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.