There is a pressing need to validate the efficacy of chelation agents such as succimer (dimercaptosuccinic acid, DMSA) not only to reduce body lead stores in young children but also to alleviate neurobehavioral and target organ toxicity. This multidisciplinary proposal tests the hypothesis that succimer therapy will attenuate the effects of lead on neurobehavioral and organ system toxicity as it reduces the body lead burden. The proposed studies, which parallel recently initiated pediatric human clinical trials (RFP NIH-ES 92-32), will use the rhesus monkey as a well-established, nonhuman primate model of childhood lead exposure. Treatment groups will be divided into no lead exposure (controls), one year of daily lead intake, and two years of daily lead intake. Lead administration will begin at birth. The monkeys receiving lead will be maintained at a target blood lead concentration of 35 micrograms Pb/d during lead intake, which falls near the midrange of the planned clinical trials of succimer. The regime for succimer treatment will follow the treatment chosen for the human clinical-trials. Monkeys will receive three treatment regimes of succimer beginning at approximately 12, 16, and 18 months of age. The groups given lead until two years of age will parallel cases in which a child is returned to a lead contaminated environment following chelation therapy. The efficacy of succimer in reversing neurobehavioral deficits will be monitored using a broad range of behavioral tests administered over the course of the three chelation therapies and after completion of all chelations, the latter to evaluate the long term efficacy of succimer therapy on neurobehavioral processes. Lead-induced alterations in the heme biosynthetic pathway will be used as a sensitive biomarker of systemic organ lead toxicity. An established stable-lead isotope technique will be used to determine the removal of lead from skeletal and soft tissue stores. K-X-ray fluorescence techniques will be used to assess long-term changes in reduction of skeletal lead due to chelation in adolescent monkeys. The monkey studies will utilize tightly controlled environmental conditions. Results of the studies should provide valuable interpretive scientific data concerning the efficacy of succimer to alleviate neurobehavioraI and target organ toxicity in children.
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