Quantitative Exposure Assessment: Application of Physiologically Based Pharmacokinetic Modeling of Low-Dose, Long-Term Exposure of Organic Acid Toxicant in the Brain. C. S. Kim, Food and Drug Administration, Division of Toxicological Research, Center for Food Safety and Applied Nutrition, Washington, D.C.; J. A. Sandberg, W. Slikker, Jr., Z. Binienda, and T. A. Patterson, National Center for Toxicological Research, Division of Neurotoxicology, Jefferson, AR; and P. M. Schlosser, Chemical Industry Institute of Toxicology, Research Triangle Park, NC
The objective of this study was to construct a physiologically based pharmacokinetic (PBPK) model describing the kinetic behavior of 2,4-dichlorophenoxyacetic acid (2,4-D) following low-dose, long-term exposures, and to demonstrate its ability to simulate uptake of 2,4-D in discrete areas of the rat brain. The model we used was derived from the generic PBPK model that was first developed for high-dose, single exposures for rats or rabbits (Kim et al., Toxicol. Lett. 74: 189-201, 1994; Neurotoxicol. Teratol. 17: 111-120,1995), to which the subcutaneous compartment was incorporated for low-dose, long-term infusion. It consists of two body compartments along with compartments for venous and arterial blood, cerebrospinal fluid, brain plasma and seven brain regions. Uptake of the 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 2,4-D levels in brain and blood over a 28-day period that compared well with concentrations obtained from in vivo studies with rats that had been chronically administered 2,4-D (1 or 10 mg/kg/day) with [14C]-2,4-D subcutaneously for 7, 14, and 28 days, respectively. This PBPK model should be an effective tool for evaluating the target tissue doses that produce the potential neurotoxicity of organic acid toxicants from contaminated foods or environment after low-dose, long-term exposures.
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