Document ypewRG77R29GmZYqjwjmQQNDE

CHEMICAL MANUFACTURERS ASSOCIATION March 21, 1980 To: Vinyl Chloride Project Panel Subject: Second Quarterly Report covering research performed under the Agreement for Fiscal Year 1979-1980 on "Research Techniques and Methods for Detection and Prevention of Carcinogenesis in Industrial Workers", University of Louisville. Gentlemen: Enclosed is your copy of the subject report. Dr. Tamburro extends his regrets to the Panel members for the delay in the preparation of this report. Family illness and hospitalization of staff members are the causes for the late mailing. Dr. Tamburro informs us^that he expects to mail the third quarterly report within the next several weeks. Sincerely JTS:das Enclosure J. T. Seawell Project Administrator Vinyl Chloride CMA 004346 Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872. 1825 Connecticut Avenue, NW Washington. DC 20009 Telephone 202/328-4200 Telex 89617 (CMA WSH) School of Medicine Department of Medicine Division of Digestive Diseases and Nutrition University of Louisville Health Sciences Center VC ?.o-jyp/b^ev-L Louisville, Ky. 40232 P.O. Box 35260 Walnut & Preston Streets j, _'0--'eC37 Mr. Joseph T. Seawell Program Manager Manufacturing Chemists Association 1825 Connecticut Avenue, N.W. Washington, D.C. 20009 RE: 2nd Quarterly Repor#for the Manufacturing Chemists Association's Agreement with the University of Louisville for the 1979-80 Fiscal Year. Dear Mr. Seawell: The following describes what has been completed during the 2nd quarter of the Manufacturing Chemists Association's agreement with the University of Louisville entitled, "Research Techniques and Methods for Detection and Prevention of Carcinogenesis in Industrial Workers". Progress for each technical proposal will be reported separately. Technical Proposal A -- Immunological Systems for the Detection of Vinyl Chloride and Other Chemical Injury. H.P. Fortwengler Fortwengler's laboratory has continued evaluating the immune system of industrial workers to determine whether cancer can be detected earlier or to identify those at high risk. HLA Frequencies in V.C. Workers. A compilation of HLA frequencies in V.C. workers is continuing to determine if a possible increased association of certain "tissue types" can be determined in individuals with angio sarcoma or other chemically related disease. To date, approximately 494 individuals from the Louisville vinyl chloride polymerization plant have had their lymphocytes isolated and typed for more than 27 different HLA-A and HLA-B antigens. A Search for Evidence of a VC-Induced Tumor Antigen. A search for evidence of a VC-Induced tumor antigen has lead to a finding that these tumors have an increased concentration of antigenic coagulation Factor VIII. Factor VIII is a known CMA 004347 Mr. Joseph T. Seawell 2nd Quarterly Report Page 2 `JTl lTOt;nr V^V^J^SSSS U'y J.O g-^-O v U-- rX"v 1 w i- - ii0SVH` " marker for vascular lining cells of the endothelial tvpe. Further experiments in animals gave us results indicating that normal endothelial cells found lining the liver sinusoids had little, if any, Factor VIII fluorescence (content). Endo thelial cells found lining larger vessels, on the other hand, demonstrated a striking fluorescence as did experimentally transplanted mouse angiosarcomas. Conversely, mouse hepatic Kupffer cells, a second type of hepatic lining cells, dis tinguished in histological cross section following engorge ment with carbon particles, failed to demonstrate positive fluorescence. An increase in antigen Factor VIII in hepatic angiosarcomatous endothelial cells as compared to normal, leads us to believe that the aberrant cells have increased production or storage capacity for antigenic Factor VIII. Technical Proposal B -- Biochemical Enzymatic Systems for the Detection of Vinyl Chloride and Other Chemical Injury and Cancer Development in Industrial Workers. J.T. Du Staining techniques have been applied to various liver cell types to help identify the isolated liver cells. In the nonhepatocytes, the Kupffer cell is the peroxidase positive and the endothelial cell is the peroxidase negative cell. In a non-hepatocyte preparation, we found 18% peroxidase positive. After further separation of the non-hepatocytes by elutriation, only about 1% of the endothelial cell fraction was peroxidase positive. We also did some experiments feeding chloroethanol, a vinyl chloride metabolite, to rats (30 mg/kg/day for 10, 20 and AO days). The non-protein sulphydryl content, (mostly glutathione), was increased after 20 days, but the glutathione-related enzyme activities, glutathione transferase and glutathione reductase, were not altered, suggesting either the dose is not high enough or that chloroethanol and vinyl chloride metabolize via different routes. Further experiments with higher doses will be performed to elucidate the mechanism. Technical Proposal C -- Glycosaminoglycan Changes in Earlier Detection of Fibrotic Injury and Hepatic Cancer. C.E. Kupchella The original aim of this study was to determine the useful ness of urinary and tissue glycosaminoglycan (GAG) measure ments in the detection of chemically-induced liver injury. We have made substantial progress toward this end and this has been described in previous reports. Within the period July 1979 - September 1979, specifically, we accomplished the following: CMA 004348 Mr. Joseph T. Seawell 2nd Quarterly Report Page 3 -.637 1) We have completed data reduction and have a manuscript now under review by all co-authors for January or February, 1980 submission to the Journal of Clinical Pathology relative to the following study. We developed complete urinary GAG excretion profiles from 24 hour urines from 24 vinyl chloride workers, half with and half free of liver disease. Our conclusion is that GAG profiles may reflect active liver disease. A copy of the final manuscript will be submitted with the final report. 