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Mechanism Involved in Trichloroethylene-Induced Liver Cancer: Importance to Environmental Cleanup

Description: The objective of this project is to develop critical data for improving risk-based cleanup standards for trichloroethylene (TCE). 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 satisfied.
Date: June 1, 1999
Creator: Bull, Richard J. & Thrall, Brian D.
Partner: UNT Libraries Government Documents Department

Mechanisms Involved in Trichloroethylene-Induced Liver Cancer: Importance to Environmental Cleanup

Description: The project is organized around two interrelated tasks: Task 1 develops the basic dosimetry parameters and provides in vivo data describing the mode of action tumorigenic and for the metabolites of TCE that produce liver cancer in mice, dichloroacetate (DCA) and trichloroacetate (TCA). Early work suggested that TCA was primarily responsible for TCE-induced liver tumor. More recent, mechanistic observations indicated that DCA played a prominent role. Therefore, studies were designed to determine whether the effects of DCA were mediated through a mode of action that affects primarily tumor growth rates. Task 2 seeks specific evidence that TCA and DCA are capable of promoting the growth of spontaneously 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 a linear (i.e. no threshold) and non-linear low-dose extrapolation models.
Date: June 1, 2000
Creator: Bull, Richard J. & Thrall, Brian D.
Partner: UNT Libraries Government Documents Department


Description: Trichloroethylene (TCE) is a common contaminant of groundwater as a result of poor disposal practices of the past. As a consequence, this solvent is the focus of many clean-up operations of uncontrolled hazardous waste sites. TCE is carcinogenic in both mice and rats, but at different sites, the liver and kidney, respectively (NCI 1976; NTP 1988; NTP 1990). Liver tumor induction in mice has been the tumor most critical from the standpoint of environmental regulation (Bull 2000). Under the proposed cancer risk guidelines of the Environmental Protection Agency (EPA 1996), identifying the dose-response behavior of key events involved in carcinogenic responses can be used for developing alternative risk assessments. A major difficulty in developing alternative approaches for TCE is the fact that three of its metabolites are capable of inducing liver cancer in mice (Bull et al. 1990; Daniel et al. 1992; DeAngelo et al. 1999; Pereria 1996). Two of these metabolites have distinct modes of action, dichloroacetate (DCA) and trichloroacetate (TCA). The third metabolite, chloral hydrate, is probably active as a result of its conversion to one or both of these two metabolites. Ordinarily, the first approach to assigning causality to a metabolite in tumorigenesis would be an attempt to measure its concentration in the body and associate that with tumorigenic concentrations observed when the compound is itself administered. This can be done with relative ease with TCA. However, it has been more difficult with DCA since blood levels of this metabolite after exposure to carcinogenic doses of DCA fall rapidly below detection limits (Kato-Weinstein et al. 1998; Merdink et al. 1998). Mutations in the ras protooncogene have been used to determine if distinct patterns of DNAsequence alterations can provide indications of the type of DNA damage that might be produced by carcinogens. The presence of ras mutations in ...
Date: December 31, 2001
Creator: Bull, Richard J. & Thrall, Brain D.
Partner: UNT Libraries Government Documents Department

Cancer Risk Assessment: Should New Science be Applied? Workgroup summary

Description: OAK-B135 A symposium discussing the implications of certain phenomena observed in radiation biology for cancer risk assessment in general. In July of 2002 a workshop was convened that explored some of the intercellular phenomena that appear to condition responses to carcinogen exposure. Effects that result from communication between cells that appear to either increase the sphere of damage or to modify the sensitivity of cells to further damage were of particular interest. Much of the discussion focused on the effects of ionizing radiation that were transmitted from cells directly hit to cells not receiving direct exposure to radiation (bystander cells). In cell culture, increased rates of mutation, chromosomal aberration, apoptosis, genomic instability, and decreased clonogenic survival have all been observed in cells that have experienced no direct radiation. In addition, there is evidence that low doses of radiation or certain chemicals give rise to adaptive responses in which the treated cells develop resistance to the effects of high doses given in subsequent exposures. Data were presented at the workshop indicating that low dose exposure of animals to radiation and some chemicals frequently reduces the spontaneous rate of mutation in vitro and tumor responses in vivo. Finally, it was concluded that considerable improvement in understanding of how genetic variation may modify the impact of these phenomena is necessary before the risk implications can be fully appreciated. The workshop participants discussed the substantive challenge that these data present with respect to simple linear methodologies that are currently used in cancer risk assessment and attempted to identify broad strategies by which these phenomena may start to be used to refine cancer risk assessment methods in the future.
Date: December 15, 2002
Creator: Bull, Richard J. & Brooks, Antone L.
Partner: UNT Libraries Government Documents Department