PNNL

Abstract

This chapter will describe the development of physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models that are capable of simulating organophosphorus insecticide dosimetry and cholinesterase (ChE) inhibition dynamics. The primary focus will be on the computational model structure for the pharmacodynamic modeling of ChE inhibition in blood, and brain. Organophosphorus insecticides represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific and dose-dependent differences in biological response. These studies have been conducted with OP insecticides in multiple species, at various dose levels, and across different routes of exposure to understand the in vivo kinetics of OPs and how they contribute to the observed toxicological response. In this chapter we will provide a detailed discussion of the the pharmacodynamic model for ChE inhibition, which will include information of sources of parameter estimates, a discussion of modeling assumptions, as well as the strengths and weaknesses of the model.