A Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Paraoxon in Rainbow Trout

Abstract

Trout were exposed to an aqueous solution of 75 ng/ml paraoxon for 5 days at 12 degrees C. The relationships among paraoxon concentration in water and target organs, AChE inhibition, and carboxylesterase (CaE) detoxification of paraoxon were characterized quantitatively by development of a PBPK-PD model. The PKPD model structure consisted of brain, heart, liver, kidney, and remainder of the body, which were interconnected by blood circulation. The paraoxon tissue/blood partition coefficients were: plasma/water, 1.46; liver/plasma, 5.89; brain/plasma, 3.90; heart/plasma, 2.91; kidney/plasma, 0.45; and blood/plasma, 0.91. Turnover of AChE was characterized from a dose-response study, in which its zero-order synthesis rate and first-order degradation rate constant were determined in several tissues; for brain they were 7.67 pmol/min and 7.31 x 10(-5) hr(-1). The uptake and depuration clearances of paraoxon (Cl(u) = 0.651 and Cl(d) = 0.468 ml min(-1) g body wt(-1)) were determined using a compartmental model. During continuous water exposure to paraoxon, AChE activity in the tissues declined to new steady state values that were maintained by the synthesis of new AChE. CaE was shown by simulation to be an important pathway for detoxification of paraoxon.

Cholinergic and Behavioral Neurotoxicity of Carbaryl and Cadmium to Larval Rainbow Trout (Oncorhynchus mykiss)

“…Organisms have several potential adaptations to ChE inhibition, including increased synthesis of ChE (Abbas and Hayton, 1997), decreased synthesis of ACh (Liu and Pope, 1996), and desensitization and downregulation of MChR (Jett et al, 1993;Nostrandt et al, 1997). Regression of B and K " against ChE activity is a measure of the response of MChR to ChE inhibition.…”

A PBTK/TD modeling‐based approach can assess arsenic bioaccumulation in farmed tilapia (Oreochromis mossambicus) and human health risks

“…The PBTK model structure consisted of muscle (compartment 2), gill (compartment 3), alimentary canal (compartment 4), and liver (compartment 5), which are interconnected by blood (compartment 1) circulation (Figure 2). The essence of almost all PBTK models can be described by a linear dynamic equation (Abbas and Hayton 1997; Thomann et al 1997; Nichols et al 1998; Liao et al 2000; Lien et al 2001) (see Appendix A for details)…”

“…The use of PBTK models in toxicology research and chemical risk assessment today is primarily related to their ability to make more accurate predictions of target‐organ dose for different exposure situations in different animal species. PBTK/TD models have been extensively used in risk assessment and prediction of TK and TD behavior in several aquatic species, e.g., Cd in rainbow trout Salmo gairdneri (Thomann et al, 1997), paraoxon in rainbow trout Oncorhynchus mykiss (Abbas and Hayton 1997), Zn in abalone Haliotis diversicolo supertexta (Liao et al 2000), and waterborne organic chemicals in brook trout Salvelinus fontinalis (Nichols et al 1998) and in lake trout Salvelinus namaycush (Lien et al 2001).…”

The development of a physiologically-based pharmacokinetic model using the distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the tissues of the eastern oyster (Crassostrea virginica)

“…Similar approaches to other PBPK models developed for mammals and fish were applied to our model, such as binding components, elimination parameters, and depuration parameters for individual organs to allow inter-species comparisons (Abbas & Hayton, 1997;Jones et al, 2001;Maruyama, Yoshida, Tanaka, & Nakanishi, 2002;Young, Wosilait, & Luecke, 2001). The initial PBPK model formulation assumes that each tissue compartment is a single well mixed compartment.…”