It has been demonstrated that lead exposure is associated with lowered IQ scores in children, but the specific behavioral processes impaired and the underlying neurobiological substrates remain unknown. Because IQ tests assess, in the aggregate, verbal, spatial, memory, problem- solving, attention, and speed components of information processing, impairment of these components in different combinations can yield the same total IQ score, thus masking specific deficits. Studies of lead exposure in experimental animals reveal deficits in memory, attention, and speed of processing, and many have linked these behavioral deficits to disruptions of mesolimbic and mesofrontal dopaminergic neurotransmitter systems which project to nucleus accumbens and prefrontal cortex. The proposed study is the first to attempt to bridge these human and experimental animal findings. It hypothesizes that behavioral functions for which prefrontal dopamine system mediation has been shown to be critical will also be adversely affected by increasing blood lead levels in humans. This proposal requests 60 months of support to longitudinally evaluate these behavioral functions and blood lead levels at 6 month intervals in a cohort of 275 children enrolled in an ongoing study. Assessments include a) the memory, inhibition, and shifting set functions of the dorsolateral prefrontal cortex, b) processes of attentional engagement and disengagement, vigilance, active and passive inattention, and c) speed of information processing. The inclusion of standardized global assessments at the 30 and 60 month time points (Bayley 2 and WPPSI-R, respectively) permits an assessment of the relative sensitivity of the global and specific measures of behavioral function and characterizes the cohort relative to those employed in previous longitudinal studies. if this proposed study confirms that lead exposure appears to disrupt cognitive functions known to involve mesofrontal dopaminergic systems, it raises the possibility that lead exposure could act as a predisposing factor in other conditions associated with dopaminergic system disruptions, such as attention deficit disorder, drug abuse and neurologic diseases such as Parkinson's. Furthermore, delineation of the specific behavioral processes impacted by lead exposure should serve as the most cogent guide for any development of behavioral or chemical therapeutics for lead-exposed populations and the blood lead levels at which such effects occur should provide the most cogent guide to any further revision of the definition of adverse blood lead concentrations in a regulatory context.
