Many chemicals produce neurotoxicity in humans and some animal species. Toxicological studies and epidemiological evidence implicated that simultaneous exposure to the organophosphorus insecticide leptophos and the industrial solvents, n-hexane and toluene, caused an outbreak of neuropathy among workers handling these chemicals. Leptophos belongs to a group of chemicals capable of causing delayed neurotoxicity (OPIDN). The adult hen is the animal of choice to study OPIDN since rodents are not as sensitive. n-Hexane and some of its related chemicals produce neurotoxicity in humans and in animals. Toluene has been implicated in causing neurologic deficits in humans. Because humans are often exposed concurrently to chemicals from these groups, we have been studying the neurotoxicity produced by these chemicals alone and in combination. During the first phase of these studies we have tested the hen as a laboratory animal to investigate the neurotoxicity produced by simultaneous administration of the organophosphorus insecticide EPN (O-ethyl 0-4-nitrophenyl phenylphosphonothioate) and n-hexane, 2-hexanone (MnBK), 2,5-hexanediol (2,5-HDOH), and 2,5-hexanedione (2,5-HD). The results showed that simultaneous exposure to EPN and MnBK potentiated neurotoxicity produced by each chemical alone. Also, the non-neurotoxic methyl iso-butyl ketone (MiBK) synergized the neurotoxicity of the weak neurotoxicant n-hexane. The mechanism of this joint neurotoxic action seems to be related, at least in part, to the induction of liver microsomal cytochrome P-450. We propose to investigate the molecular mechanism(s) for aliphatic hexacarbon-induced neurotoxicity and liver microsomal enzyme induction by these neurotoxicants. This will include the isolation of the cross-linked neurofilament proteins from hens exposed to vapors of n-hexane/MiBK and the use of these proteins as markers for aliphatic hexacarbon neurotoxicity and neurotoxic esterase for EPN-induced neurotoxicity. The cytochrome P-450 form(s) that is inducible by hen exposure to n-hexane related chemicals and EPN alone and together will be determined in hen liver microsomes. The in vitro metabolism of [14C]labeled n-hexane, 2,5-HDOH, 2,5-HD, and EPN by chicken hepatic microsomes will be determined. Absorption and pharmacokinetics of a single dermal dose of [14C]EPN following repeated doses of n-hexane and its metabolites will be studied. The neurotoxicity of toluene vapor will be determined following inhalation by chickens. The joint neurotoxic action of toluene, n-hexane, and/or EPN will be investigated.
