Description:

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.

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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.

Cost :$524,928.00

Research Component :Drinking Water

Risk Paradigm :EXPOSURE

Approach :

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.

Cost :$524,928.00

Research Component :M/DBP (DBP)

Risk Paradigm :EXPOSURE

Approach :

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.

Cost :$524,928.00

Research Component :M/DBP (MICROBIAL)

Risk Paradigm :EXPOSURE

Approach :

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.

Cost :$524,928.00

Research Component :ARSENIC

Risk Paradigm :EXPOSURE

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