Document JwqnVgpgXRR8V9j38VERznJK
CHEMICAL MANUFACTURERS ASSOCIATION
June 6, 1994
Dear Vinyl Chloride Research Coordinators:
The following items are enclosed:
1) agenda for the June 13, 1994 conference call;
2) the May 19, 1994 Record of Meeting;
3) Dr. Richard Reitz's vinyl chloride risk assessment presentation;
4) historical perspective on the inter-industry vinyl chloride study;
5) benefits of updating the inter-industry study of vinyl chloride workers; and,
6) revised scope of work for the update of the 1986 epidemiology study.
Item numbers 3 and 4 were sent to you earlier; however, they are enclosed again for reference in your discussions with your management. When deciding whether to commit your company to update the vinyl chloride epidemiology study, please use $300,000 as the estimated budget. This budget includes: epidemiology study cost; Dow Chemical's cost for designing and monitoring the study; data transfer cost from ENSR to another contractor if necessary; other consultant costs; contingency; and, CMA administration. The CMA administrative services will address: the epidemiology update; short-term exposure effects study; EPA's anticipated TSCA Section 4 testing; other ATSDR activities; EPA's risk assessment activities; and, response to the American Chemical Society on the TIME Magazine article.
Your company's pro-rata share will be based on your 1993 nameplate capacity for vinyl chloride. One-half of the actual commitment must be received by CMA prior to the execution of a contract and the other half would be due six months after the contract execution date. We will review the company responses to update the vinyl chloride epidemiology study on our June 13 conference call.
Prior to the conference call, Dr. Jonathan Ramlow should send me the estimated cost to provide designing and monitoring services for the update of the epidemiology study.
All other company representatives should call me with their decisions relating to participation in the update prior to the June 13 conference call.
SL 107248
2501 M Street, NW, Washington, DC 20037 Telephone 202-887-1100 Fax 202-887-1237
L&ResparatteCaiB*
| f A" n*-lMUM*lW--iVim--Bni
VCRC June 6, 1994 Page 2
David Penney should send me a draft response to the American Chemical Society on the TIME Magazine article.
If you have any questions, please call me at (202) 887-1192. I looking forward to talking to you on June 13.
Sincerely
Enclosures
Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel
SL 107249
CHEMICAL MANUFACTURERS ASSOCIATION
Vinyl Chloride Panel
Vinyl Chloride Research Coordinators
Tentative Agenda
DATE:
June 13, 1994
TIME:
10:00 a.m., EDT
1.0 Approval of May 19, 1994 Record of Meeting
2.0 Review of Company Decisions to Update the Epidemiology Study
3.0 Review of the Revised Scope of Work to Update the Vinyl Chloride Epidemiology Study
4.0 Discussion of Dow's Cost Estimate to Design and Monitor the Update of the Epidemiology Study
5.0 Status Report on Short-term Exposure Effects Study .
6.0 Status Report on EPA's Risk Assessment of Vinyl Chloride
\r *'
7.0 Status'Report on Dow Chemical's Review of Vinyl Chloride Teratology and Reproductive Effects Studies
8.0 Status Report on Response to TIME Magazine's Article,on Vinyl Chloride1Exposure and Development of Lymphoma
9.6 Set Date for Next Conference Call or Meeting
"'
''
Subject to Approval
Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel
SL 107250
ANTITRUST CHECKLIST FOR CMA MEETINGS
This antimisi checklist is for use by CMA staff and member representatives in the conduct of CMA-sponsored meetings. Pro hibited discussion topics apply equally to social gatherings inddenal to CMA-sponsored meetings. The Checklist is not 4 haustre and does not address antitrust issues relating to activities other than CMA meetings. Participants in CMA meetings a3o should be thoroughly familiar with: (1) "Antitrust Guide for CMA Committee Members;" and, (2) "General Principles Applica ble io the Structure and Operations of Committees." Both of these documents may be found in the CMA Directory.
DO
Ensure stria performance in areas of:
OAEKSIGHT/SUPERVISION:
Have a CMA staff representative at each CMA-sponsored meet ing (unless an exception has been authorized by the appro priate CMA vice-president);
consu/r with an attorney ofthe GM Office ofGenera/Counsel on *1! anatusr questions relating to CMA-sponsored mcermgs.
taut meeting discussions to agenda topics (unless additional topics have been approved by the appropriate CMA staff rep resentative), and
provide each member company representative and CMA Staff representative attending a CMA-sponsored meeting wfch a copy of this checklist, and have a copy available for reference at all CMA-sponsored meetings.
RECORDKEEPING-,
Have an agenda and minutes which accurately reflea the mar ten which occur.
provide agendas and minutes to the CMA Office of General Counsel for review and approval in advance of distribution; and.
fuDy describe the purposes and authorities of all task group*, work groups, ad hoc or ocher standing committee subgroups in the minutes of the appropriate parent committee.
VIGILANCE:
Protest against any discussion or meeting activities which ap pear to violate this checklist: disassociate younetf from any such discussion or activities and leave any meeting in which they continue
Revised V80 (single page version) Reformated 1/89 MDB
DON'T
Do not, in ha or appearance, discuss or exchange infor mation on:
PRICES, INCLUDING:
Individual company prices, price changes, price differentials, markups, discounts, allowances, credit terms, etc.,
individual company data on costs. production, capacity, inventories, tales, at and,
industry pricing polities, price levels, price changes, differentiab, etc.
PRODUCTION, INCLUDING:
Hans of individual companies concerning the design, produ tion, distribution or marketing of particular products, tndud tag proposed territories or cusmmers: and,
changes in industry production, capacity or inventories.
TRANSPORTATION RATES:
Rates or me policies for individual shipments, including bas ing point aystems, zone prices, freight equalization, etc.
MARKET PROCEDURES, INCLUDING:
Company bids on coneacts for particular products; company procedures for responding to bid imitauans. and.
matters relating id actual or potential individual suppliers or customers that might have the effect of excluding them from any market or influencing the business conduct of firms to ward them.
CONSENT DECREE SUBSTANdi
Any matter relating to trisodium phosphate (s restriction re quited by a 1962 consent decree to which CMA is a parry).
SL 107251
SL 107252
Estimating Human Risk from Exposure to VC
Quantification with PB-PK Modeling
Richard H. Reitz Michael L. Gargas
McLaren/Hart, ChemRisk Division
for CMA Vinyl Chloride Panel
May 19,1994
5/20/9*
j
Collaborators!
McLaren/Hart:
R. H. Reitz M. L. Gargas
1C1 Toxicology Lab (Zeneca)
T. L. Green W. M. Provan
U. S. E. P. A. (Res Tri Park)
M. E. Andersen
S.'2IV94
2
SL 107253
VC History |
Low Acute Toxicity Occup. Expos. Limits - 500 ppm Viola (1970,1971)
Rats, Increased Tumor Incidence Maltoni (1974)
Confirmed Viola's Results Identified Rare Liver Angiosarcoma Dose Response Plat > 1,000 ppm Creech & Johnson (1974) Found Same Cancer Type (Liver
Angko&acroma) In Humans Human Tumor Registry (to Present)
14,000 Subjects, 19 VC Plants
$(?0/94
3
Objectives / Opportunity [
Develop A Process for Quantitatively Estimating Risk in Humans + Low, Non-Occupatlonal Exposures - Superfund Sites - Fugitive Emission - Drinking Water
Test the Utility of our Cancer Risk Assessment Procedures + Rkb Animal Data Set in Rats and Mke + Unique Opportunity to Compare Risk Assessment with Actual Results in Humans
S/2Ck9*
4
SL 107254
Expectations for Pharmacokinetic Modeling
Modeling Cannot Eliminate ALL Uncertainty from Risk Assessments
Modeling Can Quantitatively Describe: Metabolic Saturation Changes In Dose Route * Physiological Differences la Species
PREMISE: * Risk Assessments based on Estimates of "Delivered Dose" wtli be More Reliable than Risk Assessments based Only on Administered Dose
VKV9*
S
Classical Pharmacokinetics:
"Stripping the Curve11__________
Curve Stttuafrra fEarnncntlaisi C(t) - Aj . e * i!
V2cm
6
SL 107255
Classical Pharmacokinetics: Compartmental Models
C2 = A2 / V2
ir
K21 K12
J____
Input lea
C1 = AI/V1
_Elim
ke
dU/dt -k*DoH dkl/dt - ka*Doaa - K13*C1 + U1*C2 - ka*Cl dkS/dt - +K21*C1 - K31*C2 dXlia/dt - -ks*Cl
iao/H
7
Advantages of PB-PK Models:
Compound Specific Information Vapor Pressure Solubilities (Partitioning) In Tissues
Species Specific Information Physiology Metabolism
Route Specific Information Oral Route, 1st Pass Through Liver
Allow Extrapolations Between Dose Routes Between High Dose / Low Dose Between Specks
V20V4
g
SL 107256
A PB-PK Model for VC
Metabolites Ekeed oa Ruawy Jt Aadcnei, 1964.
9
Capabilities of PB-PK Models
Will use examples from studies of Reitz et al., at Dow Chemical Co., with 1,1,1-tiichloroethane (Methylchloroform, MC)
Data used to illustrate potential applications for VC PB-PK Model.
sawn
to
CP
r1
MC Rat Inhalation
(Blood Levels)
Mcthylchtoroform, (MC) used as an example of Ihe technique.
MC Mouse Inhalation
(Blood Levels)
MUM
Methylchloroform, (MC) used as an example of the technique.
11 MOM
it
SL 107258
MC Mouse Inhalation
(Other Endpoints)
2 1.5
mm
B 150 ppm D 1500 ppm
to
MC Human Inhalation |
(Exhaled Air)
1
Humans - Inhalation
10 .............................................. 10
fr........................ ........
i'
.f= 01 fe 1.. I O
ft Ul V *
0.001
1 jfii
.
01
^
* u 'I ...---I
It I
a 00 BO 120 ISO 200 240
Time (hr)
StM/W
14
SL 107259
MC Rat Water
(Exhaled Air)
15
Approach^VCPBPKModeQ
(1) Parameterize Model Physiological Constants
- Andersen et al, 1987 Partition Coefficients
- Vial Equilibration - Fat, Liver, Muscle, Blood Metabolic Rate Constants - In Vivo (Rats, Mice)
(2) Validate Model Independent Rat, Mouse and Human In Vivo Studies
(3) Extrapolate Risks Rats to Mice Rats to Humaas
niom
it
SL 107260
VC Partition Coefficients Vial Equilibration
Measure:
Blood/Air Liver/Air Fat/Air Mwck/Alr
Calculate: Tfant/nood
VC Metabolic Rate Constants Gas Uptake Apparatus
mas*
17 3/70/9*
IB
T 9 tL 0 t
cn t*
Gas Uptake Data
(Male Rats)
Gas Uptake Data
(Female Rats)
19 5i2Qm
SL 107262
Validation of Rat Model
(Watanabe etal., 1976)
21
Estimating Mouse Metabolic Rate Constants
Small, Halogenated Hydrocarbons Metabolized by CyP450 2E1
In Vivo VMax's from Experiments * Methylene Chloride (MeCI,) (Rats, Mice, Humaas) Chloroform (CHClj) (Rats, Mice)
Calculate VMax / gram Liver
Normalize to Rat In Vivo
MeCl2 CHClj Average
Mouse 2.57 2.71 2.64
Human 0.21 0.21
2094
22
SL 107263
Testing Estimated Mouse Metabolic Constants
Optimized Mouse Data |
ram
ZJ mom
u
SL 107264
Validation of Human Model
___ (BareUa et al., 1969)
5WW
25
DerivingRatJPot^^
Rsgfd op Malteni's EsporinioBte
12 Months Exposure 0,1,5,10,25,50, lit, 150,20*,250,5m,
2500, MOO, 10000, 30000 ppm tested Poor Survival 10000 and 30000; Use
Remaining 13 Dose Groups Use PB-PK Model to Calculate Pose
Average Amount VC Metabolites per day per Liter of Liver Tlssae
Howe & Crump's GLOBAL83 Multistage Model Dose Response (Maximum Likelihood Estimate)
Comparison: Linear Model Fitted to Top Two Doses (MTD, MTD/2)
2V94
26
SL 107265
5WM
HCOom
PPM Vinyl Chloride --1 AdwtoPo-- a ineUme
27
Extrapolating Rat -> Mouse
(Maitoni, Swiss Albino Mice)_______
Cone 0
50 250 500 2,500
Males 0/80 1/30 9/30 6/30 6/29
Females 0/70 0/30 9/30 8/30 10/30
LADD 0.0
38.4 173.1 265.2 331.0
Equivalent Amounts of Metabolite produce Equivalent Tumor Yields
No Surface Area Correction Factor Used.
The 1CF* RSD = 0.80 x tO-1
S/20SM
28
SL 107266
ComparingRSD^
Maltoni et at., (Rat) Maltoni et al., (Mouse) Lee et al., (Mouse)
0.177 0.080 0.120
Drew et al., (B6 Mouse)^^r4).0032
Drew^ttrT reported angiosacromas in Is. Lee and Maltoni saw none.
B6C3FI VltnrengltlYf?
Reported to have partial oncogene activation in absence of any chemical treatment.
VWM
29
Extrapolating Rat -> Humans
(Maltoni, Rat Potency)
Equivalent Amounts of Metabolite produce Equivalent Tumor Yields No Surface Area Correction Factor Used. Calculated "Unit Risk", Lifetime Exposure to l/qj/m3,24 hr/day.
PBPKMLE = 4xl07 PBPK UCL = 6 x lO7 IRIS Number = 840 x Hf7
V2OT*
30
SL 107267
VC Tumor Registry
(Simonatoetal., 1991)
12,706 Individuals from Population of 14,351
Completeness of Followup = 97.7%
Cohort has > 25 Years since 1st Exposure to VC
Exposure Groupings:
+ 0 - ION ppot years + 2,0M - *,** ppu year* + 6,S68* 10^00 pfNU yean + > IS^OS ppat yean
Absolute Risks Estimated to Range from 6.2/100,000 to 280/100,000
V2VM
31
PBPK Risk Assessment Versus Simonato et al (1991)
PPM
rm
TaVnlnMi
50 500
100 1X00
200 2X00
-- *XOO
500 5X00
_ exoo
1000 10XH0
-- >10X00
2000
20X00
IWMhVmiEiMar
50 1XOO 100 2X00 200 4X00 -- 8XO0 500 1(1000
--
1000 2000
15.000
20X00 40X00
rB-FK LADD
FB-rtC FnSMiaa
p10MM
OtlOTlI Can
pttUMOO
3.33 6.63 1206
--
2668
--
3120
--
36.03
188 374 736
--
1,497
--
1253
--
2,532
--
(62)*
--
422
--
1523 -- (mo>* --
666 1326 2611
--
5335
--
6257 7207
376 747 1,465
--
2971
--
3,476 3,993
(621*
--
422 1523
2800)6
yw
n
SL 107268
Summary!
Straight-Forward Modification of Existing PBPK Model
Based on Rat In Vivo Studies, Validated with Mouse and Human Data
Described Tumor Data 1-6,000 ppm in Rats and Predicted Tumor Data in Mouse Studies
Unit Risk Based on PBPK Principles ISO Fold Lower than Current IRIS Value.
Tumor Predictions Most Accurate WITHOUT Surface Area Correction Factor
When Mechanism Is Known, PBPK Procedures Should Be Capable of Giving Much More Accurate Estimates of Risk.
s/vm
33
SL 107269
CHEMICAL MANUFACTURERS ASSOCIATION Vinyl Chloride Panel Research Coordinators Record of Meeting
DATE: TIME:
May 19, 1994 10:00 a.m. - 2:00 p.m.
List of Participants:
James Barter Ed Beeler Greg Bond Frank Borrelli Mike Gargas (PT) Mark Gruenwald Jim Knaak Dave Penney David Pun Jonathan Ramlow Richard Reitz (PT)
PPG GEON Dow Chemical Georgia Gulf CHEMRISK - McLaren/Hart Borden Oxy Vista Formosa Dow Chemical Consultant
Kim Reed
CMA
Has Shah
CMA
1.0 The Panel approved the February 14, 1994 Record of Meeting as written.
2.0 Jonathan Ramlow reviewed the draft scope of work for the update of the mortality among vinyl chloride workers. The scope of work asks contractors to provide an additional ten years of follow-up to the cohort previously studied by Environmental Health Associates (1986). The Panel also would like the update to incorporate state of the art modelling methods for data analyses and use the Eighth or Ninth Revision of the International Classification of Disease to code all death certificates. The 1986 study used the Seventh Revision. The new update also would compare the worker mortality with regional and national averages, as compared to only the national average in the 1986 study.
Due to the shifting of ownership of many plants, some plant data are no longer directly available to Panel members. Has Shah will contact non-Panel companies that produce or produced vinyl chloride to see if they will participate in the update. Panel members should contact their Vinyl Institute Executive Board members to have them encourage Westlake to participate in the update.
The Panel discussed the potential contractors for the update. Potential contractors include: Howard Rockette (University of Pittsburgh); Kenneth Mundt (Applied Epidemiology, Inc.); Roy Shore (New York University Medical Center); and, Don Whorton (ENSR).
SL 107270
ROM VCRC May 19, 1994 Page 2
Panel members favored a cost-sharing formula based on the nameplate capacity of VCM for 1993 with an off-set for Dow Chemical as compensation for providing extensive staff resources in designing and monitoring the study. Dr. Ramlow will provide an estimate of an off-set amount to Dr. Shah within the next several weeks.
Panel members will determine whether their companies will participate in the update based on the 1993 nameplate capacity cost-sharing formula by June 2 and contact Dr. Shah with their decisions. Immediately following company commitments, each Panel member should send nameplate capacity data (in pounds) to Dr. Shah so that a financial share can be determined based on the total estimated cost of the study.
Dr. Ramlow will revise the scope of work for the update and send it to Dr. Shah for distribution to the Panel. Once commitments are received from the member companies, Dr. Shah will solicit requests for proposals from the potential contractors.
3.0 Richard Reitz presented a pharmacokinetics model for estimating human risk from exposure to vinyl chloride. Copies of Dr. Reitz's model and methodology will be distributed to Panel members. Dr. Reitz suggested that Dr. Shah contact Bill Farlin of EPA to determine if the Agency plans to conduct a risk assessment for vinyl chloride. If the response is positive, Dr. Shah will suggest that Dr. Reitz speak to the Agency about his physiologically-based pharmacokinetic risk assessment model for vinyl chloride.
4.0 Jim Knaak discussed the decision-making process of when to close major highways due to the threat of a chemical release. The Panel discussed the types of information on which the members generally base such decisions. The Panel identified a potential need for short-term exposure data in making such decisions. Dr. Shah and Dr. Knaak will prepare a program for developing short-term exposure effects data. Frank Borrelli will keep the Vinyl Institute aware of any research programs that the Panel undertakes.
5.0 Dr. Shah reviewed the proposed ATSDR research data needs for vinyl chloride. Of the seven data needs discussed in the Federal Register notice, EPA plans to fill the teratogenicity and 2-generation reproduction effects data needs by TSCA Section 4 rulemaking. The other five will be addressed by ATSDR under different options in the future. Dr. Ramlow will review and summarize the reproductive and teratogenic studies completed by Dow and provide a summary to Dr. Shah for distribution to the Panel.
6.0 Dr. Shah informed the Panel that a law firm, Cohen Milstein, solicited vinyl chloride information on behalf of a client involved in litigation, and that he sent the law firm the EHA epidemiology study report.
7.0 Panel members discussed a TIME magazine article entitled, "Stopping Cancer in Its Tracks," which associates lymphomas with vinyl chloride exposures. The source of the article appears to be th
SL 107271
ROM VCRC May 19, 1994 Page 3
American Chemical Society. David Penney will draft a letter to send to the American Chemical Society responding to this article. The letter will accompany a statement from the Wong, et al., study stating that vinyl chloride does not appear to cause lymphoma. The letter will be distributed to the Panel for review prior to its release.
8.0 The Panel elected Dr. Ramlow as Chairman. Dr. Ramlow replaces Dr. Bond who will no longer be active on the Panel. The newly elected Chairman will serve until July 1, 1995. A Vice Chairman will be elected at a later date.
9.0 Dr. Shah distributed the financial statement to the Panel.
10.0 The next Panel conference call is scheduled for June 13, 1994 at 10:00 a.m., EDT.
Subject to Approval
Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel
SI, 107272
HISTORICAL PERSPECTIVE ON INTER-INDUSTRY VINYL CHLORIDE STUDY
1960-1963
Report published documenting
anesthetic effects in animals and humans and liver injury in animals from chronic exposure.
1967
Acroosteolysis reported in humans exposed to high levels of VCM.
1971
Carcinogenicity of VCM discovered in animals, including angiosarcoma of the liver.
1973
CMA sponsors Tabershaw-Cooper Associates to conduct an epidemiologic study of 8,384 vinyl chloride workers from 34 plants.
1974
First reports of angiosarcoma of the liver cases in VCM workers.
1974
Tabershaw-Cooper report preliminary results confirming high risk of angiosarcoma of the liver and suggesting excess cancers of respiratory system, brain and
lymphoma.
GGB 3/1 S/94
107273
SI*
HISTORICAL PERSPECTIVE ON
INTER-INDUSTRY VINYL
CHLORIDE STUDY
(cont.)
1974
OSHA holds hearings and revises PEL down to 1 ppm.
1981
Cooper expands original epidemiology study to include 10.173 workers from 37 plants-- reports show angiosarcoma and brain cancer to be in excess through
1972.
1986
EHA updates inter-industry study with follow-up through 1982reports angiosarcoma, brain cancer and emphysema to be in excess--no excess respiratory cancer or lymphoma/leukemia.
1991
EHA study is published.
1993
CMA letter to the editor and EHA response are published clarifying the brain cancer and emphysema findings.
1994
GGB 3/1 S/M
CMA Vinyl Chloride Research Coordinators meet to discuss updating study.
SL 107274
"The study carried out by Environmental Health Associates on behalf of the U.S. Chemical Manufacturers Association is the largest and most informative investigation thus far undertaken."
Sir Richard Doll Scand J Work Enviom Health 1988; 14:61-78
GGB 3/1 S/94
SL 107275
BENEFITS OF UPDATING INTER-INDUSTRY STUDY OF VINYL CHLORIDE WORKERS
Product Stewardship - Demonstrates to workers, community residents, customers, and other audiences our collective commitment to characterize cancer risks associated with employment in VCM/PVC processes.
Scientific Knowledge - Refines the estimate of the number of cases of human angiosarcoma of the liver (ASL) associated with operating VCM/PVC plants in the pre-1972 era in North America. - Provides basis for refining human cancer risk assessments which are used by government agencies for permitting facilities, etc. - Contributes ASL cases to the international registry. - Helps to resolve unanswered questions about alleged links to cancers of the brain, lung, and hematopoeitic system as well as address non cancer causes of death such as emphysema.
Litigation Defense - VCM/PVC manufacturers continue to face toxic tort litigation alleging that numerous other types (non-ASL) of cancer are related to VCM/PVC employment. This type of research is useful in defending such litigation.
GQB 3/1 S/94
SL 107276
BENEFITS OF UPDATING INTER-INDUSTRY STUDY OF VINYL CHLORIDE WORKERS
(cont.)
Chlorine Issue - VCM/FVC continue to be a part of the general debate on health and environmental impacts of chlorinated organics. This type of research serves a valuable role in helping to debate the issues on the basis of good science.
GGB 3/15/94
SL 107277