Comparisons of the acute effects of cholinesterase inhibitors using a neurobehavioral screening battery in rats.
The clinical signs of intoxication produced by cholinesterase inhibitors, many of which are used as pesticides, are considered important information for regulatory purposes. We conducted acute studies of cholinesterase inhibitors to compare their effects as determined by a functional observational battery (FOB) and motor activity. The acute effects of two carbamates (carbaryl, aldicarb) and five organophosphates (OP) (chlorpyrifos, diazinon, parathion, fenthion, and diisopropyl fluorophosphate, or DFP) were evaluated on the day of dosing at the time of peak effect, at 1 and 3 days, and 1 week after dosing (oral gavage, in corn oil). A high dose was selected that produced clear cholinergic signs, and lower doses were chosen to produce a range of effects. Generally all cholinesterase inhibitors produced autonomic signs of cholinergic overstimulation (salivation, lacrimation, and miosis), hypothermia, mild tremors and mouth-smacking (chewing motions), lowered motor activity, decreased tail-pinch response, and altered neuromuscular function (gait changes and increased foot splay). The measures generally found to be most sensitive on the day of dosing were body temperature, motor activity, gait, and the presence of mouth-smacking and fine tremors. However, no single measure was the most sensitive across all compounds; for example, the lowest dose of fenthion decreased motor activity by 86% but did not alter the tail-pinch response, whereas the lowest dose of parathion did not lower activity but did decrease the tail-pinch response. For some measures, differences in the slopes of the dose-response curves were evident. Many effects were still observed at 24 h, but recovery was apparent for all compounds. Interestingly, residual effects at 72 h were obtained with the carbamates (carbaryl, aldicarb) as well as with the Op fenthion, but not with the other compounds. Thus, the overall clinical picture of toxicity was similar for these cholinesterase inhibitors, but compound-specific differences emerged in terms of the individual measures, dose-response, and time course.
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US Environmental Protection Agency, Neurotoxicology Division (MD-74B), Research Triangle Park, NC 27711, USA.
D000448:Aldicarb / Q000633:toxicity; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D012721:Carbaryl / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007306:Insecticides / Q000633:toxicity*; D007531:Isoflurophate / Q000633:toxicity; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009069:Movement Disorders / Q000209:etiology; D009469:Neuromuscular Junction / Q000187:drug effects; D010278:Parathion / Q000633:toxicity; D051381:Rats; D012018:Reflex / Q000187:drug effects; D018675:Toxicity Tests
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D007531:Isoflurophate; D010278:Parathion; D000448:Aldicarb; D012721:Carbaryl