![[logo] US EPA](https://webarchive.library.unt.edu/eot2008/20081107075037im_/http://www.epa.gov/epafiles/images/logo_epaseal.gif){kind=logo}
2003 Progress Report: Bioavailability of Haloacetates in Human Subjects
EPA Grant Number: R828044Title: Bioavailability of Haloacetates in Human Subjects
Investigators: Schultz, Irvin R. , Shangraw, Robert
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 Period Covered by this Report: September 30, 2002 through September 29, 2003
Project Amount: $524,928
RFA: Drinking Water (1999)
Research Category: Drinking Water
Description:
Objective:The objective of this research 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 naturally occurring mixture of these compounds. In controlled dosing experiments, we will directly test the hypothesis that prolonged exposure to low concentrations of dihaloacetates reduces their metabolism and increases their systemic bioavailability in humans. These latter studies are using dichloroacetate (DCA) as a model dihaloacetate in human volunteer studies. A parallel experiment will be performed using mixtures of chlorinated and brominated haloacetates in rhesus monkeys.
The project consists of three Specific Aims. In Specific Aim 1, volunteers (or monkeys) consume only purified bottled water for 2 weeks. Volunteers are then given an oral dose of 12C-DCA (2 mg haloacetate/kg subject weight) within a pint of water. Monkeys will be dosed with a mixture of brominated trihaloacetates. After 10 minutes, 13C-labeled DCA is administered by intravenous injection (via a catheter placed in the arm), and 12C-/13C-DCA measured in plasma over a 12-hour time period. In Specific Aim 2, Aim 1 is repeated in the same volunteers after a 2-week period of consuming a daily dose of 0.02 mg DCA/kg of subject weight. Specific Aim 3 will study the absorption of haloacetates that are naturally occurring in a finished municipal drinking water supply. These experimental results will be used to validate a physiologically based pharmacokinetic (PBPK) model for haloacetates in humans.
Progress Summary:Work Status
All volunteer studies performed as part of Specific Aims 1 and 2 are now complete. A total of 18 volunteers participated in these studies. The parallel study using rhesus monkeys dosed with a mixture of brominated trihaloacetates also is complete. The study protocol and informed consent form for Specific Aim 3 has been written and submitted to the human subject review board for approval.
Work Progress
All plasma samples obtained in Specific Aim 1 have been analyzed for 12C-DCA and 13C-DCA. Preliminary pharmacokinetic analysis has been completed and results are presented below. Analysis of rhesus monkey plasma for the brominated haloacetates also is complete. Repeat analysis of selected plasma samples for quality assurance purposes currently is underway.
Preliminary Data Results
The average plasma concentration-time profiles for male and female volunteers are shown in Figure 1.
Figure 1. Average DCA Concentration-Time Profiles in Male (Left Panel) and Female (Right Panel Volunteers After a 2 mg/kg Oral Dose (12C, Black Squares) and a 0.3 mg/kg IV Dose (13C Labeled, Open Circles). The IV dose was administered 10 minutes after consumption of the oral dose that was dissolved in 0.5 L of bottled water. Note the difference in the Y-axis and the higher peak plasma concentration observed in female volunteers.
Estimation of oral bioavailability of DCA in these volunteers also is shown in Table 1 (bioavailability estimates for seven of eight male volunteers is currently available). For all subjects, peak 12C-DCA was typically observed between 15 and 30 minutes after consumption of one pint of purified bottled water spiked with the oral dose. In all subjects, plasma levels of DCA declined below limits of detection by 2 hours. Based on the results presented in Table 1, the oral bioavailability of DCA in humans varies widely, ranging from 3.7 to 69 percent. A key finding from these studies is the apparent increased bioavailability of DCA in female subjects (mean value is 31 percent for females and 19 percent for males; see Figure 1 and Table 1). With regard to trihaloacetates and the rhesus monkey studies, Figure 2 summarizes the average plasma levels for bromodichloroacetate (BDCA), chlorodibromoacetate (CDBA) and tribromoacetate (TBA) after semisimultaneous dosing of 12C (oral) and 13C (intravenous [IV]) in a manner analogous to that described for DCA. Initial pharmacokinetic analysis indicates that trihaloacetate pharmacokinetics in monkeys is similar to rodents, although the reduced elimination half life in monkeys probably reflects the lower doses used in this study (Table 2).
Figure 2. Average Concentration-Time Profiles After Various Oral Dose (12C, Open Circles) and I.V. Doses ( 13C Labeled, Black Squares) of A Mixture of BDCA, CDBA and TBA. Oral bioavailability for each haloacetate is shown. Mean ± SD (n=5). Solid lines are predicted values using a 1 compartment clearance-volume PK model
Table 1. Oral Bioavailability of DCA in Male and Female Volunteers After Consumption of 2 mg/kg DCA in 0.5 L Purified Water. Values are percent dose absorbed.
Table 2. Selected Pharmacokinetic Parameters of DCA in Humans, Rats, and Mice After I.V. Injection
We will be obtaining approval of protocols for Specific Aim 3 and subsequent recruitment of volunteers.
Supplemental Keywords:stable isotope, simultaneous bioavailability, renal elimination, drinking water, monitoring, modeling, exposure assessment, haloacetates, health effects, human exposure, human health risk, metabolism, pharmacokinetics, risk assessment,
,
Ecosystem Protection/Environmental Exposure & Risk, Toxics, Water, Scientific Discipline, Waste, Health, RFA, PHYSICAL ASPECTS, Toxicology, Biology, Drinking Water, Risk Assessments, Disease & Cumulative Effects, Health Risk Assessment, Physical Processes, Bioavailability, Fate & Transport, National Recommended Water Quality, Monitoring/Modeling, Environmental Monitoring, drinking water contaminants, exposure assessment, risk assessment, treatment, water quality, elimination, renal eliminatio, dichloroacetate, exposure and effects, health effects, metabolism, DBPs, cellular physiology, PBPK, DBP exposure, brominated DPBs, chlorinated DBPs, absorption, human health risk, monitoring, pharmacokinetics, PBPK modeling, disinfection byproducts (DPBs), dose-response, dose response, stable isotope, haloacetates, dose estimates, dosimetry, exposure, DBPs , microbial exposure, human exposure
Progress and Final Reports:
2001 Progress Report
2002 Progress Report
Original Abstract