Document aBMED5DzxkZydREMJgZDerpeb

CMA 9/19/97 trusts-* t//// C-" PAGE 2/4 CMA rww*a or h // f > ^ <7 ; j Vi' ^ <: 7^- C /nr !K- ( Lh: kx '/ .' /, c ( c -7 c^~ 7 ^ Molecular Dosimetry of Vinyl Chloride James A. Swenberg, D.V.M., Ph.D. 4-e- Research Report and Budget Request July 28,1997 7 ckt 'C r7 l / '/ l- /V 33 0 CD CD O' o to CMA . 9/19/97 ttitwnMniy iv; vvonay anflrman PAGE chib; <xiTrt7 Tima: iS:ao:li 3/4 CMA Pago 3 of 4 Research Report Year 1 (1996-1997 Budget) The laboratory portion of this project began this spring by sending teams of 3-4 of our laboratory personnel to New Jersey to collect tissues anti 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, hut 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 lor the experiment as a whole. It was unfortunate that the [,9C,]-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 arc currently isolating DNA from the 4-week hepatocytcs, as these arc the most plentiful cells. A new immuiioaffinity ohromatograph-GC/MS method is replacing our previous low pressure strong cation exchmigc-GC/MS method for the analysis of ethenoguauine. After this shakedown, wc will begin working with the [,JC2]-VC liver cells. Parallel to this effort will be the analysis of urines for excretion of ethenoadenine using iinmunoatTinity chromatography and LC-MS. Likewise, we will begin examining the major DNA repair pathway for VC DNA adducts including methyl purine glyoosylase (MPG) and AP-endonuclcasc (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 cdl-spcoific differences in DNA repair, determining effects of exposure on endogenously formed DNA adducts, mid doing initial studies related to incorporating these data into a PR/PK risk assessment model. We are also developing new methods for the ^^-ctlicnoguaiiiiie adduct, which lias never been characterized in vivo. Year 3 (1998-1999) We expect to complete this research during the third year. At this time, we will have analyzed all ol the relevant tissues and cells for DNA adducts, will establish the role of defects in DNA repair and the effect of induction of DNA repair on exogenous and endogenous DNA adducts, and incorporate these data into a biologically-based risk assessment model. R&S154510 CMA 9/19/97 rrom; James . awenoera to; wenay Snerman PAGE Date; mmi Time; is;4i;2o 4/4 CMA rage 4 or 4 Research Budget My understanding ofthe funding available for this project is that between $50,000-75.000 will be available per year far three years. The cost ofthis research project will greaLly exceed this, wiih personnel costing --$140,000 this year. However, since VC has been and continues to be one of the chemicals that we are investigating under our NIEHS Superfund Basie Research Program Project 1 can offset part of the cost, providing that the CMA agrees to share acknowledgement with NIEHS. Should we need additional [UC,]-VC exposures, they can he done at INC, since the EOIC has 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, UiaL 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 wem 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 timo ($25/hr) Travel Equipment maintenance agreements $8172 752 11771 35000 24000 2500 3000 2000 $20,095 66,500 TOTAL BUDGET REQUEST $87,195 R&S154511 TQTfiL P.003 Page 1 of 5 R&S15' Vinyl Chloride Health Committee Activities MEMORANDUM OF UNDERSTANDING (MOU) WITH THE AGENCY FOR TOXIC SUBSTANCES AND DISEASE REGISTRY (ATSDR) The MOU has been signed. A revised study plan was sent to ATSDR because of the delay in the initiation of the study. IMPORTANCE ACTION ITEMS 04/11/97 DEADLINES Initial progress reports are due at ATSDR April 25 with subsequent reports due every 6 months thereafter until studies are completed and final reports submitted. The MOU was developed to meet the research needs of ATSDR and the Environmental Protection Agency in lieu of a TSCA Section 4 testing requirement. REPRODUCTIVE & DEVELOPMENTAL TOXICITY STUDIES AT HUNTINGDON LIFE SCIENCES (HLS) The contract with Huntingdon has been signed. Analytical work on the test material is complete and the animal exposure has begun. Preliminary results of the analytical work were delivered to CMA for inspection. Jim Knaak reviewed the material and approved it. ACTION ITEMS Continue monitoring progress of study. DEADLINES Progress reports are due to CMA at intervals specified in the agreement. Jim Knaak, David Penney, and Wendy Sherman will visit Huntingdon in mid-April to monitor progress of studies. IMPORTANCE This research is in lieu of a potential TSCA Section 4 testing requirement. MOLECULAR CARCINOGENESIS SATELLITE STUDIES AT HLS/ UNIVERSITY OF NORTH CAROLINA-JAMES SWENBERG Ray Schroeder (HLS) and James Swenberg (UNC) revised the protocols for the satellite studies. Fewer animals will be needed to conduct the studies and studies will not be subject to GLP standards. This significantly reduces the cost of the satellite studies. IMPORTANCE ACTION ITEMS Execute agreement with HLS for in-life portion of satellite study. Prepare a gift letter for S50K to University of North Carolina for the post-exposure treatment of animals and the adducts analyses. DEADLINES This series of studies on the formation and repair of DNA adducts induced by vinyl chloride should provide a better understanding of the mechanisms of vinyl chloride carcinogenesis. Page 2 of 5 Vinyl Chloride Health Committee Activities 04/11/97 SYNTHESIS OF 13C2 VINYL CHLORIDE / CAMBRIDGE ISOTOPE LABORATORIES The product was delivered to Huntingdon. According to Gary Hoffman (HLS) the analytical specifications of the material