Document o9aR1OpX500Yr2GpZ75d92jMD

From: jam** A. S*rU)*ra To: W*nay Shannon Oau: 0/27/07 Tim*: 13:40:02 Pag* 2 ofi Molecular Dosimetry of Vinyl Chloride James A. Swenberg, D.V.M., Ph.D. Research Report and Budget Request July 28,1997 SL 109624 From: jamas *. Swnoero To: W*ndy Sherman Data: 0/27/97 Tima: 19:40:31 Page 3 of 4 Research Report Year 1 (1996-1997 Budget) TRc laboratory portion of this project began this spring by sending teams of 3-4 ofour laboratory personnel to New Jersey to collect tissues and liver cell types from rats that were exposed to 0.10. 100. or 1100 ppm vinyl chloride (VC) for 1-20 days. Procedures were rather difficult during the first set of necropsies, but went much better for subsequent procedures after we sent an additional person and shipped up our own centrifuge. We were able to harvest good yields of cells and tissues for the experiment as a whole. It was unfortunate that the ["Cj-VC experiment was the first to come off. as this was the least smooth running of all. Even so, adequate numbers of cells were able to be harvested to meet our objectives. We are currently isolating DNA from the 4-weck hcpatocytes. as these are the most plentiful cells. A new iminunoaffinity chromatograph-GC/MS method is replacing our previous low pressure strong cation exchange-GC/MS method for tile analysis of cthcnoguaninc. .After this shakedown, we will begin working with the [UCJ-VC liver cells. Parallel to this effort will be the analysis of urines for excretion of ethenoadenine using iminunoaffinity chromatography and LC-MS. Likewise, we will begin examining the major DNA repair pathway for VC DNA adducts including methyl purine glycosylase (MPG) and AP-endonuclcase (AP). Year 2 (1997-1998 Budget) During Year 2 we will continue to work up the many samples collected in New Jersey. Priority will be given to establishing exposure response relationships, identifying cell-specific differences in DNA repair, determining effects of exposure on endogenously formed DNA adducts, and doing initial studies related to incorporating these data into a PB/PK risk assessment model. We are also developing new methods for the 'N^-ethenoguanine adduct, which lias never been cliaracterized in vivo. Year 3 (1998-1999) We expect to complete this research during the third year. At this time, we will have analyzed all ofthe relevant tissues and cells for DNA adducts, will establish the role of defects in DNA repair and tlie effect of induction ofDNA repair on exogenous and endogenous DNA adducts, and incorporate these data into a biologically-based risk assessment model. SL 109625 From. James A. Swenoero To; Wendy Sherman Date; (VZ7/87 Tima: 13:41:20 Page 4 of 4 Research Budget Mv understanding ofthe funding available for diis project is that between S50.000-75.000 will be available per year for three years. The cost of this research project will greatly exceed this, with personnel costing -SI40.000 this year. However, since VC has been and continues to be one of the chemicals that we are investigating under our NTEHS Superfund Basic Research Program Project I can offset pan of the cost, providing that the CMA agrees to share acknowledgement with NIEHS, Should we need additional [UCJ-VC exposures, they can be done at UNC, since the EOIC lias agreed to fund new research that includes funds to set up a small nose-only exposure system for similar studies on ethylene oxide. Thus, we can maximize our future research dollars to fund critical studies. We need to move forward as fast as possible, as the EPA has already developed a new risk assessment on VC that suggests increased risk compared to their previous estimates. The new assessment incorporates metabolism data, but not information on DNA adducts or DNA repair. Finally, we incurred major expenses during the four trips to New Jersey that were not included in Year l's budget. These are listed under sample collection in the budget. 1997-1998 Budget request Sample collection Travel expenses Shipping Supplies Research budget Personnel Supplies LC-MS/MS time (S25/hr) Travel Equipment maintenance agreements $8172 752 11771 35000 24000 2500 3000 2000 520.695 566.500 TOTAL BUDGET REQUEST $87,195 SL 109626