental effect, as seen in some occupational studies (Hanninen et al. 1998; Stewart et al. 2002). Few studies have focused specifically on executive function in young children. Canfield et al. (2004), using the Cambridge Neuropsychological Testing Automated Battery in a population of 174 children exposed to low levels of lead, suggested that lead exposure affects working memory, attentional flexibil- ity, planning, and problem solving. However, this association was not supported by another study in 170 preschool children (Canfield et al. 2003) in which the authors reported a signifi- cant association with deficits in performance, attention, and the inhibition of automatic responses, but failed to find consistent effects on tasks requiring attention switching and the combination of inhibition and switching. This result may be attributable to the difficulty of the test administered and the relatively low blood lead levels of the children tested. Our study demonstrates that, across the range of exposure in this population of school- children in India and using a measure that focuses on observed behavioral regulation in daily life, higher blood lead levels are asso- ciated with deficits across multiple domains of executive function (including inhibition of automatic responses and attention shift- ing). This finding is consistent with studies that report significant associations with perse- verative errors (indicating an inability to shift attention) in the Wisconsin Card Sorting Test and the California Verbal Learning Test (Stiles and Bellinger 1993; Surkan et al. 2007). The results of this study are consistent with animal data showing lead exposure–in- duced changes in myelination, oxidative stress, cellular signaling, and multiple neurotrans- mitter pathways related with behavior and executive function. Studies by Cory-Slechta (2003) suggest that lead affects the dopamin- ergic pathway and that these changes are connected to changes in perseveration and impulsivity errors in animals. There is also considerable evidence that the glutamatergic system, specifically the N-methyl d-aspartate (NMDA) receptor complex, which is associ- ated with learning and memory, is affected by lead exposure in animals (Finkelstein 1998). This study has several limitations. The cross-sectional design precludes consideration of the temporal relationships between expo- sure and outcome. It is possible that behav- ioral changes precede lead exposure and could even induce lead exposure through behavioral pathways such as increased hand-to-mouth behavior. The lack of validation of the BRIEF, CADS, and CTRS within the Indian popu- lation is another potential limitation. We ovlume 117 | number 10 | October 2009 • Environmental Health Perspectives