Work will continue on studies concerned with the delayed toxicity of trialkyl phosphorothioate and phosphorodithioate esters in mammals. A variety of trialkyl phosphorothioates and phosphonothioates are currently being synthesized and evaluated for delayed toxic activity using the rat as the primary test animal. Since recent results have revealed that O,S,S-trimethyl phosphorodithioate also is delayed toxic, analogs of this compound will be examined. Because of the potent antagonistic activity of O,O,O-trimethyl phosphorothioate to the delayed toxicity of the O,O,S-trimethyl isomer, other isomeric O,O,O-trialkyl phosphorothioates and phosphorodithioates will be examined as antagonist. Sublethal chronic feeding studies with O,O,S-trimethyl phosphorothioate, with and without antagonist, are in progress. Studies on the mode of delayed toxic action will focus on O,O,S-trimethyl phosphorothioate. A methoxy-14C synthesis of this compound has been achieved and work is in progress on tissue localization of radioactivity and pharmacokinetics in the rat. Work also is in progress on the in vivo and in vitro inhibition of different esterases in different rat tissues, including carboxylesterase, cholinesterase and chymotrypsin. The effect of the antagonist O,O,O-trimethyl phosphorothioate on in vivo and in vitro inhibition of the esterases also is being examined.