Grantee Research Project Results
1999 Progress Report: Physiologically Based Pharmacokinetic Modeling of Haloacid Mixtures in Rodents and Humans
EPA Grant Number: R825954Title: Physiologically Based Pharmacokinetic Modeling of Haloacid Mixtures in Rodents and Humans
Investigators: Schultz, Irvin R. , Corley, Richard A. , Stenner, Robert D. , Bull, Richard J.
Institution: Pacific Northwest National Laboratory
EPA Project Officer: Hahn, Intaek
Project Period: January 1, 1998 through December 31, 2000
Project Period Covered by this Report: January 1, 1998 through December 31, 1999
Project Amount: $536,857
RFA: Drinking Water (1997) RFA Text | Recipients Lists
Research Category: Drinking Water , Water
Objective:
The objectives of this project are two-fold: (1) characterization of the comparative pharmacokinetics of chloro, bromo, and mixed chloro-bromo haloacids (HAs) in rodents; and (2) development of a physiologically based pharmacokinetic (PBPK) model that can accurately predict the tissue distribution and elimination of HAs during chronic oral exposure in mice, rats, and humans.
Progress Summary:
Work during 1999 centered on better understanding the differences in the pharmacokinetics of haloacetates with particular emphasis on metabolism. Major findings and conclusions are: the disposition of HAs can be broadly grouped into three categories: (1) trichloroacetate (TCA) is the most biologically persistent HA exhibiting low metabolism and moderate urinary excretion; (2) di-HAs are highly metabolized and undergo low urinary excretion; and (3) brominated tri-HAs are intermediate in character between TCA and the di-HAs, exhibiting both high metabolism and urinary excretion. Studies on the interactions between the chlorinated di- and tri-HAs indicated that di-HAs alter their metabolism, but prior exposure to TCA has no significant effect on elimination. The brominated tri-HAs undergo more complex metabolism than the di-HAs and experiments using bromo-dichloroacetate (BDCA) provided unambiguous proof that reductive de-bromination occurs in rodent microsomes. This was accomplished by trapping of the dichloroacetate radical intermediate using a spin-trapping agent pyrolytic boron nitride (PBN), and its subsequent identification by gas chromatograph/mass spectrometer (GC/MS). This result had previously been difficult to establish because the PBN/dichloroacetate radical adduct underwent an intramolecular rearrangement that prevented characterization with electron paramagnetic resonance (EPR) techniques. We hypothesize that an internal condensation reaction between the acetate and the nitroxide radical moieties forms a cyclic adduct with the elimination of an OH radical and loss of the EPR signal. Overall, these results indicate that several simplifying assumptions regarding the disposition of HAs can be made to aid future PBPK modeling efforts. In particular, modeling should focus on the role of halogen substitution in determining metabolism and urinary excretion of the HAs.
Future Activities:
Work during the upcoming year will concentrate on establishing the linearity of HA pharmacokinetics at low doses and experimentally measure the tissue distribution of HAs in rodents after exposure to mixtures of HAs. These results will be incorporated into the working PBPK model for HAs to predict tissue dosimetry during low exposure rates.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
| Other project views: | All 31 publications | 10 publications in selected types | All 10 journal articles |
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Gonzalez-Leon A, Merdink JL, Bull RJ, Schultz IR. Effect of pre-treatment with dichloroacetic or trichloroacetic acid in drinking water on the pharmacokinetics of a subsequent challenge dose in B6C3F1 mice. Chemico-Biological Interactions 1999;123(3):239-253. |
R825954 (1999) R825954 (Final) |
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Schultz IR, Merdink JL, Gonzalez-Leon A, Bull RJ. Comparative toxicokinetics of chlorinated and brominated haloacetates in F344 rats. Toxicology and Applied Pharmacology 1999;158(2):103-114. |
R825954 (1999) R825954 (Final) |
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Supplemental Keywords:
drinking water, bioavailability, metabolism, enzymes, mixtures, halogenated acetic acids, toxicology, toxicokinetics, mass spectroscopy., RFA, Scientific Discipline, Water, Health Risk Assessment, Environmental Chemistry, Analytical Chemistry, Drinking Water, metabolism, toxicokinetics, PBPK modeling, dose response, treatment, DBP risk assessment, haloacids, haloacetic acids, pharmacokinetics, drinking water system, drinking water contaminants, exposure, chemical byproducts, halogenated disinfection by-products, enzyme inactivation, disinfection byproducts (DPBs), human health effects, rodents, biomarkers, tissue distributionProgress 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.