title: Major intermediates in organophosphate synthesis (PCl3, POCl3, PSCl3, and their diethyl esters) are anticholinesterase agents directly or on activation.
abstract: Three phosphotrichlorides [phosphorus trichloride (PCl(3)), phosphorus oxychloride (POCl(3)), and thiophosphoryl chloride (PSCl(3))] with an annual U.S. production of >500,000,000 pounds and their diethyl esters are intermediates in the production of organophosphorus pesticides, plastics, flame retardants, and hydraulic fluids. They are classified as highly toxic to mammals based on acute oral and inhalation data with rats. This study considers their mechanisms of toxicity. PCl(3) and POCl(3) inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) from several species with in vitro IC(50) values of 5-36 and 88-1200 microM, respectively; PSCl(3) is a less potent inhibitor. These phosphotrichlorides have high vapor toxicity to houseflies with in vivo inhibition of brain AChE activity correlating with mortality. PCl(3) and POCl(3) produce cholinergic poisoning signs on ip administration to mice, and all three phosphotrichlorides give marked in vivo inhibition of serum BChE but not brain AChE activity. PCl(3) is a direct acting AChE inhibitor. Our earlier proposed activation of POCl(3) is confirmed here by preparing pure Cl(2)P(O)OH and its potassium and dicyclohexylamine salts that reproduce the action of POCl(3) as in vitro AChE inhibitors and toxicants in mice. PSCl(3) on hydrolysis yields Cl(2)P(O)SH [which oxidizes with peracid to Cl(2)P(O)SOH] as the proposed activation product. Vapors of (EtO)(2)PCl, (EtO)(2)P(O)Cl, and (EtO)(2)P(S)Cl are lethal to houseflies as in vivo AChE inhibitors, the first two acting directly and the last one on oxidative activation to (EtO)(2)P(O)Cl (possibly by P450) or (EtO)(2)P(O)SCl (a phosphorylating agent in a peracid oxidation system). Thus PCl(3), (EtO)(2)PCl, and (EtO)(2)P(O)Cl act directly as AChE inhibitors whereas POCl(3) and PSCl(3) undergo hydrolytic activation and (EtO)(2)P(S)Cl undergoes oxidative activation. In contrast, the toxicity to mice of phosphofluorides [FP(O)Cl(2), F(Cl)P(O)OH, and F(2)P(O)OH; studied as model compounds for comparison] may be due to liberating fluoride ion.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
authors.forename: Yoffi
authors.initials: Y
authors.lastname: Segall
authors.forename: Gary B
authors.initials: GB
authors.lastname: Quistad
authors.forename: Susan E
authors.initials: SE
authors.lastname: Sparks
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000378:metabolism; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004952:Esters / Q000737:chemistry / Q000633:toxicity*; D006793:Houseflies / Q000201:enzymology; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000633:toxicity*; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007306:Insecticides / Q000138:chemical synthesis; D007928:Lethal Dose 50; D051379:Mice; D009943:Organophosphorus Compounds; D010084:Oxidation-Reduction; D017553:Phosphorus Compounds / Q000737:chemistry / Q000633:toxicity*; D010766:Phosphorylation; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D004952:Esters; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; D009943:Organophosphorus Compounds; D017553:Phosphorus Compounds; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D012697:Serine Endopeptidases