The long term objective is to provide a means for reducing delayed neuropathy in man and animals exposed to certain organophosphates. As organophosphorus compounds are widely used today in agriculture and industry, risk is relatively high for accidental and occupational exposure. Although antidotes for acute toxicities are available, no specific treatment has been developed for the irreversible neuropathy that occurs weeks to months after exposure to some of these compounds. As recently demonstrated in our laboratory and others, adrenocorticoid hormones appear promising as agents to provide some moderation of the delayed neurotoxic effects of organophosphorus compounds. Using triorthotolyl phosphate (TOTP) to induce delayed neuropathy in chickens, we will examine a wide range of dietary concentrations of a natural corticoid, corticosterone, for effects on indices of this delayed neuropathy, such as clinical signs, histopathology, electrophysiology and neurotoxic esterase activity. We will observe effects of the corticosterone per se on the health of the birds by monitoring the heterophil/lymphocyte ratio, liver function, and feed efficiency. Also, as part of the work proposed, some properties of corticoids that may be relevant in moderation of organophosphate induced delayed neuropathy will be examined. These will include type of corticoid, by using a mineralocorticoid (deoxycorticosterone), a glucocorticoid (triamcinolone), and corticosterone, which has both properties, to modify TOTP-induced delayed neuropathy. The possibility that corticoids may alter metabolism of organophosphates, thereby providing protection, will be examined by comparing delayed neuropathy induced by a protoxicant (TOTP) with that induced by its active metabolite (phenyl saligenin phosphate) in the presence of corticosterone. The possibility that endogenous steroid may be substituting for exogenous steroid, as organophosphates inhibit steroidgenesis, will be examined by attempting to use ACTH rather than corticosterone to protect the birds from TOTP-induced delayed neuropathy. These studies should enhance our understanding of the basic pathogenetic mechanisms in organophosphate-induced delayed neurotoxicity, and, hopefully, lead to rational therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES003384-03S1
Application #
3250641
Study Section
Toxicology Study Section (TOX)
Project Start
1985-04-01
Project End
1988-11-30
Budget Start
1987-04-01
Budget End
1988-11-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Type
Schools of Veterinary Medicine
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24060
el-Fawal, H A; Ehrich, M F (1993) Calpain activity in organophosphorus-induced delayed neuropathy (OPIDN): effects of a phenylalkylamine calcium channel blocker. Ann N Y Acad Sci 679:325-9
Dyer, K R; el-Fawal, H A; Ehrich, M F (1991) Comparison of organophosphate-induced delayed neuropathy between branches of the tibial nerve and the biventer cervicis nerve in chickens. Neurotoxicology 12:687-95
el-Fawal, H A; Correll, L; Gay, L et al. (1990) Protease activity in brain, nerve, and muscle of hens given neuropathy-inducing organophosphates and a calcium channel blocker. Toxicol Appl Pharmacol 103:133-42
Lidsky, T I; Manetto, C; Ehrich, M (1990) Nerve conduction studies in chickens given phenyl saligenin phosphate and corticosterone. J Toxicol Environ Health 29:65-75
el-Fawal, H A; Jortner, B S; Ehrich, M (1990) Use of the biventer cervicis nerve-muscle preparation to detect early changes following exposure to organophosphates inducing delayed neuropathy. Fundam Appl Toxicol 15:108-20
el-Fawal, H A; Jortner, B S; Ehrich, M (1990) Modification of phenyl saligenin phosphate-induced delayed effects by calcium channel blockers: in vivo and in vitro electrophysiological assessment. Neurotoxicology 11:573-92
Jortner, B S; Shell, L; el-Fawal, H et al. (1989) Myelinated nerve fiber regeneration following organophosphorus ester-induced delayed neuropathy. Neurotoxicology 10:717-26
Dunnington, E A; Siegel, P B; Ehrich, M (1989) Differences in response of chickens from two genetic lines to diisopropyl phosphorofluoridate. Neurotoxicology 10:71-8
el-Fawal, H A; Jortner, B S; Ehrich, M (1989) Effect of verapamil on organophosphorus-induced delayed neuropathy in hens. Toxicol Appl Pharmacol 97:500-11
Shell, L; Jortner, B S; Ehrich, M (1988) Assessment of organophosphorus-induced delayed neuropathy in chickens using needle electromyography. J Toxicol Environ Health 25:21-33

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