The neurotoxic action of inhaled technical grade methyl butyl ketone and dermally applied (O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) was studied. Three groups of five hens each were treated 5 days/week for 90 days with a dermal dose of 1.0 mg/kg of EPN (85%) on the unprotected back of the neck. These groups were exposed simultaneously to 10, 50, or 100 ppm of technical methyl butyl ketone (MBK; methyl n-butyl ketone:methyl isobutyl ketone, 7:3) in inhalation chambers. A fourth group was treated only with the dose of EPN and a fifth group with only 100 ppm MBK. The control consisted of a group of five hens treated with a dose of 0.1 ml acetone. Treatment was followed by a 30-day observation period. Simultaneous exposure to EPN and MBK greatly enhanced the neurotoxicity produced when compared to the neurotoxicity produced by either chemical when applied alone. Continued exposure to EPN and MBK resulted in earlier onset and more severe signs of neurotoxicity than exposure to either individual compound. The severity and characteristics of histopathologic lesions in hens given the same daily dermal dose of EPN in combination with inhaled MBK depended on the MBK concentration. Histopathologic changes were more severe and prevalent in the 100 ppm MBK:1 mg/kg EPN group than in the others. In this group, Wallerian-type degeneration was seen along with paranodal axonal swellings. The morphology and distribution of these lesions were characteristic of those induced by MBK. In the 50 ppm MBK:1 mg/kg EPN group axonal swelling was evident but not clearly identifiable as paranodal. Hens treated with 10 ppm MBK:1 mg/kg EPN had minimal lesions with low incidence of axonal swellings. These were not as large as those seen in MBK neurotoxicity, but instead resembled the histopathologic lesions caused by EPN. The results indicate that the combined treatment gave a value for neurotoxicity coefficient which was two times the additive neurotoxic effect of each treatment alone. Pretreatment with three daily ip doses of 5 mmol/kg technical grade MBK or methyl n-butyl ketone (MnBK), equally increased chicken hepatic microsomal cytochrome P-450 content. Also, hepatic microsomes from MBK-treated hens metabolized [14C]EPN in vitro to [14C]EPN oxon to a much greater extent than those from control hens. These results suggest that MBK potentiates the neurotoxic effect of EPN, at least in part, by increasing the metabolic activation of EPN to the more neurotoxic metabolite EPN oxon. A similar mechanism may account for the potentiating effect of EPN on MBK neurotoxicity, by increasing the formation of the more neurotoxic agent 2,5-hexanedione.
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