Document 3Jgq5YR2BGVbVxgonpeD2JJw6

MAY-08--1996 10!33 5-08-1396 11:12 CHEMSTAR PAGE 1/11 i& Chemical Manufacturers Association Via Electronic FAX p.001/011 Vinyl Chloride Panel Health Committee FAX May 8,1996 TO; Jim Barter Ed Beeler John Gamble Mark Gruenwald James Knaak Caffey Norman Dave Penney Dave Pun Jonathan Ramlow Jay Strange PPG Industries GEON Westlake Borden Occidental Patton Boggs Vista Formosa Dow Georgia Gulf 412/434-2137 216/930-3034 713/963-1540 614/225-7638 716/286-3141 202/457-6315 713/588-3478 201/716-7283 517/636-1875 504/687-0294 FROM: Has Shah CMA RE: Conference Call MESSAGE Please review the enclosed information in preparation for the Vinyl Chloride Health Committee conference rail, scheduled for May 9,1996, at 10:00 a.m. EDT. Please call me at 703/741-5637 if you have any questions. I look forward to talking with you then. SENDER: Elena Howell PHONE: 703/741-5638 PAGES: 11 (including coversheet) mRnpmafeCan* 1300 Wilson Boulivaxd, Asuncion, VA 22209 TFifiHONt 703-741-S000 Fax 703-741-6000 ^ W AftfieQBnmBi** SL 110386 FROM: CMA MAY-08-1996 10:33 5-08-1936 11:12 CHEMSTAR PAGE 2/11 Via Electronic FAX P.002/011 RUSH TO: Dr. Robert Venezia*, Chem Manu Assoc FAX: 703 741-6091 FROM: RHR Toxicology Consulting PAGES (INCLUDING THIS COVER): 3 May 7,1996 Dear Dr. Venezia, Here is a copy of the EMAIL which Ie submitted to IRIS In connection with the project which Mike Gargas and I have proposed to carry out for CMA's VC panel. I apologize for submitting material prematurely -- I did NOT want to miss the submission deadline and took the liberty of preparing a list for IRIS. I understand from Mike that CMA had planned to ask for an extension of the submission deadline. Sorry about that! None of the materials have been submitted to ISIS; just the list as requested In the Federal Register Notice. Hope this has not caused you any Inconvenience, and we look forward to your response to our proposal. Dick Reitz SL 110387 FROM: CMA MAY-08-1996 10:33 5-08-1996 11:12 CHEMSTAR PAGE 3/11 Via Electronic FAX P.003/011 IRIS SUBMISSION----- to IRI8,comments6pamail.epa.gov, on May 2, 1996 RESPONSE TO REQUEST FOR SUPPLEMENTAL INFORMATION (VINYL CHLORIDE) Federal Register Noticet Vol. 61, NO. 64, April 2, 1996 (pages 14570-14571) Gentlemen, we believe you may find the following documents/items useful during your re-evaluation of the carcinogenic potency of vinyl chloride (CAS 75-01-4). (D- Reitz, R.H., Gargas, M.L., Andersen, M.E., Provan, W.M., and Green, T.L. (1996). Predicting cancer risk from Vinyl chloride exposure with Physiologically Based Pharmacokinetic model. Toxicol. Appl. Pharmacol. 137, 253-267. (2). VCD0SE2 > CSL The extensively commented source code for a Physiologically Based Pharmacokinetic model capable of describing the uptake, distribution, and conv rsion of vinyl chloride to its reactive and genotoxic metabolites. This source code may be compiled to an executable model with the software packages ACSL-FC and/or SimuSolv. (3) VCDOSB2.CMD-----The associated parameter definitions and procedures used simulat different species and exposure conditions with the PBPK model described above. (4) Baretta, E.D., Stewart, R.D., and Mutehler, J.E. (1969) Monitoring exposures to vinyl chloride vapor 1 Breath analysis and continuous air sampling. Amer. indust. Hygi n Assoc. Journal, 30,'537- 544. (5) Buchter, A., Bolt, H.M., Filser, J., Goargens, H.W., Laib, R.J., and Bolt, W. (1978). Fharmakokinetlk and karzlnogenese von vinylchlorid abreitraedizinische rislkobeurteilung.Verh. Dtsch. Ges. Arbeitsmed., 18, 111-124 <ENGLISH TRANSLATIONS (6) Creech, J.L., & M.N. Johnson (1974), Angiocarcoma of the liver in the manufactur of PVC.J. QCcup. Med., 16, 150-151. (7) Drew, R.T., <3.A. Boorman, J.K. Baseman, E.E. McConnell, W.M. Busey, & J.A. Moore (1983) The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxicol. Appl. Pharmacol., 68, 120-130. (8) ECETOC (1988), Technical Report No. 31 "The mutagenicity and carcinogenicity of vinyl chloride: A historical review and assessment." ISSN 0773-8072-31, Brussels, Belgium. (9) Gargas, M.L., Andersen, M.E. and Clewell, H.J. III. (1986). A physiologically-based simulation approach for determining metabolic constants from gas uptake data. Toxicol. Appl. Pharmacol. 