Succimer and the reduction of tissue lead in juvenile monkeys

The extent to which succimer (2,3-dimercaptosuccinic acid, DMSA) chelation reduces target organ lead (Pb) levels, including the skeleton, relative to the cessation of Pb exposure is a primary consideration in evaluating its e fficacy for reducing toxicity in children. Here, we utilized a rhesus monke y model of childhood Pb exposure and a sensitive stable Pb-204 isotope trac er methodology to determine the efficacy of succimer for reducing Pb in blo od, liver, and skeletal tissues from chronic (greater than or equal to 1 ye ar) versus short-term (3-4 days) Pb exposures. Specific attention was paid to the efficacy of succimer treatment compared to the cessation of Pb expos ure. Infant rhesus monkeys (n = 48) were exposed to Pb daily for 1 year or >1 year postpartum to reach and maintain a target blood Pb level of 35-40 m u g/dL. Two successive 19-day succimer treatment regimens were administered at 53 and 65 weeks of age (30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days). Blood was collected over the course of treatment, and liver and bone biopsy samples were collected on days 0, 5, and 20, relative to the s tart of treatment (day 0). Complete 24-h urine collections were conducted o ver the course of treatment. Results of the first chelation indicate that a single regimen of succimer treatment led to significant reductions in bloo d and liver Pb levels, relative to the placebo group. However, the cessatio n of Pb exposure alone (i.e., placebo) also led to significant reductions i n blood and liver compared to pretreatment levels. Neither succimer nor the cessation of Pb exposure had a significant impact on bone lead levels. Blo od Pb levels in the succimer-treated group rebounded within 5 days after tr eatment ended, becoming comparable with levels in the placebo group from th at point on. Results from the second chelation indicate that succimer treat ment is essentially equally efficacious in reducing blood Pb at moderate (2 0 mu g/dL) levels where exposures ended >3 months previously and more eleva ted (40-50 mu g/dL) levels where exposures ended just prior to treatment, r elative to the placebo treatment. Finally, similar overall outcomes were ob served for tissue Pb from recent exposures (i.e., Pb-204 tracer levels), in dicating little or no apparent difference in the chelation of Pb from recen t (3-4 days) versus long-term exposures. These data demonstrate that succim er does not reduce skeletal Pb levels, and they show that the efficacy of s uccimer for reducing blood Pb levels does not persist beyond the completion of treatment due to posttreatment rebounds in blood Pb from endogenous sou rces. They also demonstrate the relative benefit of eliminating Pb exposure s, which serves to underscore the importance of primary prevention of Pb ex posure. The extent to which these data reflect the efficacy of succimer for reducing neurocognitive impairment is not yet known, although those data a re forthcoming. (C) 2000 Academic Press.