Development of a Physiologically-Based Model for Diisopropylfluorophosphate-Induced Toxicity in Human

Abstract

Diisopropylfluorophosphate (DFP), an organophosphorous pesticide, is a highly toxic compound that affects a variety of physiological processes. The toxicological effects of DFP are primarily mediated through its inhibition of acetylcholinesterases, which results in the accumulation of acetylcholine at neuronal junctions. A physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to investigate the effects of intramuscular administration of DFP on acetylcholinesterase (AChE) activity in human. The prediction by a mathematical model is essential since information on humans can scarcely be obtained experimentally. The PBPK/PD model was constructed based on the time course of AChE activity in venous blood following a single intramuscular administration of DFP (33μg DFP/kg bodyweight) to human. The model was parameterised by using reference physiological parameter values (organ volumes and blood flow rates) and partition coefficients, while pharmacodynamic parameters governing the degradation of AChE, and the regeneration and aging of inhibited AChE, were allometrically scaled from those used in a previously developed rat model. The synthesis rate constant for AChE, as well as the absorption rate constant and bioavailability corresponding to intramuscular administration were optimised by manual adjustment until the best visual fit of the simulations with the experimental data was observed. The PBPK/PD model was next verified by simulating the recovery of AChE activity in venous blood in vivo after multiple intramuscular doses (20μg DFP/kg bodyweight every 24 hours for 50 days) and comparing the simulated results with the experimental data. Results showed a close fit of simulated AChE inhibition dynamics in venous blood to experimental data. The development and further refinement of a human PBPK/PD model for organophosphate- induced toxicity could potentially translate to improved accuracy of human health risk assessment, as well as evaluation of prophylaxis protocols.