Quantitative exposure assessment: application of physiologically-based pharmacokinetic (PBPK) modeling of low-dose, long-term exposures of organic acid toxicant in the brain

Our objective was to construct a physiologically-based pharmacokinetic (PBP K) model describing the kinetic behavior of 2,4-dichlorophenoxyacetic acid (2:4-D) on rats after long-term exposures to low doses. Our study demonstra ted the model's ability to simulate uptake of 2,4-D in discrete areas of, t he rat brain. The model was derived from the generic PBPK model that was fi rst developed for high-dose, single exposures of 2,4-D to rats or rabbits ( Kim, C.S., Gargas, M.L., Andersen, M.E., 1994. Pharmacokinetic modeling of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats and rabbits brain following single dose administration. Toxicol. Lett. 74, 189-201; Kim, C.S., Slikker, W., Jr., Binienda, 2., Gargas, M.L., Andersen, M.E., 1995. Development of a physiologically based pharmacokinetic (PBPK) model for 2,4-dichlorophenox yacetic acid (2,4-D) dosimetry in discrete areas of the brain following a s ingle intraperitoneal or intravenous dose. Neurotox. Teratol. 17, 111-120.) , to which a subcutaneous (hypodermal) compartment was incorporated for low -dose, long-term infusion. It consisted of two body compartments, along wit h compartments for venous and arterial blood, cerebrospinal fluid, brain pl asma and six brain regions. Uptake of the toxin was membrane-limited by the blood-brain barrier with clearance from the brain provided by cerebrospina l fluid 'sink' mechanisms. This model predicted profiles of 2,4-D levels in brain and blood over a 28-day period that compared well with concentration s measured in vivo with rats that had been given 2,4-D (1 or 10 mg/kg per d ay) with [C-14]-2,4-D subcutaneously (s.c.) for 7, 14, or 28 days, respecti vely. This PBPK model should be an effective tool for evaluating the target tissue doses that may produce the neurotoxicity of organic acid toxicants after low-dose, long-term exposures to contaminated foods or the environmen t. (C) 2001 Elsevier Science B.V. All rights reserved.