Quantitative low-dose assessment of seafood toxin, domoic acid, in the rat brain: application of physiologically-based pharmacokinetic (PBPK) modeling

Abstract

The purpose of this study was to construct a physiologically based pharmacokinetic model and demonstrate its ability to predict low-dose uptake of domoic acid, a seafood contaminant, in discrete areas of the rat brain. The model we used was derived from the generic PBPK model of our previous studies with 2,4-dichlorophenoxyacetic acid ( Kim et al., 1994. Pharmacokinetic modeling of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats and in rabbits brain following single dose administration. Toxicol. Lett. 74, 189; Kim et al., 1995. Development of a physiologically based pharmacokinetic model for 2,4-dichlorophenoxyacetic acid dosimetry in discrete areas of the rabbit brain. Neurotoxicol. Teratol. 17, 111), to which physiological- and chemical-specific parameters for domoic acid were applied. It incorporates two body compartments along with compartments for venous and arterial blood, cerebrospinal fluid, brain plasma and seven brain regions. Uptake of the blood-borne toxin is membrane-limited by the blood-brain barrier with clearance from the brain provided by cerebrospinal fluid `sink' mechanisms. This model generated predicted profiles of toxin level in brain and blood over a 1-h period that compared reasonably well with concentrations calculated from in vivo data of rats that had been given [ 3H]domoic acid intravenously ( Preston and Hynie, 1991. Transfer constants for blood–brain barrier permeation of the neuroexcitatory shellfish toxin, domoic acid. Can. J. Neurol. Sci. 18, 39). This PBPK model should be an effective tool for evaluating the target doses that produce the potential neurotoxicity of domoic acid found in foods.