86, 341-352. (10) Gargas, M.L., Burgess, R.J., Voisard, D.E., Cason, G.H., and Andersen, M.E. (1989) Partition coefficients of low molecular weight volatile chemicals in various liquids and tissues. Toxicol. Appl. Fharamcol., 98, 87-99. (11) Gehring, P. J., F.G. Watanabe, & C.N. Park (1978) Resolution of dose-response toxicity data for chemicals requiring metabolic activation. Toxicol. Appl. Pharmacool., 44, 581-591. (12) Guengerich, F.P. & P.G. Watanabe (1979) Metabolism of (14C) and (36C1)-labeled vinyl chloride in vivo and in vitro. Bioehem. Pharmacol, 28, 589-596. (13) Guengerich, F.P., Kim, D.H., and ivasaki, M. (1991) Role of human cytochrome P-450 IIEl in the oxidation of many low molecular weight cancer suspects. Chem. Res. Toxicol., 4, 168-179. Kappus, H,, H.M. Bolt, A. Buchter, & W. Bolt (1976) Liver microsomal uptake of 14C-VC _ ^ j A m w (E _^ j __ ____ . 1 t #1 M ^ J A - . J-- nJ 4h* fti ---- J SL 110388 FROM: CMA nAY-08-1996 10:34 5-08-1996 11:12 CHEMSTAR PAGE 4/11 Via El ctronic FAX P.004/011 (15) R.L., and Woods, J.s. (1978) Carcinogenicity of vinyl chloride and.vinylidene chloride. J. Toxicol* Envir. Hlth., 4, 15-26* (16) Maltoni, C. (1974). "Vinyl Chloride Carcinogenicity! An Experimental Model for Carcinogenesis studies.", monograph from the Institute of Oncology and Tumour Center, Bologna, Italy 40138. (16) Maltoni, C., C. Lefemlne, F. Chisco, k D. carrettu (1974), Vinyl chloride carcinogenesist Current results and perspectives* Med. Lav., 65, 421. (-17) Raucy, J.L., J.c. Kraner, S J.M. Lasker (1993) Bioactivation of halogenated hydrocarbons by Cytochrome P4502E1. critical Reviews in Toxicology, 23, 1-20. (18) Reitz, R.H., Mendrala, A.L. and Cuengerich, F.P. (1989). In Vitro Metabolism of Methylene Chloride in Human and Animal Tissues1 Use in Physiologically-Based Pharmacokinetic Models. Toxicol. Appl. Pharmacol. 97, 230-246. (19) simonato, L., L'Abbe, K.A., Andersen, A., Belli, 8., Comba, P., Engholm, Q., Ferro, G., Hagmar, L., Langard, 8., Lundberg, X., Perastu, R., Thomas, F., Winkelmann, R., and Saraccl, R. (1991) a collaborative study of cancer incidence and mortality among vinyl chloride workers, scand. J. Work Environ. Health, 17, 159-169. (20) Viola, P.L. (1970), Pathology of vinyl chloride. Med. Lav., 61, 174. (21) Viola, P.L., A. Bigotti, and A. Caputo (1971)-Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res., 31, 516-522. (22) Watanabe, F.G., G.R. McGowan, E.O. Madrid, & P.J. Gehring (1976) Fate of 14C-vinyl chloride following inhalation exposure in rats. Toxicol. Appl. Fharmacool., 37, 49-59. SL 110389 FROM: CMA MAY-08--1996 10:34 5-08-1996 11:12 CHEMSTAR PAGE 5/11 ins Via Electronic FAX P.005/011 r. ui/ur LABORATORY OF MOLECULAR CARCINOGENESIS AND MUTAGENESIS THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL CAMPUS BOX 7400, ROSENAU HALL SOUTH COLUMBIA STREET CHAPEL HILL, NC 27599 PHONE 919-966-6142 FAX 919-966-6123 FACSIMILE TRANSMISSION To: Bob Venezia Address: CMA FAX number: 703-741-6091 From: lames A. Swenberg, D.V.M., Ph.D. Date: May 7, 1996 Bob; Here is the research proposal/protocol. I made a flew changes from our discussions In New Jersey. I sent a copy to Jim Knaalc for his comments. He said that the issue of dynamic