Comparison of the role of esterases in the differential age-related sensitivity to chlorpyrifos and methamidophos
Padilla, S.; Buzzard, J.; Moser, V.C.
Neurotoxicology 21(1-2): 49-56
2000
ISSN/ISBN: 0161-813X PMID: 10794384 Document Number: 518502
More than 30 years ago, scientists recognized that, at a given dosage, the young rat was more sensitive than the adult to the toxicity of many organophosphorus, anti-cholinesterase pesticides. This observation went basically unexamined until recently. Renewed interest has emerged in scrutinizing this age-related sensitivity to pesticides, especially in light of the many new pesticides which are currently marketed. Our laboratory has been involved in comparing the age-related sensitivity of young and adult rats to chlorpyrifos (Dursban(R), Lorsban(R); O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate) and methamidophos (Monitor(R); O,S-dimethyl phosphoamidothioate). Using chlorpyrifos, there is marked age-related sensitivity: direct oral dosing of the preweanling rat (postnatal day 17; PND17) with chlorpyrifos causes a toxic response (defined either behaviorally or biochemically) at aapprx5-fold lower dosage than in adults (oral, maximum tolerated dose for the PND17 is 20 mg/kg versus 100 mg/kg for the adult). Other studies have indicated that the rat detoxifies chlorpyrifos and its oxon by binding to carboxylesterases and hydrolysis by A-esterases. The young rat is deficient in both these detoxification enzymes, which may explain the increased sensitivity of the young to chlorpyrifos toxicity. The age-related pattern for methamidophos is distinctly different: the oral, maximum tolerated dose is the same (8 mg/kg) whether the animal is 17 days old or an adult. We present data which indicate that methamidophos is not detoxified appreciably either in vivo or in vitro by A-esterases or carboxylesterases. Therefore, we submit the following hypothesis: organophosphorus pesticides, like chlorpyrifos, which are detoxified via A-esterases or carboxylesterases are more likely to exhibit age-related differences in sensitivity than pesticides which are not detoxified via these routes.