Effect of subchronic dermal application of O-ethyl O-4-nitrophenyl phenylphosphonothioate on producing delayed neurotoxicity in hens.
Abou-Donia-MB; Graham-DG; Makkawy-A; Abdo-KM
Neurotoxicology 1983 Jan; 4(2):247-260
The effect of subchronic dermal application of O-ethyl-O-4- nitrophenyl-phenylphosphonothioate (2104645) (EPN) on delayed neurotoxicity was studied in hens. Technical grade (85 percent) EPN in acetone was applied in doses of 0.01 to 10 milligrams per kilogram (mg/kg) to the back of the neck of leghorn-hens for 90 days. Controls received vehicle, 5 or 10mg/kg tri-o-cresyl- phosphate (78308) (TOCP) (positive controls), or 1.0mg/kg parathion (56382) (negative controls). Hens treated with 2.5 to 10mg/kg EPN were also given atropine-sulfate (55481) (atropine) daily just prior to EPN for 5 or 6 days to protect against cholinergic effects. The animals were observed for signs of toxicity. Sciatic, tibial, and peroneal nerves, and the brain and spinal cord were taken from dead and all surviving hens at the end of the study and examined for histopathological changes. Plasma butyrylcholinesterase (BuChE) and brain acetylcholinesterase (AChE) activities were determined. All hens given 2.5 to 10mg/kg EPN developed signs of cholinergic poisoning despite being treated with atropine. The severity of the signs was dose dependent. Hens given parathion showed signs of cholinergic poisoning after 19 to 22 doses. TOCP did not induce cholinergic poisoning. All hens given EPN except those receiving the 0.01mg/kg dose developed signs of delayed neurotoxicity, such as ataxia, paralysis, and death, that were dose dependent. All animals given 10mg/kg TOCP developed paralysis and died after 43 to 95 days. Parathion did not induce delayed neurotoxicity. EPN and TOCP caused degeneration of axons and myelin in the spinal cord, except for 0.01mg/kg EPN which caused only poorly expressed changes. EPN and TOCP inhibited plasma BuChE to a greater extent than brain AChE activity. Parathion exerted a greater effect on brain AChE. The authors conclude that the threshold dose for inducing delayed neurotoxicity in hens is 0.01mg/kg EPN per day.
NIOSH-Grant; Sensitization; Toxic-materials; Enzymes; Body-regions; Tissue-distribution; Laboratory-animals; Toxic-effects; Enzyme-activity; Physiological-measurements; Tissue-disorders; Skin
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
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Duke University, Durham, North Carolina