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

Discussion

The results of this study provide important insights into the efficacy of succimer for the treatment of lead poisoning. First, both succimer regimens were significantly more effective than vehicle treatment in lowering lead levels in both blood and brain, although the reductions in brain lead temporally lagged behind reductions in blood lead over both treatments. In addition, a rebounding of lead levels was seen in blood but not brain after cessation of each chelation regimen. Each of these conclusions is discussed below.

One 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 tissues across the 4-week follow-up period. However, several findings revealed that succimer-induced reductions in brain lead lagged behind treatment reductions in blood lead. First, when assessed immediately after the first round of chelation, the succimer-induced reduction in lead levels (relative to vehicle levels) was greater for blood than for brain. The finding that a single chelation regimen is less effective in reducing brain lead than blood lead has been observed in other studies using either Versenate or succimer (Cremin et al. 1999; Flora et al. 1995; Seaton et al. 1999; Smith et al. 1998). This effect likely reflects two factors: First, lead in the blood is more accessible for chelation than is lead in the brain, based on the indications that chelators remove lead primarily by forming a soluble lead chelate that can be more readily eliminated via urinary or fecal routes, and by creating increased concentration gradients that favor lead efflux from tissues into the circulation. A second contributing factor is the inherently different toxicokinetics of lead in blood and brain. This phenomenon is best illustrated by the relatively slow rate of lead reduction in brain compared with blood of vehicle-treated animals over the entire study period (Figure 2). It follows, therefore, that the most effective means of reducing lead levels in well-perfused tissues exhibiting slow lead toxicokinetics (brain), as well as poorly perfused tissues (e.g., the skeleton), is to maximize the lead concentration gradient between these tissues and blood for prolonged periods of time, thereby favoring continued efflux of lead into the circulation and elimination via urinary or fecal routes.

When assessed at the end of the study (PND118), the added benefit of the second succimer regimen was more apparent for brain lead levels than for blood lead levels. This pattern also reflects the lag of brain lead reduction (relative to blood) and the different lead toxicokinetics of the two tissues. Because of the slower rate of lead efflux from brain, lead levels in this tissue were still elevated after the first regimen, whereas at this time blood lead levels were very low and appeared to have reached an asymptote. This apparent "floor" effect may be the result of both a lower amount of chelatable lead in blood and also blood lead toxicokinetics (i.e., the relative rates of lead influx to blood from other tissues vs. the rate of efflux of lead out of the circulation). Nevertheless, the finding that the second succimer regimen offered a significant benefit in terms of reducing lead levels in both blood and brain, at all exposure intensities, is important because it indicates that multiple chelation regimens continue to lower brain lead levels, even at time points when blood lead levels have appeared to "stabilize" at a relatively low level. This observation may be particularly important in the clinical management of lead-poisoned children, because it suggests that chelation treatment may need to continue past the point at which blood lead levels have reached an acceptably low level, to achieve the maximal benefit of the treatment on brain lead levels, the primary goal in lessening cognitive dysfunction.

Experimental studies in rodents and nonhuman primates have yielded different results concerning the efficacy of succimer in reducing lead in blood and brain. For example, Cory-Slechta (1988), Flora et al. (1995), and Smith et al. (1998) found that succimer significantly reduced both blood and brain lead levels in rats. In contrast, a recent study in adult rhesus monkeys found that succimer treatment measurably reduced lead levels in blood but not brain (Cremin et al. 1999). The recent studies of succimer efficacy that included cognitive assessments have also yielded inconsistencies between species. Cognitive functioning was not improved by succimer treatment in the recent TLC clinical trials with children (Rogan et al. 2001), whereas a significant benefit was seen in recent studies with juvenile nonhuman primate (Laughlin and Smith 2001; Laughlin et al. 1999) and rat (Stangle et al. 2003) models of childhood lead exposure. The basis for these inconsistencies between the rodent and primate studies is not clear. However, two possibly important factors may be differences in the lead exposure history of the subjects and/or the functional duration of succimer treatment (i.e., considering species differences in metabolic rate). In particular, the results presented here suggest that chelation treatment may not have been of sufficient duration in the human and adult nonhuman primate studies to be maximally effective in terms of reducing brain lead levels.

