Citation:

Ross, M. K., R TORNERO-VELEZ, C. Granville, A. Gold, M V. Evans, AND D M. DeMarini. METABOLISM OF 1,1- AND 1,3- DICHLOROPROPENE: A MECHANISM OF BIOACTIVATION BY GLUTATHIONE. Presented at International Society for the Study of Xenobiotics, Vancouver, Canada, August 29-September 2, 2004.

Impact/Purpose:

Research will be conducted to develop and apply integrated microenvironmental, and physiologically-based pharmacokinetic (PBPK) exposure-dose models and methods (that account for all media, routes, pathways and endpoints). Specific efforts will focus on the following areas:

1) Develop the Exposure Related Dose Estimating Model (ERDEM) System.

Includes: Updating the subsystems and compartments of the ERDEM models with those features needed for modeling chemicals of interest to risk assessors;

Designing and implementing the graphical user interface for added features.

Refining the exposure interface to handle various sources of exposure information;

Providing tools for post processing as well as for uncertainty and variability analyses;

Research on numerical and symbolic mathematical/statistical solution methods and computational algorithms/software for deterministic and stochastic systems analysis.

2) Apply ERDEM and other quantitative models to understand pharmacokinetics (PK) and significantly reduce the uncertainty in the dosimetry of specific compounds of regulatory interest.

Examples of the applications are:

exposure of children to pesticides

study design

route-to-route extrapolation

species extrapolation

experimental data analysis

relationship between parametric uncertainty and the distribution of model results

validity of scaling methods within species

validity of scaling methods from one species to another species

reduction of uncertainty factors for risk assessment

Description:

Glutathione transferases (GST) catalyze the reaction of glutathione (GSH) with haloalkenes via a nucleophilic vinylic substitution mechanism (SNV reaction). The source water contaminants 1,1-dichloropropene and 1,3-dichloropropene, which are under scrutiny by the U.S.EPA, were examined for their ability to produce S-conjugates of GSH and to produce genotoxic species as a result. Following in vitro reactions of 1,1- and 1,3-dichloropropenes with mouse liver cytosol and supplemented GSH, the products were examined by LC-MS and LC-MS/MS analyses. The presence of m/z 382/384 ions following reaction with both 1,1-dichloropropene and 1,3-dichloropropene confirmed the production of stable mono S-conjugates of GSH containing a single Cl atom. LC-MS/MS analysis (SRM m/z 382 - m/z 253) provided a sensitive means of detecting the GSH conjugate of 1,1-dichloropropene since it was much less reactive than 1,3-dichloropropene toward GSH. The significance of GSH conjugation of 1,1-dichloropropene is that Salmonella typhimurium transformed with GSTT5 (rat) or GSTT1 (human) cDNA produced mutations following exposure to 1,1-dichloropropene. The mutations were dependent on the presence of the GST isozyme. In contrast, 1,3-dichloropropene was not mutagenic in the same strains of bacteria. An addition-elimination mechanism is proposed that can account for the production of the stable S-conjugate(s) of 1,1-dichloropropene (m/z 382/384) in addition to the formation of a transient episulfonium ion that may be the genotoxic species responsible for the mutations produced in the bacterial strains.

This work has been funded by the United States Environmental Protection Agency. It has been subjected to Agency review and approved for publication.

Record Details: