Electrophysiological and biochemical effects of single and multiple doses of the organophosphate diazinon in the mouse.
Diazinon is an organophosphorus compound (OP) widely used in pesticides. The relationship between dose of diazinon, inhibition of acetylcholinesterase, and effect on neuromuscular transmission has been studied in a mouse model. Inhibition of acetylcholinesterase activity occurred within 1 h, was maximal by 3 h and remained inhibited for at least 24 h. Blood, brain, diaphragm, and soleus acetylcholinesterase activities were differentially affected by diazinon. Brain and soleus activities were not affected by low doses. Multiple daily dosing of diazinon caused a cumulative decrease in acetylcholinesterase activity, although to a lesser extent in brain and soleus. Diazinon had no effect on the activity of neuropathy target esterase. Plasma and brain levels of diazinon peaked at 15 min after dosing and declined with a half-life of 2.5 h. Metabolic products of diazinon were cleared from the urine within 24 h. Increased miniature end-plate current half decay times occurred in a dose-dependent manner. Single doses of diazinon caused an increase in the jitter (variability of latencies) of evoked action potentials recorded in the diaphragm but did not affect end-plate potential (EPP) jitter. Multiple lower doses of diazinon caused an increase in EPP jitter after 28 days. This effect on nerve function was delayed and occurred when acetylcholinesterase activity had returned to control levels. The results indicate that diazinon produces long-term electrophysiological changes in neurotransmission following repeated dosing in the mouse. This has implications for the current use of diazinon; however, there is a need to further define the mechanism of this effect.
de Blaquière
G E
GE
Department of Environmental and Occupational Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom.
Waters
L
L
Blain
P G
PG
Williams
F M
FM
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D003964:Diaphragm / Q000187:drug effects / Q000201:enzymology; D003976:Diazinon / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019054:Evoked Potentials, Motor / Q000187:drug effects* / Q000502:physiology; D007306:Insecticides / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009045:Motor Endplate / Q000187:drug effects* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D011930:Reaction Time / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase; D003976:Diazinon