The role of pharmacokinetics and metabolism in species sensitivity to neurotoxic agents.
Fundam Appl Toxicol 1986 Feb; 6(2):190-207
The roles of pharmacokinetics and metabolism in interspecies sensitivity to neurotoxic agents was discussed. The general principles of metabolism were summarized. Enzymes involved in metabolic processes were considered. Hepatic microsomal monooxygenase systems are the most important enzymes involved in the metabolism of xenobiotics. The hepatic cytochrome-P-450 monooxygenase system was described. The effects of route of administration on neurotoxicity were discussed using S,S,S-tri-n- butyl-phosphorotrithioate (78488) (DEF) as an example. DEF administered dermally, subcutaneously, or intraperitoneally to chickens produced cholinergic and delayed neurotoxic symptoms similar to those induced by other organophosphorous compounds. When given orally, DEF induced a late acute effect characterized by leg weakness and unsteadiness that appeared on the second day after dosing. This effect was not associated with acetylcholinesterase inhibition or histopathological changes in nervous tissues. The concentrations of n-butyl-mercaptan (109795), a putative DEF metabolite, in the plasma were much higher after oral administration than by the other routes. Age related changes in susceptibility to organophosphate neurotoxicity were discussed. Studies of the effects of O-ethyl-O-4-nitrophenyl-phenylphosphonothioate (2104645) (EPN) and leptophos (21609905) in chicks and hens have shown that young animals are more resistant to delayed neurotoxicity and other toxic effects than adult birds. The age dependency in susceptibility was due to faster metabolism and clearance of EPN and leptophos occurring in the chicks than in adult birds. Variations in species sensitivity to neurotoxic agents were discussed. EPN and leptophos cause delayed neurotoxicity in chickens, but not in rats. The resistance of rats to EPN and leptophos neurotoxicity is attributed to these compounds being metabolized to a greater extent and being cleared more rapidly in this species than in chickens.
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Organo-phosphorus-pesticides; Biotransformation; Pharmacodynamics; In-vivo-studies; Laboratory-animals; Genetic-factors
Pharmacology Duke University Department of Pharmacology Durham, NC 27710
78-48-8; 109-79-5; 2104-64-5; 21609-90-5
Neurotoxic Disorders; Neurotoxic-effects
Fundamental and Applied Toxicology
Duke University, Durham, North Carolina