Reductions in blood lead overestimate reductions in brain lead following repeated succimer regimens in a rodent model of childhood lead exposure.
Although many studies have demonstrated the efficacy of succimer chelation in reducing blood and brain lead levels, the relative efficacy of the drug in the two tissues is less well understood. This issue is important because blood lead levels after chelation are used clinically to estimate reductions in the brain, the most critical organ in considering lead-induced neurotoxicity. The present study was designed to further investigate this issue, using multiple chelation regimens. Long-Evans rats were exposed to one of three lead exposure regimens from birth until postnatal day 40, followed by treatment with succimer (one or two 3-week regimens) or vehicle. The results indicated that one succimer regimen was significantly superior to vehicle treatment in lowering lead levels in both blood and brain across the entire 8-week follow-up period. Similarly, a second succimer regimen offered significant additional benefit relative to one regimen for both blood and brain across the 4-week follow-up period. However, several findings revealed that succimer-induced reductions in brain lead lagged behind reductions in blood lead and were generally smaller in magnitude. Furthermore, a rebound was detected in blood, but not brain, lead levels after both succimer regimens. Given the results of this study, we urge caution in using blood lead as a surrogate for brain lead levels, particularly during and immediately after chelation treatment when reductions in blood lead levels overestimate reductions in brain lead levels. The present results suggest that, in clinical use, succimer treatment may need to extend beyond the point at which blood lead levels have dropped to an "acceptable" target value in order to effectively reduce brain lead levels and minimize neurotoxicity.
Department of Psychology, Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
Diane E
DE
Stangle
Myla S
MS
Strawderman
Donald
D
Smith
Mareike
M
Kuypers
Barbara J
BJ
Strupp
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain; D002614:Chelating Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D023381:Endpoint Determination; D005260:Female; D005544:Forecasting; D007854:Lead / Q000097:blood / Q000493:pharmacokinetics*; D007855:Lead Poisoning / Q000188:drug therapy* / Q000503:physiopathology / Q000662:veterinary; D008297:Male; D008962:Models, Theoretical; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D004113:Succimer / Q000627:therapeutic use*; D014018:Tissue Distribution; D016896:Treatment Outcome
D015415:Biomarkers; D002614:Chelating Agents; D007854:Lead; D004113:Succimer