Comparison of the role of esterases in the differential age-related sensitivity to chlorpyrifos and methamidophos.
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, anticholinesterase 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, Lorsban; O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate] and methamidophos (Monitor; 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 a approximately 5-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.
Padilla
S
S
Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. Padilla.Stephanie@epa.gov
Buzzard
J
J
Moser
V C
VC
D000110:Acetylcholinesterase / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects; D004390:Chlorpyrifos / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002802:Cholinesterases / Q000378:metabolism; D004950:Esterases / Q000502:physiology*; D005260:Female; D008658:Inactivation, Metabolic / Q000502:physiology; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D051379:Mice; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009946:Organothiophosphorus Compounds; D011994:Recombinant Proteins; C014655:methamidophos; D004950:Esterases; D000110:Acetylcholinesterase; D002802:Cholinesterases; D004390:Chlorpyrifos