Rauh et al. subjects with detectable CPF levels only. Analysis with detects alone is known to give unbiased estimates of the parameters of inter- est (Little 1992). In the present sample, we observed no consistent differences in estimates when we excluded imputed CPF data (data not shown). Discussion Results of this study showed that higher pre- natal CPF exposure, as measured in umbili- cal cord blood plasma, was associated with decreases in cognitive functioning on two different WISC-IV indices, in a sample of urban minority children at 7 years of age. Specifically, for each SD increase in exposure (4.61 pg/g), Full-Scale IQ declined, on aver- age, by 1.4% (0.94–1.8 points) and Working Memory Index scores declined by 2.8% (1.6–3.7 points). The dose–effect relationships between CPF exposure and log-transformed Working Memory Index and Full-Scale IQ scores are linear across the range of exposures in the study population, with no evidence for a threshold. Of the WISC-IV indices used as end points, the Working Memory Index was the most strongly associated with CPF expo- sure in this population. Although no other epidemiologic studies have evaluated the neurotoxicity of prenatal CPF exposure on cognitive development at the time of school entry, several prior stud- ies, using the present biomarker of exposure, have reported evidence of early cognitive and behavioral effects associated with a urinary biomarker of nonspecific OP exposure (Engel et al. 2007; Eskenazi et al. 2007; Young et al. 2005). Outcomes associated with exposure in these studies, as well as in our own ear- lier work (Rauh et al. 2006), have included attentional problems (e.g., Marks et al. 2010). These prior findings are consistent with the present 7-year results, because working memory skills involve attentional processes. More important, problems in working mem- ory may interfere with reading comprehen- sion, learning, and academic achievement, although general intelligence remains in the normal range (Blair 2006). Working memory is less likely than full-scale IQ to be affected by socioeconomic or cultural conditions (Wechsler 2003), providing a useful, more targeted measure of possible neurotoxic effects on brain function. Several different theories or models address how working memory operates in the human brain, but most agree that it involves a system of limited attention capacity, supplemented by more peripherally based storage systems (Baddeley and Logie 1999). Some theories emphasize the role of attentional control in working memory (e.g., Cowan 1999), whereas others stress a multicomponent model, includ- ing a control system of limited attentional capacity (the central executive control system), assisted by phonological and visuospatial stor- age systems (see review by Baddeley 2003). To date, most studies of the anatomical localiza- tion of working memory problems are based on clinical populations (individuals with spe- cific brain lesions) (Vallar and Pagano 2002) and some neuroimaging studies in small num- bers of normal subjects (Smith and Jonides 1997). More refined neuropsychological tests and neuroimaging studies are needed to deter- mine whether CPF-related working memory deficits are primarily auditory (part of a pho- nological loop with implications for language acquisition) or primarily related to visuospa- tial short-term memory (reflecting nonverbal intelligence tasks). Few human studies have focused on pos- sible mechanisms underlying neurodevelop- mental deficits associated with OP exposure, Table 2. Estimated associations between CPF (pg/g) and log-transformed Full-Scale IQ and each of four Composite Index scores from the WISC-IV from LASSOa and fully adjustedb linear regression models B-coefficientc –0.003 –0.003 –0.006 –0.006 NAd –0.002 –0.002 0.001 95% CI –0.006 to 0.001 –0.006 to 0.000 –0.009 to –0.002 –0.010 to –0.002 –0.005 to 0.001 –0.006 to 0.002 –0.004 to 0.005 p-Value 0.064 0.048 < 0.001 0.003 0.208 0.290 0.728 (n = 265). WISC-IV scalec Full-Scale IQ LASSO Fully adjusted LASSO Fully adjusted LASSO Fully adjusted LASSO Fully adjusted Working Memory Index Verbal Comprehension Index Perceptual Reasoning Index Processing Speed Index LASSO Fully adjusted NA, not assessed. 1200 aLASSO models were adjusted for maternal education, maternal IQ, and the HOME Inventory. bFully adjusted models were adjusted for child sex, race/ethnicity, maternal IQ, maternal education income, child age at testing (months), ETS, and PAH. cAll scales wereln transformed. dCPF was not retained in the final LASSO model. but there is evidence that certain genetic poly- morphisms can affect CPF metabolism (e.g., Berkowitz et al. 2004). Such findings suggest that some populations may be more vulner- able and may exhibit adverse neurodevelop- mental effects at much lower exposures than other populations (Berkowitz et al. 2004). Again, neuroimaging studies would be use- ful to determine if population differences in vulnerability to CPF are also reflected in population differences in brain abnormalities associated with exposure. Although behavioral alterations observed in rodents may be imperfect analogues for humans, they have guided human studies by identifying specific deficits in locomotor activity, learning, and memory (e.g., Aldridge et al. 2005). In light of experimental evidence suggesting that CPF effects in rodents may be irreversible (Slotkin 2005), it will be impor- tant to determine how any neurocognitive deficits associated with prenatal CPF exposure might respond to treatment or early interven- tion. Here, we may benefit from studies of lead-exposed children that have demonstrated evidence of reversals in learning deficits as a result of environmental enrichment (Guilarte et al. 2003). Some limitations of this study should be noted. Our sample consists of low-income, urban, minority children who may experience other unmeasured exposures or underlying health problems that could potentially con- found or modify associations with pesticide exposure. Furthermore, in the absence of firm mechanistic evidence linking brain anomalies to more refined neuropsychological testing, the observed functional deficits at 7 years of age should be interpreted with caution. We cannot directly compare our findings with the results from the other epidemiological studies that have relied on urinary OP concentrations as the biomarker of exposure. In June 2000, the U.S. EPA announced a phase-out of the sale of CPF for indoor res- idential use, with a complete ban effective 31 December 2001 (U.S. EPA 2000, 2002). After the ban, levels of CPF in personal and indoor air samples in our own cohort decreased by more than 65%, and plasma blood levels dropped by more than 80% (Whyatt et al. 2005), despite some linger- ing residential residues (Whyatt et al. 2007). From other parts of the country, there is evi- dence of continued low-dose exposures in children from food residues (Lu et al. 2006). Because agricultural use of CPF is still permit- ted in the United States, it is important that we continue to monitor the levels of expo- sure in potentially vulnerable populations, including pregnant women in agricultural communities, and evaluate the long-term neurodevelopmental implications of exposure to CPF and other OP insecticides. ovlume 119 | number 8 | August 2011 • Environmental Health Perspectives