NBTS10

In utero exposure to pesticides and child neurodevelopment in aNew York City cohort

Mary Wolff, Stephanie EngelMount Sinai School of Medicine, United States

Among 404 women enrolled in a prospective multiethnic birthcohort between 1998 and 2002, the NIEHS/EPA Children's Centerat Mount Sinai investigated the relationships between pesticideswith child neurodevelopment at birth (using the Brazeltonneonatal behavioral assessment, n=311), ages 1 and 2 (using theBayley Scales of Infant Development and the Infant and ToddlerBehavior Questionnaires Year 1 n=200, Year 2 n=276), and age 4(Behavior Assessment System for Children and the Brief, n=148).Pesticides were measured as biomarkers in 3rd trimester ma-ternal urine of di alkyl phosphates (DAPs) and in blood plasma(DDT, PCB). Interactions of DAPs with paraoxonase activity, a keymetabolizer of organophosphate pesticides.

DAPs were associated with the number of abnormal reflexeselicited at birth, but there was no negative association betweenPCBs or DDE and any of the BNBAS domains. DDE had an inverse,nonsignificant association with the Bayley MDI but not PDI at age1–2 yr. DAPs were significantly associated with the Bayley MDI atage 2 yr. The DAP-reflex association was limited to mothers withlow 3rd trimester paraoxonase, as was the Bayley MDI depression.Infant behavior (2 scales) was reduced for DAPs among infantswhose mothers had lower paraoxonase. Prenatal exposure topesticides and BASC/brief will also be described.

Our cohort has shown weak associations between pesticidesand child neurodevelopment, with effects of the organopho-sphates influenced by maternal metabolic capacity.

doi:10.1016/j.ntt.2008.03.013

NBTS11

Pesticide exposure in children: Evidence for a take home pathway

Elaine FaustmanUniversity of Washington, United StatesCenter for Child Environmental Health Risks Research, United States

This presentation will share lessons learned from children'scohort studies examining environmental contributions to pesti-cide exposure in early childhood. Using a public health frameworkto examine factors contributing to children's exposure, the studiespresented in this talk will discuss recent findings on factorsaffecting within and between child variability in exposure andearly response. Results from field studies in Washington Stateagricultural communities were modeled using an integrativeframework that uses object based Bayesian modeling techniques.These methods were developed to evaluate the exposure diseaseparadigm and then used to evaluate individual, household,community and population level effects across years, behavioralinterventions and seasons. Of interest to our assessments hasbeen understanding the potential contribution of genetic varia-bility of pesticide metabolizing enzymes to children's exposureand response. This contribution has also been modeled using asimilar common modeling tool. Since exposures to organopho-sphate pesticides can be very complex within agricultural com-munities, the effects of specific exposure pathways, public health

interventions and individual behaviors tominimize exposures canbe difficult to sort out. Using this tool the effects of communitylevel interventions and regulatory actions are able to be identifiedand separately evaluated. Likewise contributions of geneticvariability in individuals can be modeled and specific designs inbiomarker studies modified to incorporate these factors and toimprove our ability to link exposure and identify response. (Thiswork was supported by NIEHS grant number 5 P01ES009601,EPA grant number RD-83170901 and EPA grant number RD-83273301).

doi:10.1016/j.ntt.2008.03.014

NBTS12

Interpreting epidemiologic studies of neurotoxicity: Conceptualand analytic issues

David BellingerChildren's Hospital Boston, United StatesHarvard Medical School, United StatesHarvard School of Public Health, United States

Risk assessors frequently question the importance of the smalleffect sizes reported in epidemiological studies of neurotoxicantexposures. Arguments are marshaled in support of the contentionthat the conceptual and data analytic approaches conventionallyapplied systematically bias inferences about neurotoxicant effectstowards the null. One factor is a failure to appreciate the dif-ferences between individual risk and population risk. It is well-accepted with regard to chronic diseases such as hypertensionand obesity, but not regard to neurotoxicity, that small shifts inthe mean value of a health index in a study sample can, undercertain circumstances (e.g., a monotonic dose–effect relationshipbetween an index of exposure and the risk of disease) havesubstantial implications for the health of the population fromwhich the study sample was drawn. With regard to data analyticstrategies, apportioning shared outcome variance solely tocovariates and assuming that none of the time variation in co-variates reflects the effect of neurotoxicant exposure can result inerrors in causal reasoning. To estimate accurately the morbidityassociated with neurotoxicant exposures, we need to applyanalytical approaches that model neurodevelopment and its con-text as a complex system of interdependent relationships thatevolve over time.

doi:10.1016/j.ntt.2008.03.015

NBTS13

Biomarkers of genetic susceptibility to metal neurotoxicity

Robert WrightHarvard School of Public Health, United States

Complex diseases (ADHD autism, and neurodevelopmentaldelays/disorders) often have high estimates of heritability,suggesting that they arise from primarily genetic factors. Surpris-ingly, many of these diseases are increasing in annual incidence, afinding which would be counter-intuitive for a genetic diseaseand more consistent with an environmental cause. Gene–envi-ronment interaction could explain both phenomena and provide a

