Reductions in Blood Lead Overestimate Reductions in Brain Lead After Repeated Succimer Regimens in a Rodent Model of Childhood Lead Exposure

Diane E. Stangle; Myla S. Strawderman; Donald Smith; Mareike Kuypers; Barbara J. Strupp

Disclosures

Environ Health Perspect. 2004;112(3) 

In This Article

Abstract and Introduction

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.

Epidemiologic studies over the past several decades have suggested that even slightly elevated lead levels during early childhood can produce cognitive impairments and behavioral problems that endure long past the period of exposure (e.g., Bellinger et al. 1984, 1992; Dietrich et al. 1993; Fergusson et al. 1993; Needleman et al. 1990). In fact, Canfield et al. (2003) recently reported a significant inverse correlation between IQ and blood lead levels across the range of 2-10 µg/dL, suggesting adverse effects at lead levels lower than previously recognized. Importantly, studies using animal models have also demonstrated lasting cognitive and affective changes in animals exposed to lead early in life (e.g., Garavan et al. 2000; Levin and Bowman 1986; Morgan et al. 2001; Rice 1992; Stangle et al. 2003). These latter findings provide important evidence that early lead exposure can, in fact, cause these lasting deficits, an inference that has remained tentative in human studies because of the correlational nature of the data and frequent confounding of lead exposure and other risk factors for impaired cognitive and affective development.

Several studies have shown that interventions focusing on abatement and education produce only moderate reductions in lead levels over prolonged periods of follow-up. For example, Roberts et al. (2001) showed that blood lead levels of 25-29 µg/dL required 24 months to decline to < 10 µg/dL (the current level of concern for children), although all families received education, counseling, lead hazard identification, and relocation when possible. These data underscore the need for therapeutic chelating agents to reduce body lead levels more rapidly than can be achieved through environmental efforts alone.

Therapeutic chelation treatment has been used for decades to treat childhood lead poisoning (for reviews, see Graziano 1986; Graziano et al. 1985). According to current Centers for Disease Control and Prevention (CDC) guidelines (2002), chelation with Versenate (CaNa2EDTA) is indicated for children with blood lead levels ≥ 45 µg/dL, but more ambiguity exists regarding optimal therapeutic intervention for children with moderately elevated lead levels (25-45 µg/dL). The use of the oral chelating agent succimer has increased over the last several years because of its benefits over Versenate. Succimer is orally effective and is more specific for lead than is Versenate, thereby avoiding the diuresis of essential elements (e.g., calcium and zinc; Bentur et al. 1987; Chisolm 2000; Flora et al. 1995; Graziano et al. 1988; Kostial et al. 1999; Smith et al. 2000a; Thomas and Chisolm 1986).

Most studies demonstrating the effectiveness of succimer (and Versenate) in reducing tissue lead levels have assessed efficacy soon after the completion of treatment. However, recent clinical and nonhuman primate studies have suggested that succimer may be no more effective in reducing body lead levels than the simple cessation of lead exposure, when treatment efficacy is evaluated over longer periods of time after chelation (Cremin et al. 1999; Liu et al. 2002; O'Connor and Rich 1999; Rogan et al. 2001; Ruff et al. 1993; Smith et al. 2000b). Moreover, the one clinical trial of succimer treatment that has included cognitive outcomes [Treatment of Lead-Exposed Children (TLC) Trial Group 2000] was unable to detect a benefit of succimer treatment (relative to placebo) on cognitive functioning (Rogan et al. 2001). It is possible that the duration of succimer treatment in the TLC study was insufficient to significantly lower brain lead levels, despite the lowering of blood lead levels. This possibility is based on the evidence from animal studies that succimer-induced reductions in brain lead lag behind reductions in blood lead (Cremin et al. 1999; Smith et al. 1998), and that extended succimer treatment can continue to lower brain lead levels without continued reductions in blood lead (Smith et al. 1998).

In clinical practice, blood lead levels are used to determine the duration of chelation therapy (i.e., number of regimens) and assess its efficacy. Yet, as noted above, recent animal studies indicate that chelation-induced reductions in brain lead significantly lag behind changes in blood lead. As a result, in the short term, changes in blood lead may greatly overestimate the efficacy of chelation in reducing brain lead (Cremin et al. 1999; Smith et al. 1998). It follows that extending the duration of succimer treatment will significantly increase the efficacy of the drug in removing brain lead and, ideally, lessen the resulting cognitive dysfunction. For these reasons, there is a pressing need to determine the efficacy of varying durations of succimer treatment on blood and brain lead levels, as well as the more general issue of the correspondence between blood and brain lead levels, particularly after chelation therapy.

In the present study we used a rodent model of childhood lead exposure to systematically investigate a) the efficacy of single versus repeated succimer treatment regimens for reducing blood and brain levels, b) the extent to which blood lead can serve as a proxy for brain lead during and after chelation, and c) whether rebounds in blood and brain lead levels occur after chelation therapy, in the absence of environmental reexposure.

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