Document YDQwEy442RowaQJ6Rbp9Dmz6k

CHEMICAL MANUFACTURERS ASSOCIATION April 15, 1994 Dear Vinyl Chloride Research Coordinators: The next VCRC meeting is scheduled for May 19, 1994. The agenda for the meeting is enclosed. Also enclosed are: 1) a draft scope of work for an update of the mortality among vinyl chloride workers; 2) an historical perspective on inter-industry vinyl chloride study; and, 3) the benefits of updating the inter-industry study of vinyl chloride workers. Please review these documents in conjunction with Dr. Richard Reitz's abstract on physiologically-based pharmacokinetics model for vinyl chloride and the ATSDR Federal Register notice on vinyl chloride research data needs that were sent to you with my March 30 letter. I am looking forward to seeing you on May 19. Sincerely, Enclosures Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel SL 107216 2501 M Street, NW, Washington, DC 20037 Telephone 202-887-1100 Fax 202-887-1237 L& Responsible Care* if APi^Commitment CHEMICAL MANUFACTURERS ASSOCIATION Vinyl Chloride Panel Vinyl Chloride Research Coordinators Tentative Agenda DATE: TIME: PLACE: May 19, 1994 10:00 a.m. - 3:00 p.m., EDT CMA Offices 2501 M Street, NW Washington, D.C. Approval of February 14, 1994 Record of Meeting Discussion of Scope of Work of the Epidemiology Study Discussion of Potential Contractors for the Epidemiology Study Discussion of Cost Sharing Formula for the Epidemiology Study Presentation by Richard Reitz on Predicting Cancer Risk from Vinyl Chloride Exposure with a Physiologically-Based Pharmacokinetic Model - TENTATIVE >6/0 Discussion of Course of Action with EPA on Vinyl Chloride Risk Assessment Discussion of ATSDR Research Data Needs for Vinyl Chloride Discussion of Course of Action with ATSDR on Its Priority Data Needs 9.0 Financial Statement 10.0 Schedule Date for Next Meeting or ^Conference Call br-w, Subject to Approval Hasmukh C. Shah, PhTEl^ Manager, Vinyl Chloride Panel 4*^1- SL 107217 ANTITRUST CHECKLIST FOR CMA MEETINGS This antitrust checklist is for use by CMA staff and member representatives in the conduct of CMA-sponsored meetings. hibited discussion topics apply equally to social gatherings incidental to CMA-sponsofcd meetings. The Checklist is nol^P haustlve and does not address antitrust issues relating to activities other than CMA meetings. Participants in CMA meetings also should be thoroughly familiar with: (l) "Antitrust Guide for CMA Committee Members;" and. (2) "General Principles Applica ble to foe Structure and Operations of Committees." Both of these documents may be found in foe CMA Directory. DO Ensure stria performance in areas of: OVntSIGHT'SUPEKVISION: Have a CMA naff representative at each CMA-sponsored meet ing (unless an exception has been authoriaed by the approprate CMA vice-president): const* with an attorney ofthe CMA Office ofGeneral Cbtaiael on all anucusr questions idMting to QfA-sponsored meet*** taut meeting discussions to agenda topics (unless additional topics have been approved by the appropriate CMA soff rep resentative); and provide each member company representative and OtKtutt representative attending a CMA-sponsored meeting wkh a copy of this checklist, and have a copy available far reference at aD CMA-sponsored meetings. RECORDKEEPING* Have an agenda and minutes which accurately reflect the ma ters which occur. provide agendas and minutes to the CMA Office of General Counsel for review and approval in advance of dtaffiution; and. fully describe the purposes and authorities of all task groups, workgroups, ad hoc ot other sunding committee subgroups in the nunutes of the appropriate parent committee. VIGILANCE) Protest against any discussion or meeting activities which ap pear to violate this checklist, disassociate yourself from any such discussion or activities and leave any meeting in which they continue. Revised 3'80 (single page version! Reform*ed 1'89 MDB DON'T Do OCX, in fra Of appearance, discuss or exchange infor mation OO: IVCZS, INCLUDING. Individual company prices, price change*, price differentials, matinipa. discounts. allowances, credit toms, etc.; individual company data on cons, production, capacity. kwemories. sales, etc; and. mdumy pricing policies, price levels, price changes, differen tials, etc. nODUCnON. INCLUDIPiGt Plans ofindividual companies concerning the design, produc tion. dbtrttxaion or marketing of particular products, includ ing proposed territories or cunotnets; and, changes m mdumy production, capacity or inventories TRANSPORTATION EATESi Kates or tare policies for individual shipments, including bas ing point systems, xone prices, freight equalization, etc. MARKET PROCXDURZS. INCLUDING. Company bids on contracts for particular products; company procedures far responding to bid invttauoro- and. masers relating to actual or potential individual suppliers or customers that might have die effect of exdudmg them from any market or influencing the business conduct of firms to ward them. CONSENT DECREE SUBSTANCE* Any matter relating to trisodium phosphate (a restriction re quired by a 1962 consent decree to which CMA is a pira^ SL 107218 APPLIE EPIDEMIOLOGY INC. April 4,1994 Hasmukh C. Shah, Ph.D. Vinyl Chloride Panel Chemical Manufacturers Association 2501 M Street, NW Washington, D.C. 20037 Dear Dr. Shah: As you suggested in our brief telephone conversation about two weeks ago, I am writing to express my interest in preparing and submitting a proposal should the Chemical Manufacturers Association decide to update the vinyl chloride cohort study. This study has provided valuable information on a large sample of employees occupationally exposed to vinyl chloride, and should continue to elucidate a number of important issues. My colleague Dr. Harris Pastides and I have worked with CMA on a number of occasions, mainly with Ms. Sandra Tirey and the Epidemiology Task Group. We authored the CMA Occupational Epidemiology Resource Manual, a practical guidebook on establishing epidemiology programs and conducting epidemiological research. Related to this, we presented an Epidemiology Resource and Information Center (ERIC) Workshop on "Establishing and Maintaining an Effective Occupational Epidemiology Program." Most recently, we authored another CMA manual entitled. Establishing an Occupational Epidemiologic Surveillance Program: A Resource Guide. We have worked and continue to work with several member companies, and have established excellent relationships with many of their corporate epidemiologists. Perhaps the most recent and relevant of this work is a P.O. BOX 2424 AMHERST, MA 01004 W (413) 256-3556 FAX (413) 256-3503 Dr. Shah, April 4,1994, p.2 cohort mortality study of employees in the VCM and PVC division of the Vista Chemical Company, which will begin this month. I have enclosed a copy of my Curriculum Vitae, and will be happy to send additional information, including Dr. PasTides's CV, if needed. We look forward to discussing with you