Efficacy of succimer chelation for reducing brain Pb levels in a rodent model.
Increasing evidence indicates that early low-level lead (Pb) exposure produces enduring cognitive impairment in children, underscoring the need to develop improved therapeutic intervention. Although chelating agents have been shown to effectively reduce body Pb levels, it is not yet known whether this treatment ameliorates Pb-induced cognitive dysfunction. Clinical research in this area is hampered by the need to rely on reductions in blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greatest relevance to neurocognitive outcomes. The present studies were designed to provide information that will aid future research in this area in both human and animal models. The objectives of these studies were (1) to evaluate the efficacy of different doses and durations of succimer (meso-2,3-dimercaptosuccinic acid; DMSA) chelation for reducing brain and blood Pb levels and (2) to determine the extent to which blood Pb can serve as a surrogate of brain Pb following chelation. Long-Evans hooded rats were exposed to Pb from birth until day 31 (Study 1) or day 40 (Study 2) of life, followed by oral treatment with a vehicle or one of two succimer regimens for a duration of either 7 or 21 days. Results indicated that 7 days of succimer treatment produced a 1.5- to 2.5-fold greater reduction of Pb in blood than in brain, relative to time-matched vehicle groups. Prolonged treatment (21) days did not further reduce blood Pb levels (relative to 7-day succimer treatment), but did produce further reductions in brain Pb level compared to time-matched vehicle groups. Thus, chelation-mediated reductions in brain Pb did not parallel reductions in blood Pb over the course of treatment. While the relevance of these data to humans may be confounded by anatomical and physiological differences between rodents and primates, as well as differences in the metabolism of succimer (DMSA), they suggest that clinical studies should exercise caution when using blood Pb as an index of the efficacy of chelation treatment for reducing brain Pb levels.
Smith
D
D
Department of Environmental Toxicology, University of California, Santa Cruz 95064, USA.
Bayer
L
L
Strupp
B J
BJ
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002614:Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000139:chemically induced / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007854:Lead / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D007855:Lead Poisoning / Q000150:complications / Q000188:drug therapy*; D008297:Male; D011897:Random Allocation; D051381:Rats; D004113:Succimer / Q000008:administration & dosage / Q000627:therapeutic use*
D002614:Chelating Agents; D007854:Lead; D004113:Succimer