The list of 22 chemicals of specific interest to the Superfund cleanup efforts provided to NIEHS by the EPA Office of Solid Waste and Emergency, contains eight metals: lead, chromium, arsenic, cadmium, zinc, copper, mercury, and nickel. Many human health problems, including cancer and heart/circulatory diseases, are linked to external exposure to toxic metals or disruption of normal cellular processes involving endogenous metals. The overall objectives of the Program Project Toxic Metals in the Northeast: From Biological to Environmental Implications are to understand, assess and attenuate the adverse effects on human health resulting from environmental exposure to the toxic metals lead, chromium, arsenic, cadmium, zinc, copper, mercury, nickel and iron. These toxic metals emanate from highly contaminated Superfund sites and lead to high levels of exposure to living organisms. Most of these same metals also are often found ubitquitously in low to moderate levels in the environment and lead to chronic low levels of exposure to living organisms. The combination of acute high level exposure to toxic metals coupled with chronic lower level exposure to toxic metals may result in unique biological and environmental consequences. The Program Project addresses these complex issues using a multidisciplinary approach. This Program Project consists of both biomedical and non-biomedical studies of toxic metals in the Northeast, and consists of 7 individual research projects (4 biomedical and 3 non-biomedical: biogeochemical; hydrogeological; ecological; and engineering) and 4 cores (Administrative Support Core, Molecular Biology Core, Inductively Coupled Plasma-Mass Spectrometer (ICP-MS) Core and Training Core). The participating faculty will create a unique intellectual interface among the various fields and thereby facilitate multidisciplinary integrated research and training. Biochemical and molecular biology studies (Project 1 - Induction of Oxidative Stress and Activation of Transcription Factors by Toxic Metals, Project 2 - Molecular Basis for Effects of Carcinogenic Metals on Inducible Gene Expression, and Project 3 - Effect of Toxic Metals on Heme Biosynthesis and Degradation in Hepatic and Erythroid Cells) and epidemiological studies (Project 4 - Epidemiology of Arsenic and Other Toxic Metals) will be directed toward elucidating the fundamental mechanisms of metal toxicity and measuring human exposure to toxic metals. The mechanisms of metal release and dispersion into the environment will be addressed using biogeochemical (Project 5 - Investigations of the Sources and Mobility of Lead and Cadmium in Soil, Soilwater, Groundwater and Vegetation in the Northeastern US.: Potential for Human Exposure), hydrogeological (Project 6 - Subsurface Transport and Fate of Cadmium, Arsenic, and Lead: Groundwater Flow and Chemical Speciation in Heterogeneous, Unconsolidated Geological Materials) and ecological (Project 7 - Variation in Bioaccumulation and Biomagnification of Metals in Lakes Throughout the Northeastern Region of the U.S.A.) approaches. Every Project will examine arsenic as well as other toxic metals. These studies should lead to significant new basic and applied research on metal toxicity and therefore should produce results that will lead to reduction of human exposure and reduction of human health risks due to toxic metals. The Training Core will produce a new kind of scientist, uniquely trained from a multidisciplinary approach, who will be able to tackle and solve future complex problems associated with environmental health.