Lead (Pb) is a frequently encountered pollutant from superfund sites, urban and agricultural soils, and other hazardous wastes which may be ingested or inhaled, particularly by children. There is increasing evidence that low-level Pb exposure and even slight elevations in blood lead (BPb) level in early childhood are associated with significant, enduring, cognitive neurobehavioral deficits, thereby creating a pressing need both to reduce exposure to Pb and to develop more effective means of treating children with even slightly elevated BPb levels. One promising new therapeutic chelating agent, dimercaptosuccinic acid (DMSA), is highly effective in reducing BPb and tissue Pb levels, can be administered orally on an outpatient basis, and does not cause the many side effects associated with current chelation therapy. To date, no studies have examined either the efficacy of this compound in alleviating Pb neurobehavioral toxicity or the possible behavioral teratogenicity of DMSA itself. Such studies are essential before the drug can be approved for widespread use; moreover, these studies can provide additional insight into the extent and duration of these deficits and the applicability of this model as a probe for assessment of neurotoxicants in hazardous wastes. The major purpose of the proposed studies is to determine if chelation with DMSA lessens the neurobehavioral deficits associated with rodent models of either childhood and adult Pb exposure. Separate groups of animals will be subjected to Pb exposure po via a regime already established as to BPb levels and neonastal deficits. Pb-exposed animals and controls will be euthanized before and after the three DMSA regimens so that performance in the battery of neurobehavioral measures can be correlated with both brain and blood Pb levels. This proposed study is a continuation of neurobehavioral Pb toxicity studies under the Cornell Superfund Basic Research and Education Program and parallels two studies recently funded by NIEHS to examine the efficacy of DMSA in alleviating the neurobehavioral toxicity of Pb - a multicenter pediatric trial (RFP NIH-ES 92-93) and a similar study using a non-human primate model. The proposed project will cooperatively provide important information about the efficacy of DMSA in alleviating (or exacerbating) Pb-induced cognitive dysfunction that will not be provided by either of the parallel studies and therefore should aid in interpretation of their results. They in turn provide technical services assisting evaluation of Pb mitigation. Briefly, this project, relative to the two parallel studies, would provide (1) dose-response information about DMSA in alleviating Pb- induced cognitive dysfunction; (2) determination of DMSA efficacy as a function of BPb level under conditions in which Pb exposure and DMSA treatment can be carefully controlled and monitored, and sociodemographic factors affecting cognition can be controlled; (3) the relationship between changes in neurobehavioral function and brain Pb levels; and (4) assessment of DMSA efficacy in alleviating neurobehavioral deficits in cases of adult Pb exposure.
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