the prospects of assisting with this research. Please do not hesitate to call me if you have any questions or need additional information. Sincerely yours, enclosure Kenneth A. Mundt, Ph.D. SL 107220 Curriculum Vitae KENNETH ARTHUR MUNDT, Ph.D. CURRENT POSITIONS Assistant Professor (1989-present) Department of Biostatistics and Epidemiology School of Public Health 403 Arnold House -- University of Massachusetts Amherst, MA 01003 Telephone Fax (413) 545-2861 (413) 545-1645 Visiting Associate Professor (1991-1996) Institut fur Epidemiologie und Sozialmedizin Univeisitat Munster Von-Esmarch StraBe 56 D-48129 Munster GERMANY Telephone Fax 49 (251) 83-5520 49 (251) 83-5300 Senior Epidemiologist (1991-present) Applied Epidemiology, Inc. P.O. Box 2424 Amherst, MA 01004 Telephone Fax (413) 256-3556 (413) 256-3503 EDUCATION Ph.D., Epidemiology University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 1990. M.S., Epidemiology University of Massachusetts at Amherst, Amherst, Massachusetts, 1986. M.A., English University of Virginia at Charlottesville, Charlottesville, Virginia, 1982. A.B., English Dartmouth College, Hanover, New Hampshire, 1981. SL 107221 Mundt C.V., p. 2 university research 1994 1993 1992 1991 1990 Principal Investigator Healy Endowment Award. Lead Prevalence Study (1993-4) $5,000 Co-Principal Investigator Occupational Upper Extremity Disorders Clinic University of Massachusetts Medical Center (1993-4) $57,000 " Principal Investigator. El. Du Pont de Nemours Company. Educational Aid Program. Occupational Epidemiology Unit. (1992-4) $15,000/year Principal Investigator/Convenor. Second National Conference on Occupational Surveillance, University of Massachusetts, Amherst, MA. (March 9-11,1993) $26,000 Co-Investigator. Chemical Manufacturers of America. Definition and Strategies for Developing Occupational Surveillance. (1992-3) $38,000 Principal Investigator. Faculty Research Grant. Epidemiological Surveillance. (1992-3) $4,940 Principal Investigator. Faculty Research Grant for Conference/Performance Travel. Third Annual Symposium on Environmental and Occupational Health in Central & Eastern Europe in Poland. (1992) $600 Co-Investigator. Occidental Chemical Corporatioa Development of a Corporate Epidemiological Surveillance System. (1991-2) $50,000/year Principal Investigator/Convenor. National conference, "Occupational Surveillance" University of Massachusetts, Amherst, MA. (April 28-30, 1991) $22,000 Co-Investigator. Chemical Manufacturers of America. Development of Resource Materials for Occupational Epidemiology. (1990) $75,000 SL 107222 Mundt C.V., p, 3 UNIVERSITY RESEARCH (continued) 1990 (cont'd) Principal Investigator. National Institute of Occupational Safety and Health. Immuno-Epidemiology of Crab-Induced Occupational Asthma. (1989-1990) $43,500. 1989 Principal Investigator. United Way of North Carolina. Immuno-Epidemiology of Crab-Induced Occupational Asthma: Pilot and Preparatory Phases. (1989) $4,000. Principal Investigator. Biomedical Research Support Grant, School of Public Health, University of North Carolina. Production of Antigen Solutions for Skin Testing. (1988-1989) $5,886. RELEVANT EXPERIENCE 1994 1993 - present 1993 - present 1993 - present 1993 1992 - present 1992 - present 1992 - present 1991-1993 Guest Editor, Journal of Ambulatory Care Management "Epidemiological and Managerial Challenges in the Workplace" Volume 17(2), April, 1994. Director, Occupational Epidemiology Unit School of Public Health, University of Massachusetts. Consultant to the Medical Director, The World Bank, Washington, D.C. ATSDR Peer Reviewer in Epidemiology. Member, 1993 Internship Program Objective Review Committee, Association of Schools of Public Health/Centers for Disease Control/Agency for Toxic Substances Disease Registry. Founder and Director, Surveillance Resource Center, Occupational Epidemiology Unit. Epidemiologist, Northeast Regional Environmental Public Health Center, School of Public Health, University of Massachusetts. Member, Human Subjects Committee, School of Public Health, University of Massachusetts. Assistant Director, Occupational Epidemiology Unit, University of Massachusetts SL 107223 Mundt C.V., p. 4 RELEVANT EXPERIENCE (continued) 1991 - present Member, Union Carbide Scientific Board of Advisors. 1990-1992 Member, International Chrome Development Association, Health, Safety and Environment Committee, Paris, France. 1990 -1992 Epidemiologist, Chromium Environment, Health and Safety Committee, Industrial Health Foundation, Pittsburgh, PA. 1988 -1989 Research AssistariTto Carl M. Shy, M.D., Dr.P.H., on Oak Ridge Universities Occupational Studies of Department of Energy Employees, and on North Carolina Dusty Trades Occupational Health Studies, University of North Carolina. 1988-1989 Visiting Researcher, Duke University Marine Biomedical Center, Duke Marine Laboratory, Pivers Island, Beaufort, North Carolina. 1983 -1984 Commissioned Officer Student Training Extern Program (COSTEP). United States Public Health Service, Health Resources and Services Administration, Silver Spring, Maryland. TEACHING EXPERIENCE 1989 - present 1987-1988 Assistant Professor University of Massachusetts, School of Public Health: "Principles of Epidemiology" "Applied Epidemiology" "Occupational Epidemiology" "Special Topics in Occupational Epidemiology" "Departmental Doctoral Seminar" Numerous Independent Study Projects Teaching Assistant to David G. Kleinbaum, Pb.D. University of North Carolina, School of Public Health. "Special Topics in Epidemiological Methods" "Advanced Methods in Epidemiology" SHORT COURSES 1993, 1994 Applied Epidemiology, Inc. and Akademie fiir offentliche Gesundheit, Wennelsckirchen, Germany: "Intensive Course in Occupational Epidemiology" SL 107224 Mundt C.V., p. 5 SHORT COURSES (continued) 1991 Cancer Registry of Norway, Oslo, Norway. August 12-16: "Occupational and Environmental Epidemiology" 1989, 1990, 1991 International Summer School for Epidemiology, World Health Organization and the Akademie fur offentliche Gesundheit, Bochum, Germany "Occupational and Environmental Epidemiology" HONORARY AND PROFESSIONAL SOCIETIES American Conference of Governmental Industrial Hygienists (Full Member) American Public Health Association Delta Omega, Public Health National Honor Society International Society for Environmental Epidemiology Sigma Xi, Scientific Research National Honor Society Society for Epidemiologic Research PRESENTATIONS 1994 Birk T, Mundt KA Schumann J, Person M, Weiland S, Keil U. "Cost-center Accounting Codes ("Kostenstellen") as Exposure Indicators in an Epidemiological Study of the German Rubber Industry." Conference on Retrospective Assessment of Occupational Exposures in Epidemiology, Lyon, France, April 13-15,1994. Weiland S, Birk T, Mundt KA Person M, Schumann J, Keil U. "The Epidemiologic Study of Cancer in the Rubber Industry in Germany: An Update." International Conference on Occupational Health in the Rubber Industry, The Netherlands, May 31-June 1,1994. 