2) We completed the laboratory work involved in a repeat of the study we reported in Gastroenterology 73:1229 in 1977. At the end of the quarter, we had not yet started data reduction on this project. 3) We completed an extension and a repeat of the Morris Hepatoma study. We reported in Gastroenterology 75:972, 1978. In the earlier study, we evaluated three tumor lines; in 1979 we looked at these three plus three more. A paper will be submitted in January for presentation at next May's meeting of the American Federation for Clinical Research in Washington. These studies address the role of GAGs in the behavior of hepatic malignancy as well as the usefulness. Some recent presentations made as a result of our work are listed below. Secskas, E., Kupchella, C.E., Kennedy, J. and Espinosa, E. Glycosaminoglycan Changes Associated with Hepatic Tumors: The Contributions of Regeneration and Necrosis. Presented at the Association for American Physicians/ American Society for Clinical Investigation/American Federation for Clinical Research National Meeting, Washington, D.C., May 7, 1979. Kupchella, C.E., Drake, E. and Secskas, E. Glycosamino glycan Patterns in Necrotic Liver, Regenerating Liver, and in Three Morris Hepatomas having Different Growth Rates. Presented at the Seventh Bi-Annual Hepatoma Conference, Washington, D.C., May 10, 1979. CMA 004349 Mr. Joseph T. Seawell 2nd Quarterly Report Page 4 Technical Proposal D -- Histological Systems of Detection. C.H. Tamburro, G. Barrows, R. Schrodt. The means of analyzing light electron microscopic sections of liver tissue quantitatively for the amount of collagen (scar tissue) in individuals exposed to vinyl chloride has demonstrated a great variation in the amount of stainable collagen present. This can vary from non-detectable collagen without the use of special collagen stains, such as the trichrome, to 35-AO% of the total biopsy being occupied by fiberous tissue in the terminal stages of the disease. At this point all 11Q biopsies from the vinyl chloride workers have been reviewed as to the degree of collagen deposition - present. Morphometric analysis previously had been delayed in order to develop standards for the normal human collagen content at various ages. The study of the normal distribution of collagen content at the various ages in individuals without history of chemical, viral or medical disease, or injury to the liver, has had 14 individuals accessed. Approximately 4 are in the under 25 age group, 6-7 in the 25-40 age group, and 3 in the 40-50 age group. Preliminary data demonstrates an increase in the collagen deposition in the normal human liver associated with age. In the younger age group less than 1% of the studied area is occupied by stainable collagen. In the older age group stainable collagen in the sinusoidal areas may range as high as 5-6%. There is considerable overlap between individuals but close agreement be tween biopsies in the same individual. At present, the lower age ranges has sufficient cases to develop standards. A few additional cases are needed in the upper ranges. The acquisition of these additional cases depends on the availability of acci dental deaths occurring in normal individuals of the older age group without evidences of hepatic disease. However, sufficient data is available for us to resume the morphometric analysis of the vinyl chloride exposed worker's liver biopsies utilizing the Hewlett-Packard 9864-A digitizer and a 9815-A micro computer. Technical Proposal E -- Chemical Systems of Detection of Toxicity of Vinyl Chloride. J.L. Wong In the previous report we have delineated the reaction path ways of chlorooxirane with 3,4-dichlorobenzenethiol and Nacetylcysteine. In both cases, the major product is the sulfur conjugate S-acetaldehyde. Since chlorooxirane can spontaneously rearrange to chloroacetaldehyde, we have proceeded to investi gate the reaction intermediates of the latter in the detoxifica tion by cellular sulfhydryl compounds. The reaction of chloro acetaldehyde with N-acetylcysteine under controlled pH conditions in aqueous medium at 0C produced an intermediate compound. Upon warming up the reaction mixture to room temperature, our previously identified thiazene was isolated as the final product. In order to CMA 004350 Hr. Joseph T. Seawell 2nd Quarterly Report Page 5 r r'"^~ elucidate the stepwise formation of the thiazene-N- acetylcysteine methyl ester was allowed to react with chloro- acetaldehyde in chloroform at QC. The initial product, plausibly the hemithioacetal '-CH-(nhcoch3)ch2s-H-ch2ci OH eliminated HC1 upon neutralization with aqueous sodium hydrox ide to produce the corresponding epoxide H^COCOGH(HHCOCH^) CH-S-CH - CH,,. This structural assignment is supported 11 by its prar spectrum. Furthermore, when this epoxide was ex tracted into chloroform, it rearranged to the S-acetaldehyde H3COCOCH(NHCOCH3)CH2-S-CH2CHO, identified by its pmr spectrum and comparison with that