We observed a significant increase (i.e., rebound) in blood lead levels but not brain lead levels after both chelation regimens. Rebounds in blood lead levels have been reported after succimer treatment in nonhuman primates (Smith et al. 2000b) and in humans (Chisolm 2000; Graziano et al. 1985, 1988, 1992; Liebelt et al. 1994; Liu et al. 2002; Rogan et al. 2001). The consistency of this rebound across laboratory (rodent and primate) and clinical studies, including the recent TLC study (Rogan et al. 2001), demonstrate the importance of mobilized lead from endogenous sources such as the skeleton as a predominant contributor to the rebound, although reexposure to environmental lead may also have occurred in the clinical studies.

The rebound in blood lead levels observed here was not accompanied by a rebound in brain lead levels after either one or two cycles of succimer. The most likely explanation for this is that the lead concentration gradient between the blood and the brain postchelation continued to favor brain lead efflux, because of the slower reduction in brain lead levels relative to blood lead levels. Nonetheless, it is likely that the rebound in blood lead levels may have reduced the rate of decline in brain lead levels by reducing the concentration gradient between blood and brain lead postchelation. However, the larger within-group variance in brain lead levels compared with blood lead levels may have limited our ability to detect a rebound in brain lead levels.

In clinical practice, decisions about chelation therapy are based on blood lead levels. However, the present results raise concerns about the adequacy of this practice. As noted above, the present findings demonstrate that after cessation of lead exposure, reductions in brain lead levels lag behind blood lead reductions in both nonchelated and chelated animals, though particularly in the latter. This finding is consistent with results from earlier rodent and nonhuman primate studies (Cremin et al. 1999; Smith et al. 1998). An obvious consequence of this lag is that brain lead levels are likely to still be elevated at times that blood leads have reached some lower value that may no longer indicate the need for additional chelation. For example, consider the data for the low and medium exposure groups in the present study (the range of blood lead levels that approximates those seen clinically): Immediately after the first chelation treatment (PND62), all 15 animals in these two exposure groups had blood lead levels at or below the analytic detection limit (5 µg/dL), whereas their brain lead levels remained quite elevated and to varying degrees (i.e., mean, 423 ± 197; range, 200-941 ng/g, compared with expected brain lead levels in non-lead-exposed animals of ~50 ng/g dry weight). These findings, as a group, point to serious limitations in using blood lead level as an indicator of brain lead when making decisions about the need for chelation therapy, particularly after a single chelation regimen when decisions are being made about the need for additional regimens.

Our findings have implications for the clinical use of succimer and its potential to ameliorate lead-induced cognitive dysfunction. Some studies have suggested that declines in blood lead levels in children are associated with improved cognitive outcomes (Ruff et al. 1993; Tong et al. 1998). Given the present finding that succimer treatment reduced blood and brain lead levels significantly faster than did vehicle treatment (i.e., simple abatement), it follows that therapeutic use of the drug would reduce the amount of time that brain lead levels are elevated. As a result, the severity of the cognitive dysfunction should be reduced, based on evidence that lead interferes with brain development (e.g., Wilson et al. 2000). However, the TLC study, which is the only clinical study to date examining neuropsychologic functioning in lead-exposed subjects receiving succimer (Rogan et al. 2001), was unable to detect a significant benefit of succimer in terms of cognitive outcomes (relative to placebo), despite a significant lowering of blood lead levels in the treated subjects. The present findings suggest that although the treatment regimen used in the TLC study was sufficient to reduce blood lead levels below the level of concern in that study (15 µg/dL), it is likely that brain lead levels remained elevated after the cessation of treatment, because of the substantial lag in reduction of brain lead compared with blood lead levels. In the present study, the average blood lead level before receiving a second course of succimer treatment was < 15 µg/dL for all exposure groups; yet this second regimen produced a very significant further reduction in lead levels in both blood and brain for all groups. Thus, the present results suggest that treatment regimens may need to extend beyond the point at which blood lead levels have dropped to some "acceptable" low level in order to achieve the greatest possible benefit in terms of brain lead reduction and hence in terms of minimizing cognitive dysfunction.

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