1993 Mundt KA "Occupational Epidemiology in a White-Collar Setting" Invited Speaker, The World Bank, May 11-12,1993. Mundt KA "Occupational Surveillance: Concepts and Goals." Second National Conference on Occupational Surveillance, University of Massachusetts, Amherst, MA March 9-11,1993. SL 107225 Mundt C.V., p. 6 PRESENTATIONS (continued) Mundt KA "Practical Stretcgy for Developing Epidemiological Surveillance." Design and Analysis Workshop, Second National Conference on Occupational Surveillance, University of Massachusetts, Amherst, MA, March 9-11,1993. 1992 Mundt KA and Weiland S. "The Association of Asthma Symptoms and Allergic Rhinitis with Traffic Density on Street of Residence." Annual meeting of the International Societies for Environmental Epidemiology and of Exposure Analysis, Cuernavaca, Morelos, Mexico, August 26-29, 1992. Pastides H and Mundt KA "Retrospective Estimation of Exposure to Hexavalent Chromium in an Occupational Cohort." Annual meeting of the International Societies for Environmental Epidemiology and of Exposure Analysis, Cuernavaca, Morelos, Mexico, August 26-29,1992. Pastides H and Mundt KA "Epidemiological Occupational Surveillance." Surveillance in Europe and the EEC, Devonshire Park Centre, Eastbourne, Sussex, United Kingdom, July 1-3, 1992. Mundt KA "Occupational Surveillance as a Strategy for Policy Development and Disease Prevention." Protecting Workers, the Environment and Health in a Market Economy: Translating Science into Policy and Action. The United StatesCentral and Eastern Europe Exchange for Occupational and Environmental Health, third annual symposium, Pultusk, Poland, June 26 - July 1,1992. Pastides H, Austin R, Lemeshow S, Klar J, Noess R, and Mundt KA "A Retrospective Cohort Study of Health Risks Among Chromate Production Workers." Annual Meeting of the Society for Epidemiologic Research, Minneapolis, MN, June 10-12,1992. Weissman L and Mundt KA "Prevalence of Immediate Hypersensitivity in Black Women: A Re-evaluation of Skin Prick Test Data from the Second National Health and Nutrition Examination Survey (NHANESII) and Comparison with an Occupational Study." Annual Meeting of the Society for Epidemiologic Research, Minneapolis, MN, June 10-12, 1992. Mundt KA, Leeser J, Adams R. "Establishing a Mercury Biological Exposure Index (BEI)." American Conference of Governmental Industrial Hygienists (ACGIH) BEI and Threshold limit value (TLV) Committees, Orlando, Fla., March 21-22,1992. 1991 Mundt KA "Epidemiological Approach to Occupational Health." Annual Scientific Meeting, Industrial Health Foundation, Pittsburgh, PA, November 6-7,1991. Mundt KA "Role of Epidemiology in an Occupational Medical Department." Bayer Chemical, Leverkusen, Germany, June 19,1991. SL 107226 Mundt C.V., p. 7 PRESENTATIONS (continued) Mundt KA. "Occupational Epidemiological Studies and the Social Context" Department of Epidemiology, State University of New York at Albany, April 18, 1991. Mundt KA. "Use of Skin Tests in Epidemiological Research." Clinical Epidemiology Department University of Pennsylvania, Philadelphia, PA, March 14,1991. Pastides H and Mundt KA. "Establishing'an Occupational Epidemiology Program." Chemical Manufacturers Association, Washington, D.C., March 12,1991. 1990 Mundt KA. "Studies to Document the Healthy Worker Effect" Department of Work Environment University of Lowell, Lowell, MA, December 11,1990. Mundt KA and Miller J. "Use of Industrial Hygiene Data in Epidemiology Research." Occidental Chemical Industrial Hygiene Annual Meetings, Houston TX and Atlantic City, NJ, November 12-14,1990. Mundt KA and Shy C "Occupational Allergies and the Healthy Worker Effect" Annual Meeting of the Society for Epidemiologic Research, Snowbird, Utah, June 12-15, 1990. Mundt KA, "Health Effects of Vinyl Chloride Monomer (VCM)." Occidental Chemical Company, Plastics and Polymers Group, Berwyn, PA, May 11, 1990. 1989 and earlier Mundt KA. "Skin Testing for Allergies in an Occupational Setting." Clinical Epidemiology Seminar Series, University of Massachusetts Medical Center, Worcester, MA, December 20,1989. Mundt KA. "Immuno-Epidemiology of Crab-Induced Occupational Asthma: Methodological Issues." Visiting Researcher Program, Duke University Marine Biomedical Center, Beaufort, North Carolina, January, 12-13,1989. Mundt KA and Heiss G. "Measuring Ankle Systolic Blood Pressure: Interaction Between Ankle Geometry and Method of Applying Blood Pressure Cuff" National Heart, Lung and Blood Institute Seminar, Bethesda, Maryland, November 3,1987. Mundt KA and Pastides H. "Microcomputer-Based Instruction: Applications in Epidemiology." Annual Meeting of the American Public Health Association, New Orleans, Louisiana, October 18-22,1987. Mundt KA. "Distribution of Selected Mineral Concentrations in Urban Children's Hair." Annual Meeting of the American Public Health Association, Las Vegas, Nevada, September 28 - October 2,1986. SL 107227 Mundt C.V., p. 8 PUBLICATIONS AND REPORTS 1994 Mundt KA, Dell LD. Neuropsychological effects of environmental dioxins and furans? (accepted for publication) Occupational and Environmental Medicine Report 1994. Pastides H, Austin R, Mundt KA, Ramsey F, Feger N. Transforming industrial hygiene data for use in epidemiology studies: A case study of hexavalent chromium (accepted for publication) Journal of Occupational Medicine and Toxicology 1994. Mundt KA. Epidemiological surveillance: A management tool for occupaitonal health. Journal of Ambulatory Care Management 1994;17(2):20-29. Weiland SK, Mundt KA, Riickmann A and Keil U. Self-reported wheezing and allergic rhinitis in children and traffic density on street of residence. Annals of Epidemiology 1994;4:79-83. Pastides H, Austin R, Lemeshow S, Klar J, Noess R and Mundt, K. A retrospective cohort study of occupational exposure to hexavalent chromium (accepted for publication) American Journal of Industrial Medicine 1994. Gehlbach SG and Mundt KA. Evaluating Worksite Health Programs. Journal of Ambulatory Care Management l994;17(2):88-94. 1993 Pastides H and Mundt KA. Establishing an Epidemiological Occupational Surveillance Program. Chemical Manufacturers of America, Washington, D.C, 1993. Mundt KA. Occupational surveillance as a strategy for policy development and disease prevention. In: Proceedings of the Third Annual Symposium on Environmental and Occupational Health during Societal Transition in Central and Eastern Europe. Protecting Workers, the Environment and Health in a Market Economy: Translating Science into Policy and Action, June 26 - July 1,1992 Published by Management Sciences for Health, Boston, Massachusetts, 1993. 