Toxicodynamic analysis of the inhibition of isolated human acetylcholinesterase by combinations of methamidophos and methomyl in vitro.
The applicability of dose addition to combinations of OP-esters and carbamates has been questioned based on theoretical considerations, but these have not been well supported by experimental findings. In the present study, the inhibition of AChE by combinations of methamidophos (an OP-ester) and methomyl (a carbamate) was examined in vitro. AChE inhibition was measured by the Ellman assay. We addressed the question of interaction between the OP-ester and carbamate by a toxicodynamic (TD) model reflecting the mechanism of action of the individual chemicals, without incorporating any interactions between them. The model was extended by including the experimental actions in the Ellman assay to correct for the difference in reactivation rates between phosphorylated and carbamylated AChE, which caused a bias in the observations from the assay. This zero-interactive TD model described the observations well, indicating that the OP-ester and carbamate did not interact. The applicability of dose addition was further explored by applying dose addition to the predicted inhibition by the TD model. Despite the differences in dynamics between methamidophos and methomyl, their dose-response curves were close to parallel, and dose addition gave a reasonably accurate prediction of the combined effects.
Institute for Risk Assessment Sciences, Utrecht University, PO Box 80.177, NL-3508 TD Utrecht, The Netherlands. sietobosgra@gmail.com
Sieto
S
Bosgra
Jan C H
JC
van Eijkeren
Marcel J
MJ
van der Schans
Jan P
JP
Langenberg
Wout
W
Slob
D000110:Acetylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D007700:Kinetics; D008724:Methomyl / Q000633:toxicity*; D008954:Models, Biological; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D010766:Phosphorylation; D015203:Reproducibility of Results; D018570:Risk Assessment
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009946:Organothiophosphorus Compounds; D008724:Methomyl; C014655:methamidophos; D000110:Acetylcholinesterase