Mechanism Involved in Trichloroethylene-Induced Liver Cancer: Importance to Environmental Cleanup Page: 3 of 15
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The objective of this project is to develop critical data for improving risk-based cleanup standards for
Importance to DOE. Cleanup costs for chlorinated solvents found on DOE sites are most frequently
driven by TCE because it is the most widespread contaminant and is generally present at the highest
concentrations. Data that would permit increases in risk-based standards for TCE would reduce complex-
wide cleanup costs by hundreds of millions of dollars.
Current Regulatory Actions that Research will Impact. EPA is currently reviewing its risk
assessment for TCE. Richard J. Bull has worked with EPA on this review by writing the mode of action
section of their determination. A presentation by James Cogliano of EPA at the 1999 Annual Society of
Toxicology Meeting indicates that they have accepted the concept of nonlinear extrapolation for liver tumor
induction by TCE. This project will end in FY 1999 with its major technical and policy objectives
One impetus for this research was data that indicated that TCE induced a shift in the mutation spectra
observed in the H-ras codon 61 in mouse liver tumors. Such effects have been generally interpreted as
indicating that the chemical is acting as a mutagen. As the project progressed, additional data were
published that indicated that one metabolite of TCE, dichloroacetate (DCA), has mutagenic activity in vivo
(Leavitt et al. 1997). Adaptations were made in the experimental design to address the importance of these
effects to the induction of liver tumors by DCA. The results of this project argue strongly that selection (or
promotion) is more likely responsible for these observations than are DCA-induced mutagenic effects.
The project is organized around two interrelated tasks:
Task 1 addresses the tumorigenic and dosimetry issues for the metabolites of TCE that produce liver
cancer in mice, DCA, and trichloroacetate (TCA). Early work had suggested that TCA was primarily
responsible for TCE-induced liver tumors, but several more mechanistic observations suggest that DCA
may play a prominent role. This task is aimed at determining the basis for the selection hypothesis and
seeks to prove that this mode of action is responsible for TCE-induced tumors. This project will supply the
basic dose-response data from which low-dose extrapolations would be made.
Task 2 seeks specific evidence that TCA and DCA are capable of promoting the growth of spon-
taneously initiated cells from mouse liver in vitro. The data provide the clearest evidence that both
metabolites act by a mechanism of selection rather than mutation. These data are necessary to select
between linear (i.e., no threshold) and nonlinear low-dose extrapolation models.
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Bull, Richard J. & Thrall, Brian D. Mechanism Involved in Trichloroethylene-Induced Liver Cancer: Importance to Environmental Cleanup, report, June 1, 1999; Richland, Washington. (digital.library.unt.edu/ark:/67531/metadc779866/m1/3/: accessed October 19, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.