versus static exposures will be determined in the future. Dr. Rudy Jager has some dynamic exposure systems that win use even less thaw the 27 gm. As I do not have access to the needed information, I cannot go any farther today. I hope that this is what you need. If you have any questions, please give me a call tomarrow. i} SL 110390 FROM: CMA MAY-08-1996 10`-34 5-08-1996 11:12 CHEMSTAR PAGE 6/11 l IU3 Via Electronic FAX P.006^011 r.U4/ur PROTOCOL FOR MOLECULAR DOSIMETRY STUDIES ON VINYL CHLORIDE James A. Swcnberg, D.V.M., Ph-D. University of North Carolina May 7,1996 Listed below is a series of studies 00 the formation and repair of DMA adducts fridnng.it by vinyl chloride (VC), that will provide a vastly improved understanding of the meehnnignia ofvinyl chloride carcinogenesis. These studies will provide information relevant to cancer risk assessments of vinyl chloride. The studies would be conducted in a manner that will complement the two generation reproductive and developmental toxicity studies that will be conducted at Huntingdon Life Sciences Laboratory. Pose-raspOTiae Studies Presently, yve have data showing that preweanling rats are more susceptible than adults to VC carcinogenesis, that preweanlings develop 3-fold greater numbers of VC DNA adducts, and that preweanlings have 3-fold higher expression of CYP 2E1. The adduct and carcinogenesis data arc all fix)m "high" exposures of-500 ppm. No information exists on lower exposures. In addition, we have clearly demonstrated that DNA adducts identical to those formed by VC are formed endogenously in unexposed rats, mice and humans. We have developed ultrasensitive and highly specific assays for the DNA adducts ofVC. These include iTmrnmnMfBnity/^-pntflahleing methods for 1 ,N6-cthenodeoxyadeoosine (EdA) and 3,N*-etheuodcoxycytidiiie (EdC), and GC/MS methods for N*,3-eihenoguanine (EG). By adding animals to the reproductive and developmental toxicity studies, we will be able to assess the effect of exposure concentration on 1) the molecular dose of etheno adducts, the primary promutogemo DNA adducts ofVC; 2) determine ifthere are differences in the dose-response between adult and weanling rats; 3) examine the mqor DNA repair pathways for VC DNA adducts; and 4) characterize the utility of using DNA adducts excreted in the urine as a biomarker of exposure. 1 SL 110391 FROM: CMA MAY-08-1996 10=34 5-08-1996 11:12 CHEMSTAR PAGE 7/11 iioy so 13-1/ Via Electronic FAX P.007/011 r.us/ue Molecular Dosimetry Studies in NonpareiwftvmaJ Celia fNPCt versus Henatnovtt* Understanding why VC targets the endothelial cell for its carcinogenic effect is critical for proper risk assessment We have preliminary data on EG in vinyl fluoride-exposed rats (2500 ppm, 6 hrfday, 5 days/wk, 4 wks) which shows that the numberof adducts Is ~2.5*fold higher in NPC than hepatocytes, even though metabolism of VF to its electrophile is thought to only take place in hepatocytes. Since the NPC are exposed by diffusion of VC or VF electrophiles from neighboring hepatocytes and therefore have lower exposures, this suggested that NPC were deficient in DNA repair activity for EG. To test this hypothesis, we have developed a RT-PCR method for quantitating methylpurine-DNA glycosylasc (MPG) in tissues and cells. Preliminary data have shown that NPC have <20% ofthe MPG activity present in hepatocytes. In addition, we have shown that NPC have 5-fold greater numbers ofabasic sites in their DNA. Abasic sites are fanned when MPG excises a damaged base, such as EG, EA and EC. These data suggest that NPC are deficient in a second step in the DNA repair of VC adducts. We think that die most likely candidate is a deficiency in AP endonuclease. The difference between hepalocyte and