Long Term Toxicity of Di- and Tri-Chloroacetate

University Of Toledo, Toledo OH

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Trichloroacetate (TCA) and dichloroacetate (DCA) are by-products found in the chlorinated drinking water. The compounds are found to produce liver toxicity and cancer, in animals. We propose that long term exposure to TCA and DCA induces oxidative stress (OS) in mice. These mechanisms occur earlier than production of any detectable toxic, or carcinogenic effects in the liver. The effects are also produced in response to much lower doses than those required to produce detectable liver toxicity or cancer. We also propose that long term exposure to mixtures of DCA and TCA, produces more effects than those produced by the individual compounds. Also, marginal vitamin E deficiency increases the toxic/carcinogenic risks of the compounds. Groups of male B6C3F1 mice will be treated post orally, with daily doses of TCA and DCA, for 4-30 weeks. At the end of the treatment periods, mice will be sacrificed and phagocytic cells will be collected and assayed for production of reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha). Livers will be collected and investigated for development of histopathological changes, as well as for the determination of various biomarkers of OS, including ROS, lipid peroxidation, DNA damage, glutathione level, and activities of different antioxidant enzymes. The doses of TCA and DCA and times required to produce significant changes in the biomarkers of OS, will be determined and compared with those required to produce detectable liver toxicity or cancer in the same animals. Human risk due to exposure to toxic chemicals is, in general, based on the doses and times required to produce cancer in rodents. This project will identify markers of toxicity/carcinogenicity that are significantly changed in response to TCA and DCA. These changes occur at doses and times that are much less than those required to produce detectable cancer. Hence cancer production will underestimate humans risk when used as an end point, while that risk will not be underestimated if based on induction of markers of OS as proposed in this project. Furthermore, the results can be used as basis for studies on human populations to determine the association between changes in biomarkers of OS and consumption of the chlorinated drinking water, as well as with the risk of that human population for cancer development. The study will also be the first to determine the possible increases in effects when TCA and DCA exist in the form of mixtures. This is important since humans are exposed to mixtures of the compounds in the drinking water, rather than to the individual compounds. Results from studies on the mixtures can be used as bases for adjustment of the allowable levels of the compounds in the chlorinated drinking water. The study will be also the first to determine any possible increases in the toxic/carcinogenic risks of the compounds, associated with marginal vitamin E deficiency. Dichloroacetate (DCA) and trichloroacetate (TCA) are toxic and carcinogenic by-products formed during the process of drinking water chlorination. The present study will determine indicators for the toxic effects of the compounds that can be detected much earlier than cancer production in animals. These can be used as basis to determine similar indicators for human risks from exposure to the compounds in the drinking water, and also to adjust the allowable amounts of the compounds in the drinking water. [unreadable] [unreadable] [unreadable] [unreadable]