| Citation | Dr John E Casida (Professor of Entomology, Director of the Pesticide Chemistry and Toxicology Laboratory, and Principal Investigator of the National Institute of Environmental Health Sciences Program Project at the University of California at Berkeley) is recognized as the world's leading authority on the toxicology of pesticides. He directs an exceptionally vigorous and intensive programme of fundamental research on the mode of action, metabolism, interactions and environmental fate of almost every major insecticide and of many other pesticides and toxicants. For more than four decades this research has been a basis for evaluating the benefits and risks of established pesticides and for the rational design and use of safer and more effective insecticides. Particularly significant advances have been made with natural product insecticides, pesticide toxicology, and inhibitors of the gamma-aminobutyric acid (GABA)-gated chloride channel.
Research on pyrethrum flower constituents and their synthetic analogues covering their chemistry, structure-activity relationships, metabolism, photodecomposition and mode of action, greatly influenced pyrethroid discovery, development and safety evaluation. The principal active ingredient of the botanical insecticide ryania wasa identified as 9,21-dehydroryanodine, which was convertid to [3H]ryanodine to locate the binding site in the calcium release channel of insect and mammalian muscle. Investigations on rotenone and lipid amides established their photosensitive sites, and routes of degradation to indicate modifications required for improved effectiveness. The vesicant and purported aphrodisiac from blister beetles, Spanish fly or cantharidin, was shown by radioligand approaches and target site isolation to inhibit protein phosphatase 2A, thereby explaining its profound pharmacological properties.
Toxicological investigations provided biochemical explanations for (a) the delayed neuropathy of tri-o-cresyl phosphate via a saliginen cyclic phosphate metabolite in hens, (b) the teratogenesis of several organophosphorus and methylcarbamate insecticides in avian species by inhibition of kynurenine formamidase, (c) the bioactivation of phosphorothiolate toxicants via highly-reactive sulfoxides, (d) the synergistic activity of methylenedioxyphenyl compounds by inhibition of cytochrome P450-mediated oxidases, (e) the mutagenesis and carcinogenesis of several nematicides and herbicides via haloacrolein metabolites, and (f) the mode of action of dichloroacetamide safeners for thiocarbamate herbicides in plants by serving as inducers of detoxification for the important organophosphorus and methylcarbamate insecticides.
Fortuitously discovered simple and highly toxic bicyclophosphates and bicycloorthocarboxylates had a totally unexpected mode of action, established by receptor binding and neurobiology studies with radiolignds (known commonly as [35S]TBPS and [34]EBOB), as non-competitive blocking of the GABA-gates cholride channel. Their binding site is closely coupled to that of dieldrin, toxaphene, lindane and their analogues, thereby defining the mode of action of polychlorocycloalkane insecticides after 3 billion pounds of use. The discoveries were then applied to rational design of totally new classes of insecticides, leading to 1,4-disubstituted-2,6,7-trioxabicyclo[2.2.2]-octanes and 2,5-disubstituted-1,3-dithianes, which are non-halogenated and non-phosphorus compounds of unusually simple chemical structure, some of which are more active than many commercial compounds. These developments provide powerful neurochemical probes, pointing ways to new insecticides working at an underutilized target in the GABAergic system. |