NPC abasic sites was seen in rats exposed to VF, but not in controls. The combination oftwo defects in DNA repair in the target cells for VC carcinogenesis provides a strong scientific basis for the induction of hemangiosarcomas by this important chemical. In view of the fact that the increase in abasic sites was only seen in highly exposed rats shows the need to understand the dose response relationship for this endpoint. By conducting 4 week exposures to 0,10,100, and 1000ppm. VC and measuring etbeno adducts, MPG expression and abasic sites, we will be able to determine ifnonliuearities exist in .the molecular dose of VC, in MPG expression, and in the number of abasic sitespresent in the DNA. Our hypothesis is that EG will show a supralincar dose response; that MPG will be similar in exposed and unexposed hepatocytes, but lower in both exposed and unexposed NPC; but that abasic sites will exhibit a sublinear dose response characteristic of saturation of DNA repair in NPC, but not hepatocytes. FROM: CMA MfiY-08-1996 10=35 5-08-1996 11:12 CHEMSTflR PAGE 8/11 Via Electronic FAX P.008/011 Studies Using 3-YC Our data showing endogenous formation ofethane DNa adducts that are identical to those induced by VC have important implications. We had previously published a paper that concluded that the DNA adducts ofVC were highly persistent. We now believe that this was not correct, in that what we were calling persistent DNA adducts were actually the endogenously framed adducts at steady-state. By utilizing [^CJ-VC, the formation and repair of VC-induced DNA adducts can be studied relative to those adducts formed endogenously. I believe that these studies will critically impact on any risk assessment dealing with low exposures, such as might be associated with accidental releases that reach the fcncciine. We will examine the amount of ["CJ*VC induced EG in mis exposed to 10,100, or 1000 ppm for 5 days (6 hrs/day). These same nimal< will be housed in metabolism cages for 3 days prior to exposure and during each day's post exposure holding period (days 1-4) so that urine can be collected. The urine will be analyzed for endogenous and induced DNA adducts that have been repaired by the MPG pathway using GC/MS. We will alsodevelop ixnmunoafQnity-LC/MS methods for all three etheno. bases. In addition, it may be possible to identify and quantitate [''CJ-VC metabolites in the urine using NMR. A second set of [IJC2]-VC exposures is contemplated that would consist of single exposures. These will be designed after we get data from the above study. Significance We have developed highly sensitive and specific assays for the promutagcnic DNA adducts ofvinyl chloride over the past 10 years. By exposing additional animals in the Huntingdon study, we can use these methods to answer several questions related to improved risk assessment of VC. First, the molecular dosimetry data will be the only information of its type that addresses doseresponse. All other data have come from high exposures of 500-600 ppm. Second, we will address the issue of differences between weanling and adult animals. While we already know that preweanling rets are more sensitive than adults to the formation ofDNA adducts and carcinogenesis at high concentrations, it is not known ifthis is true for low exposures. Since the only VC exposures that children cncoumer would be extremely low, the 10 ppm data are ofparticular importance. Just 3 SL 110393 FROM: CMA my-08-1996 10:35 5-08-1996 11:12 CHEMSTfl-R---- ----- PAGE 9/11 ' "-3 Via Electronic FAX P.009^011 because preweanling rats exposed to concentrations that saturate metabolism develop more adducts does not necessarily mean that young animals exposed to low concentrations will also develop more DNA adducts than adults. Our recent development of an assay for MPG and the finding that NPC are deficient in this DNA repair pathway provides thefirst mechanistic data that explains why VC causes hemangiosarconias. The additional finding of greatly increased numbers ofabasic sites in the NPC DNA further highlights the importance of cell-specific differences in DNA repair. The experiments outlined above will provide compelling data on the importance of DNA repair in VC carcinogenesis. Finally, the use of [l3CJ-VC will allow us to differentiate between induced and endogenous DNA adduct formation. If large numbers ofinduced EG are formed, they may lead to increased numbers of endogenous adducts dps to competition for DNA repair. On the other band, we will be able to determine the extent of increased DNA damage relative to endogenous adducts for all three exposure groups. For example, we might find that .10 ppm VC for 5 days only doubles the amount ofEG present endogenously. Such a finding should have great impact on low dose risk assessments. We would then look at various single exposures to simulate fenceline exposure scenarios to determine ifthere was any detectable increase in risk. Similar studies could be used to mimic occupational or environmental exposures to VC. Protocols Study /. Adult Rats Exposed to Vinyl Chloridefor 1 Week Route: Whole body exposure conducted during the two generation animal portion ofthe main study Exposure groups: 0,10,100, or 1000 ppm No. ofrats/group; 32 Total: 128 Exposure duration: 1 week (6 hr/day, 5 days) Spccies/strain: CD Rat Age: Approximately 12 weeks of age Sex: Males Sacrifice: 8 rats/ group at end of last exposure (non-peift$ed), and 8 rats/ group at end of last exposure and at 3 and 7 days post-exposure (perfused) Urine collections: during Days 1-4 of exposure (collected during nonexposure times) 4 SL 110394 FROM: CMA mY-08-1996 5-08-1996 11:12 10=35 _ - . ----. m. CHEMSTPR , ws . jW UJ.AW PAGE 10/11 roy 30 Via Electronic FAX P.010/011 K,Ub/Ui' 1 //. Weanling Rats Exposed to Vinyl Chloridefor 1 Week Route: Whole body exposure conducted during the two generation animal portion ofthe main study Exposure groups: 0,10,100, or 1000 ppm No. of rats/group: 32 Total: 128 Exposure duration: 1 week (6 hr/day, 5 daysAveek) Species/strain: CD Rat Age: Approximately 21 days ofage Sex: Males Sacrifice: 8 rats/ group at end. of last exposure (non-perftrsed), and 8 rats/ group at end of last exposure and at 3 and 7 days post-exposure (perfused) Urine collections: during Days 1-4 of exposure (collected during nonexposure times) Study III. Adult Rats Exposed to Vinyl Chloridefor 4 Weeks Route: Whole body exposure conducted during the two generation animal portion of the main study Exposure groups: 0,10,100, or 1000 ppm No. of rats/group: 32 Total: 128 Exposure duration: 4 weeks (6 hr/day, 5 daysAveek) Species/strain: CD Rat Age: Approximately 12 weeks of age Sex: Males Sacrifice: 8 rats/ group at end of last exposure (non-pertUsed), and 8 rats/ group at end of last exposure and at 3 and 7 days post-exposure (perfused) Urine collections: during last week ofexposure (collected during nonexposure times) 5 SL 110395 FROM: CMA mY-08-1996 10=36 5-08-1996 11:12 CHEMSTAR PAGE 11/11 i ! Via Electronic FAX P.011/011 Study IK AdultXais Exposed to I,3CJ-Vbtyl Chloridefor i Week Route: Nose only exposure Exposure groups: 10,100, or 1000 ppm No. ofiats/gFOUp: 8 Total: 24 Exposure duration: 5 days (6 hr/day) Speeies/strain: CO Rat Age: Approximately 12 weeks of age Sex: Males Sacrifice: 8 rats/ group at end of last exposure (perfUsed) Urine collections: 3 days prior to exposure and Days 1-4 during exposure (collected during nonexposure times) 6 SL 110396 TOTAL P.011