Superfund Research Program
An Investigation of the Behavioral Toxicity of Lead
Although the United States has made great progress in the reduction of lead (Pb) emissions and in the prevention of human exposure, lead poisoning is still one of the most common environmental health problems affecting young children. Lead poisoning affects virtually every system in the body. Childhood exposure to lead, even at levels that do not produce signs of overt toxicity, is associated with decreased intelligence, impaired neurobehavioral development, decreased stature and growth, and impaired hearing acuity.
The only treatment currently available for children with elevated blood lead levels is to administer a chelating agent that binds to the lead. Chelated lead is then eliminated from the body in the urine. Scientists at Cornell University are conducting two interrelated projects to test the efficacy of the chelating agent dimercaptosuccinic acid (DMSA or Succimer(r)) in removing lead from the body and in reducing the enduring cognitive impairments that result from early exposure to lead. DMSA is widely used clinically, yet there is no information available about whether chelation with this drug reduces lead-induced neurocognitive deficits, or whether the drug itself has adverse effects on the developing brain. The studies at Cornell are designed to answer both of these questions.
In preparation for studies examining the efficacy of the drug in preventing lead-induced cognitive dysfunction, it was necessary for the Cornell scientists to first conduct a series of laboratory studies with rats to determine the DMSA treatment regime that is most effective in removing lead from various tissues, particularly the brain. This critical component of the evaluation of the drug's therapeutic potential must be obtained from animal studies because information concerning the efficacy of DMSA in removing brain lead is impossible to obtain from clinical studies. The Cornell researchers discovered that prolonged DMSA treatment is more effective in reducing brain lead levels than was a shorter regimen. They also identified numerous differences in the rate and magnitude of the chelation response of lead in the brain and lead in the blood. This indicates that the blood lead response to chelation cannot be used to accurately estimate a drug's efficacy in removing lead from the brain, which is the major target organ of interest in studies of low-level exposure.
In parallel, the Cornell scientists are conducting behavioral studies to identify the specific cognitive functions that exhibit lasting changes as a result of early exposure to low levels of lead. This information is needed to identify the most sensitive endpoints to include in the subsequent study on DMSA efficacy. In these studies, the Cornell researchers have administered tasks that tap a broad range of cognitive functions and have applied novel data analytic techniques. They have used in-depth analysis to identify the types of errors committed and the stage of learning that is affected, rather than concentrating on overall rate of learning. These techniques, coupled with the broad range of tasks administered, have provided insight into the specific cognitive processes that are impaired, as well as those that are spared, by early lead exposure.
These studies have demonstrated that a short period of early lead exposure produces a lasting impairment in associative ability - the ability to associate particular environmental cues with reward. These studies also revealed that the ability to sustain and focus attention exhibits lasting impairment in adult animals that were exposed to lead early in life. Lead-exposed rats exhibit lasting changes in emotional reactivity, specifically in their reaction to making errors. In contrast, several other cognitive functions appear to be spared, including long- and short-term memory, inhibitory control, and distractibility. This delineation of the specific functions affected by early lead exposure may help explain the problematic classroom behavior and increased delinquency of lead-exposed children, as well as their IQ deficits. Specifically, disruptive classroom behavior may reflect deficits seen in these studies - reduced reaction to negative reinforcement and a reduced ability to modify behavior to attain positive reinforcement. Deficient sustained attention, also seen in these studies, may also contribute to these behavior problems. In contrast, the evidence that lead exposure does not impair inhibitory control or distractibility argues against the notion that these behavior problems reflect an "ADHD-like" disorder.
There are several implications of these findings. First, the completed studies on DMSA efficacy demonstrate the efficacy of the drug in removing brain lead, with a regimen similar to that used clinically. Second, the in-depth analysis of performance in the battery of cognitive tasks has provided new information on specific cognitive functions that are impaired by early lead exposure, information that has not been provided by the human studies due to a reliance on global measures of functioning such as IQ. This information is critical to the design of optimal educational intervention for lead-exposed children. Third, this delineation of the spared and impaired functions sheds light on specific neural systems that are likely to be impaired and those that are not, information that is important for developing pharmacotherapy strategies to ameliorate lead-related cognitive deficits for children exposed to lead. Finally, building on this delineation of the lead-induced cognitive impairment, a large study is currently underway at Cornell that will provide information on the efficacy of DMSA in reversing these lead-induced cognitive deficits, as well as information on the potential neurotoxic effects of the drug itself. This information is needed to evaluate the clinical utility of this important new chelating agent.
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To learn more about this research, please refer to the following sources:
- Garavan H, Morgan RE, Levitsky DA, Hermer-Vasquez L, Strupp BJ. 2000. Enduring effects of early lead exposure: Evidence for a specific deficit in associative ability. Neurotoxicol Teratol 22(2):151-164. PMID:10758344
- Morgan RE, Levitsky DA, Strupp BJ. 2000. Effects of chronic lead exposure on learning and reaction time in a visual discrimination task. Neurotoxicol Teratol 22(3):337-345. PMID:10840177
- Hilson J, Strupp BJ. 1997. Analyses of response patterns clarify lead effects in olfactory reversal and extra-dimensional shift tasks: Assessment of inhibitory control, associative ability, and memory. Behav Neurosci 111(3):532-542.
- Alber SA, Strupp BJ. 1996. An in-depth analysis of lead effects in a delayed spatial alternation task: assessment of mnemonic effects, side bias and proactive interference. Neurotoxicol Teratol 18(1):3-15. PMID:8700040
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