title: A role for solvents in the toxicity of agricultural organophosphorus pesticides.
abstract: Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE); however, AChE-reactivating drugs do not benefit poisoned humans. We therefore studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents. Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and arterial lactate concentration were monitored for 12h to assess poisoning severity. Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest within 30 min, severe distributive shock and NMJ dysfunction, that was similar to human poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mM in poisoned pigs compared to 1.4 [0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include solvents as well as the AIs which currently dominate the assessment. Reformulation of OP insecticides to ensure that the agricultural product has lower mammalian toxicity could result in fewer deaths after suicidal ingestion and rapidly reduce global suicide rates.
authors.affiliation: Clinical Pharmacology Unit, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK. m.eddleston@ed.ac.uk
authors.forename: Michael
authors.initials: M
authors.lastname: Eddleston
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Street
authors.forename: Ian
authors.initials: I
authors.lastname: Self
authors.forename: Adrian
authors.initials: A
authors.lastname: Thompson
authors.forename: Tim
authors.initials: T
authors.lastname: King
authors.forename: Nicola
authors.initials: N
authors.lastname: Williams
authors.forename: Gregorio
authors.initials: G
authors.lastname: Naredo
authors.forename: Kosala
authors.initials: K
authors.lastname: Dissanayake
authors.forename: Ly-Mee
authors.initials: LM
authors.lastname: Yu
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Harald
authors.initials: H
authors.lastname: John
authors.forename: Sionagh
authors.initials: S
authors.lastname: Smith
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: John B
authors.initials: JB
authors.lastname: Harris
authors.forename: R
authors.initials: R
authors.lastname: Eddie Clutton
mesh_terms: D000383:Agriculture; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000506:poisoning*; D003512:Cyclohexanones / Q000737:chemistry*; D004117:Dimethoate / Q000008:administration & dosage / Q000506:poisoning*; D004655:Emulsions; D006801:Humans; D007306:Insecticides / Q000008:administration & dosage / Q000506:poisoning*; D019344:Lactic Acid / Q000097:blood; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D012131:Respiratory Insufficiency / Q000139:chemically induced; D012769:Shock / Q000139:chemically induced; D012997:Solvents / Q000737:chemistry*; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature
chemical_list: D002800:Cholinesterase Inhibitors; D003512:Cyclohexanones; D004655:Emulsions; D007306:Insecticides; D012997:Solvents; D019344:Lactic Acid; C036468:cyclohexanone; D004117:Dimethoate