ensured internal validity in this study by using Z-scores, standardized within the population. Nevertheless, caution must be exercised in the generalizability of the reported absolute mag- nitudes of effect estimates, as the effect of lead within the Indian population may be modified by sociocultural, genetic, and nutritional factors particular to the Indian subcontinent. Residual confounding in the relationship between lead and neurobehavior could exist, because it was not feasible to assess home environment and parental behavior or IQ. However, we did control for family size, socioeconomic status, and maternal education, all of which are corre- lated with a nurturing environment for a child (Seifer 2001). The association of lead with anxiety and sociability may reflect residual con- founding due to co-occurrence of high-stress environments and high lead exposures associ- ated with low socioeconomic status. However, in all analyses, we accounted for socioeconomic status using three measures (income, family size, and parental education). Of course, there is always a chance that some confounding remains, and it is possible that the effects of lead and stress may be synergistic in affecting anxiety and social behavior in young children (Cory-Slechta et al. 2008; White et al. 2007). Despite the limitations, this is the first large, population-based study of lead and neurobehavior to be carried out in India and the first study to assess differential sensitivity of the effects of lead on behavior. The use of the BRIEF questionnaire allows assessment of executive function in 3- to 7-year-old children as observed by teachers in tasks required in a regular school day compared with other stud- ies that use computer-based tasks, which have often proven too difficult for young children. Conclusion Overall, this study suggests that lead expo- sure affects behavior across multiple domains, including anxiety and social behavior. The results also suggest that executive functions and attention are especially vulnerable to insult by lead among young children. We identified no threshold for these effects, and all dose– response relationships were linear. This is an important finding for policy decision making, as it suggests that there might be no safe level of lead exposure. In terms of societal disease burden, the behavioral and psychiatric morbidities associ- ated with lead might be even more important than cognitive morbidities (Bellinger 2001). A conservative estimate of cost of illness of ADHD among children and adolescents in the United States in 2005 amounted to $42.5 billion/year, assuming a 5% prevalence in the country (Pelham et al. 2007). This may have policy implications for a country such as India that is rapidly undergo- ing industrialization, where elevated childhood lead exposures are prevalent, and where 31% of the population is < 15 years of age (National Health and Family Survey 2001) and vulner- able to the long-term effects of lead exposure. These findings likely have implications not only for the Indian population, but for other popu- lations in developing countries where similar lead exposure scenarios exist. Ref Rencs Ahamed M, Verma S, Kumar A, Siddiqui MK. 2006. Delta- aminolevulinic acid dehydratase inhibition and oxidative stress in relation to blood lead among urban adolescents. Hum Exp Toxicol 25(9):547–553. Anderson P. 2002. Assessment and development of executive function (EF) during childhood. Child Neuropsychol 8(2):71–82. Arnsten AF, Li BM. 2005. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57(11):1377–1384 [review]. Bellinger D. 2001. Future directions for neurobehavioral studies of environmental neurotoxicants. Neurotoxicology 22(5):645. Bellinger DC, Hu H, Kalaniti K, Thomas N, Rajan P, Sambandam S, et al. 2005. A pilot study of blood lead levels and neurobehavioral function in children living in Chennai, India. Int J Occup Environ Health 11(2):138–143. Bellinger DC, Hu H, Titlebaum L, Needleman HL. 1994. Attentional correlates of dentin and bone lead levels in adolescents. Arch Environ Health 49(2):98–105. Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP. 2006. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect 114:1904–1909. Brockel BJ, Cory-Slechta DA. 1998. Lead, attention, and impul- sive behavior: changes in a fixed-ratio waiting-for-reward paradigm. Pharmacol Biochem Behav 60(2):545–552. Burns JM, Baghurst PA, Sawyer MG, McMichael AJ, Tong SL. 1999. Lifetime low-level exposure to environmental lead and children’s emotional and behavioral development at ages 11–13 years. The Port Pirie Cohort Study. Am J Epidemiol 149(8):740–749. Canfield RL, Gendle MH, Cory-Slechta DA. 2004. Impaired neu- ropsychological functioning in lead-exposed children. Dev Neuropsychol 26(1):513–540. Canfield RL, Kreher DA, Cornwell C, Henderson CR Jr. 2003. Low-level lead exposure, executive functioning, and learn- ing in early childhood. Child Neuropsychol 9(1):35–53. CDC (Centers for Disease Control and Prevention). 1997. Update: Blood lead levels—United States, 1991–1994. MMWR Morb Mortal Wkly Rep 46(7):141–146. CDC (Centers for Disease Control and Prevention). 