Determination of Carcinogenic Mechanisms for Furan in Fischer 344 Rats

<OL> <LI> Develop and validate LC-ES/MS/MS assays to quantify the major furan-derived DNAadducts in liver, the major furan-derived hemoglobin adduct(s), and the major furan-derived urinary glutathione-derived metabolite. </LI>
<LI>Determine dose-response relationships for liver furan-derived DNA and hemoglobin adduct formation and repair/turnover and the major furan-derived urinary glutathione-derived metabolite in male and female Fischer 344 rats following single and multiple dose exposures of rodents to furan.</LI>

<LI>Determine concentration of furan in irradiated NIH-31 diet using headspace-GC/MS.</LI>

<LI>Determine toxicokinetics of furan in male and female Fischer 344 rats following exposure by single gavage administration.</LI>

<LI>Combine all data from single and repeated dose toxicokinetics of furan in rat blood and liver with the corresponding levels of liver DNA adducts, hemoglobin adducts, and urinary mercapturates to construct a PBPK model for future use in determining carcinogenic risks from human exposure to furan through the diet.</LI>

<LI>Determine mutagenicity of furan in liver in vivo
using male Big Blue rats.</LI>

<LI>Determine the dose-response relationships for furan-mediated hepatotoxicity and cell proliferation in liver of male and female Fischer 344 rats.</LI>

<LI>Determine effects of furan on methylation status in rat liver and kidney DNA and histones as epigenetic changes related to carcinogenic process.</LI>
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