Mechanisms of joint neurotoxicity of n-hexane, methyl isobutyl ketone and O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens.
The joint neurotoxic action of simultaneous exposure to vapors of n-hexane and methyl iso-butyl ketone (MiBK) and dermally applied O-ethyl O-nitrophenyl phenylphosphonothioate (EPN) was studied in groups of five adult hens. Four groups of hens were concurrently exposed to a dermal 2.5 mg/kg of EPN, 1000 ppm of n-hexane and 100, 250, 500 or 1000 ppm of MiBK. Two groups were each exposed to binary mixtures of a dermal dose of 2.5 mg/kg of EPN and 250 ppm of MiBK or 1000 ppm of n-hexane. Another three groups of hens were exposed to either 250 ppm of MiBK, 1000 ppm of n-hexane or a dermal dose of 2.5 mg/kg of EPN. A Group of hens was kept untreated. All hens were terminated after 30 days of treatment. Hens exposed to MiBK or n-hexane vapor did not exhibit any toxicity signs. In contrast, hens treated with EPN alone or in combination with n-hexane and/or MiBK developed acute cholinergic and delayed neurotoxicity signs. Hen brain acetylcholinesterase and neurotoxic esterase activities were inhibited in hens treated concurrently with EPN, n-hexane and MiBK. MiBK alone or in combination with EPN and n-hexane induced liver microsomal cytochrome P-450 content and phenobarbital-inducible cytochrome P-450 enzyme activities. Microsomes from hens treated with EPN, n-hexane, MiBK or mixtures of EPN, n-hexane and MiBK significantly enhanced the biotransformation of EPN to the more neurotoxic oxidation metabolite O-ethyl O-4-nitrophenyl phenylphosphonate.(ABSTRACT TRUNCATED AT 250 WORDS)
Abou-Donia
M B
MB
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina.
Hu
Z H
ZH
Lapadula
D M
DM
Gupta
R P
RP
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002645:Chickens; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006586:Hexanes / Q000633:toxicity*; D007527:Isoenzymes / Q000032:analysis; D008742:Methyl n-Butyl Ketone / Q000633:toxicity*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009420:Nervous System / Q000187:drug effects*; D004849:Phenylphosphonothioic Acid, 2-Ethyl 2-(4-Nitrophenyl) Ester / Q000378:metabolism / Q000633:toxicity*
D006586:Hexanes; D007527:Isoenzymes; D004849:Phenylphosphonothioic Acid, 2-Ethyl 2-(4-Nitrophenyl) Ester; C026385:n-hexane; D008742:Methyl n-Butyl Ketone; D003577:Cytochrome P-450 Enzyme System; C005458:methyl isobutyl ketone