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CHEMICAL MANUFACTURERS ASSOCIATION August 1, 1994 Clark Heath Jr., M.D. Vice-President for Epidemiology and Surveillance American Cancer Society 1599 Clifton Rd. NE Atlanta, 6A 30329-4251 Dear Dr. Heath: 1 am writing this letter on behalf of the Chemical Manufacturers Association Vinyl Chloride Panel to express our concerns regarding a statement in the first full sentence of page fifteen of the ACS publication Cancer Facts and Figures 1994 (as well as in earlier issues). Referring to the risk factors associated with malignant lymphoma, this statement reads as follows: "Other possible risk factors include exposures to herbicides, industrial solvents, and vinyl chloride." We believe that a misunderstanding of this statement may have lead to the association of vinyl chloride exposure with risk of lymphoma in an article by J. Madeleine Nash in the April 25, 1994 issue of TIME magazine (page 60). A copy of this page is enclosed. The description in the table entitled "The Big Killers" implies, we believe, that vinyl chloride is a "proven" rather than a "possible" risk factor for malignant lymphoma. We are concerned that others may similarly misinterpret the statement appearing in Cancer Facts and Figures 1994. A large number of epidemiologic studies have been conducted on well-defined occupational cohorts with potential exposure to vinyl chloride. In some of these studies an elevation in lymphoma mortality was observed, but not in others. The largest and most recent such study, published by Wong et al. in 1991, did not observe any excess of lymphatic or hematopoietic cancer deaths, even among workers who were first exposed prior to 1950. In contrast, mortality due to cancer of the liver, with which vinyl chloride exposure is certainly causally associated, was most elevated in the subcohort of workers exposed prior to 1950. We believe that the epidemiologic evidence does not lead to an inference of a causal association between vinyl chloride exposure and malignant lymphoma. Our view is consistent with that of Sir Richard Doll, who reviewed the evidence in 1988. We note that Doll refers to the studies by Tabershaw and Gaffey (1974) and Waxweiler et al. (1976) as having raised the possibility of an association between vinyl chloride and lymphoma. We hasten to point out that these were early studies conducted on workers who were eventually included in the much larger cohort studies by Wong et al. and referred to in this letter. 2501 M Street, NW, Washington, DC 20037 Telephone 202-887-1100 Fax 202-887-1237 Ly ReSporabteCare* R&S 144715 August 1, 1994 Pago 2 We respectfully requ st that the statement in Cancer Facts and Figures 1994 b amended to better refl ct the current state of knowledg about the suspected association of vinyl chloride exposure with lymphoma* The suggested wording to be added is (underlined and in italics): "Other possible risk factors include exposures to herbicides, industrial solvents, and vinyl chloride, although the evidence supporting an association with vinyl chloride exposure is limited." An alternative to this change of wording would be to remove the specific reference to vinyl chloride from the statement. We note that vinyl chloride is not mentioned specifically as a possible risk factor for cancer of the lung, although there is also equivocal epidemiologic evidence for an association between vinyl chloride exposure and this type of malignancy. We feel that our suggestion encompasses the current state of the evidence concerning vinyl chloride and lymphoma and would minimize th possibility for the kind of misinterpretation we observed in the TIMS magazine article. At the same time, we wish to point out that this letter was intended solely to address possible misinterpretations with respect to lymphoma and vinyl chloride. In no way do we acknowledge the existence of any association between exposure to herbicides or industrial solvents and the occurrence of malignant lymphoma. We trust that this letter and the attachments will serve to provide you with a comprehensive view of the evidence concerning the health effects of vinyl chloride exposure in humans. If you have any questions or would like more information, please contact me at (202) 887-1192. Sincerely, Enclosures Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel R&S 144716 August 1, 1994 Pag 3 References Cited and Enclosed: American Cancer Society. Cancer Facts and Figures, 1994; 1-28. Doll R. Effects of exposure to vinyl chloride. An assessment of the evidence. Scand J Work Environ Health 1988;14:61-78. Nash JM. Stopping Cancer in its Tracks. TIME Magazine 1994; April 25: 54-61. Tabershaw IR and Gaffey WR, Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 1974;16:509-18. Waxweiler RJ et al. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 1976;271:40-48. Wong 0 et al. An industry-wide epidemiologic study of vinyl chloride workers, 1942-1982. Am J Ind Med 1991;20:317-34. R8tS 144717 lilt was like a mi s*lot^or m measles or malfunctions. When she introduced a nor mal nm23 gene (nm stands for non metastatic) into highly malignant human breast cells, then injected these cells into mice, their tendency to form metacm^ dropped as much as 90%. mumps. I do GUARDING THE MASTER SWITCH Until last week, p53, the subject of some L000 scien f not expect any tific papers in 1993 alone, was considered the most important cancer gene. The jour side effects, nal Science even named it Molecule of the Year. But now there is a new contender for except to feel notoriety--mtsi, as Alexander Kamb and his colleagues refer to the multiple tumorsuppressor gene they have just discovered better-77 "Multiple" refers to the fact that defects in this gene can cause many kinds of cancer, including melanoma, lung, breast and brain JACK SWEPSTON, 48. Pancreatic Cancer. On March 31 this Dallas dentist trav tumors. In fact, functional copies of mtsi eled to the National Cancer Institute in Bethesda, Maryland, to receive a new type of anticancer vaccine. Prepared by a team of researchers, including Drs. David Carbone and John Minna of the University of Texas Southwestern Med may be missing in more than 50% of all hu man cancers. What makes mtsi so significant is its clear role in the cell-division cycle. A cell di ical Center, the vaccine was a synthetic version of a mutant protein fragment vides not at will but in response to specific found in Swepston's tumor. Hie hope is that the immune system will learn to signals, such as growth factors produced by recognize this target and destroy the cells that mnlre it "I haven't felt a signifi cant improvement yet" he says, "but the doctors are tremendously excited." white blood cells rushing to repair a wound. These signals are picked up by re ceptors on the membrane of the cell and passed along-like batons in a high-speed enues of escape. Not all the myriad cells ulate new areas. Butwhile an embryonic cell relay--through the interior, all the way to a shed by tumors survive the turbulent voy stops proliferating and matures into adult master "on" switch positioned deep in the age through the bloodstream, notes exper tissue, the cancer cells just keep dividing. nucleus. Not surprisingly, many onco imental oncologist Ann Chambers of the One reason for the difference may lie in genes, including one called ras, the first London Regional Cancer Centre in On a gene known as nm23, first identified by human cancer gene ever identified, are in tario. But those that do eventually slip Steeg in 1988- It seems to help mature cells volved in this type of signaling pathway. through blood-vessel walls with ease. Using stop dividing and arrange themselves in an But there are other molecules that deter a video camera attached to a microscopic orderly fashion. Steeg's research suggests mine whether the cell should heed these lens. Chambers has watched in wonder as that in cancer cells this crucial gene often signals. And the small protein produced by melanoma and breast-cancer cells, injected into mice, become lodged in capillary walls, then crawl out into the liver. Three days later, her camera resolves the spidery shapes of tiny metastatic growths. The les son, Chambers believes, is depressingly clear. Cancer cells zip in and out of blood THE BIG KILLERS Estimates in ttie U S . 1994 Caned Deaths Five-year Survival New cases rale Lung 153,000 172,000 13% Risk Factors to asbestos, chemicals, redinon, radon , . vessels so readily that, once angiogenesis occurs, they should be presumed to have al ready spread around the body. Metastasis is an event of awesome com plexity, one that requires multiple genes to Colon/Rectum Female Breast Prostate 56,000 149,000 58% 46,000 182,000 79% 38,000 200,000 77% Farr-'y history: high-fat. low-fiber diet Age; family history; no pregnancies; late menopause: eariy menarche Age: family history, possibly (at intake cooperate as closely as musicians in an or chestra. Some of these genes code for chem ical solvents that enable the advancing cell to dissolve surrounding tissue. Others order pMcrees 25,900 Lymphoma 'Wckm's 22,750 Non-Hod?,kin s 27,000 3% 52,900 78% 52% Agaismotanfc fatkjtake Reduced immune function: exposure to herbicides, solvents, vinyl chloride up the production of adhesion molecules that, like treads under a tank, move the cell forward. Why would genes do that? The an swer, notes Patricia Steeg of the National Uafcamia Ovary 19,100 13,600 28,600 38% 24,000 39% Genetic abnormalities; exposurets ionizing radiation, chemicals: wises Age. family history, genetic disorders, no pregnancies Cancer Institute, is that while the genes im portant to metastasis are abnormally turned on. they are not necessarily abnormal them Kidney Bladder 11,300 .27,600 55% Smoking 10,600 51,200 79% Smoking ......... selves. A cancer cell, in many ways, is not that different from an embryonic cell on its | way to becoming a patch of skin or a bundle I (Rents Cwvica' , Endometrial 10,500 46,000 67% Intercourse at an early age; multiple set partners; smoking 83% tarty menarche: late menopause; obesity of nerves. Both embryonic and cancer cells j Oral 7,925 29,600 53% Smoking: eicessive use of alcohol divide and form ill-defined clumps. Both get j up and move around. Both migrate and pop- ! Skin Melanoma AramCw Sotr 6,900 32,000 84% Sunburn; fair completion; exposure to coal tar, pitch, creosote, arsenic, radium R&S 144718 fit) nMI-:.AI'HU.25.]9S4