1992 Mundt KA. The Workplace as Laboratory. Business Digest, June 1992;34. Mundt KA, Chambless LE, Burnham CB and Heiss G. Measuring ankle systolic blood pressure: Validation of the Dinamap 1846 SX. Angiology, 1992:43(7);555-566. Mundt KA. Letter to the Editor: RE: "Exposure to residential electric and magnetic fields and risk of childhood leukemia" and "Case-control study of childhood cancer and exposure to 60-HZ magnetic fields." American Journal of Epidemiology 1992:135(9); 1070-1075. Si* Mundt C.V., p. 9 PUBLICATIONS AND REPORTS (continued) Health, Safety and Environment Committee, International Chromium Development Association. Health, Safety and Environment: Industry Guidelines. Paris, France, April, 1992. Pastides H, Miller JR, Mundt KA Klar J, Adams RF, Olendorf T. A characterization of occupational static magnetic field exposures at a diaphragm-cell and a mercury-cell chlor-alkali facility. Applied Occupational and Environmental Hygiene 1992;7:42-48. 1991 and earlier Mundt KA, Epidemiological Review of the American Conference of Governmental Industrial Hygienists (ACGIH) Recommended Biological Exposure Index (BEI) for Urinary Mercury. The Chlorine Institute, September 30,1991. Pastides H and Mundt KA. Resource Manual for Occupational Epidemiology, Chemical Manufacturers of America, Washington, D.C., 1991. Walker A and Mundt KA. Feasibility of Conducting an Industry-wide Study of Respiratory Cancer Related to Ceramic Fiber Inhalation, Final Report to Thermal Insulators Manufacturers Association (TIMA), Epidemiology Resources, Inc., Boston, MA November, 1990. Mundt KA Immuno-epidemiology of crab-induced occupational asthma, doctoral dissertation, University of North Carolina, 1990. Pastides H, Mundt KA, McKnight CJ and Tuthill RW. Formulating case definitions and identifying cases for analysis (computer-assisted instructional software). In "Applied Epidemiology," Centers for Disease Control, Atlanta, Georgia, 1986. Pastides H, Mundt KA, McKnight CJ and Tuthill RW. Descriptive analysis of the disease outbreak (computer-assisted instructional software). In "Applied Epidemiology," Centers for Disease Control, Atlanta, Georgia, 1986. Pastides H, Mundt KA McKnight CJ and Tuthill RW. Formulating and testing hypotheses (computer-assisted instructional software). In "Applied Epidemiology," Centers for Disease Control, Atlanta, Georgia, 1986. Mundt KA Distribution of selected mineral concentrations in urban children's hair. Masters thesis, University of Massachusetts, 1986. Tuthill RW and Mundt KA An evaluation of hazard abatement activities in selected state-funded lead screening programs. Final report to Massachusetts House of Representatives Post Audit and Oversight Committee, June 27,1985. Mundt KA and Polk BF. Identification of site urinary-tract infections by antibody-coated bacteria assay. Lancet 1979;2:1172-5. Mundt KA and Polk BF. Predictive value of a single diagnostic test: a belated correction. New England Journal of Medicine 1979;300(15):859. Revised 3/94 SL 107229 POTENTIAL CONTRACTORS Howard Rockette, Ph.D. Department of Biostatistics Graduate School of Public Health University of Pittsburgh 130 DeSoto Street Pittsburgh, PA 15261 (412) 604-3022 Harris Pastides, Ph.D. School of Public Health Occupational Epidemiology University of Massachusetts Room 407 Arnold House Amherst, MA 01003 (413) 545-6167 0. J `/b A^A 0(003 C4(^ StfS'AtU Dr. Roy E. Shore Professor Environmental Medicine New York University Medical Center 341 E. 25th Street, Room 204 New York, NY 10010-6500 (212) 340-6500 SL 107230 * DRAFT Scope of Work Update of Mortality Among Vinyl Chloride Workers The Chemical Manufacturers Association (CMA) is interested in receiving proposals to update the mortality experience among an established cohort of workers employed in the vinyl chloride/polyvinyl chloride (VC/PVC) industry. This cohort was previously studied by Tabershaw and Gaffey (1974), Cooper (1981) and Wong, et al. (1991). The Scope of Work for this project is outlined below and includes some key elements which should be addressed in any proposals submitted. As you will note, the CMA is interested in receiving two major work products at the conclusion of the project: 1) A written technical report summarizing an epidemiologic evaluation of the mortality experience of the workers through 1992 and 2) A manuscript which is suitable for publication in the peer-reviewed scientific literature. Background The original records which formed the basis for prior reports of the mortality experience of this cohort are currently in the possession of ENSR Health Sciences located in Alameda, California. If a different study group is awarded the contract to conduct the update study, CMA will arrange the transfer of all pertinent records from ENSR to that contractor. However, ENSR did make confidentiality agreements with some states (see attached list) precluding a direct transfer of death certificates for some of the cohort members. Therefore, submitted proposals will need to indicate how other contractors would proceed to obtain such death certificates for persons dying prior to 1983, the end date for follow-up in the most recent update. Projected Scope of Work All proposals submitted in response to this request should address the following issues: 1. Verification of the completeness of the database in comparison with the results of the most recent update (see Wong, et al. 1991, attached.) SL 107231 2. How to obtain death certificates for employees dying before 1983 which could not be transferred directly from ENSR. 3. Ascertainment of vital status of cohort members who survived through the end of the previous update period (i.e., 12/31/92.) 4. Obtaining death certificates for employees determined to have died after 1982 and assigning a nosologically valid cause of death to each. 5. Conduct of a Standardized Mortality Ratio analysis comparing the cause-specific mortality experience of the cohort with age-, race-, gender-, and' period-specific rates for the U.S. male population and individual state male populations. The analyses conducted should consider at least the following factors: Age at first exposure Year of first exposure Type of plant (VCM or PVC) Length of exposure Elapsed time since first exposure In addition to these points, any proposal should also include the investigators' thoughts on the feasibility and technical merit of the following: 1. Updating the exposure histories of surviving cohort members from 1982 through 1992. 2. Performing internally standardized mortality comparisons using such methods as Peis&n regression for comparing SMR's. J-fr< y ti Lx , u l L t j SL 107232 Technical Criteria You may be interested in some of the criteria that the CMA Vinyl Chloride Research Coordinator's Group will use to evaluate the proposals received. These are listed below for your consideration when preparing your response. The criteria are not listed in any particular order and should not be viewed as having equal weight. 1. The curriculum vitae for each of the scientists who will comprise your project team. 2. Your proposed approach to each of the technical items listed in the Scope of Work. 3. Your proposed schedule for completion of the required deliverable work products listed below. 