Efficacy of succimer chelation for reducing brain lead in a primate model of human lead exposure

The extent to which succimer (meso-2,3-dimercaptosuccinic acid [DMSA], Chem et) reduces brain lead (Pb) levels may be a primary consideration in evalua ting its efficacy for reducing neurotoxicity. Clinical research in this are a has been hampered by the need to use blood Pb levels as the index of trea tment efficacy, despite the fact that brain Pb level is the exposure parame ter of greater relevance to cognitive outcomes. Here, a nonhuman primate mo del of human Pb exposure was used to determine: (1) The efficacy of oral su ccimer for reducing brain Pb derived from chronic or recent exposures, and (2) The extent to which blood Pb levels reflect brain Pb prior to and follo wing chelation. Adult rhesus monkeys were chronically exposed to Pb orally for 5 weeks to reach and maintain a target blood Pb level of 35-40 mu g/dL. Chelation of Pb from recent exposures was assessed using a stable Pb-204 i sotope tracer administered over 4 days prior to treatment. immediately prio r to chelation, a prefrontal cortex (PFC) biopsy was collected to determine pretreatment brain Pb levels. Subsequently, monkeys were assigned to vehic le (n = 5) or succimer (n = 6, 30 mg/kg/day x 5 days followed by 20 mg/kg/d ay x 14 days) groups. Blood and brain PFC, frontal lobe (FL), hippocampus ( H), and striatum (S) were analyzed for total Pb and Pb-204 tracer concentra tions by magnetic sector inductively coupled plasma-mass spectrometry. Ther e were no measurable differences in brain Pb concentrations between the suc cimer and vehicle groups, indicating that succimer treatment was not effica cious in reducing brain Pb levels. In contrast, the cessation of Pb exposur e significantly reduced brain (PFC) Pb (approximate to 34%) when compared t o pretreatment levels (succimer and vehicle groups). Pb concentrations also varied among brain regions (PFC > FL approximate to H > S), Finally, pretr eatment PFC Pb concentrations were significantly correlated with the integr ated blood Pb level (AUC) over the Pb exposure period, but not with the sin gle pretreatment blood Pb collected concurrently with the PFC biopsy, Follo wing treatment, blood Pb levels correlated only with Pb in the PFC, and not the other brain regions measured (FL, H, S), These data indicate that, und er the conditions of this study, succimer treatment did not reduce brain Pb levels beyond the cessation of Pb exposure alone. Moreover, a single blood Pb measurement may be a poor predictor of brain Pb levels, reflecting limi tations in the use of blood Pb level as an indicator of treatment efficacy. (C) 1999 Academic Press.