title: Organophosphorus-induced delayed neurotoxicity: a comparative study of the effects of tri-ortho-tolyl phosphate and triphenyl phosphite on the central nervous system of the Japanese quail.
abstract: The neurotoxic effects of single oral doses of tri-ortho-tolyl phosphate (TOTP) (500 mg/kg body weight) or single subcutaneous injections of triphenyl phosphite (TPP) (62.5-500 mg/kg body weight) were investigated in the Japanese quail (Coturnix coturnix japonica). Oral doses of TOTP resulted in no detectable clinical signs while injections of TPP resulted in mild ataxia to severe paralysis depending upon the dosage level. At 24 hr postdosing, whole-brain activity of neuropathy target esterase (NTE) was inhibited by 90% in birds exposed to TOTP and by 11-87% in birds injected with TPP. Oral doses of TOTP resulted in only sparse Fink-Heimer silver-impregnated degeneration in the white matter of the cerebellum with no degeneration noted in any other region of the brain. Injections of TPP resulted in widespread degeneration in large numbers of brainstem nuclei and tracts and in all cerebellar foliae and deep nuclei. These results indicate that the Japanese quail responds differentially to exposure to TOTP and TPP. Oral doses of TOTP do not result in clinical signs or in significant amounts of degeneration in the brain even though NTE activity is inhibited by 90%. In contrast, injections of TPP at higher dosage levels yield severe clinical signs, widespread axonal and terminal degeneration in the CNS, and significant inhibition of NTE activity. This sharp dichotomy in relative sensitivity to TOTP and TPP in the Japanese quail suggests that each compound may have its own unique effect on CNS structure and function. In addition, the relationship between levels of NTE inhibition and the onset of clinical signs or neuropathology remains unclear.
authors.affiliation: Department of Animal Science, Michigan State University, East Lansing 48824, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Varghese
authors.forename: S J
authors.initials: SJ
authors.lastname: Bursian
authors.forename: C
authors.initials: C
authors.lastname: Tobias
authors.forename: D
authors.initials: D
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000201:enzymology*; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003370:Coturnix; D004305:Dose-Response Relationship, Drug; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000633:toxicity; D017905:Phosphites / Q000633:toxicity*; D013997:Time Factors; D014317:Tritolyl Phosphates / Q000633:toxicity*
chemical_list: D009943:Organophosphorus Compounds; D017905:Phosphites; D014317:Tritolyl Phosphates; C013318:triphenyl phosphite; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; C025541:tri-o-cresyl phosphate