Project #4 With the exception of research on lead, alterations in cognitive and behavioral function as a result of exposure to metals has to date received little systematic attention. Even less attention has been placed on the effects of exposures to combinations of metals or such exposures on a background of external environmental stressors--scenarios that are unfortunately all too common. The use of animal models to study the neurotoxic effects of such exposures allows for more tightly controlled experimental design than is possible in human studies and allows for a more in depth examination of the effects of the exposures on the nervous system and the mechanisms that underlie those effects. The enhanced understanding of the sites and mechanisms of the toxic action of these exposures that animal models can provide may result in development of more effective interventions. Development in the nervous system is marked by tremendous cellular plasticity as the highly intricate and specific connections within and between brain regions that provides the basis for intellectual and behavioral functioning are established. As such development is a period of unique susceptibility to the toxic actions of environmental contaminants. Two important mechanisms by which such contaminants can adversely affect the proper establishment of neuronal structure are disruption of normal synaptic transmission, which can have dramatic effects on cellular plasticity, and the induction of cell death. Such effects at the cellular level could lead, at the behavioral level, to deficits in a variety of functions including intellectual, and social behaviors. In this project (#4), we propose to examine neurotoxic effects in juvenile rats of in utero and postnatal exposure to individual metals found in mining waste (chat) from the Tar Creek Superfund site, specific mixtures of these metals, and actual chat from the site. In addition, we will explore how stress may modify the effects of metal exposures, as the psychological stresses that accompany life at a Superfund site have been raised as an issue of concern in the community in Tar Creek. Our aim is that these animal studies will help elucidate mechanisms of toxicity responsible for behavioral outcomes of concern to the community and in so doing complement the research conducted in Project #1. To accomplish this we will look at both the cellular and behavioral levels in our rat models, and take advantage of experiments being conducted as part of Projects #2 and #3 so that the exposures in our experiments reflect the actual exposures experienced by the Tar Creek community. When data from Project #4 are combined with exposure assessment in Project #2 and body burden data from Project #3, we will be able to better identify which routes of exposure result in the most significant neurological effects and the contribution of manganese and lead in chat to the neurological impacts of exposure to the chat. Thus, we will improve our understanding of the neurological effects of exposure to mixtures of metals, and in so doing, support our overall goal to craft optimal strategies in Tar Creek to reduce the neurological effects of toxic metals in humans.