formed from the reaction of Nacetylcysteine with chlorooxirane. Even though chlorooxirane and chloroacetaldehyde eventually give the same final product with N-acetylcysteine, the rate of reaction and the intermediates in the two reactions are different. The chlorooxirane conjugates instantaneously with the sulfhydryl compound, while chloroacetaldehyde takes about 21/2 hours for a comparable reaction. The reaction pathway for chloroacetaldehyde is proposed as follows. R-SH + C1CH2CH0 --} R-S-^H-CH NIH Shift ---------- NHAe R = CH-OC-CH-CH - J0 These two metabolites are therefore both similar and different in their detoxification reaction with the RSH. Further study will continue to unravel the significance of either or both of chlorooxirane and chloroacetaldehyde in the mutagenesis/ carcinogenesis problem of vinyl chloride. Technical Proposal F -- Assays for the Carcinogenic Potential of Industrial Chemicals Utilizing Prokaryotic and Eukaryotic Systems. U.N. Streips in collaboration with G. Sonnenfeld During the 2nd quarter we have concentrated on developing the interferon induction assay as a valid test for the carcino genic potential of industrial chemicals. To this end the following results have been obtained: CMA 004351 Mr. Joseph T. Seawell 2nd Quarterly Report Page 6 1) Benzo-(a)-pyrene, M fraction of tobacco smoke condensate, 1,2-dimethylbenz (a) anthracene, 2-aminofluorine, aflatoxin-B^, and styrene oxide all inhibited the induction of interferon by Newcastle disease virus. - OU J ' ^ V -.5 <n )o 2) MMS, a highly carcinogenic mutagen, inhibited the induc tion of interferon, while its analog, EMS, a rarely carcinogenic mutagen, had no effect on interferon induction. 3) Chloroacetaldehyde, the metabolite of vinyl chloride that is believed to be responsible for the actual carcinogenic event perpetrated by vinyl chloride, inhibited the in duction of interferon by virus, but chloroethanol and chloroacetic acid, benign metabolites of vinyl chloride, had no effect on interferon induction. These results suggest that the inhibition of interferon induc tion by chemicals may be a useful marker of the carcinogenic potential of a chemical, after extensive further study and collaboration of the results. The results were presented at the 1979 Annual Meeting of the American Society for Micro 00 biology and at the International Symposium on Interferon of the Wadley Institutes of Molecular Medicine, and will appear in the form of two manuscripts. The Manufacturing Chemists Association has been recognized for its support to the completion of the data in the manuscripts. Technical Proposal G -- Tissue Antigens and Antibodies in the Detection of Vinyl Chloride Injury. Enrique Espinosa In order to further investigate antigen production by hepatoma application of the indirect immunofluorescent procedure to this question was investigated during this quarter. To accom plish this, several conditions for optimal growth of tumor cells sheets (FLC/PRF/5) in culture were studied. Satisfactory results were obtained by growing stationary cultures on coverslips in Leighton tubes at 37C in a modified Eagle's medium containing 10% fetal calf serum. Cell morphology appeared excellent after 1/2 to 1/3 of confluency had developed in the coverslips. This was accomplished following seeding of 300,000 cells and culturing for 5-6 days. For the immunofluorescent staining the coverslips were then rinsed in Eagle's medium at room temperature and in cold ethanol in order to get rid of medium proteins. After fixation in ethanol (~75C) for 10 minutes, The cells were tested for presence of several serum proteins (albumin, fibrinogen, transferrin, alpha 1-antitrypsin and alpha 2-macroglobulin). Specificity of the staining was CMA 004352 Mr. Joseph T. Seawell 2nd Quarterly Report Page 7 shown by absence of fluorescence with absorbed antiserum, non-immune serum or buffered saline. With each protein, the fluorescence was restricted to the cell cytoplasm and an in tense degree of fluorescence indicated relatively high levels of these proteins in a large proportion of the cells. Other individual cells showed varied degrees of fluorescence suggesting heterogenicity of the cell population with respect to the synthesis of these plasma proteins. Demonstration of presence of these proteins in the tumor cells by immuno fluorescence is in agreement with results obtained by immuno diffusion as previously reported and thus provide another approach for the study of serum proteins and possibly other protein antigens by hepatoma. Technical Proposal I -- Vinyl Chloride Metabolism in Isolated Liver Cells. Richard C. Feldhoff As reported for the preceding quarter we have experienced some difficulty in purchasing all of the special supplies needed for the iij situ liver perfusion technique using our recently acquired liver perfusion apparatus. In the meantime, we have continued to produce and purify rabbit anti-rat albumin antiserum. The antibodies which we are purifying will be used to quantitate the effects of ethanol and chemical monomers on the synthesis of serum albumin relative to total protein synthesis. Albumin is a constitutive product of the liver and perturbations in its rate of synthesis reflect alterations in normal cellular metabolic processes. Albumin synthesis has been reported to be particularly influenced by the levels of essential amino acids and ethanol. One of the primary intracellular effects is polysome disaggregation. Techniques are being developed to quantitatively recover undegraded polysomes from detergent-treated post-mitochondrial supernatants. This completes the quarterly report from the University of Louisville Chemical Monomer Research Group. If there is need for further information or clarification, please do not hesitate to contact me. Sincerely yours, CHT:vb Carlo H. Tamburro, M.D. Professor of Medicine Chief, Division of Digestive Diseases and Nutrition CMA 004353 CM CHEMICAL MANUFACTURERS ASSOCIATION March 20, 1980 Gentlemen: u Enclosed is a copy of a communication to Mr. Frank D. Kover that serves as a letter of transmittal for the report from Experimental Pathology Laboratories, Inc. (EPL) entitled "Vinyl Chloride Pathology Report". Please note the last paragraph of the letter and the fact that CMA has not at tempted to evaluate the report as a Section 8(e) TSCA report because CMA does not have a reporting obligation under Section 8(e). Also enclosed is a record of the Panel meeting held on March 18, 1980. A copy of the EPL report is being sent to all Panel members who were unable to attend the March 18 meeting. Sincerely, J. T. Seawell Project Administrator Vinyl Chloride JTS:db Enclosures CMA 004354 Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872. 1825 Connecticut Avenue. NW Washington. DC 20009 Telephone 202/328-4200 Telex 89617 (CMA WSH) by messenger CHEMICAL MANUFACTURERS ASSOCIATION March 19, 1980 Mr. Frank D. Kover - TS 792 Chief Chemical Hazards Identification Branch Assessment Division Environmental Protection Agency401 M Street/ S.w. 611 East Tower Washington, D.C. 20460 Dear Mr. Kover: On January 14, 1977, Mr. Albert Clark forwarded to Mr. Robert McGaughy of EPA, on behalf of the Manufacturing Chemists Association (now the Chemical Manufacturers Asso ciation) , a copy of the protocol and the 23-raonth status summary for the Association-sponsored research on vinyl chloride at Industrial Bio-Test Laboratories (IBT). Mr. Clark stated in that letter that the final report was expected to be submitted soon, and when available, would be forwarded to the Agency. As you know, all testing undertaken at IBT has come under a cloud. In particular, serious flaws were discovered in the vinyl chloride study, and no final report of the IBT study was ever issued. The Association undertook to deter mine whether the vinyl chloride study could be validated through am audit of the pathology by Experimental Pathology Laboratories (conducted by Dr. William Busey). Dr. Busey subsequently submitted a report of his audit to the Associa tion on January 9, 1979. It was reviewed by an Association task force and, because it was paurt of a larger audit (including a review of compliance of IBT with good laboratory practices), was not further distributed at that time. Unfor tunately, because of the interim change in the management of the Association and the extraordinary increase in the scien tific work of the Association caused by the Toxic Substances Control Act and related environmental legislation, we failed to send it to the Agency as a follow-up to Mr. Clark's letter of January 14, 1977. CMA 004355 Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872. 1825 Connecticut Avenue. NW Washington. DC 20009 T leohone 202/328*4200 Telex 89617 (CMA WSH) Mr. Rover March 19, 1930 Page Two Recently, the Association has established a task force to oversee and coordinate all scientific tasting projects. In the course of reviewing existing projects, this group discovered that we had not made Dr. 3usey's audit report on the vinyl chloride study available to the Agency. Accordingly, I am enclosing a copy of the audit report as a follow-up to Mr. Clark's letter of January 14, 1977. As shown in the interim report sent to the Agency in January, 1977, three suspect brain tumors were noted in male rats at the high dose level. These brain tumors, plus one at the lower dose level, were confirmed by patho logy subsequently conducted by I3T and then by Dr. Busey. Unfortunately, not all of the brain specimens were retained by I3T and not all retained specimens were examined. The Association has therefore concluded to determine whether additional information can be obtained from whatever brain specimens remain at I3T from this highly-flawed study by conducting histopathological examination of all remaining brain tissues. We have not identified any other findings that would appear to warrant further attempts to salvage other information from this study. We apologize for failing to follow-up on Mr. Clark's earlier letter, and wish to assure you that we will, in the future, keep you apprised of any additional relevant infor mation as it becomes available to us. While CMA does not itself have a Section 8(e) reporting obligation, and while it appears that this information would not be reportable under Section 8(e) in any event, pursuant to our earlier commitment we are submitting it to the Agency. Sincerely yours, Hasmukh C. Shah, Fh.D. Director, Special Projects cc: (with enclosure) Mr. Robert McGaughy Office of Research & Development Environmental Protection Agency l: Chemical Manufacturers Association Record of Meeting VINYL CHLORIDE PROJECT PANEL March 13, 1980 Washington Hilton Hotel Washington, D. C. MEMBERS PRESENT: W. M. Smith H. W. Blakeslee T, R. Torkelson T. j. Benya R. Park M. N. Johnson 2 . G. Bell R. N. Wheeler J. T. Seawell CONFIDENTIAL Subject to Protective Order in Ross v. Conoco, Inc., Ho. 90-4837 14th Judicial District Court i; Calcasieu Parish,, Louisiana Air Products & Chemicals, CertainTeed Products Dow Chemical Company Ethyl Corporation Firestone Plastics Co. BPGoodrich Company PPG Industries, Inc. Union Carbide Corporation Inc. CMA Staff PRESENT BY INVITATIONi C. R. Hopper J. P. Murphy R. M. Walter H, Shaw R. w. Hill G. K. Hatfield J. Hanson D. F. Zoll E. Frost W. Busey W. F. Carroll R. T. Gottesman Gulf oil Chemicals Co. Stauffer Chemical Co. Firestone Plastics Co. CMA Staff Diamond Shamrock Diamond Shamrock Dow Chemical Co. CMA Staff CMA Staff Experimental Pathology Labs., Firestone Plastica Co. Tenneco Chemicals, Inc. Inc. MEMBERS ABSENTi J. T. Carter W. Bittenbender F. Kennedy R. W. McBumey BP Chemicals, Ltd. Borden Chemical Continental Oil Co. Diamond Shamrock CMA 004357 J. Lynch A. w. launarie J. Gabbett C. A. Johnson R. B. Judge P. Cohen R. L. Gibson R. J. Abramowitz G. Roush A. G. Wheeler S. K. Law R. L. O'Connell R. Brookman V. L. Kirkland J. Stauffer P. M. Reed w. D. Harris 2 Exxon Chemical Co. General Tire & Rubber Co. Georgia-Pacific Corp. Goodyear Tire & Rubber W. R. Grace & Company Great American Chemical Co. Gulf Oil Chemicals Co. Hooker Chemicals & Plastics Corp. Monsanto Company ICI Americas, Inc. Keysor-Century Corp. Olin Corporation Pantasote Company Shell Chemical Co. Stauffer Chemical Co. Tenneco Chemicals, Inc. Uniroyal, Inc. 1.0 2.0 3.0 Edmund Frost, Esq., summarized the purpose of the meeting and briefly described the history of the Panel's research project with Industrial Bio-Test and an audit of the study by the Experimental Pathology Laboratory (EPL). Following a discussion of EPL'a January 9, 1979 "Vinyl Chloride Pathology Report" a motion was made, duly seconded and passed to submit the Report forthwith to the U. S. Environmental Protection Agency. Following a discussion of the research project conducted by Industrial Bio-Test, a motion was made, duly seconded and passed to immediately conduct further pathologic analysis of all remaining brain tissue salvageable from the study. CMA 004358 3 ^\'i\v- -ft*' V ` 1:, i *' s>. JTS:md Record Subject to Approval March 20, 1980 J. T. Seawall Project Administrator Vinyl Chloride . eC-fc ^ CalaS ^ CO^ ia.^9- CMA 004359 4.0 Following discussion of CMA 1 s efforts to terminate the Industrial 310-Test contract and to seek reimbursement of funds, it was the consensus of the Panel that no additional efforts were required at this time and that the CMA Legal Department would handle the remaining aspects of the matter. JTS:md Record Subject to Approval March 20, 1980 J. T. Seawell Project Administrator vinyl Chloride CMA 004359 Chemical Manufacturers Association VINYL CHLORIDE PROJECT PANEL Washington Hilton Georgetown West March 18, 1980 11:00 a.m. r vci Ca^a PROPOSED AGENDA L0^s 1. Introduction and Purpose of the Meeting 2. Background Information on Industrial BIO-TEST research project and an audit of this study by Experimental Pathology Laboratory 3. Disposition of Busey Report 4. Additional treatment and disposition of Industrial BIO-TEST data and tissues 5. Termination of Industrial BIO-TEST Contract and legal claim 6. Other follow-up work CMA 004360 CHEMICAL MANUFACTURERS ASSOCIATION February 29, 1980 To: Vinyl Chloride Project Panel Subject: Vinyl Chloride Epidemiological Studies The enclosed proposal prepared by CMA is based, in part, on the letter-proposal dated January 15, 1980 submitted by Environmental Health Associates, Inc. (EHA) (see copy of EHA letter-proposal enclosed). As shown in the schematic diagram (see page 2 of CMA proposal) the overall proposal is comprised of five investigations. Some of these are prerequisites for studies that would follow and all of them are interrelated. Cost estimates and analyses of all study components are presented on pages 3, 4, 5, 7 and 8 of the CMA proposal and on pages 3, 4, 5, 8, 9 and 10 of the EHA letter-proposal. Should there remain excess funds upon completion of the seperate brain study, these funds will be applied to the five-year epidemiological update and its allied investigations. You are requested to complete the enclosed questionnaire and return it to the undersigned no later than March 17, 1980. Sincerely JTS:das Enclosures J. T. seawell Project Administrator Vinyl Chloride CMA 004361 Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872. 1825 Connecticut Avenue. NW Washington. DC 20009 Telephone 202 328-4200 Tele* 89617 CMA WSH ZA\ CHEMICAL MANUFACTURERS ASSOCIATION _ ,, A--??"""' Al Order in: Subject to 90-48321 Boss, v- 'iot Court To: 14th Juaicis Vinyl Chloride Project Panel Calcasieu Pari Louisiana Subject: Proposal for Vinyl Chloride Epidemiological Studies and Five-Year Update Introduction and Background Information Five year ago Tabershaw-Cooper Associates (TCA) conducted their epidemiological study of workers engaged in the synthesis and/or the polymerization of vinyl chloride (VC). Equitable Environmental Health, Inc. (EEH), the successors to TCA, completed the study and the final report that issued during January, 1978. The employment period covered by the TCA/EEH mortality study ended December 31, 1972. Therefore, it is now possible to add at least five years' experience if deaths through 1977 are included. Practically, it might not be feasible to go beyond December 31, 1977 since all death records might not be available. Due consideration should be given to the fact that in the final EEH report (see pages 19, 20, 21 and 24 as well as Table 23) the investigators include the recommendations to 1} conduct a thorough investigation of the brain cases, and 2) complete a five-year epidemiological update of the vinyl chloride cohort. In the original study, the investigators were prompted to suggest an excess of deaths under the classification entitled, "Malignant Neoplasm, Brain and Other Parts of Nervous System (193)." In this cause of death category, 12 cases were observed against an expected 5.90. Prima facia, this is a doubling of risk in the study populatxon-an3TTequires further investigation. In addition to the five-year update, the VC Research Coordinators are of the opinion that it is advisable to 1) study in depth the 12 brain tumors identified in the 1978 EEH report, 2) determine the feasibility of studying subpopulations exposed to PVC dusts, and 3) the feasibility of studying subpopulations exposed to ethylene dichloride. We have discussed with representatives of Environmental Health Associates (EHA) a number of possible approaches to the study parameters cited in the preceding paragraph. EHA responded with a formal letter-proposal, a copy of which is enclosed. CMA 004362 Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872. 1825 Connecticut Avenue NW Washington DC 20009 Telephone 202 328-4200 Telex 89617 CMAWSH -2- The following diagram shows the sequence in which the inter related investigations will progress and affords a schematic picture of the overall study: Schematic of Interrelated Epidemiological Studies and Five-Year Update Evaluation of Current Data Base Applicable to: Brain Study Protocol Design Five-Year update Braun Study Protocol Design Five-Year EEppiidemiological Update____________ Possible Study Designs: Plan A Plan B Plan C CMA 004363 Evaluation of Current Data Base and Development of a Protocol for the Five-Year Update As shown in the schematic presented above, the evaluation and assessment of the current data base is a necessary prerequisite to all three study components, which are, 1) the brain study, 2) the protocol design, and, ultimately and primarily, 3) the five-year epidemiological update. Therefore, Panel members deem it important that this phase of the overall study begin as soon as possible. Perhaps it is advisable to cite at this point some of the imponderables that would mitigate against preparation of a definitive protocol without benefit of an evaluation of the data base. For example, in the original study, raw data were collected in two ways: for approximately 6,700 of the total cohort of 10,173, complete job histories were collected by the contractor for each individual identified as having held a job involving VC exposure for at least one year. Job titles involving VC exposure were identified by plant management. For the remaining 3,300, job histories were supplied by plant managements on forms provided by the contractor. Only those job periods which involved exposure to VC were included on the form. The identity of plants participating in these two types of raw data collecting systems is not known at this time, but must be ascertained by examining the unit files. The foregoing may or may not affect the ability of an investigator to assess the effect of exposure to PVC dusts or to ethylene dichlor-- ide. If the VC study cohort includes all individuals at risk from exposure to these two substances, then such an assessment would be feasible without the necessity of collecting additional data from the plants. If it contains only a portion of them, it would be necessary to re-search plant records for individuals so exposed. This would significantly affect cost and performance time. Cost of Evaluation of Current Data Base. Costs of an evaluation of the current data base are summarized as follows: Personnel Consultants Other Direct Costs Meeting Costs Total Costs $5,232 865 100 3,210 $9,407 The Brain Study The VC Research Coordinators recommend that a follow-up study of the 12 cases identified as "brain cancer" be initiated as soon as possible. EHA will require early assistance from CMA and personnel of sponsoring companies to identify a contact person at each plant who will be responsible for expediting EHA requests for i " CMA 004364 4 EHA proposes to obtain copies of the following files for each brain case: a) Company medical file b) Company personnel file c) Company cr insurance carrier Worker's Compensation file a) Additional information from supervisors or fellow workers concerning work history, previous employment, hobbies, etc. The extent to which this search can be performed depends on information obtained from the company's files. If adequate data are available from the sources listed above, SHA will attempt to obtain: Pertinent medical history from personnel physician Surgical and/or autopsy histopathology results Where this information is obtained on a confidential basis, no source citation will be provided. t0tcoj0-* 1 r,,g coj Oo m m ao t"; oa p jm-j pC* a p M r-t b o |.2< o o p o a "o 1 ra 2 -p a rat sia> *-3 > ^5 o -p 1-1 C0 P co tel At the decision of the sponsoring/participating companies, EHA will contact the deceased's family for additional information. This can be decided on a case-by-case basis in consultation with both sponsoring and participating companies. If a particular case has been adjudicated, there is little reason to avoid family contacts as these can be valuable information sources. On the basis of'data collected for each case, EHA will establish, to the extent possible, the following: 1) Verification of diagnosis 2) Histologic diagnosis 3) Complete job history to include: Likelihood of exposure to other chemicals Employment before and after vinyl chloride exposure, and Other sources of confounding exposures such as hobbies, etc. Information concerning the validity of the association between the 12 deaths from brain cancer and exposure to VC will be evaluated by Drs. Whorton and Milby of EHA. The investigators will examine these data for commonality of exposure variables, time between onset of exposure and disease development, cell type, association with exposure to other agents, and other related factors. Cost of Brain Study. Based on the assumptions presented above the cost of this study is as follows: Basic Study Personnel Costs Other Direct Costs Total Estimated Cost $ 9,780 800 $10,580 CMA 004365 5 Cost of meeting with Drs. Milby and Whorton to discuss matters pertaining solely to the brain study. Total Meeting Costs $4,270 ccw 0) o1 $ g u to ; 0 l"o"4 4* -3 3H .o-i E"* > -Iii -CpQ SO r=-l o 3I CO %^ cd 3 *t3o9 twoo The Five-Year Epidemiological Update At the onset of the original study during 1972, it was recognized that this cohort was relatively young and thus would generate only a modest number of deaths for analysis. Two thirds of the cohort contributed less than 20 years of observation since the onset of exposures. To offset this deficiency a large cohort was collected in an effort to generate sufficient personyears of observation to detect increases in short-latency diseases at an acceptable level of statistical significance. Nonetheless, the disease associations detected by. this study were tenuous at best. While the original investigators were careful to report this fact, subsequent reporters have at times failed to recognize the tentativeness of these conclusions, and some associations have been accepted at times as proved facts. GHA is of the opinion that the additional five years of observation now available for this population would begin to clarify the validity of reported associations. Person-years of observation will be increased by 40 per cent. An additional 350 to 400 deaths will be generated for analysis. While the population will still be at the front-end of its maturity curve, the additional data should prove meaningful. A second justification for further study of this population concerns the specific question of the association between death rates from brain tumors and exposure to VC. The present data indicate the presence of a doubling of risk from this cause, if this association is real, the five-year follow-up should generate seven or eight additional brain tumor deaths. Should only three or four be found, the validity of this association will be diminished. Re-examination of the VC population offers still another opportunity to the chemical industry. The original data represent a working population exposed to relatively high levels of vinyl chloride monomer. At a single point in time, this exposure level dropped dramatically. Employees entering this population beginning in 1972 experienced a substantially lower exposure them those employed in the industry prior to that time. With the passage of time, this difference should begin to manifest itself by a leveling off of certain cause-specific death rates if the suspected disease associations are valid. This trend should continue into the future. Because of this unique situation, EHA recommends that CMA 004366 C O N FID EN TIAL Subject" to "P ro te ctive Order in Eoss_v. Conoco, I n c . . Nn 9 0 -4 8 3 ^ 14th J u d ic ia l D is tric t Court Calcasieu P arish, Louisiahli the present data base be converted to a registry and individuals employed since December 31, 1972 be added to the population for future investigation. The experience of the current 9,677 individuals could then be compared to the experience cf those entering after 1972 with potential noteworthy results. Development of Cost Estimates Relevant to the Five-Year Follow-Up. The development by EHA of an accurate estimate of the probable costs to complete the five-year follow-up requires more precise data than is currently available. Until existing data are reviewed, it is not possible to ascertain the study design that will be the most productive and cost effective. As a result, EHA has developed several study plans or proposals that are summarized as follows under their respective headings: Study Plain A This plan is a straight-forward five-year follow-up of the existing data base. This basic approach will be the most economical. It represents the least rigorous of the three plans and has some intrinsic deficiencies that would influence the cost/effectiveness ratio. The tasks required for Study Plan A would include: 1) Develop computer programming to translate current study cards to tape format and provide master tape. 2) Select all "Alives" and "Unknown Vital Status" by plant and return names to plants for update. 3) Submit master roster of all "Unknowns" (both from original data base and from update) to SSA. 4) Request Death Certificates for those identified as "Dead" by SSA. 5) Reduce new vital status data to computer comparability format. 6) Develop computer programming for update of data bank and update present data . 7) Analyze for cause-specific SMR's and PMR's. 8) Interpret results and prepare report. CMA 004367 Cost of Study Plan A. Based on the study requirements listed above the cost of Study Plan A is as follows: Total EHA staff charges $30,256 Consultants Biostatistician $10,175 Physician/Epidemiologist 2,720 Other Direct costs 12,895 11,700 Total Cost $54,851 Study Plan B In addition to the work required under Study Plan A, the existing data base would be augmented with complete job histories for the approximately 3,300 cohort members for which job histories are now deficient. This more rigorous plan may make it possible to control for exposure to PVC dust and ethylene dichloride. While this work will substantially increase the cost, it may prove to be worth the effort. In addition, study Plan B would require the following: 1) Secure complete job histories for the approximate 3,300 cohort members with incomplete job histories. This would involve nine study plants. Costs, according to EHA, will vary greatly depending on the data collection technique employed. If plants will provide the data on EHA prepared forms, the cost of this study will be minimized. If EHA must send a researcher to each plant to collect the data, the cost will be greater. 2) Determine jobs with exposure to PVC dust and ethylene dichloride. 3) Code complete cohort for these variables. 4) Update master tape. 5) Analyze data for the effect of these variables. CMA 004368 8 Study Plan C In addition to the work performed under Study Plan A and B, Study Plan C would include the following: 1) Collect full study data from 37 plants for all individuals employed since 1972, estimated to be between 1,500 and 2,500. 2) Code new cohort member data. t' 6 3) Update master tape. 4) Analyze the enhanced population data. Recapitulation of Cost of All Study Components ^ }r 'J< 7,, " I<0 *** Preparatory study components, the basic study (Study Vlan A), and the elective studies, Study Plans B and C have costs that are summarized as follows: Assessment of the current vinyl chloride mortality study data base (with meeting) $ 9,407 . Case study of 12 brain tumor cases (with meeting) 14,350 Five-Year follow-up, StudyPlan A 54,851 Five-Year follow-up, StudyPlan B 36,564 Five-Year follow-up. StudyPlan C 55,910 Total $171,082 Complete Cost of study Program The costs of the entire study program are as follows: Preparatory studies, Brain study, and Study Plans A through C $171,082 Supplemental or Elective Research 25,662 Administrative Costs 40,000 JTS:das Total Cost $236,744 CMA 004369 Panel Survey of Interest in and Possible Financial Support for Preparatory Studies and Five-Year Epidemiological Update on Vinyl Chloride Item No. ^n<3uiry 1. / / We agree to permit CMA's contractor to use the records provided by our company for the Tabershaw-Cooper Associates (TCA)/Equitable Environmental Health (EEH) study completed and reported January, 1978. / / We do not agree. 2. / / We agree that it is important to preserve the continuity of the cohort and we agree to assist in the update of the mortality records for those employees alive on December 31, 1972 who have died prior to December 31, 1977. / / We do not agree. 3. / 7 We agree that Environmental Health Associates (EHA) be authorized to examine the current records, prepare a protocol for a five-year update, and conduct a re-analysis of death certificates according to the EHA letter-proposal dated January 15, 1980, a copy of which is attached. / / We do not agree. 4. 4.1 Introductory Comment. As is described in the attached CMA proposal, the preparatory evaluative and protocol design studies, the brain study, and the component studies can be important integral parts of a five-year update. All constitute a program comprised of five interrelated studies. To permit CMA to arrive at fair and equitable pro rata estimates of individual company funding, the following expressions of interest are necessary: / / We are interested in financially sponsoring an assessment and evaluation of the current vinyl chloride study data base. CMA 004370 Item No. Inquiry 4.2 / / We are interested in financially sponsoring a thoroughgoing case study of the brain tumor cases. / / We are not interested. 4.3 4.4 / / We are interested in financially sponsoring Study Plan A (see pages 6,7, and 8 of CMA Proposal and pages 6,7, and 9 of EHA letter-proposal) under th five year epidemiological follow-up. /--7 We are not interested. /' We are interested in financially sponsoring Study Plan B (see pages 7 , 8 of CMA Proposal and pages 6, 7,8 and 9 of EHA letter-proposal) under the five-year epidemiological follow-up. / / We are not interested. 4.5 / / We are interested in financially sponsoring Study Plan C (see page 8 of CMA proposal and pages 6 , 8 and 9 of EHA letter-proposal) under the five-year epidemiological follow-up. / / We are not interested. 5. introductory Comment. The importance of a follow-up on brain tumor cases (and the preparatory assessment of data that is a necessary prerequisite to this follow-up) is, in the opinion of a number of companies, a separate study that should be initiated as soon as possible. / / We intend to financially sponsor the preparatory study and the follow-up of brain tumor cases and ar willing at this time to commit up to a maximum of $3,000. / / We do not intend at this time to financially sponsor this study. r.OHFlDS^TIAL Subject to Protective l^der in Ross v. Conoco, IncHo 9 --iith Judicial District Court Calcasieu Parish,, Louisiana CMA 004371