Physiologically Based Pharmacokinetic Modeling of Haloacid Mixtures in Rodents and HumansEPA Grant Number: R825954
Title: Physiologically Based Pharmacokinetic Modeling of Haloacid Mixtures in Rodents and Humans
Investigators: Schultz, Irvin R. , Bull, Richard J. , Corley, Richard A. , Stenner, Robert D.
Institution: Battelle Memorial Institute, Pacific Northwest Division
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: January 1, 1998 through December 31, 2000
Project Amount: $536,857
RFA: Drinking Water (1997) RFA Text | Recipients Lists
Research Category: Drinking Water , Water
Description:Objectives/Hypothesis: The purpose of this project is the development and validation of a physiologically based pharmacokinetic (PBPK) model for haloacetates (HAs) which accurately predicts the tissue distribution and elimination of chloro, bromo and mixed chloro-bromo acetic acids during chronic oral dosing in mice, rats and humans. Our hypothesis is that chronic exposure to di-haloacetates causes a permanent decrease in their metabolism due to enzyme inactivation. We also hypothesize that dichloroacetate (DCA) is the most potent inhibitor of the haloacetates and chronic exposure to this di- haloacetate will increase the tissue exposure of other di- haloacetates which may also be present in drinking water or formed from tri-haloacetates such as (TCA), bromodichloroacetate (BDCA) and dibromochloroacetate (DBCA). Furthermore, we propose a threshold dose exists for di- haloacetates which does not cause enzyme inactivation and where oral bioavailability is zero due to complete first pass extraction by the liver.
Groups of mice and rats will be pretreated with DCA for 14 days at several drinking water concentrations starting at 0.05 g/L and given either intravenous injections or gavage doses of DCA or a tri-haloacetate and the blood concentration-time profile and urinary excretion characterized. The blood elimination and oral bioavailability of the haloacetates in pretreated and control animals will be characterized using standard compartmental and statistical moment analysis. The in-vitro metabolism and the determination of Vmax and Km of haloacetates will be characterized in rodent and human liver fractions. Metabolism experiments will also be performed in liver fractions isolated from rodents pretreated with a di-haloacetate. A PBPK model will be developed for di- and tri- haloacetates in the F344 rat, B6C3F1 mouse and humans and used to predict tissue levels during chronic, low dose exposures to haloacetates.
The development of a detailed data set that measures the effects of chronic DCA exposure on the pharmacokinetics of haloacetates in mice and rats. The dose dependency of the bioavailability and elimination of DCA will also be characterized. These data sets are crucial for accurate low dose extrapolation of haloacetate tissue levels from the high doses used in carcinogenic bioassays to the low levels that humans are exposed to as a result of drinking water disinfection. The establishment of in vitro methodologies to estimate the kinetics of haloacetate biotransformation and the inhibitory effects of di-haloacetates on their metabolism. The development of a PBPK model for haloacetates based on a combination of in-vivo testing with a potent di-haloacetate (DCA) in rodents and in-vitro studies of the metabolism of haloacetates in rodent and human liver fractions. This model will allow prediction of tissue concentrations of di- and tri-haloacetates after chronic oral dosing at high and low drinking water concentrations and can be used to predict the tissue concentrations of haloacetates in humans after exposure to haloacetate mixtures.