NTBS26

Correspondence between experimental and epidemiologicalfindings: How good is it?

Deborah RiceMaine Center for Disease Control and Prevention, United States

Screening tests are adequate to identify a chemical asneurotoxic at some dose, which may not be environmentallyrelevant. Of more interest and importance is the ability ofexperimental studies to predict the functional domains impairedby a particular neurotoxicant, and the degree to which appro-priate toxicity values (e.g., RfDs) can be derived from experi-mental data. Answers to both of these questions necessarily relyon having data from both human and animal studies for com-parison. Perhaps the two best-studied chemicals are the metalslead andmethylmercury. It is clear that lead produces impairmentin cognitive function on numerous tasks, decreased attention,increased impulsivity, and problems in sensory processing in bothanimals and children. There is a good correspondence betweenhumans and animals with respect to the body burden at whichtoxicity is observed, whereas external dose may not be a goodpredictor. For methylmercury, the ability of animal studies topredict effects in children may be dose- and species-dependent,perhaps in part as a result of differential kinetics. For pesticides,there is a much less detailed literature, either with respect toepidemiological studies documenting the pattern of functionalimpairment in children or animals, or the body burdens at whichthey occur.

doi:10.1016/j.ntt.2008.03.029

NBTS27

Developmental pesticide exposure: A new risk factor for ADHD?

Jason RichardsonRobert Wood Johnson Medical School, United States

Attention-deficit hyperactivity disorder (ADHD) is estimatedto affect 8–12% of school-aged children worldwide. Althoughthere is a significant genetic component to ADHD, no single genehas been linked to a significant percentage of cases, suggesting arole for environmental factors in ADHD. Recent data from mylaboratory suggest that pesticide exposure may be a risk factor forADHD. Mice exposed during development to the pyrethroidpesticide deltamethrin exhibit symptoms similar to thoseobserved in children with ADHD, including elevated dopaminetransporter (DAT) levels, hyperactivity, impulsive-like behavior,and a paradoxical calming response to methylphenidate (Ritalin).Data reveal that deltamethrin interacts with Na+ channels tocause persistent depolarization and increased transcription ofNurr1 and Pitx3 transcription factors. This leads to an increasedexpression of the DAT, which in turn causes increased levels of theD1 dopamine receptor that contributes to the behavioral deficitsobserved. To determine whether our laboratory findings weresupported by observations in the human population, we carriedout a cross-sectional study of pyrethroid pesticide exposure as arisk factor of ADHD using data from the National Health andNutrition Examination Survey. Parents of children aged 6–15 withdetectable levels of pyrethroid metabolites in their urine weremore than twice as likely to report that a doctor or health

professional had told them their child had ADHD. The parallelsbetween mice developmentally exposed to deltamethrin andindividuals with ADHD reinforce the epidemiological datasuggesting that developmental pesticide exposure is a risk factorfor ADHD.

doi:10.1016/j.ntt.2008.03.030

NBTS28

Long-term cognitive effects of low-level developmentalorganophosphate pesticide exposure: Divergent effects ofchlorpyrifos, diazinon and parathion

Edward Levin, Olga Timofeeva, Frederic Seidler, Theodore SlotkinDuke University, United States

Organophosphate (OP) pesticides all share the ability to inhibitcholinesterase which is responsible for high dose systemictoxicity and used to set “safe” exposure limits. However, recentresearch demonstrates that OPs cause developmental neurotoxi-city at doses below those that inhibit cholinesterase. Becausethis involves mechanisms other than the shared property ofcholinesterase inhibition, different OPs are likely to havedisparate low dose effects. In rats, we compared persistent neu-rocognitive effects of neonatal (PND 1–4) exposure to chlorpyr-ifos, diazinon or parathion at doses below and just above thethreshold for detectable cholinesterase inhibition. Each agentcaused significant persisting effects in adulthood on the radial-arm maze but effects with each agent differed. Chlorpyrifoscaused a sex-selective working memory effect, with malesshowing a significant increase in errors and females showing asignificant decrease, eliminating the normal sex difference inspatial discrimination. Postnatal diazinon significantly impairedworking memory without regard to sex. Parathion during thesame period caused a significant reduction in working memoryerrors, without regard to sex. Similarly, for cognitive effects ofcholinergic and serotonergic antagonist challenges and tests ofemotionality, low doses of each agent produced different spectraof persisting effects. Our studies show that apparently “safe”developmental OP exposures nevertheless cause persistent be-havioral effects that differ among the various agents. Mechanismsother than cholinesterase inhibition contribute to the develop-mental neurotoxicity of OPs and need to be considered in settingexposure limits. The disparate actions provide key information toidentify, which OPs may pose greater neurotoxic risk.

doi:10.1016/j.ntt.2008.03.031

NBTS29

The efficacy of succimer chelation in an animal model of pediatriclead exposure

Barbara Struppa, Diane Stanglea, Myla Strawdermana,Stephane Beaudina, Donald Smithb

aCornell University, United StatesbUniversity of California at Santa Cruz, United States

In light of growing evidence that even slightly elevated leadlevels can lead to lasting cognitive and behavioral alterations,there is pressure to administer chelating agents to children with

251M. Stanton et al. / Neurotoxicology and Teratology 30 (2008) 243–259