4. Your description of the technical and physical resources at your disposal for completion of this project. Required Deliverable Work Products The deliverables expected by CMA include the following: 1. A series of timely progress reports addressing the following: Verification of completeness of the existing database against the tables presented in the 1986 report to CMA prepared by Wong, et al. (see attachment.) Outcome of efforts to ascertain vital status of cohort members through 1992. Outcome of efforts to obtain death certificates for employees dying after 1982, and for employees dying before 1983 if necessary. 2. A detailed technical report summarizing the epidemiologic analysis submitted to CMA for review and commentary by participating member companies. SL 107233 3. A manuscript suitable for publication in the peer-reviewed scientific literature, submitted to CMA for review and commentary by participating member companies. Timing Investigators wishing to submit proposals should do so by June 15, 1994. CMA would like to receive proposals in two separate documents--one containing the technical proposal and one containing the cost and time-schedule proposals. This will allow us to evaluate the technical merits of the proposal independent of cost and timeschedule considerations. Please supply an original plus ten copies of the technical proposal, and an original plus two copies of the cost/time-schedule proposal. CMA proposes to evaluate all proposals received in late June 1994, and will select a contractor in July 1994. CMA proposes to award a fixed-price contract to the successful applicant. If your project team prefers a different form of contract, please indicate your preference in your cost proposal. Additional Information Please contact Dr. Has Shah at (202) 887-1192 if you have any questions about this request or about contract administrative details. Our lead scientist for this effort is Dr. Jonathan Ramlow of The Dow Chemical Company. You may contact him at (517) 636-1276 with questions about the scientific aspects of this Scope of Work. SL 107234 Status of ENSR Confidentiality Agreements with Individual States ENSR had to enter into agreements with different entities to obtain death certificates. In some states, there were no restrictions with whom who we could share, while with others there are variable restrictions. The following summarizes the options by the states that know: Group A: States will allow ENSR to give the death certificates to individual companies or CMA as long as we document what is being transmitted This group includes the following states: Alaska, California, Connecticut, Washington, D.C., Illinois, Iowa, Maryland, Massachusetts, Minnesota, Nevada, Ohio, and Washington. Group B: ENSR can provide state file numbers, dates of death, and names to companies or CMA. This group includes the following states: Colorado, Georgia, Idaho, Indiana, Kentucky, Louisiana, Maine, New Mexico, New York, Oregon, Rhode Island, South Carolina, West Virginia, Wisconsin, and Wyoming. Group C: These states require both ENSR and the companies or CMA to write and request the death certificates based on the studies. This involves completing application forms for each state (not all the same), entering the state file numbers, and communicating with each company or CMA. There is then the additional cost of the death certificates. This group includes the following locations: Alaska, Arizona, Arkansas, Delaware, Florida, Kansas, Michigan, Missouri, Mississippi, Montana, New Hampshire, New Jersey, New York City, North Carolina, North Dakota, Oklahoma, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Virginia, and Puerto Rico. We are still investigating the process for three states: Hawaii, Nebraska, and Vermont. They have not responded to multiple inquiries. SL 107235 4 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 3/15/94 SL 107236 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-industiy 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 107237 "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 3/15/94 SL 107238 t 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 noncancer 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. \ GGB 3/ISAM SL 107239 BENEFITS OF UPDATING INTER-INDUSTRY STUDY OF VINYL CHLORIDE WORKERS (cont.) Chlorine Issue - VCM/PVC 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. GQB 3/15/94 SL 107240 t BY J. MADELEINE NASH/CHICAGO TEALTHY AS A PIRATE SUPPINC FROM A COVE, the cancer cell severs the moorings that attach it to surrounding tissue. Slowly it extends Sone, two, three fingerlike probes and begins to creep. Then it detects the pulsating pres ence of a nearby capillary and darts between the cells that compose the blood-vessel wall. It dives into the red river that courses through lung and liver, breast and brain. An hour or so later, it surfaces on some tran quil shore, settles down and--at the expense of its hap less neighbors--begins to prosper. Gradually the cancer cell invades the turfoccupied by its normal counterparts, killing all those in its path. It triqjcs nSarhy cells into forming food-bearing blood ves sels, then compels them to chum out growth-spurring chemicals. To shield itself from patrolling immune cells, the cancer cell sprouts spiny armor like a sea urchin's. To expel the agents physicians send to kill it, the cancer cell deploys along its membrane a battery of tiny pumps. Is there a way to fight such a foe? Until now, medicine has tried to overwhelm the can cer cell with brute force, slicing it out with surgery, zap ping it with radiation or poisoning it with chemotherapy. All too often, however, a few cells manage to survive the onslaught and germinate, sometimes years later, into tu mors that are impervious to treatment. The ability of the cancer cell to outmaneuver its attackers has long been re flected in mortality statistics. Despite gains made against cancers such as childhood leukemia and Hodgkin's lymphoma, the overall death rate remains dismally high. This year more than half a million Americans will succumb to cancer, making it the nation's second SCIENCE ~vv. SL 107241 fi t SL 107242 leading killer after cardiovascular disease. Yet despite the continuing casualties, there is reason to believe the war against cancer has reached a turning point. During the past two decades, a series of stunning discoveries has pned open the black box that governs the behavior of the cancer cell and revealed its innermost secrets. Now the insights gleaned from basic research are being translated into novel approaches to cancer therapy. It still looks difficult to eradicate malignant cells, but scientists are exploring ways to tame them, to make them behave and thus greatly prolong the lives of people with the disease. The new therapies carry the promise of being not only more effective than the current slashand-bum strategy but also much gentler to the patients who must endure the treat ment. Exclaims