Research | Children’s Health Cadmium Exposure and Neurodevelopmental Outcomes in U.S. Children and Robert O. Wright1,4,7 Timothy Ciesielski,1 Jennifer Weuve,1,2 David C. Bellinger,1,3,4 Joel Schwartz,1 Bruce Lanphear,5,6 1Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 2Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois, USA; 3Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts, USA; 4Harvard Medical School, Boston, Massachusetts, USA; 5Cincinnati Children’s Environmental Health Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 6Child and Family Research Institute, BC Children’s Hospital and Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada; 7Department of Pediatrics, Children’s Hospital, Boston, Massachusetts, USA Background : Low-level environmental cadmium exposure in children may be associated with adverse neurodevelopmental outcomes. o Bjectiv : Our aim was to evaluate associations between urinary cadmium concentration and reported learning disability (LD), special education utilization, and attention deficit hyperactivity disorder (ADHD) in U.S. children using National Health and Nutrition Examination Survey (NHANES) data. Methods : We analyzed data from a subset of participants in NHANES (1999–2004) who were 6–15 years of age and had spot urine samples analyzed for cadmium. Outcomes were assessed by parent or proxy-respondent report. We fit multivariable-adjusted logistic regression models to esti- mate associations between urinary cadmium and the outcomes. r sulte : When we compared children in the highest quartile of urinary cadmium with those in the lowest quartile, odds ratios adjusted for several potential confounders were 3.21 [95% confidence interval (CI): 1.43, 7.17] for LD, 3.00 (95% CI: 1.12, 8.01) for special education, and 0.67 (95% CI: 0.28, 1.61) for ADHD. hTere were no significant interactions with sex, but associations with LD and special education were somewhat stronger in males, and the trend in the ADHD analysis was only evident among those with blood lead levels above the median. c onclusi : hTese findings suggest that children who have higher urinary cadmium concentra- tions may have increased risk of both LD and special education. Importantly, we observed these associations at exposure levels that were previously considered to be without adverse effects, and these levels are common among U.S. children. k ey w ords : attention deficit hyperactivity disorder, cadmium, learning disability, neurodevelop- ment, neuropsychological development, NHANES, risk assessment, special education. Environ Health Perspect 120:758–763 (2012). http://dx.doi.org/10.1289/ehp.1104152 [Online 27 January 2012] Cadmium is a heavy metal found in the earth’s crust that is disseminated in the envi- ronment both by natural processes and by human activities such as fossil fuel burning, waste incineration, smelting procedures, and the use of phosphate fertilizers (Agency for Toxic Substances and Disease Registry 2008). Uptake of environmental cadmium in plants and animals results in human exposures via food or tobacco smoke, and occupational exposures can occur as well [European Food Safety Authority (EFSA) 2009]. Cadmium is known to be nephrotoxic (EFSA 2009), but there is also a growing body of evidence suggesting that cadmium exposure may have adverse neurodevelopmental consequences. Several animal studies have reported effects of cadmium on electrophysiologi- cal parameters, markers of neurotransmit- ter function, and neurobehavioral outcomes (Ali et al. 1986; Desi et al. 1998; Lehotzky et al. 1990; Nagymajtenyi et al. 1997; Nation et al. 1983, 1984, 1989, 1990). Studies in children have reported associations between higher cadmium levels and mental retarda- tion (Jiang et al. 1990; Marlowe et al. 1983), decreased verbal IQ (Thatcher et al. 1982), lower neuropsychological test performance 758 (Bonithon-Kopp et al. 1986; Stellern et al. 1983), learning disability (LD) (Capel et al. 1981; Ely et al. 1981; Pihl and Parkes 1977), poor reading performance (Thatcher et al. 1984b), neurophysiological evoked poten- tial differences (Thatcher et al. 1984a), and behavioral problems in the presence of con- currently elevated lead levels (Marlowe et al. 1985a). In contrast, other human studies have failed to detect significant multivari- able-adjusted associations between markers of cadmium exposure and neurodevelopmental outcomes (Cao et al. 2009; Gillberg et al. 1982; Lee et al. 2007; Marlowe et al. 1985b; Moon et al. 1985; Wright et al. 2006). These studies varied in size, quality, and design. In addition, they used several different expo- sure metrics, evaluated different windows of susceptibility, and differed in their consider- ation of potentially important confounders. These factors may help explain the inconsis- tent results, and further research could help resolve some of the discrepancies. In this study, we analyzed a large repre- sentative sample of U.S. children 6–15 years of age from the National Health and Nutrition Examination Survey (NHANES), to determine whether higher levels of urinary cadmium were associated with attention deficit hyperactivity disorder (ADHD), LD, or placement in special education. To our knowledge, this is the largest study to evalu- ate associations between urinary cadmium and neurodevelopmental outcomes, and the first to do so in a nationally representative sample of U.S. children. Methods Data source and study population. NHANES is an ongoing series of cross-sectional question- naires, examinations, and laboratory analyses that evaluate nutritional and environmental exposures as well as various health parameters in the U.S. population [Centers for Disease Control and Prevention National Center for Health Statistics (CDC-NCHS) 2010b]. Detailed documentation on NHANES is available online (CDC-NCHS 2010b). For this study we used NHANES data collected 1999–2004. We restricted our analyses to children 6–15 years of age because urinary cadmium was evaluated in a subsample of participants ≥ 6 years of age, and informa- tion on several covariates was not available for participants > 15 years of age. There were 2,282 children between 6 and 15 years of age in this subsample, and urine cadmium mea- surements were available for 2,199 (96.4%) of these. Because some children were miss- ing outcome data, 2,189, 2,196, and 2,195 children were included in the analyses of LD, special education, and ADHD, respectively. The NHANES website notes that approval (protocol 98-12) was obtained from the NCHS Ethics Review Board (referred to as the NHANES Institutional Review Board before 2003) (CDC-NCHS 2012). Exposure assessment. Cadmium exposure was assessed using urinary cadmium concen- tration, which is an indicator of body burden/ Address correspondence to T. Ciesielski, Exposure, Epidemiology, and Risk Program, 401 Park Dr. West, P.O. Box 15677, Boston, MA 02215 USA. Telephone: (617) 384-8823. E-mail: TimothyHCiesielski@gmail.com This work was supported in part by National Institutes of Health grants T32 MH073122, T42 OH008416, R01 ES014930, R01 ES013744, P42 ES016454, and P30 ES00002. The authors declare they have no actual or potential competing financial interests. Received 6 July 2011; accepted 17 January 2012. ovlume 120 | number 5 | May 2012 • Environmental Health Perspectives