A physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for the insecticide dimethoate

AbstractDimethoate is an organophosphate insecticide that is converted in vivo to omethoate, the active toxic moiety. Omethoate inhibits acetylcholinesterase (AChE) in the brain and red blood cells (RBCs). This paper describes the development of rat and human physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models for dimethoate. The model simulates the absorption and distribution of dimethoate and omethoate, the conversion of dimethoate to omethoate and to other metabolites, the metabolism and excretion of omethoate, and the inhibition of RBC and brain AChE. An extensive data collection program to estimate metabolism and inhibition parameters is described. The suite of models includes an adult rat, post-natal rat, and human model. The rat models were evaluated by comparing model predictions of dimethoate and omethoate to measured blood time course data, and with RBC and brain AChE inhibition estimates from an extensive database of in vivo AChE measurements. After the demonstration of adequately fitted rat models that were robust to sensitivity analysis, the human model was applied for estimation of points-of-departure (PODs) for risk assessment using the human-specific parameters in the human PBPK/PD model. Thus, the standard interspecies uncertainty factor can be reduced from 10X to 1X.DisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. FundingThe author(s) reported there is no funding associated with the work featured in this article.