Dr. Dennis Slamon, a ucla cancer specialist: "This is the most exciting time imaginable!" The excitement was running especial ly high last week, as encouraging news poured out of several labs all at once. From Thomas Jefferson University in Philadel phia came word that an experimental vac cine had given patients unusually long remissions from advanced melanoma, a deadly form of skin cancer. From Canada's McMaster University came a report identi fying a telltale enzyme found in cancer cells--but conspicuously absent from most normal cells If cancer researchers can find a was to deactivate this enzyme, known as telomerase. thev may at last have the mag ic bullet they have long been seeking. Equally tantalizing was the article pub lished in Science by molecular biologist Alexander Kamb and his colleagues at Myriad Genetics, a Salt Lake City, Utah, biotech firm. A majority of cancer cells, they found, lack functioning copies of a gene that serves as a circuit breaker and shuts down the abnormal cell growth that causes malignancy. Already Kamb is dreaming up ways to fix this seemingly simple glitch. "The route to therapy," he says, "seems surprisingly clear." GOOD GENES GONE BAD The conceptual revolution that is just now sweeping into the clinic began in the 1960s, when re searchers started to realize that cancer is a disease of dna, the master molecule that encodes the genetic script of life. One of dna's most important jobs is to govern cell division, the process by which a cell makes a copy of itself and splits in two. Ordinari ly, cell division is tightly regulated, but a cancer cell divides uncontrollably, pushing into surrounding tissue. A pivotal discovery came in 1976, when Drs. J. Michael Bishop and Harold Varmus at the University of California, San Francis co, made a startling observation. They saw that a viral gene known to cause cancer in chickens was practically a carbon copy of a normal gene found in animal and human cells. The virus had somehow stolen a per fectly good gene and put it to bad use. This finding helped lead to a general conclusion: cells become cancerous because their nor mal genetic machinery goes awry. The cul prits that initiate the damage can be virus es, radiation, environmental poisons, de fective genes inherited from parents--or a combination of all of the above. THE DEADLY TRANSFORMATION O Normal cell Benign Q tumor G tumor-suppressor ^ W 1 DNA contains oncogenes and tumor-suppressor genes. In a nojmal cell, these genes work together to control cell growth. 2 eitti rad, viro gro\ SL 107243 r'-.i! 1V+4 By last week researchers had found make are minor and quickly repaired by Johns Hopkins and Boston's Dana-Farber perhaps 100 cancer genes, at least three proteins that serve as miniature mechanics. Cancer Institute have identified four new dozen of them important in human tu Occasionally, though, cells with defects in genes associated with a form of early onset mors. Some, known as oncogenes, turn on their dna will continue to divide, eventual colon cancer known to afflict particular cel) division, whereas others, called tumor- ly forming small growths. The more cell- families. These genes are carried by as suppressor genes, are responsible for division cycles an organism undergoes, the many as 1 in every 200 Americans, making switching the process off. In their normal more likely it is to accumulate colonies of them the most common cause of cancer form, both lands of genes work as a team, abnormal cells, each the offspring of a sin susceptibility yet discovered. In their nor enabling the body to perform such vital gle progenitor. By the time humans reach mal form, these biological versions of com tasks as replacing dead cells or repairing middle adulthood, then, their bodies con puterized spelling checkers produce pro defective ones. But mutations in the chem tain millions of cells that have taken at least teins that scoot along strands of replicating ical makeup of these genes, whether inher one step toward cancer. dna, searching for tiny typos. When a pro ited or acquired later in life, can disrupt tein finds an error in one of the words these finely tuned checks and balances. A ven so, cancer is hardly in- spelled out by dna's four-letter chemical cell containing a faulty oncogene is often evitable. For example, 50% of alphabet, it flashes an alarm. A person likened to a car with a stuck accelerator, a Americans will develop at least bom with only one good copy of any of cell with a damaged tumor-suppressor gene to a car with no brakes. Scientists have thus stripped away can cer's mystery and revealed the malignant cell for what it is: not an intrinsically evil villain but an ordinary machine that has broken down in very specific, and poten tially reparable, ways. They have studied Eone precancerous polyp in their these genes is fine, until some cell in his or colon at some point, but only a her colon loses or mutates its backup copy. fraction of such polyps will devel Without a spelling checker, mutation piles op into aggressive tumors. Why? upon mutation, telescoping the time it Usually it takes so long for colon takes for cancer to develop. cancer to unfold that most people end up dying of other causes. Indeed, contraBrEyNtTo OUT OF SHAPE Cancer-causing mu popular perception, getting cancer is tnaotitoants can occur quite by accident. But the life history of a cancer cell and found er all easy. To begin with, a cell must acccuhmroun ic exposure to carcinogens--chemi rant genes at almost every step of the way, late mutations not in just one or two genes cals whose by-products bind to dna and from the initial formation of a tumor to the but in several. In the case of colon cancer, damage it--gready accelerate the rate at advanced stages of metastasis, the lethal Dr. Bert Vogelstein and his colleagues at which dividing cells make errors. Proven spread of the disease through the body. Baltimore's Johns Hopkins Oncology Cen carcinogens include asbestos, benzene and ter have shown that a cell must sustain some ingredients of cigarette smoke. Many FATAL FLAWS Cancer is not a modem dis damage to at least three tumor-suppressor carcinogens, it turns out, are not blunder- ease, Some of our apelike ancestors un genes and one oncogene. The first muta busses but leave highly individualized fin doubtedly suffered from it; so did the tion spurs the growth of the cell, triggering gerprints m the dna they touch. At the Na dinosaurs. In fact, says Robert Weinberg, a the formation of a benign polyp. Later tional Cancer Institute, Dr. Curtis Harris, a molecular biologist at the Massachusetts changes cause the polyp to expand and be molecular epidemiologist has been exam Institute of Technology, "it is a risk all mul come increasingly irregular in shape. By ining cells from liver- and lung-cancer pa ticellular organisms run." Each time a hu the time a cell in this growing mass suffers tients, searching for mutations in a tumor- man cell divides, it must