Document RpOo75dZdGKXKGJ0pJzqvqpnv
Chemical Manufacturers Association
November 13,1995
Dear Vinyl Chloride Health Committee Members:
This is a good news letter! ATSDR informs me that EPA will not require additional neurotoxicity data at this time and that a Memorandum of Understanding can be signed between CMA and ATSDR for a combined reproduction and developmental toxicity study in one species. This represents a saving of about
$400,000.
The following items are enclosed:
1) the October 31,1995, Record of Meeting;
2) the November 8,1995, letter from ATSDR approving the combined reproduction and developmental toxicity study protocol. A copy of the August 1995 ATSDR Toxicological Profile for Vinyl Chloride referred to in the letter also is enclosed for your review and files. The ATSDR letter proposes a collaborative research to address the Agency's need for dose-response data for chronic inhalation. I will have Bill Breslin of Dow look into the ATSDR data need and put it on the agenda for our conference call on November 30 at 10:00 a.m.;
3) the October 31,1995, letter to ENSR about the unacceptability of delays caused by ENSR in transferring all required information to AEI; and,
4) a manuscript by Harvey Clewell et al on vinyl chloride risk assessment.
I will send you a commitment form for the 1996 research program and the agenda for the November 30 conference call tomorrow.
Sincerely,
it&o
Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel
Enclosures CMA IS MOVING!
Fiitctive January 1 99b, our new adurlss will be: 1 300 Wilson Boulfvard Arlington, Virginia 22209
Responsible Care* 2501 M Street, NW, Washington, DC 20037 Tfifphonl 202-887-1 100 Fax 202-887-1237 * f A PublicCommitment
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CHEMICAL MANUFACTURERS ASSOCIATION Vinyl Chloride Health Committee Record of Meeting
Date: Time: Place:
October 31,1995 10:30 a.m.~ 3:00 a.m. CMA Offices Washington, DC
List of Attendees:
Jim Barter Ed Beller Mark Gruenwald Jim Knaak Ken Mundt Caffey Norman David Penney David Pun Jonathan Ramlow Jay Strange
PPG Industries The Geon Company Borden Occidental Chemical Applied Epidemiology, Inc. Patton, Boggs LLP Vista Chemical Formosa Dow Chemical Georgia Gulf
Elena Howell Has Shah
CMA CMA
1.0 The Committee reviewed the list of questions that Jonathan Ramlow prepared for Carlo Tamboro for the proposed University of Louisville Vinyl Chloride Brain Cancer Case-Control Study. Jonathan Ramlow, Ed Beeler and Has Shah will meet with Dr. Tamboro on November 17 in Louisville to discuss the questions. The Committee agreed with the questions, and agreed to request a detailed protocol from Carlo Tamboro as a first deliverable, if a decision is made to proceed with the study. If Dr. Tamboro is amenable to have an epidemiologist as a co-investigator of the study, the Committee recommends Ken Mundt of AEI.
The Committee estimated the combined cost of Dr. Tamboro and an epidemiologist at $150,000.
2.0 Ken Mundt reported that because of delays in the transfer of data from ENSR to AEI, the update must be extended for an additional two years. The Committee agreed to fund this extension.
The Committee approved an additional letter to ENSR. The Committee was concerned about the lack of a reply from Christian Seigneur of ENSR to the September 1 letter, incomplete information regarding files on computer tape, and the failure of ENSR to forward approximately 1,000 death certificates to AEI.
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Vinyl Chloride Health Committee ROM October 31,1995 Page 2
CMA still is waiting for release forms from Montana and New York City to transfer a complete master tape of pervious data from ENSR to AEI.
Ken Mundt estimated the additional costs ot CMA resulting from ENSR's delay in transferring all relevant information. Personnel costs and costs of replacing missing materials currently are projected to be $81,864. The Panel agreed to pay the additional cost, while simultaneously seeking compensation from ENSR.
3.0 Bill Breslin of Dow Chemical revised the Protocol for the developmental/ reproductive effects study. The revised protocol was submitted to ATSDR on October 23,1995. At this time, we are waiting for ATSDR's response.
ATSDR will work with EPA on the need for neurotoxicity data on vinyl chloride.
The Committee reviewed the Memorandum of Understanding between ATSDR and the Halogenated Solvents Industry Alliance, and decided to explore a similar MOU for vinyl chloride.
Dr. Ramlow will have Dr. Breslin review James Swenberg's molecular research proposal of June 1995. He will tell Dr. Shah of feasibility of expanding the developmental/ reproductive effects protocol to include the molecular research. Dr. Ramlow will revise the protocol. Dr. Shah will send the protocol to Argus, Pharmaco LSR, RTI, and Dow, and request bids from those companies.
The Committee developed the following cost estimates for the research program:
Developmental/Reproductive Effects Testing
$650,000
Neurotoxicity Testing
350,000
Molecular Research
60,000
Legal
10,000
Contingency
30,000
4.0 Jim Knaak will send Harvey Clewell's manuscript on Vinyl Chloride Risk Assessment to CMA. Dr. Shah will coordinate with Richard Reitz to see if information from the manuscript can be referenced in Dr. Rietz's manuscript.
The Committee agreed to work with EPA on vinyl chloride risk assessments in 1996. Has Shah will find out if vinyl chloride is a candidate of the IRIS Pilot Program.
Dr. Shah will follow up with Lillian Kelly of CalEPA on the status of the vinyl chloride risk assessment at a Superfund site.
The Committee developed a budget of $10,000 for a consultant's services for vinyl chloride risk assessment.
6.0 Dr. Shah distributed the Committee's financial statement.
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Vinyl Chloride Health Committee ROM October 31,1995 Page 3 7.0 The Committee developed the following budget:
Item
Total
ATSDR/EPA Testing Req. $1,200,000
Epidemiology Study Update 100,000
Brain Cancer Case Control
150,000
Risk Assessment Activities
10,000
Administration
80.000
1996 $400,000
150,000 10,000 80.000
1997 $800,000
100,000
Total
$1,440,000
$640,000
$900,000
Dr. Shah will distribute commitment forms for the Committee activities.
8.0 The date for the next conference call is set for November 30,1995, at 10:00 a.m.
Subject to Approval
Hasmukh C. Shah, Ph.D Manager, Vinyl Chloride Panel
CHEMICAL MANUFACTURERS ASSOCIATION Vinyl Chloride Health Committee Tentative Agenda
DATE: TIME: PLACE:
October 31,1995 10:30 a.m. CMA Offices 2501M Street, NW Washington, D.C. 20037
1.0 Discussion of Brain Cancer Case Control Study
1.1 Carlo Tamburo (University of Louisville) Proposal 1.2 Cost -- { To (C
2.0 Status Report on CMA Vinyl Chloride Epidemiology Study Update
2.1 Applied Epidemiology, Inc. -- Efforts To Date 2.2 ENSR -- Contracted Obligations and Problems 2.3 CMA -- Efforts and Actions To Date 2.4 Impact on AEI Contract -- Timetable and Financial 2.5 Decision on Extending the Update Through 1994 2.6 Additional Funding Needs
3.0 Discussion of ATSDR/EPA Testing Requirements
3.1 Developmental/Reproductive Effects Study Protocol
3.2 Neurotoxicity Testing Needs
3.3 Review of Memorandum of Understanding Between ATSDR and HSIA
3.4 Identification of Laboratories for Requesting Bids for Developmental/
Reproductive Effects Study
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3.5 Expansion of the Developmental/Reproductive Effects Study Protocol to
Include Molecular Research on Vinyl Chloride
3.6 Cost Estimates 3.6.1 Developmental/Reproductive Effects Testing 6 TO Id
3.6.2 3.6.3 3.6.4 3.6.5
Neurotoxicity Testing -- Molecular Research -- Legal Contingency
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4.0 Discussion of Vinyl Chloride Risk Assessments
4.1 U.S. EPA 4.2 CalEPA 4.3 Richard Reitz PB-PK Manuscript
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5.0 Update on Vinyl Chloride Litigation ATS'O/U
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6.0 Discussion of Financial Statement
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7.0 Development of 1996 Budget
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ATSDR/EPA Testing Requirements Epidemiology Study Update Brain Cancer Case Control Study Risk Assessment Activities Administration
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8.0 Set Date for the Next Meeting and/or Conference Call
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Hasmukh C. Shah, Ph.D Manager, Vinyl Chloride Health Committee
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THE UNIVERSITY OF NORTH CAROLINA
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The University of North Carolina at Chapel Hill CB 7400. Rosenau Hall Chapel Hill. N.C. 27J99-7400
Dr. Hasmukh C. Shah Manager, Vinyl Chloride Panel Chemical Manufacturers Association 2501 M Street, NW Washington, D.C. 20037
Dear Dr. Shah:
June 6,1995
Dr. Jim Knaak asked me to write to you with a proposal for additional studies on vinyl chloride research that I would be interested in conducting in collaboration with the CMA. I FAXed Jim a copy of this and he will bring it to your meeting this week. I am sending you a copy by FAX and by Federal Express, so that you have a hard copy for the meeting. If you have any questions, please give me a call. Thank you for your continued interest in our research.
Sincerely,
James A. Swenberg, D.V.M., Ph.D. Director, Curriculum in Toxicology Professor, Environmental Sciences and Engineering, and Pathology
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PROPOSED STUDIES ON VINYL CHLORIDE
James A. Swenberg, D.V.M., Ph.D. University of North Carolina June 5,1995
Listed below is a series of studies on the formation and repair of DNA adducts induced by vinyl chloride (VC) that will provide molecular dosimetry information relevant to risk assessment _ These studies would be conducted in a manner that will complement the two generation reproductive and developmental toxicity studies currently being planned.
Dose-response Studies
Presently, we 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 2E. The adduct and carcinogenesis data are all from "high" exposures of -500 ppm. No information exists on lower exposures. By adding additional animals to the reproductive and developmental toxicity studies, we could assess the effect of exposure concentration on the molecular dose of ethenoguanine, the primary promutagenic DNA adduct of VC in adult and preweanling rats. Experimental design: 5 adult + 5 preweanling rats per dose (4 doses, including controls). The projected cost is $10,000.
Concentration x Time Studies
No information on C x T and VC molecular dosimetry are available. Such information would assist in extrapolating risks for brief exposure from carcinogenesis data. While I do not know what exposure concentrations will be used in the reproductive and developmental toxicity studies, several C x T groups could be constructed to examine this issue. For example, 1000 ppm x 1 hour, versus 500 ppm x 2 hours, versus 250 ppm x 4 hours, versus 100 ppm x 10 hours. Again, 5 adults and 5 preweanling rats per group would provide a reasonable number of samples. It would also be possible to compare naive versus pre-exposed rats. Project cost would be $10,000-20,000.
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Molecular Dncimetry Studies in Nnnparenchvmal Cells (NPC) versus Hepatocytes
Understanding why VC targets the endothelial cell for its carcinogenic effect is critical to proper risk assessment. We have preliminary data on ethenoguanine adducts in vinyl fluorideexposed rats (2500 ppm, 6 hr/day, 5 days/wk, 4 wks) that shows that the number of adducts is --10fold higher in NPC than hepatocytes. It is of great interest to determine if important differences exist between adults and preweanling rats, and between high and low exposures. I would propose using a one week exposure to the four exposure groups investigated above under dose-response in adult and preweanling rats. DNA adducts would be measured at the end of the exposure and 3,7 and 14 days post exposure (4 doses, 2 ages, 4 times, 3 tissue/cells = 96 samples). In addition, the expression of the major DNA repair pathway, N-methylpurine-DNA glycosylase (MPG) would be examined in NPC and hepatocytes from these animals. The cost of this study would be $40,000.
Studies Using r13Cf-VC
When I met with the CMA Vinyl Chloride Panel, I requested that you consider having [13CJ-VC synthesized so that studies on the formation and repair of VC-induced DNA adducts could be studied relative to those adducts formed endogenously. I believe that these studies will critically inpact on any risk assessment on accidental exposures. There are many studies that could be done.
First, the number of adducts formed by [I3CJ-VC needs to be determined at several exposure concentrations to identify the molecular dose of induced versus endogenous adducts. I propose that closed chamber exposures to 500,250,100,50, 25, 10,5, 2.5, 1 and 0 ppm (5 rats, 6 hrs) be used. The cost of this portion is $35,000 and CMA supplies the [l3CJ-VC.
Next, I would examine the rate of repair of [l3CJ-VC induced DNA adducts in a high, mid and low exposure group (3 concentrations x 5 rats x 4 times). These same animals would be housed in metabolism cages during the post exposure holding periods so that urine could be collected. The urine would be analyzed for endogenous and induced DNA adducts that had been repaired by the MPG pathway. In addition, it may be possible to identify and quantitate [13CJ-VC metabolites in the urine using NMR. Drs. Fennell and Sumner at CUT would be possible collaborators on this. The cost of this would be $40,000.
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HPRT Mutations in VC-exposed Mice versus VC Workers
As part of our Superfund grant we are determining the HPRT mutation frequency and mutational spectra in workers in the vinyl chloride plants of France. The cohort contains over 400 workers, some of who were exposed to high concentrations of VC prior to 1974. Of these workers, some have markedly elevated numbers of mutations, while others have no increase. We are determining the molecular nature of these mutations and examining possible factors involved in differences in inter-individual variability including MPG expression and GST and CYP 2E1 genotyping. We would like to be able to compare the human data with an in vivo animal model. To this extent, we would like to have B6C3F1 mice exposed to the highest concentration of VC (500 1000 ppm) that you are using in the reproductive and developmental toxicity studies for -8 weeks. We could go with as little as 4 weeks, but feel that the longer time would increase the number of mutants available for molecular analysis. The test animal would be 3 weeks old at the beginning of exposure. A total of 48 exposed and 24 control mice would be used. The mice would be shipped to UNC in groups of 12 exposed and 6 controls at 2, 4, 6 and 8 weeks post exposure, where we would isolate the HPRT mutants and conduct the molecular analyses of the type of mutations that were present. We have comparable data on human cells in culture exposed to VC, chloroethylene oxide (CEO) and chloroacetaldehyde. The cost of the HPRT analyses for this experiment would be $27,000.
Studies on VC-induced DNA Adducts in Human Endothelial Cells
Human endothelial cells are now commercially available. These cells could be used to compare the formation and repair of VC DNA adducts in human versus rat endothelial cells. We would expose endothelial cells to CEO or VC and determine the number of ethenoguanine, ethenocytidine and ethenoadenine DNA adducts at various times after exposure. In addition, the expression of MPG would be quantified. One reason that this experiment is important is that human angiosarcomas arising in VC workers have shown p53 mutations at AT base pairs, whereas, ethenoadenine adducts appear to be rapidly repaired in rodent liver, but ethenoguanine adducts accumulate. Therefore, we would expect that most mutations would occur at GC base pairs. By
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comparing both the molecular dose of DNA adducts and the expression of MPG in human versus rodent cells, we will better understand the cause of this difference and be able to select the most appropriate biomarker for humans. The cost of this research would be $13,000.
Budget The total budget for these studies is $175,000 -185,000. In addition, the CMA would need
to cover the costs of animals, exposures and the synthesis of [13CJ-VC. The studies would be conducted over a two year time frame and could begin as soon as the project is funded. The research can be provided as a gift, with no overhead, or as a grant, with 44.5% overhead. If you select the latter, I will need to submit a formal proposal once we have finalized the research program.
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