DMSA--EFFICACY IN REDUCING NEUROBEHAVIORAL TOXICITY

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There is increasing evidence that low-level lead (Pb) exposure is associated with significant neurobehavioral deficits. Of particular concern is the recent finding that even slight elevations in blood lead (BPb) level in early childhood are associated with enduring cognitive deficits. This evidence creates a pressing need to both reduce exposure to Pb and develop more effective means of treating children with even slightly elevated BPb levels. One promising new therapy is the chelating agent, dimercaptosuccinic acid (DMSA). This drug is highly effective in acutely reducing BPb and tissue Pb levels. Moreover, it can be administered orally, on an outpatient basis, and does not cause the many side effects (e.g. zinc diuresis, painful administration) associated with currently available chelators. To data, no studies have examined either the efficacy of this compound in alleviating the neurobehavioral toxicity of Pb, or the possible behavioral teratogenicity of DMSA itself. Such studies are essential before the drug can be approved for widespread use. The major purpose of the proposed studies is to determine if chelation with DMSA lessens the neurobehavioral deficits associated with Pb exposure in rodent models of both childhood and adult Pb exposure. Separate groups of analyzed will be euthanized before and after the three DMSA regimens so that changes in the neurobehavioral measures can be correlated with changes in Pb level in both brain and blood. The proposed study of developmental Pb exposure is designed to parallel two studies recently funded by NIEHS to examine the efficacy of DMSA in alleviating the neurobehavioral toxicity of Pb: a multicenter pediatric trial (REP NIH-ES 92-93) and a similar study using a non-human primate model. The proposed project will provide important information about the efficacy of DMSA in alleviating Pb-induced cognitive dysfunction that will not be provided by either of these ongoing studies and that should aid in interpreting their results. Briefly, the novel contributions of this project, relative to these two recently funded studies, include (1) dose response information about DMSA in alleviating Pb-induced cognitive dysfunction; (2) examination of DMSA efficacy as a function of BPb level under conditions in which pb and DMSA treatment can be carefully controlled and monitored, and sociodemographic factors affecting cognition can be controlled; (3) the opportunity to relate changes in neurobehavioral function to changes in brain Pb; and (4) assessment of DMSA efficacy in alleviating neurobehavioral deficits in cases of adult Pb exposure.