replicate its dna, a final, fateful hit to its dna, many decades suppressor gene known as p53 (p stands for a biochemical manuscript some 3 billion may have gone by. the protein the gene makes and 53 for the characters long. In the course of transcrib Clearly, however, some people are at a protein's molecular weight). Smokers who ing such a lengthy document, even a skilled much higher risk of developing cancer develop lung cancer, Harris has found, typist could be expected to make mistakes, than others, and at an earlier age. For show tiny alterations in the p53 gene that a and cells, like typists, occasionally err. them, heredity plays a major role. Over the differ from those in nonsmokers. They also More often than not, the mistakes they past five months, competing teams at vary from the changes found in Chinese Malignant tumor . * \ a. Chemotherapy *V New blood vessels '>* >/ m a <* . - ' ' Resistant -' tumor Resistant cell 2 Defects in these genes, either inherited or caused by radiation, chemicals or viruses, eventually let the cell grow into a tumor. 3 More mutations may cause the ceils to become malignant 4 The malignant cells stop producing a chemical that prevents Mood vessels tmm forming. New capillaries then grow into the tumor, providing it with nutrients. This also creates a route for malignant ceils to break away from the main tumor mass and travel to other parts of the body, where they start new cancers. 5 Chemotherapy can kill the malignant 1 cads, but if there is even one cancer cell that is resistant to the treatment it will survive and grow into a new tumor. This new cancer will be impervious to the treatment SL 107244 TIME.APRI1.25 1994 *3 57 liver-cancer patients. In the latter group, ailatoxin, a fungal contaminant of food, is the carcinogen, and it alters dna in an ex quisitely precise way, substituting in a sin gle location a T (thymine) for a G (guanine) in dna's four-letter chemical alphabet. How can such a small mistake--the equivalent of changing the spelling of Smith to Smyth--have such an impact? Each three-letter "word" of a gene "sen tence" spells out the instructions for pro ducing 1 of 20 amino acids, compounds that in turn link to form proteins. A change in just one letter can result in the substitu tion of one amino acid for another. The new amino acid will be larger, smaller, staffer or more elastic than the correct one. In ways radical and subtle, it will affect the shape of the protein and its activity. For if a cell is like a fac tory, then a protein is a cog in a machine that may have as many as 50 components. "If one of them develops a kink in its structure," says Harris, "then the machine doesn't fit together as well." Kinks in proteins that form the nuclear matrix--a dynamic scaffold to which dna is at tached--may be particularly di abolical. The reason cancer cells typically have a swollen and misshapen nucleus, be lieves Johns Hopkins molecular biologist Donald Coffey, is that the proteins that form the nu clear matrix are misaligned in some fashion. Inside the matrix, notes Coffey, 50,000 to 100,000 loops of dna are coiled like a Slinky, but the length of the loops, and where they begin and end, varies from tissue to tissue. The genes closest to the matrix are those that a particular cell intends to have turned on. Genes meant to stay inactive are much far ther away. The conclusion is inescapable: a mutation in a gene that changes the archi tecture of the nuclear matrix could wreak havoc by turning the wrong genes on or off. YEARNINGS FOR IMMORTAUTY Normal cells do not live forever. Under certain cir cumstances, cells are actually programmed to die. One of the most fascinating features of early development, for example, is the explosive proliferation of certain types of cells, followed by mass suicide. Human embryos start with paddles for hands; it is cell death that gives them fingers. Neurons also expire by the billions as the brain re fines its circuitry during development. In adults, the cell-death program serves as a stem disciplinarian. Cells that become ir reparably damaged are expected to fall on their swords for the greater good of the or ganism. "For an animal to live," says Dr. Samuel Broder, director of the National Cancer Institute, "it must contain within its cells the knowledge that they have to die. But the cancer cell divides at all cost. It's forgotten how to die." The tumor-suppressor gene p53 is of ten described as "the guardian of the genome" because it keeps watch over dna during cell division. When damage occurs, p53 commands other genes to bring cell di vision to a halt. If repairs are made, then p53 allows the cell cycle to continue. But in some cases, if the damage is too serious to be patched, p53 activates other genes that cause thenell to self-destruct. Mutations in A i ' % U V; IMMORTALITY on chromosome tips act as molecular clocks. Calvin Harley has found how cancer cells stop the ticktock. p53, which have been detected in more than 50% of all human cancers, are thus ex tremely dangerous. In laboratory cultures, some cancer cells that possess mutant ver sions of p53 do not die when challenged by antitumor agents, while those that have normal p53 genes go belly-up. Healthy cells apparendy have a precise system for ensuring their mortality; short strips of dna known as telomeres seem to provide a molecular clock. When a cell is young, it has more than a thousand telo meres strung along the ends of chromo somes like beads in a necklace. Each time a cell divides, 10 to 20 telomeres are lost, and the necklace grows shorter. Eventual ly, after many cell divisions, the necklace becomes so short that the cell fails an in ternal health check designed to keep old. possibly damaged cells from reproducing. Result: cell division stops, the cell begins to age rapidly, and eventually it dies. Cancer cells, in contrast, have learned to stop the ticking of the telomere clock. According to research published last week in the Pro ceedings of the National Academy of Sci ences by Calvin Harley and colleagues at McMaster University in Hamilton, On tario, malignant cells foil the clock by pro ducing an enzyme--telomerase--that pro tects the length of the telomere chains. In essence, telomerase makes the cancer cell immortal. A CALL FOR BLOOD Perhaps the most crit ical stage in the life of a tumor comes after it expands to about a million cells. At this point, it is "much smaller than a BB," says Dr. Ju dah Folkman of Harvard Med ical School. This tiny massknown as a carcinoma in situ, literally cancer in place--is ma lignant, but not yet dangerous. Why? Because the cells at the center of the tumor are too far from the bloodstream to obtain essential nutrients, they are less vigorous. Like a society with zero population growth, a carci noma in situ adds about as many new cells as it loses old ones. Months, years, even dec ades may pass. Then an omi nous transition occurs. Some cells in the tumor begin secret ing