Grantee Research Project Results
2002 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: Pacific Northwest National Laboratory , Oregon Health & Sciences University
EPA Project Officer: Hahn, Intaek
Project Period: September 30, 2000 through September 29, 2003 (Extended to April 1, 2005)
Project Period Covered by this Report: September 30, 2001 through September 29, 2002
Project Amount: $524,928
RFA: Drinking Water (1999) RFA Text | Recipients Lists
Research Category: Drinking Water , Water
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 test the hypothesis that prolonged exposure to low concentrations of di-haloacetates reduces their metabolism and increases their systemic bioavailability in humans. Dichloroacetate (DCA) will be used as a model di-haloacetate in human volunteer studies. A parallel experiment will be performed using mixtures of chlorinated and brominated haloacetates in rhesus monkeys. Overall, the project consists of three Specific Aims. In Specific Aim 1, volunteers (or monkeys) consume only purified bottled water for 2 weeks. Volunteers then are given an oral dose of 12C-DCA (2 mg haloacetate per kg subject weight) in a pint of water. Monkeys will be dosed with a mixture of brominated haloacetates. After 5-10 minutes, 13C-labeled DCA is administered by intravenous injection (via a catheter placed in the arm), and 12C/13C-DCA is 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 0.02 mg/kg dose of DCA. Specific Aim 3 will study the absorption of haloacetates 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
Initial recruitment of volunteers began in September 2002. The first volunteer participated in the study in October 2002. As of March 10, 2003, 8 of a scheduled 16 volunteers for Specific Aims 1 and 2 have now participated in the study. The parallel study using rhesus monkeys dosed with a mixture of brominated haloacetates was initiated in October 2002.
Work Progress
Plasma samples obtained from volunteers 1-7 have been analyzed for 12C-DCA and 13C-DCA. The human volunteer studies as part of Specific Aims 1 and 2 are scheduled to be completed during the summer of 2003. Dosing and sample collection from the rhesus monkey studies are completed. Analysis of monkey plasma for the brominated haloacetates is scheduled for completion during 2003.
Preliminary Data Results
The plasma concentration-time profiles and estimates of oral bioavailability of DCA in four volunteers are shown in Figure 1. Measurable 12C-DCA was typically observed within 15 minutes of consumption of the oral dose. Peak plasma concentrations occurred within 30 minutes of dosing. Plasma levels of DCA declined below limits of detection after 1-2 hours. These initial results indicate that the oral bioavailability of the 2 mg/kg 12C-DCA in humans is quite variable, ranging from 5-69 percent. Based on the three individuals for whom a complete data set is available, there does not appear to be a change in bioavailability after the 14 day treatment with 0.02 mg/kg DCA (roughly equivalent to 1 mg DCA/L). The PBPK model developed for DCA using rodent and in vitro-derived parameters for DCA human metabolism poorly estimated the DCA plasma profiles of these initial data sets. Preliminary modeling indicated that this was largely because of underestimation of the DCA absorption rate, which appears to be occurring unexpectedly faster for the dose used in this project.
Figure 1. DCA Concentration-Time Profiles After a 2 mg/kg Oral Dose (12C, Black Squares) and a 0.3 mg/kg I.V. Dose (13C Labeled, Open Circles). The I.V. dose was administered 10 minutes after consumption of the oral dose, which was dissolved in 0.5 L of bottled water.
Future Activities:
We will recruit volunteers for the final Specific Aim of the project (Aim 3) in August-September 2003. Volunteers needed to complete Specific Aims 1 and 2 have been recruited and are scheduled for participation during April-July 2003.
Journal Articles:
No journal articles submitted with this report: View all 13 publications for this projectSupplemental Keywords:
PBPK, physiologically based pharmacokinetic model, PBPK modeling, absorption, brominated DPBs, cellular physiology, chlorinated DBPs, dichloroacetate, DCA, disinfection byproducts, dose estimates, dose response, dosimetry, drinking water contaminants, elimination, exposure, exposure and effects, exposure assessment, haloacetates, health effects, human exposure, human health risk, metabolism, microbial exposure, monitoring, pharmacokinetics, renal elimination, risk assessment, stable isotope,, Health, RFA, Ecosystem Protection/Environmental Exposure & Risk, Scientific Discipline, PHYSICAL ASPECTS, Waste, Water, Toxics, National Recommended Water Quality, Health Risk Assessment, Physical Processes, Fate & Transport, Risk Assessments, Biology, Monitoring/Modeling, Bioavailability, Disease & Cumulative Effects, Toxicology, Drinking Water, Environmental Monitoring, metabolism, DBPs, PBPK modeling, health effects, stable isotope, cellular physiology, treatment, dose response, water quality, haloacetates, risk assessment, human exposure, DBPs , PBPK, dosimetry, brominated DPBs, pharmacokinetics, monitoring, physiologically based pharmacokinetic model, drinking water contaminants, exposure, dose estimates, absorption, elimination, microbial exposure, human health risk, disinfection byproducts (DPBs), dose-response, chlorinated DBPs, DBP exposure, renal eliminatio, dichloroacetate, exposure and effectsProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.