Metabolic Fate of Halogenated Disinfection By-Products In Vivo, and Relation to Biological Activity

EPA Grant Number: R825957
Title: Metabolic Fate of Halogenated Disinfection By-Products In Vivo, and Relation to Biological Activity
Investigators: Ball, Louise M.
Institution: University of North Carolina at Chapel Hill
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: January 23, 1998 through January 22, 2001
Project Amount: $460,848
RFA: Drinking Water (1997) RFA Text |  Recipients Lists
Research Category: Drinking Water , Water

Description:

Objectives/Hypotheses: Halogenated by-products of drinking water disinfection are of concern because of uncertainty over their health effects, particularly an increased risk of kidney and bladder cancer and widespread consumption. Due to their abundance relative to other halogenated disinfection by-products, haloacetic acids may form macromolecular adducts that could be useful as biomarkers of exposure to disinfectants. Mechanisms of biological activity and disposition of haloacids formed as by-products of water disinfection will be investigated. The major goal of this project is to identify the chemical nature and mechanism of formation of metabolites of the potent bacterial mutagen (Z)-2-chloro-3-(dichloromethyl)-4-oxobutenoic acid, more commonly known in its ring-closed form as 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone or MX (for Mutagen "X"), and of macromolecular adducts formed from the low molecular weight haloacetic acids (alkanoic, alkenoic and oxobutenoic acids) chloroacetic acid, dichloroacetic acid, from their brominated analogs bromoacetic and dibromoacetic acid, and from the mixed haloacetic acid bromochloroacetic acid.

Approach:

Two specific approaches will be followed towards elucidating the mechanisms of activity of biologically potent disinfection by-products at the molecular level:

I. Identification and Quantitation of Macromolecular Adducts Formed by Haloacetic Acids: Structural identification and quantitation of DNA adducts will be approached by chromatographic and mass spectrometric techniques. Quantities of adducts sufficient for detailed structural elucidation are often difficult or impossible to obtain by direct modification of DNA, hence direct chemical synthesis will be undertaken to provide standards for investigation of adduct formation in vivo.

II. Investigation of the Metabolism and Disposition of MX: Structural identification of MX metabolites, and their tissue distribution in the rat, will be carried out in order to gain an understanding of the nature of the active species present at potential target organs, and the levels and duration of internal exposure.

Expected Results:

Knowledge of the chemical structures of macromolecular adducts formed will provide information on routes of genotoxic activity. In addition, this information constitutes the foundation for development of assays to measure rates of formation and loss, and the development of biomarkers of exposure and effect.

Supplemental Keywords:

Drinking water, biomarkers of exposure, metabolism, DNA adducts, disinfection byproducts., RFA, Scientific Discipline, Water, Chemical Engineering, Environmental Chemistry, Chemistry, Analytical Chemistry, Biochemistry, Biology, Drinking Water, halogenated disinfection by-products, biomarkers, bacterial mutagen, exposure and effects, chemical byproducts, disinfection byproducts (DPBs), exposure, animal model, community water system, genotoxicity, treatment, haloacetic acids, carcinogenicity, macromolecular adducts, metabolism, drinking water contaminants, drinking water system, rat

Progress and Final Reports:

  • 1998
  • 1999 Progress Report
  • Final Report