Reactive intermediates are involved in the action of many toxicants. Detailed knowledge of the nature of those derived from pesticides (with their broad range of chemical structures and biological activities and inevitable exposure of humans) is particularly important so that any toxicological hazards can be anticipated. In this research, relationships between chemical reactivity and biological activity are evaluated at primary target sites and in relation to conjugate formation and derivatization of DNA and proteins. Reactive intermediates are identified in model chemical and photochemical systems, in enzyme preparations (e.g., cytochrome P-450- and FAD-dependent microsomal oxidases and gluthathione (GSH) S-transferases) and in rats and mice. 13C-Enriched compounds and 1H-13C correlated two-dimensional NMR spectroscopy are used to examine directly reactive intermediates in relevant systems which are also analyzed by GC-MS. The research concentrates on four types of pesticides, which are potential environmental contaminants with possible direct or derived mutagenic or carcinogenic activity. First, since diallate and its analogs are microsomally-oxidized to strongly mutagenic 2-halopropenals and ethylene dibromide gives thiiranium ions by GSH conjugation, the significance and balance of comparable processes are examined with 1,2-dibromo-3-chloropropane via 2- bromopropenal and bromochloroacetone as metabolic intermediates. Second, nitrofen is metabolically and photochemically reduced via mutagenic and highly reactive hydroxylamino and nitroso derivatives, the latter reacting with bioolefins to give nitroxide radicals. Therefore potential hazards from such products formed from other nitrodiphenyl ethers and chlordimeform and of imines from glyphosate are assessed. Third, the carcinogenic activity of alachlor may be associated with metabolic activation of the N-methoxymethyl substituent or with formation of reactive chloroacetanilide, benzoiminoquinone or nitroso/hydroxylamino metabolites; the former is the more likely from present work also concerned with N-methyl activation of other chloroacetanilides, daminozide and hexamethylphosphoramidate. Finally, tetrahaloalkanes (e.g., tralomethrin, dibrom and a dicofol impurity) undergo metabolic and photochemical activation to potentially toxic dihaloalkenes. Because some alkenes (e.g., methfuroxam and an allethrin photoproduct) undergo further epoxidation, a specific aim is to define the substituents and reactions that may create toxicological problems in formation and further activation of alkenes. The overall objectives are to recognize potentially hazardous compounds and to propose structural modifications to maximize the benefits and minimize the risks in pesticide use.
