Ciesielski et al. between exposure and outcome is not dis- cernable, and it is possible that urinary cad- mium concentration tended to decrease after ADHD diagnosis (e.g., children with ADHD may be more likely to have behaviors that decrease cadmium exposure, absorption, or excretion). In the lead-stratified analysis, we found evidence that the OR for ADHD is < 1 only among those with blood lead levels above the median. The interaction was not significant, but there is toxicologic evidence that cadmium exposure may attenuate lead- mediated increases in activity (Nation et al. 1990). Further research is needed to clarify these issues. Implications for cadmium risk assess- ments. Previous cadmium risk assessments have considered renal effects to be the most sensitive end point of cadmium toxicity, and they identified urinary cadmium threshold levels that should protect against renal damage [EFSA 2009; World Health Organization/ Food and Agriculture Organization of the United Nations (WHO/FAO) 2011]. Recent risk assessments by the European Food Safety Authority (EFSA 2009) and the WHO (WHO/FAO 2011) yielded urinary cadmium reference levels of 1 and 5.24 μg cadmium/g creatinine, respectively. When we excluded from the analyses the four study participants with urinary cadmium levels above the EFSA reference level, the associations between uri- nary cadmium and LD/special education were still evident (comparing the highest and lowest urinary cadmium quartiles: LD, OR = 3.25; 95% CI: 1.45, 7.28; special education, OR = 3.03; 95% CI: 1.14, 8.08). Thus, our work demonstrates associations with LD/special education at urinary cadmium levels below both the WHO and EFSA reference levels. If these associations are replicated in other populations, then neurodevelopmental toxic- ity may be a sensitive end point to consider in future cadmium risk assessments. The EFSA and WHO risk assessments used toxicokinetic models to link creatinine-standardized urinary cadmium levels to dietary cadmium intake in order to estimate dietary intake standards (Amzal et al. 2009; EFSA 2009; WHO/FAO 2011). These toxicokinetic models were vali- dated in adults (Amzal et al. 2009), but they are probably not appropriate to use among children, because exposure routes may differ (Weidenhamer et al. 2011) and because urinary creatinine concentration varies markedly with small increases in age among children (Barr et al. 2005). Recent work by Weidenhamer et al. (2011) suggests that mouthing or acci- dentally swallowing objects such as inexpensive jewelry may also contribute significantly to cadmium exposure in childhood. The extent to which these sources contributed to cadmium exposure in our population is unknown, but future risk assessments should not ignore the 762 potential impact of non-food-based exposures or that current toxicokinetic models are not child specific. Strengths and limitations. Exposure. The use of urinary cadmium as an exposure metric is a strength of this study. Urinary cadmium integrates exposure over many years (Lauwerys et al. 1994); thus, if brain development is sen- sitive to cadmium exposure in any of the time periods represented by this exposure metric, then this effect could be detected in our analy- sis. However, it is not possible to determine etiologically relevant time windows of exposure or to confirm the temporal sequence of expo- sure and outcomes based on the available data. A shorter time-course exposure metric such as blood cadmium (Lauwerys et al. 1994), in the context of a longitudinal prospective study that measures exposure and outcome at several time points, may be able to determine if the associations are driven by exposure that occurs in specific developmental windows. Outcomes. We believe the diversity of outcomes evaluated is a strength of this study, because the combination of these three out- comes constitutes a screen for common neu- rodevelopmental dysfunctions. One limitation of these outcome measures is that they were derived from parent or proxy-respondent reports rather than neuropsychological evalua- tions. The use of ADHD treatments as an out- come would have likely identified only a subset of ADHD cases, resulting in low case num- bers and analyses of limited power (Froehlich et al. 2007). Neuropsychiatric screening mea- sures, such as the National Institute of Mental Health Diagnostic Interview Scale for Children that includes assessment of criteria for ADHD based on the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (CDC- NCHS 2006; Froehlich et al. 2009), would have been more objective, but these outcomes were not present in the publicly available NHANES data. Although outcomes were classified based on proxy-respondent reports, it is unlikely that outcome misclassification would be differential with respect to exposure unless the accuracy of reporting was related to unmeasured factors associated with cadmium exposure. Typically, nondifferential misclassi- fication would be expected to bias associations toward the (Rothman et al. 2008). Confounding. The extensive covariate data available in NHANES, combined with the large sample size and high number of cases, allowed us to both evaluate and account for many potentially confounding variables. We sought to evaluate the association of cadmium exposure with the outcomes after accounting for other known correlates of the outcomes. We evalu- ated three sets of models: a) models adjusted only for creatinine, b) core models adjusted for primary potential confounders, and c) full models also adjusted for additional predictors of a priori interest. The conclusions from all three of these approaches were consistent. We further note that adjusting for iron deficiency using low hemoglobin had little effect on the results and does not alter the conclusions of this study (data not shown). As in any observational epidemiology study, we cannot rule out the possibility that confounding may have mean- ingfully affected our results. Potential sources of confounding in these analyses might include a lack of detailed information on the home envi- ronment (Bradley 1993) and parental psycho- pathology (Bellinger 2001). Study design. The cross-sectional design of NHANES is a limitation of this study, because the temporal relationships between variables are not discernable. It is possible that higher cadmium exposure puts children at greater risk of LD/special education, but it is also possible that children with LD/special education have behaviors or prefer foods that increase their cadmium exposure. However, we are unaware of evidence supporting this reverse causation explanation. The NHANES study design does offer strengths related to power and generaliz- ability. To our knowledge, this is the largest study to evaluate associations between urinary cadmium and childhood learning/behavioral phenotypes. Because NHANES was designed to represent the noninstitutionalized U.S. population (CDC-NCHS 2010b), our find- ings should be generalizable to U.S. children 6–15 years of age. Conclusions The results of this study are consistent with a growing body of evidence suggesting that elevated cadmium exposure may be associ- ated with LD and special education. However, given the cross-sectional design and the nature of parent-reported outcomes, interpretations should be cautious. Prospective epidemio- logic investigations and behavioral toxicol- ogy studies in animals could help to clarify if these associations are causal and if there are critical developmental windows for exposure. Prospective studies that consider co-exposures such as lead may also help reveal why the find- ings for LD/special education and ADHD differed. Given that the cadmium levels in this study represent typical exposure levels in U.S. children, our findings emphasize the need for further research into the potential neuro- developmental effects of cadmium exposure. Ref Rencs Agency for Toxic Substances and Disease Registry. 2008. Draft Toxicological Profile for Cadmium. Available: http://www. atsdr.cdc.gov/ToxProfiles/tp5.pdf [accessed 12 January 2011]. Mosby, 322–353. Ahsan S, Noether J. 2011. Hematology. In: The Harriet Lane Handbook: A Manual for Pediatric House Officers (Tschudy MM, Arcara KM, eds). Philadelphia, PA:Elsevier ovlume 120 | number 5 | May 2012 • Environmental Health Perspectives