are acceptable. ACTION ITEMS DEADLINES IMPORTANCE By utilizing 13C2-vinyl chloride, the formation and repair of vinyl chloride-induced DMA adducts can be studied relative to those adducts formed endogenously- This aspect of the satellite studies could provide important information for risk assessment dealing with low exposures, such as might be associated with accidental releases that reach the fenceline. INTERNATIONAL LIFE SCIENCES INSTITUTE (ILSI) The VCHC contributed $10,000 to ILSI for .a project on the use of non-tumor data in cancer risk assessment. Gino Scarano of ILSI provided a progress report on the project. Gino Scarano will notify CMA of the date of the meeting of the sponsors when it has been set. ACTION ITEMS Monitor ILSI activities on this project. DEADLINES IMPORTANCE Hie current scientific and regulatory climate is such that the use of endpoints other than tumors to quantitatively estimate cancer risk is on the horizon. This project was initiated to address the question of whether and how genotoxicity and other data could be used as part of a cancer risk assessment. EPA INTEGRATED RISK INFORMATION SYSTEM PILOT PROJECT EPA has selected vinvl chloride for its IRIS pilot project. According to Mike Gargas, Harvey Clewell is the EPA contractor examining vinyl chloride. ACTION ITEMS Monitor EPA activities on this project. DEADLINES IMPORTANCE IRIS is an EPA database which contains consensus scientific positions on potential human health effects from environmental contaminants. The database has expanded a R&S154513 Page 3 of 5 R&S154514 Vinyl Chloride Health Committee Activities and its use has increased over the last decade. It is the primary source of risk assessment and management information for many other agencies at the federal, state and local levels. 04/11/97 BRAIN CANCER STUDY / UNIV OF LOUISVILLE ACTION ITEMS The Study is proceeding on schedule. IMPORTANCE The Committee and University of Louisville representatives will meet on April IS"1 to explore alternative methods for analyzing data so the final study is seen as credible by both clinical and traditional epidemiological communities. The 20-year prospective assessment of B.F. Goodrich's Louisville cohort provides a unique opportunity to determine whether there is any association between brain cancer and vinyl chloride exposure. DEADLINES Study progress reports are due at CMA on dates indicated in the agreement. VINYL CHLORIDE COHORT STUDY UPDATE / APPLIED EPIDEMIOLOGY INC. ACTION ITEMS Ken Mundt received the remaining death certificate information from ENSR, He asked for assistance from Committee members to track employment and vital status on some of the cohort members. DEADLINES Study progress reports are due at CMA on dates indicated in the study agreement, IMPORTANCE ATSDR TOXICOLOGICAL PROFILE FOR WNYL CHLORIDE ACTION ITEMS Committee provided comments on the health and environmental portions of the profile to ATSDR. Data on production volume, facilities and use in the profile, is inaccurate. Caffey Norman is drafting a letter to ATSDR correct the data and suggest an alternative to the presentation of the storage data in Chapter 4 of the Tox Profile. Follow up with ATSDR on Committee comments. DEADLINES IMPORTANCE Page 4 of 5 p&si545''5 Vinyl Chloride Health Committee Activities 04/11/97 ATS DR MEDICAL MANAGEMENT GUIDELINES FOR VINYL CHLORIDE t \ 'itnnitter provided comments oil the guidelines. ACTION ITEMS Follow-up with Jennifer Hiese (617/674-735H) on when the guidelines will be finalized. IMPORTANCE DEADLINES EPA / PETITION TO RAISE THE "REPORTABLE QUANTITY' (RQ) OF VINYL CHLORIDE Tlie Vinyl Institute will take the lead on determining whether a petition to raise the RQ is feasible. The VCHC will provide technical expertise if the VI decides that it is feasible. Caffev Norman will provide background on the criteria for determining the RQ. ACTION ITEMS DEADLINES IMPORTANCE EPA / AIR TOXICS PROGRAM ACTION ITEMS EPA identified vinyl chloride and 36 other chemicals as "high priorities" for regulation under its Air Toxics Program. The Agency plans to develop a comprehensive integrated strategy for establishing an "air toxics management model." Caffey Norman provided background on EPA's activities with the Air Toxics Program, and CMA has asked to be a stakeholder. DEADLINES IMPORTANCE ASSOCIATION OF PLASTICS MANUFACTURERS IN EUROPE (APME) / REGISTRY OF CASES OF ANGIOSARCOMA APME has developed a protocol for the maintenance of a register of cases of angiosarcoma related to PVC production. IMPORTANCE ACTION ITEMS CMA will monitor the development of the registry. DEADLINES AMERICAN CONFERENCE OF GOVERNMENTAL INDUSTRIAL HYGIENISTS (ACGIH) / INITIATIVE TO LOWER THE THRESHOLD LIMIT VALUE (TLV) FOR VINYL CHLORIDE The concern from ACGIH is based on an article by Simonato, et al. in the Scand J. Work ACTION ITEMS The Committee will examine the Simonato paper and make contact with William Waddell to propose presenting information to ACGIH. Page 5 of 5 Vinyl Chloride Health Committee Activities & E.H. ACGIH met on October 5, 6, 7, 1996 in Philadelphia. Peter de la Cruz of Keller & Heckman (Vinyl institute) responded to Dr. William Waddell of the Univ. of Louisville (ACGIH) for Frank Borelli. DEADLINES 04/11/97 IMPORTANCE CALEPA / DEVELOPMENTAL AND REPRODUCTIVE TOXICANT (DART) IDENTIFICATION COMMITTEE PRIORITY LIST Vinyl chloride is a potential candidate for listing under Proposition 65. The VCHC submitted comments to CalEPA. ACTION ITEMS The Committee will monitor this issue. IMPORTANCE DEADLINES R&S 154516