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unifying framework to study their etiology and treatment. In thistalk I will present a rationale and method for combining pros-pective environmental exposure data with high density genotyp-ing data in human populations to discover, then validate geneticpolymorphisms which predispose individuals to neurotoxic envi-ronmental chemicals. I will present methods to account forpopulation stratification, multiple comparisons, and timing ofexposure into the gene–environment interaction analysis. Datawill be presented from 4 ongoing birth cohorts — Bangladesh, TarCreek OK, Mexico City, and New Bedford MA which are con-sidering the neurotoxicity of lead, manganese and arsenic. Wewill discuss different potential approaches for studying geneticsusceptibility-genome wide association studies (GWAS) vs biolo-gical pathways and the pros and cons for each option. Objectivemethodologies for linking basic science projects with humanstudies to choose biological pathways will be presented as well.Finally, data on genetics susceptibility to lead will be presented todemonstrate that such effects are in part dependent on the timingof lead exposure.

doi:10.1016/j.ntt.2008.03.016

NBTS14

Effects of early lead exposure on neuroanatomical and socialfunctional outcomes in young adults

Kim DietrichUniversity of Cincinnati College of Medicine, United States

Although environmental lead exposure is associated withdeficits in cognition and social behavior, the neuroanatomicalbasis for these impairments remains poorly understood. Data arealso lacking on the long-term consequences of early exposure tolead for psychosocial adjustment in adulthood. To address thesequestions, we examined adult brain volume using magneticresonance imaging (MRI), and adult criminality in the CincinnatiLead Study (CLS) cohort.

Volumetric analyses of whole brain magnetic resonanceimaging data revealed significant covariate-adjusted decreasesin brain volume associated with average childhood blood leadconcentrations. The most affected regions included frontal graymatter, specifically the anterior cingulate cortex.

Criminality outcomes were the covariate-adjusted rate ratiosfor total arrests and arrests for violent crimes associatedwith each5 µg/dL increase in blood lead concentration. Adjusted total arrestrates were significantly greater for each 5 µg/dL increase in pre-natal, average childhood, and 6-year blood lead concentrations.Adjusted arrest rates for violent crimes were significantly greaterfor each 5 µg/dL increase in average childhood and 6-year bloodlead concentrations.

MRI studies found that childhood lead exposure is asso-ciated with reductions in adult gray matter volume in regionsresponsible for executive functions. In the same cohort,prenatal and childhood blood lead concentrations were foundto be associated with higher rates of total arrests and/or arrestsfor offenses involving violence. This is the first prospectivestudy to demonstrate an association between developmentalexposure to lead and adult cortical gray matter loss and crimi-nal behavior.

doi:10.1016/j.ntt.2008.03.017

NBTS15

The impact of lead and other exposures on early schoolperformance

Jerome Reiter, Dohyeong Kim, Andy Hull, Marie Lynn MirandaDuke University, United States

Research has long linked childhood lead exposure to deficits incognitive function, with increasing evidence of negative impacts atblood lead levels well below the CDC blood lead action level of10 µg/dL. We sought to determine whether exposure to leadcontributes to the achievement gap between blacks andwhites andwhether the effect of lead on educational achievement demon-strates a threshold effect. We linked lead surveillance (age 1–6) andearly end of grade testing data (~age 8–10) for children in NC. Weused linear and quantile regression analysis to examine thecorrelation of lead exposure with reading and math scores for the100 counties in NC, controlling for student age, sex, andrace, parental education, poverty, and school system. Averageblood lead levels (BLLs) among students designated as “excep-tional children” were tested for statistical differences. Lead expo-sure demonstrated a dose–response impact on reading and mathscores (all pb .0001), with no demonstrable threshold effect.Quantile regression showed that the impact of lead exposure wasgreaterandmorehighly variable at the lowendof thedistribution ofreading, but notmath, scores. Childrenwith learning andbehavioraldisorders had higher early childhood BLLs (pb .0001). Studentsdesignated as “academically and intellectually gifted” had lowerearly childhood BLLs compared to “non-exceptional” students(pb .0001). Accounting for early childhood lead exposure attenu-ates, in part, the black–white achievement gap in test scores. Theresults highlight the potential for early combined environmentaland educational interventions to improve outcomes for children.

doi:10.1016/j.ntt.2008.03.018

NBTS16

Role of metal exposures in autism

Irva Hertz-Picciotto, Peter Green, Lora Delwiche, Isaac Pessah,Robin HansenUniversity of California, United States

Background. Environmental causes of autism, a pervasivedevelopmental disorder, are unknown. One hypothesis is thatchildren with autism excrete metals inefficiently. Methods. TheChildhood Autism Risks from Genetics and the Environment(CHARGE) Study enrolled children aged 2–5 years, from threegroups: with autism, with developmental delay but not autism,and from the general population. Diagnoses were confirmed bystandardized instruments, venous blood was collected, andmothers were interviewed about environmental exposures,including home product, dietary, and dental/medical sources ofmercury. Strands from the child's first haircut were collected ifavailable. Metals were measured using ICP/MS. Hg sources werecompared across groups. Multiple linear regression was used topredict blood mercury concentration from food and other sourcesand case status. Results. Children with autism consumed less fishthan other children. Children with autism were similar to thedevelopmentally delayed or typically developing controls withregard to the distribution of blood Hg concentrations. Mercury in

247M. Stanton et al. / Neurotoxicology and Teratology 30 (2008) 243–259