2005a. Blood lead levels—United States, 1999–2002. MMWR Morb Mortal Wkly Rep 54(20):513–516. CDC. 2005b. Preventing Lead Poisoning in Young Children. Atlanta, GA:Centers for Disease Control and Prevention. Conners CK. 1990. Conners’ Ratings Scales Manual. North Tonawanda, NY:Multi-Health Systems, Inc. Conners CK, Sitarenios G, Parker JD, Epstein JN. 1998. The revised Conners’ Parent Rating Scale (CPRS-R): Factor structure, reliability, and criterion validity. J Abnorm Child Psychol 26(4):257–268. Cory-Slechta DA. 2003. Lead-induced impairments in complex cognitive function: Offerings from experimental studies. Child Neuropsychol 9(1):54–75. C o r y - S l e c h t a D A , V i r g o l i n i M B , R o s s i - G e o r g e A , Thiruchelvam M, Lisek R, Weston D. 2008. Lifetime conse- quences of combined maternal lead and stress. Basic Clin Pharmacol Toxicol 102(2):218–227. Davis DW, Chang F, Burns B, Robinson J, Dossett D. 2004. Lead exposure and attention regulation in children living in pov- erty. Dev Med Child Neurol 46(12):825–831. Finkelstein Y, Markowitz ME, Rosen JF. 1998. Low-level lead- induced neurotoxicity in children: An update on central ner- vous system effects. Brain Res Brain Res Rev 27(2):168–176. Froehlich TE, Lanphear BP, Dietrich KN, Cory-Slechta DA, Wang N, Kahn RS. 2007. Interactive effects of a DRD4 polymorphism, lead, and sex on executive functions in children. Biol Psychiatry 62(3):243–249. Gioia GA, Isquith PK, Guy SC, Kenworthy L. 2000. Behavioral Rating Inventory of Executive Function (BRIEF). Odessa, FL:Psychological Assessment Resources. Environmental Health Perspectives • volume 117 | number 10 | October 2009 Lead exposure and behavior in India Hanninen H, Aitio A, Kovala T, Luukkonen R, Matikainen E, Mannelin T, et al. 1998. Occupational exposure to lead and neuropsychological dysfunction. Occup Environ Med 55(3):202–209. Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, et al. 2005. Low-level environmental lead expo- sure and children’s intellectual function: an international pooled analysis. Environ Health Perspect 113:894–899. Leviton A, Bellinger D, Allred EN, Rabinowitz M, Needleman H, Schoenbaum S. 1993. Pre- and postnatal low-level lead exposure and children’s dysfunction in school. Environ Res 60(1):30–43. Millichap JG. 2008. Etiologic classification of attention-deficit/ hyperactivity disorder. Pediatrics 121(2):e358–e365; doi: 10.1542/peds.2007-1332 [Online 5 June 2008]. Mitchell RL, Phillips LH. 2007. The psychological, neurochemical and functional neuroanatomical mediators of the effects of positive and negative mood on executive functions. Neuropsychologia 45(4):617–629. Needleman HL, McFarland C, Ness RB, Fienberg SE, Tobin MJ. 2002. Bone lead levels in adjudicated delinquents. A case control study. Neurotoxicol Teratol 24(6):711–717. Nevin R. 2000. How lead exposure relates to temporal changes in IQ, violent crime, and unwed pregnancy. Environ Res 83(1):1–22. Nichani V, Li WI, Smith MA, Noonan G, Kulkarni M, Kodavor M, et al. 2006. Blood lead levels in children after phase-out of leaded gasoline in Bombay, India. Sci Total Environ 363(1–3):95–106. Nieto-Fernandez FE, Ruiz A, Ntukogu N, Nodimelle L, Pryor SC. 2006. Short term lead exposure induces a stress-like response in adult mice. Med Sci Monit 12(10):BR325– BR329 [Online 22 April 2008]. Nigg JT, Knottnerus GM, Martel MM, Nikolas M, Cavanagh K, Karmaus W, et al. 2008. Low blood lead levels associated with clinically diagnosed attention-deficit/hyperactivity disorder and mediated by weak cognitive control. Biol Psychiatry 63(3):325–331. Pelham WE, Foster EM, Robb JA. 2007. The economic impact of attention-deficit/hyperactivity disorder in children and adolescents. J Pediatr Psychol 32(6):711–727. Qaqish BF, Liang KY. 1992. Marginal models for correlated binary responses with multiple classes and multiple levels of nesting. Biometrics 48(3):939–950. Rosner B. 1983. Percentage points for a generalized ESD many- outlier procedure. Technometrics 25(2):165–172. Sciarillo WG, Alexander G, Farrell KP. 1992. Lead exposure and child behavior. Am J Public Health 82(10):1356–1360. Seifer R. 2001. Socioeconomic status, multiple risks and develop- ment of intelligence. In: Environmental Effects on Cognitive Abilities (Sternberg RJ, Grigorenko EL, eds). Mahwah, NJ:Lawrence Erlbaum Associates, 59–82. Shannon M, Rifai N. 1997. The accuracy of a portable instrument for analysis of blood lead in children. Ambul Child Health 3:249–254. Spreen O, Risser AH, Edgell D. 1995. Developmental Neuro- psychology. New York:Oxford University Press. Stewart WF, Schwartz BS, Simon D, Kelsey K, Todd AC. 2002. ApoE genotype, past adult lead exposure, and neuro- behavioral function. Environ Health Perspect 110:501–505. Stiles KM, Bellinger DC. 1993. Neuropsychological correlates of low-level lead exposure in school-age children: a prospec- tive study. Neurotoxicol Teratol 15(1):27–35. Surkan PJ, Zhang A, Trachtenberg F, Daniel DB, McKinlay S, Bellinger DC. 2007. Neuropsychological function in children with blood lead levels <10 microg/dL. Neurotoxicology 28(6):1170–1177. Tuthill RW. 1996. Hair lead levels related to children’s classroom attention-deficit behavior. Arch Environ Health 51(3):214–220. Walter T. 1989. Infancy: Mental and motor development. Am J Clin Nutr 50(3 Suppl):655–661. Wang HL, Chen XT, Yang B, Ma FL, Wang S, Tang ML, et al. 2008. Case-control study of blood lead levels and atten- tion-deficit hyperactivity disorder in Chinese children. Environ Health Perspect 116:1401–1406. Wasserman GA, Liu X, Pine DS, Graziano JH. 2001. Contribution of maternal smoking during pregnancy and lead exposure to early child behavior problems. Neurotoxicol Teratol 23(1):13–21. White LD, Cory-Slechta DA, Gilbert ME, Tiffany-Castiglioni E, Zawia NH, Virgolini M, et al. 2007. New and evolving con- cepts in the neurotoxicology of lead. Toxicol Appl Pharmacol 225(1):1–27. 1611