Document jyk9vbmMVKz0a0Ln5K7oX63qR

A University of Louisville Louisville Kentucky 40302 April SCHOOL OF MEDICINE department of medicine DIGESTIVE DISEASES AND NUTRITION SECTION 20, 1976 ITEM 1 HEALTH SCIENCE CENTER WALNUT A PRESTON STREETS Dr. T. R. Torkelson 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 tfong (E2) (see revised budget attached). Firstly, proposal C concerning the glycosaminoglycans 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 appear 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 RSV 0001546 Dr. T.R. Torkelson page -2- Intemational 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. Concerning the proposal by Dr. Wong, and the related proposal by Dr. Strelps; 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 etiologlc 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 multlvarlent 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. RSV 0001547 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 CHT:mma 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 RSV 000154a 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. RSV 00015*9 RSV 0 0 0 1 5 5 0 INDIVIDUAL BUDGETS Proposal Title Investigator A 1-4 G ]) C E1 B3 4 F Jmmunologica1 Systems for the Detection of Vinyl Chloride and Other Chemical Injury P. Fortwengler TLssue Antigenic Systems of Detection E. Espinosa Electron Microscopic Evaluation of Liver Tissue from Chemical Workers R. Schrodt Tissue and Urinary Ac id Mucopolysaccharide Changes Related to Vinyl Chloride Injury: Use In Early Detection and Diagnosis C. Kupchella Multivar Lent Ana lysis of Biological End Products and B i ocheniicals to DuciiinenL Chemical Exposure for Early Di agmis i s J. Wong Bior hemir a 1 Euzymal1e Systems tor Detection of Vinyl Chloride and oilier Chemicals J. Du Assays for Identifi cation of the Carcino genic Potential of 1ndustrint Chemicals U. Streips Personnel Budget 34,100 9,000 8,000 10,000 27,000 12,000 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 0001551