Mechanisms of joint neurotoxicity of n-hexane, methyl isobutyl ketone and O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens.
Abou-Donia-MB; Hu-Z; Lapadula-DM; Gupta-RP
J Pharmacol Exp Ther 1991 Apr; 257(1):282-289
A study was conducted to evaluate the role of the induction of cytochrome-P-450 (P450) isozymes by concurrent exposure to methyl- isobutyl-ketone (108101) (MiBK), n-hexane (110543) and O-ethyl-O-4- nitrophenyl-phenylphosphonothioate (2104645) (EPN) on the enhanced acute and delayed neurotoxicity of the mixture over single components and to correlate such effects with their ability to induce EPN metabolism in-vitro. EPN was applied dermally to leghorn- laying-hens at a dose level of 2.5mg/kg while MiBK (at 100, 250, 500 or 1000 parts per million (ppm)) and n-hexane (1000ppm) were administered via inhalation. Hens exposed to MiBK or n-hexane vapor did not exhibit any signs of toxicity. 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. Liver microsomal P450 content and phenobarbital inducible P450 enzyme activities were induced by treatment with MiBK alone or in combination with EPN. Microsomes from hens treated with EPN, n- hexane, MiBK or mixtures of the three demonstrated a significant enhancement of the biotransformation of EPN to the more neurotoxic oxidation metabolite O-ethyl-O-4-nitrophenyl-phenylphosphonate. These results suggested that the joint neurotoxic action of aliphatic hexacarbon solvents and organophosphorus compound induced neurotoxicity is mediated, at least in part, through metabolic activation of these chemicals. These results also underlined the short term risk and long term hazard resulting from exposure to mixtures of chemicals.
NIOSH-Publication; NIOSH-Grant; Nervous-system-disorders; Metabolic-study; Laboratory-animals; Solvent-vapors; Organo-phosphorus-compounds; Neurotoxic-effects; Solvents; Inhalation-studies; Skin-exposure
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
108-10-1; 110-54-3; 2104-64-5
Journal of Pharmacology and Experimental Therapeutics
Duke University, Durham, North Carolina