Manganese and lead co-exposure and neurodevelopment exclude the possibility of a systematic dif- ference between children who provided one blood sample versus two. This may also be a chance finding. Bias due to differential loss to follow-up is unlikely to alter conclusions because the attrition rate was low (9%) over the 2-year follow-up period. Effect estimates appear fairly robust, because interaction coeffi- cients remained stable after excluding outliers, and crude estimates changed only minimally after controlling for sex, hemoglobin, gesta- tional age, maternal IQ, and maternal educa- tion [for crude estimates, see Supplemental Material, Table 2 (http://dx.doi.org/10.1289/ ehp.1003300)]. Strengths. This is the first prospective epi- demiologic study to examine manganese–lead coexposure and neurodevelopment. With blood metal measurements at two time points in early childhood, a period of rapid brain development and potentially increased sensi- tivity, we were able to begin to assess effects of coexposures during critical windows of devel- opment. In addition, our repeated measure- ments of neurodevelopment between 12 and 36 months allowed us to evaluate persistence of associations and to fit repeated measures models with greater statistical power than is possible with cross-sectional analyses. Finally, our study population was stable, with little attrition and relative homogeneity in demo- graphics that could act as confounders. Conclusion We observed evidence of increased lead toxic- ity among young children with high manga- nese coexposure. Our study findings highlight the importance of understanding health effects of mixed exposures, particularly during poten- tially sensitive life stages of development such as early childhood. Future research should emphasize coexposures to these neurotoxicants in other populations examined prospectively. Ref Rencs Aelion CM, Davis HT, McDermott S, Lawson AB. 2009. Soil metal concentrations and toxicity: associations with dis- tances to industrial facilities and implications for human health. Sci Total Environ 407(7):2216–2223. Agency for Toxic Substances and Disease Registry. 2008. Draft Toxicological Profile for Manganese. Available: http://www.atsdr.cdc.gov/toxprofiles/tp151.pdf. [accessed 28 March 2011]. Aschner M, Aschner JL. 1991. Manganese neurotoxicity: cel- lular effects and blood-brain barrier transport. Neurosci Biobehav Rev 15(3):333–340. Bayley N. 1993. Bayley Scales of Infant Development. 2nd ed. Vol. 2. San Antonio, TX:Psychological Corporation. Bellinger DC. 2008a. Late neurodevelopmental effects of early exposures to chemical contaminants: reducing uncer- tainty in epidemiological studies. Basic Clin Pharmacol Toxicol 102(2):237–244. Bellinger DC. 2008b. Lead neurotoxicity and socioeconomic status: conceptual and analytical issues. Neurotoxicology 29(5):828–832. Bellinger DC. 2009. Interpreting epidemiologic studies of devel- opmental neurotoxicity: conceptual and analytic issues. Neurotoxicol Teratol 31(5):267–274. Bellinger D, Sloman J, Leviton A, Rabinowitz M, Needleman HL, Waternaux M. 1991. Low-level lead exposure and chil- dren’s cognitive function in the preschool years. Pediatrics 87(2):219–227. Bouchard M, Laforest F, Vandelac L, Bellinger D, Mergler D. 2007. Hair manganese and hyperactive behaviors: pilot study of school-age children exposed through tap water. Environ Health Perspect 115:122–127. Bouchard MF, Sauve S, Barbeau B, Legrand M, Brodeur ME, Bouffard T, et al. 2011. Intellectual impairment in school- age children exposed to manganese from drinking water. Environ Health Perspect 119:138–143. Bressler JP, Goldstein GW. 1991. Mechanisms of lead neuro- toxicity. Biochem Pharmacol 41(4):479–484. Bronfman M, Guiscafre H, Castro V, Gutierrez G. 1988. Measuring unequality: a methodological approach, analy- sis of social and economic characteristics of the sample studied. Arch Invest Med (Mex) 19:351–360. Canfield RL, Henderson CR, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. 2003. Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 348(16):1517–1526. Chan AW, Minski MJ, Lim L, Lai JC. 1992. Changes in brain regional manganese and magnesium levels during post- natal development: modulations by chronic manganese administration. Metab Brain Dis 7(1):21–33. Chandra SV, Ali MM, Saxena DK, Murthy RC. 1981. Behavioral and neurochemical changes in rats simultaneously exposed to manganese and lead. Arch Toxicol 49(1):49–56. Chandra SV, Murthy RC, Saxena DK, Lal B. 1983. Effects of pre- and postnatal combined exposure to Pb and Mn on brain development in rats. Ind Health 21(4):273–279. Chen A, Cai B, Dietrich KN, Radcliffe J, Rogan WJ. 2007. Lead exposure, IQ, and behavior in urban 5- to 7-year-olds: does lead affect behavior only by lowering IQ? Pediatrics 119(3):e650–e658. Claus Henn B, Ettinger AS, Schwartz J, Téllez-Rojo MM, Lamadrid-Figueroa H, Hernández-Avila M, et al. 2010. Early postnatal blood manganese levels and children’s neuro- development. Epidemiology 21(4):433–439. Collipp PJ, Chen SY, Maitinsky S. 1983. Manganese in infant formulas and learning disability. Ann Nutr Metab 27(6):488–494. Cory-Slechta DA. 2005. Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk? Neurotoxicology 26(4):491–510. Cory-Slechta DA, Weiss B, Cranmer J. 2008. The environmen- tal etiologies of neurobehavioral deficits and disorders: weaving complex outcomes and risk modifiers into the equation. Neurotoxicology 29(5):759–760. Gomaa A, Hu H, Bellinger D, Schwartz J, Tsaih SW, Gonzalez- Cossio T, et al. 2002. Maternal bone lead as an indepen- dent risk factor for fetal neurotoxicity: a prospective study. Pediatrics 110(1 pt 1):110–118. Hu H, Shine J, Wright RO. 2007. The challenge posed to chil- dren’s health by mixtures of toxic waste: the Tar Creek superfund site as a case-study. Pediatr Clin North Am 54(1):155–175. Joselow MM, Tobias E, Koehler R, Coleman S, Bogden J, Gause D. 1978. Manganese pollution in the city environ- ment and its relationship to traffic density. Am J Public Health 68(6):557–560. Kalia K, Chandra SV, Viswanathan PN. 1984. Effect of 54Mn and lead interaction on their binding with tissue proteins: in vitro studies. Ind Health 22(3):207–218. Kim Y, Kim BN, Hong YC, Shin MS, Yoo HJ, Kim JW, et al. 2009. Co-exposure to environmental lead and manga- nese affects the intelligence of school-aged children. Neurotoxicology 30(4):564–571. Lanphear B, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, et al. 2005. Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect 113:894–899. Menezes-Filho JA, Novaes Cde O, Moreira JC, Sarcinelli PN, Mergler D. 2011. Elevated manganese and cognitive per- formance in school-aged children and their mothers. Environ Res 111(1):156–163. Naess O, Piro FN, Nafstad P, Smith GD, Leyland AH. 2007. Air pollution, social deprivation, and mortality: a multilevel cohort study. Epidemiology 18(6):686–694. Normandin L, Hazell AS. 2002. Manganese neurotoxicity: an update of pathophysiologic mechanisms. Metab Brain Dis 17(4):375–387. Riojas-Rodriguez H, Solis-Vivanco R, Schilmann A, Montes S, Rodriguez S, Rios C, et al. 2010. Intellectual function in Mexican children living in a mining area and environ- mentally exposed to manganese. Environ Health Perspect 118:1465–1470. Rodriguez VM, Dufour L, Carrizales L, Diaz-Barriga F, Jimenez- Capdeville ME. 1998. Effects of oral exposure to mining waste on in vivo dopamine release from rat striatum. Environ Health Perspect 106:487–491. Romieu I, Carreon T, Lopez L, Palazuelos E, Rios C, Manuel Y, et al. 1995. Environmental urban lead exposure and blood lead levels in children of Mexico City. Environ Health Perspect 103:1036–1040. Rosner B. 1983. Percentage points for a generalized ESD many- outlier procedure. Technometrics 25(2):165–172. Shukla GS, Chandra SV. 1987. Concurrent exposure to lead, manganese, and cadmium and their distribution to vari- ous brain regions, liver, kidney, and testis of growing rats. Arch Environ Contam Toxicol 16(3):303–310. Simmons JE. 1995. Chemical mixtures: challenge for toxicology and risk assessment. Toxicology 105(2–3):111–119. Spencer A. 1999. Whole blood manganese levels in pregnancy and the neonate. Nutrition 15(10):731–734. Surkan PJ, Schnaas L, Wright RJ, Tellez-Rojo MM, Lamadrid- Figueroa H, Hu H, et al. 2008. Maternal self-esteem, expo- sure to lead, and child neurodevelopment. Neurotoxicology 29(2):278–285. Takser L, Mergler D, Hellier G, Sahuquillo J, Huel G. 2003. Manganese, monoamine metabolite levels at birth, and child psychomotor development. Neurotoxicology 24(4– 5):667–674. Tellez-Rojo MM, Bellinger DC, Arroyo-Quiroz C, Lamadrid- Figueroa H, Mercado-Garcia A, Schnaas-Arrieta L, et al. 2006. Longitudinal associations between blood lead con- centrations lower than 10 microg/dL and neurobehavioral development in environmentally exposed children in Mexico City. Pediatrics 118(2):e323–e330. Verity MA. 1999. Manganese neurotoxicity: a mechanistic hypothesis. Neurotoxicology 20(2–3):489–497. Wasserman GA, Liu X, Parvez F, Ahsan H, Levy D, Factor- Litvak P, et al. 2006. Water manganese exposure and children’s intellectual function in Araihazar, Bangladesh. Environ Health Perspect 114:124–129. Wechsler H. 1968. Wechsler Adult Intelligence Scale (WAIS), Spanish Version. San Antonio, TX:Psychological Corporation. Wright RO, Amarasiriwardena C, Woolf AD, Jim R, Bellinger DC. 2006. Neuropsychological correlates of hair arsenic, man- ganese, and cadmium levels in school-age children residing near a hazardous waste site. Neurotoxicology 27(2):210–216. Zota AR, Ettinger AS, Bouchard M, Amarasiriwardena CJ, Schwartz J, Hu H, et al. 2009. Maternal blood manganese levels and infant birth weight. Epidemiology 20(3):367–373. Environmental Health Perspectives • volume 120 | number 1 | January 2012 131