Bioavailability of Haloacetates in Human SubjectsEPA Grant Number: R828044
Title: Bioavailability of Haloacetates in Human Subjects
Investigators: Schultz, Irvin R. , Bull, Richard J. , Poet, Torka , Shangraw, Robert
Current Investigators: Schultz, Irvin R. , Shangraw, Robert
Institution: Battelle Memorial Institute, Pacific Northwest Division
Current Institution: Battelle Memorial Institute, Pacific Northwest Division , Oregon Health & Sciences University
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: September 30, 2000 through September 29, 2003 (Extended to April 1, 2005)
Project Amount: $524,928
RFA: Drinking Water (1999) RFA Text | Recipients Lists
Research Category: Drinking Water , Water
The objective of this project is to characterize the absorption, disposition and oral bioavailability of chlorinated and brominated haloacetates in human volunteers after consumption of drinking water containing a natural mixture of these compounds. We hypothesize that accurate assessment of the oral bioavailability of haloacetates can be achieved by the simultaneous administration of an oral dose of 12C-labeled haloacetate with an intravenous dose of 13C-labeled haloacetate. We hypothesize that measurable plasma levels of dichloroacetate, bromochloroacetate and dibromoacetate can be detected from the de-bromination of bromo-dichloroacetate, dibromo-chloroacetate and tribromoacetate. We will directly test the hypothesis that prolonged exposure to low concentrations of di-haloacetates reduces their metabolism and increases their systemic bioavailability in humans. These experimental results will be used to validate a physiologically based pharmacokinetic (PBPK) model for haloacetates in humans, which is currently based on in-vitro metabolism parameters obtained with human tissue homogenates.
Dichloroacetate (2 mg-haloacetate /Kg) will be given to volunteers within a pint of water. After 5 minutes, 13C-labeled dichloroacetate will be given by intravenous injection (via a catheter placed in the arm). A similar experiment will be performed using mixtures of chlorinated and brominated haloacetates in rhesus monkeys. In a second experiment, volunteers will consume a pint of tap water previously verified to contain the seven haloacetates of interest. For all experiments, serial blood samples will be removed using the intravenous catheter and the blood plasma analyzed simultaneously for both the 13C- and 12C haloacetates (using GC-MS or LC-MS/MS techniques). The area-under-the-curve ratio for the oral and intravenous doses will be determined to estimate the oral bioavailability.
This project will provide critical data needed to make accurate and reliable exposure estimates of haloacetates to humans consuming municipal drinking water supplies. This project will identify the consequences of low level exposure to haloacetates on their subsequent metabolism and disposition. This information is needed to assess whether individuals who consume water containing high levels of by-products experience greater than predicted exposure due to decreased elimination of haloacetates. This project will also allow for the direct testing of physiologically based pharmacokinetic model predictions of haloacetate dosimetry in humans. The increased understanding of haloacetate pharmacokinetics obtained in this study will allow for improvements in PBPK modeling accuracy, thus providing credible, scientifically defensible measures of effective dose estimates of haloacetates to humans.