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The joint neurotoxic action of inhaled methyl butyl ketone vapor and dermally applied O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens: potentiating effect.

Abou-Donia MB; Lapadula DM; Campbell G; Abdo KM
Toxicol Appl Pharmacol 1985 Jun; 79(1):69-82
The neurotoxic effects of combined inhalational exposure to methyl- butyl-ketone (591786) (MBK) and dermal exposure to O-ethyl-O-4- nitrophenyl-phenylphosphonothioate (2104645) (EPN) were studied in hens. Leghorn-hens were treated topically with 0 or 1.0mg/kg EPN applied to the back of the neck daily, 5 days/week for 90 days and simultaneously exposed to 0, 10, 50, or 100 parts per million (ppm) MBK vapor. Surviving hens were maintained for 30 days after the last exposure and observed for clinical signs of toxicity. Dead and surviving birds at the end of the 30 day period were examined for histopathological abnormalities in the spinal cord and sciatic, tibia, and peritoneal nerves. The symptom and histology data were used to calculate neurotoxicity indices (NTIs). Leghorn-hens were injected intraperitoneally with 0 or 5 millimoles per kilogram MBK daily for 3 days. Liver microsomes were isolated and incubated with carbon-14 labeled EPN. The extent of EPN metabolism was determined. EPN alone caused mild ataxia that eventually progressed to severe ataxia. MBK alone caused mild ataxia throughout the study. EPN plus MBK caused severe ataxia that progressed to complete paralysis. No neuropathological changes were induced by MBK or EPN alone. Combined MBK and EPN exposure caused Wallerian type degeneration and paranodal axonal swelling in the spinal cord. The extent of the lesions and the number of hens affected increased with increasing MBK dose. The NTIs for birds exposed to 1.0mg/kg EPN or 100ppm MBK alone were 7.5 and 4.2, respectively. The NTIs for hens exposed to 1.0mg/kg EPN plus 10, 50, and 100ppm MBK were 13.6, 17.9, and 22, respectively. Hepatic microsomes from MBK treated hens caused a 303% increase in metabolism of EPN to 0-ethyl-0-4-nitrophenyl- phenylphosphonate (EPN-oxon) relative to microsomes from untreated birds. The authors conclude that 90 days dermal exposure to EPN combined with inhalation exposure to MBK vapor greatly enhances the neurotoxic effects of both in hens. The enhanced neurotoxicity may be due, at least in part, to MBK increasing the metabolism of EPN to its more neurotoxic metabolite EPN-oxon.
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Skin-exposure; Inhalation-studies; Ketones; Organo-phosphorus-pesticides; In-vivo-studies; Laboratory-animals; Synergism; Spinal-cord; Histopathology; In-vitro-studies; Biotransformation
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
591-78-6; 2104-64-5
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Document Type
Journal Article
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Priority Area
Neurotoxic Disorders; Neurotoxic-effects
Source Name
Toxicology and Applied Pharmacology
Performing Organization
Duke University, Durham, North Carolina
Page last reviewed: September 2, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division