Mechanisms of joint neurotoxicity of n-hexane, methyl isobutyl ketone and O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens

MB Abou-Donia, ZH Hu, DM Lapadula and RP Gupta

Department of Pharmacology, Duke University Medical Center, Durham, North Carolina.

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)

Volume 257, Issue 1, pp. 282-289, 04/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics