Document 6wBoqGw5vQppnrvpB4Ln17wpo

"T1 MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE, N. W. WASHINGTON, D. C. 20009 (202) 483-6126 May 22, 1976 TO: Vinyl Chloride Technical Panel SUBJECT: Minutes of Last Meeting and Other Items Gentlemen: Enclosed please find the minutes of the last meeting, in addition to the following: 1- Dr. Tamburro's letter of April 20 to Dr. Torkelson describing proposed studies on immunological systems and electron micro scopic evaluation of liver tissue. 2. Summaries of talks presented at the April 28 Panel meeting. 3. References for Dr. Johnston's talk on "Cytogenetic Studies of Bone Marrow Cells Prom Rats Exposed to Vinyl Chloride". 4. "Interim Report on Mortality and Gross Observations on Rats, Mice and Hamsters with Vinyl Chloride", by M. L. Keplinger, et al'r., (IBT) . This is a draft of a paper to be given at the American Association of Industrial Hygienists meeting in Atlanta the week of May 17. INFORMATION At a meeting April 7 called by Mr. R. M. Graziano, Director and Chief Inspector of the Bureau, of Explosives, discussion' centered on the concern of the Association of American Railroads over the problems of handling VCM in emergencies, particularly as they relate to the recent indication of carcinogenicity. Representatives of VCM producers, the railroads. Bureau of Explosives, trade associations and car leasing companies were present. Methods of establishing a mutual support program similar to that operated by the chlorine Institute and The National Agricultural Chemical Association were reviewed. Representatives of the Society of The Plastics Industry said see 5-0841 i they would explore the possibility of organizing a response system. Sincerely, MF:ec Enclosures Q\ v n f l. Lf) Milton Freifeld Y Project Manager Vinyl Chloride Research see 5-0842 UNIVERSITY OF LOUISVILLE Louisville. Kentucky 40202 April 20, SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE DIGESTIVE DISEASES AND NUTRITION SECTION 1976 ITEM 1 HEALTH SCIENCE CENTER WALNUT A. PRESTON STREETS Dr. T. R. Torfcelson Dow Chemical Company Corporate Medical Department 2030 Dow Center Midland, Michigan 48640 Dear Doctor Torkelson: May I express our delight in having had members of the Manufacturing Chemists Association Research Committee visit us earlier this month; we hope that their visit was both enjoyable and informative. Our post-lunch eon meeting helped to clarify a number of points concerning our Manufactur ing Chemists Association Grant proposal and I would like to take this op portunity to submit for the members consideration a modification of our original proposal in light of the expressed interests of the members of the research committee. % Since the members expressed interest in supporting proposals A and G, having to do with the study of immunological systems, it seems that these would require no further elaboration or adjustment. My understand ing is that the same would be-true for proposal G, concerning electron microscopic evaluation of liver tissue. What I would like to do here is (a) amplify on the immediate clinical applicability of some of the other proposals presented,., (b) provide a modified budget for these proposals and (c) suggest that if cuts must be made in the program, the cuts that would be least damaging in terms of ongoing efforts and in terms of a cohesive ness of the overall research program, would be the proposals by Dr. Hoffman (H) and Dr. Sigdestad (1) and parts of Drs. Du (B2 B5 B6 B7) and Wong (EZ) (see revised budget attached). Firstly, proposal C concerning the glyco- saminoglycans in.the early detection and etiology of angiosarcoma of the liver presented by Dr. Charles E. Kupchella: this has already produced significant results. Most chemical injury and cancer apipear to be as sociated with "scar" or collagen formation. This collagen formation is as sociated with the increased production of glycosaminoglycans. Dr. Kupchella*s preliminary study indicates that there is a characteristic pattern of glycosaminoglycan urinary excretion among long-term vinyl-chloride-exposed in dividuals not seen in individuals with alcoholic liver injury, hepatitis, and cancers not directly involving the liver. These urinary excretion pat terns appear to change as one develops primary liver cancer such as angio sarcoma. At this point, the findings reported by Dr. Kupchella at the Third see 5-0843 Dr. T.R. Torkelson page -2- International Symposium on the Detection and Prevention of Cancer, require additional verification and modifications of this method for use as spot urine testing in large worker population. If future studies continue to verify our present finding, i.e. that this test is indicative of early vinyl chloride injury, it could be applicable throughout the industry where chemically induced fibrosis may occur. This proposal could yield a sensi tive, simple and inexpensive means of surveillance for early liver injury. 'A copy of the paper to be presented in New York is enclosed. a Concerning the proposal by Dr. Wong, and the related proposal by Dr. Streips; I would like to elucidate on the value of this work in deter mining and directing priorities as to which metabolite should be studied for their potential carcinogenicity. Dr. Wong's ability to synthesize metabolic products of various chemicals allows immediate mutagenic bac terial studies for the identification of those chemicals with greatest car cinogenic capability. In order to control costs and increase benefits for the amount of time and money invested, these mutagenic studies must be per formed in order to realistically develop strategies for blocking the etiologic chemical changes leading to the initiation of angiosarcoma. Con sidering the overall complexity of studies of this sort, we feel that the combined work of Drs. Wong and Streips provides a reasonably straight for ward approach to unravelling sequences leading to angiosarcoma. In addition, Dr. Wong's work will develop a method of detecting trace amounts of chemicals and their metabolic products by use of multivarient analysis in biological tissue. Our present system of storing bloods, urines, and tissue on all workers in the medical surveillance program gives us the equivalent of an immediate clinical trial in a care fully observed worker population with known exposure. This procedure could give us an applicable test system within three years. Finally, Dr. Du's work will make use of animal studies in deter mining the most specific and earliest enzymatic and biochemical alterations produced by chemical exposure. Although some have expressed the view that biochemical alterations have all been identified and worked out, our clini cal experience indicates the need for studies which will objectively deter mine which screening methods should be applied and to which of the exposed industrial population. The animal studies proposed by Dr. Du will allow us to apply these methods under controlled conditions of exposure, dose and duration, providing useful information in just a few years. This will be far more efficient means of determining the best screening methods to employ based on hard scientific data rather than clinical opinion. Simultaneously, Dr. Wong will utilize these same animal tissues for verifying the sensitivity and specificity of the muLtivarient analysis system for trace organic element detection in biological tissue. The de tection of a trace product does not by itself prove a causal relationship nor indicate recent or past exposure. Therefore, it is vital that these studies be done (simultaneously with the studies for sensitivity and specificity) for verification of the relationship of detection to cause of injury. This information will greatly help in the interpretation of our findings from our stored human blood, urine and tissue samples. see 5-0844 Dr. T.R. Torkelson page -3- We would like to again, point out the importance of our being able to continue to pursue this multidisciplinary research approach in the study of the vinyl chloride problem. By addressing the vinyl chloride problem as a model and in this systematic manner we feel that this unique combination of investigations will go far toward providing understanding . chemical carcinogenesis in general and the etiology of angiosarcoma. Our program can be left essentially intact with the attached budget. The work proposed, we feel, is clearly defined and should produce positive results well in excess of investment. In addition, we would also like to point out that funding of such a program will sharpen our overall skills and further develop this approach applicability to other chemicals and in other situ ations. I believe that the budget proposed is well within the desirability and capability of the Manufacturing Chemists Association's constituency. In essence, we are asking the vinyl chloride industry to support -the program at somewhat less than a level that has been supported by the B.F. Goodrich Company alone for the past two years. Thank you for your serious consideration. Sincerely yours. Carlo H. Tamburro, M.D. Associate Professor of Medicine Chief, Digestive Diseases & Nutrition Section CHTsmma Enclosures cc: Dr. Zeb G. Bell, Jr. Dr. Walter D. Harris Dr. Maury Johnson Mr. Howard L. Kusnetz Dr. W.E. Rinehart Dr. W. Mayo Smith Mr. R.N. Wheeler see 5-OB45 REVISED BUDGET UNIVERSITY OF LOUISVILLE RESEARCH PROPOSAL RESEARCH TECHNIQUES AND METHODS FOR DETECTION AND PREVENTION OF CARCINOGENESIS IN INDUSTRIAL WORKERS This revised budget is for proposals Al-4, G, D, C, El, B3-4, and F, all of which have the most clinical appli cability. We have excluded proposals Bl, B2, B5, B6, B7, E2, H, and I. see 5_0B46 see -0847 In. -.VIDUAL BUDGETS Proposal Title Investigator Personnel Budget ' A 1-4 Immunological Systems for the Detection of Vinyl Chloride and Other Chemical Injury P. Fortwengler 34,100 G Tissue Antigenic E. Espinosa Systems of Detection 9,000 D Electron Microscopic R. Schrodt Evaluation of Liver * Tissue from Chemical Workers C Tissue and Urinary . Kupchella 8,000 Acid Mucopolysaccharide Changes Related to Vinyl Chloride Injury: Use In Early Detection and Diagnosis E1 Multivarient Analysis of Biological End Products and Biochemicals to Document Chemical Exposure for Early Diagnosis J. Wong 10,000 B3 &4 Biochemical Enzymatic Systems for Detection of Vinyl Chloride and Other Chemicals J. Du 27,000 F Assays for Identifi U. Streips 12,000 cation of the Carcino genic Potential of U7 Industrial Chemicals Indirect Costs Subtotals Total 100,100 65,065 Supplies 16,795 Total 50,895 5,000 7,000 14,000 7,000 7,500 15,500 15,000 25,000 7,332 11,000 34,332 23,000 69,627 169,727 234,792 A. SUMMARY OF BUDGETS Salaries: Supplies: Indirect Cost: 65% 100,100 69,627 65,065 TOTAL: 234,792 B. POSSIBLE ALTERNATE FUNDING SUGGESTION: Salaries: Supplies: Indirect Cost: 30% 100,100 69,627 30,035 TOTAL: 199,757 see 5-0848