This is an interdisciplinary proposal involving 6 departments (biochemistry, botany, crop science, entomology, genetics, and statistics) which is primarily directed toward the determination of cellular and subcellular events associated with pesticide toxicity. There are also components on in vivo genetic effects and hazards to agricultural workers. A major effort is directed to elucidation of metabolic pathways involving oxidative and transferase enzymes. These studies include enzyme purification, enzyme reconstitution, and structure-activity relations. Also included will be cooperative studies concerning the neuropathological action of EPN isomers. Purification of cholinesterase from a number of animal sources will continue and a study of the biochemical differences among these enzymes will be undertaken. In studies on the mode of action of herbicides, attention will be given to the manner whereby membrane fluidity and permeability are altered through the use of fluorescent membrane probes. Ultrastructural examination will be used to confirm these studies. In studies on penetration in vivo, 13 toxicants will be studied by following cutaneous and oral administration comparing the rates of penetration. Genetic studies will be continued using Habrobracon as a model system to determine adverse effects of a number of toxicants on reproduction. Further, the disposition of methotrexate will be determined following oral administration, and detailed analysis of the mode of action will be undertaken.