chemicals that attract en dothelial cells--the key compo nents of blood vessels. These cells form capillaries that grow into the tumor. They also pump out molecular messengers called growth factors that stimulate the tumor to divide more quickly. What triggers blood-vessel formation, or angiogenesis, as the process is known? A major factor, scientists believe, is a sudden drop in the cancer cell's production of thrombospondin, a protein that inhibits the growth of new blood vessels. In the normal adult, angiogenesis is not only a rare event, but one cells strive to prevent, save for special circumstances like wound healing. For blood vessels invading joints can cause arthritis, and those invading the retina of the eye can cause blindness. Tb prevent such damage, cells keep blood ves sels at bay by pumping out throm bospondin. At a recent scientific confer ence, Noel Bouck, a molecular biologist from Northwestern University Medical School, stunned her colleagues by present ing preliminary data suggesting that thrombospondin production may be regu lated by that ubiquitous gene, p53. PULLING UP STAKES Angiogenesis is the harbinger of metastasis. The same vessels that feed the tumor also provide it with av- 58 SL 107245 HMF, \PRIi 25 malfunctions. When she introduced a nor mal nm23 gene (nm stands for non metastatic) into highly malignant human breast celk, then injected these cells into mice, their tendency to form metastases dropped as much as 90%. GUARDING THE MASTER SWITCH Until last week, p53, the subject of some 1,000 scien tific papers in 1993 alone, was considered the most important cancer gene. The jour nal Science even named it Molecule of the Year. But now there is a new contender for notoriety--mtsi, as Alexander Kamb and his colleagues refer to the multiple tumor- suppressor gene they have just discovered. "Multiple" refers to the fact that defects in this gene can cause many kinds of cancer, including melanoma, lung, breast and brain 1ACK SWEPSTON, 48. Pancreatic Cancer. On March 31 this Dallas dentist trav 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 tumors. In fact, functional copies of mtsi 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. The hope is that the immune system will learn to recognize this target and destroy the cells that make it "I haven't felt a signifi cant improvement yet," he says, "but the doctors are tremendously excited." signak, such as growth factors produced by white blood celk 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. But while 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 thk 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 celk thk crucial gene often signak. And the small protein produced by melanoma and breast-cancer cells, injected into mice, become lodged in capillary walk, then crawl out into the liver. Three days later, her camera resolves the spidery THE BIG KILLERS shapes of tiny metastatic growths. The les son, Chambers believes, is depressingly clear. Cancer cells zip in and out of blood 153,000 172,000 13% Curette smoking; orposura to asbestos, chemicals, radiation, 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 FsmataBraaat Prostate 56,000 149,000 58% 46,000 182,000 79% 38,000 200,000 77% ' ' , : . : i! . * 1: Am family history; no pregnancies, late menopause, early menarthe A;\- * i1v,:, 'is-C', ;ir: .v'j'y ):\\ ,n`/jvp cooperate as closely as musicians in an or chestra. Some of these genes code for chem tacnaa 25,900 27,000 3% Age smoking; fat intake ical solvents that enable the advancing cell to dissolve surrounding tissue. Others order Lymp.homa hoi! 22,750 No:. Huih'ki n s 52,900 78% 52% up the production of adhesion molecules that, like treads under a tank, move the cell Uafcamta 19,100 28,600 38% Genetic aOnormaiAes, exposure to ionizing radiation, chemicals; viruses forward. Why would genes do that? The an swer, notes Patricia Steeg of the National Cancer Institute, is that while the genes im portant to metastasis are abnormally turned on, they are not necessarily abnormal them Ovary KMaay Bladder 13,600 11,300 10,600 24,000 39% 27,600 55% Smoking 51,200 79% SlTi'JHi-t' selves. A cancer cell, in many ways, is not that different from an embryonic cell on its wa> to becoming a patch of skin or a bundle Wares Cwvkal Endometrial 10,500 46,000 67% 83% Intercourse at an early age; multiple sex partners; smoking Early menarthe; fate menopause; obesrty of nerves. Both embrvonic and cancer celk Oral 7,925 29,600 53% Smoking eicesMvtj u&e of alcohol divide and form ill-defined clumps. Both get $lda Melanoma up and move around. Both migrate and pop Sarat Attm Cm* Siitfy 6,900 32,000 84% Sunburn; fair complexion; exposure to coal tar, pitch, creosote, arsenic, radium SL 107246 fir) TIMF *PKIL2? 1W4 mts l appears to be among the most impor- T - m . # V tant inhibitors of cell division. Last year re- searchers at New York's Cold Spnng Har- ^ 's # I tfTheywill bor Laboratory discovered that a protein | they called pl6 stifled an enzyme that is a S j have surgical growth promoter. Last week it became | clear that pl6 and the mtsi protein are one ; | options not and the same. TARGETS FOR CANCER FIGHTERS Theo retically, any gene that goes awry in a can r ! available to ^ me. For that cer cell offers a way to attack the problem. But those that directly influence a cell's de cision to divide are spurring particular in reason I decid terest. The protein made by the mtsi gene seems exceptionally promising, for it has ed they would characteristics suggesting it may be easily fashioned into a drug, which then might be \\X> be tested. I'm able to stop tumor cells in their tracks. "In terms of therapeutic potential," declares a real advo- Kamb, "mtsi may be the most important tumor-suppressor gene yet discovered." ^ cate for early Still, as pharmaceutical companies well know, many surprises can pop up on ft detection.?? the way to developing a new drug, and oth er approaches to cancer therapy may win out in the end. Among the possibilities are "WlHffffmn anticancer vaccines designed to stimulate ANN FAGAN, 37, Cotoractal Cancar Ten years ago, when Ann Fagan, a paralegal the immune system to combat tumors. Currently being tested in the U.S. and Canada is a vaccine that spurs an assault on the weirdly configured carbohydrates that protrude from tumor cells like spikes on a from Conyngham, Pennsylvania, 'was found to have cancer, she underwent an ileostomy, a procedure that constructs an opening for die bowels through the abdominal wall Last year tests revealed that her daughters Katie (loll), 13, and Sarah, 11, had inherited a genetic defect that puts them at high risk for the same medieval ball and chain. At the meeting of the American Society for Cancer Research last week, Dr. David Berd of Thomas Jef ferson University presented the most en type of cancer. But this diagnosis has a silver lining, since the girls will be able to have surgery before rather than after cancer develops. Cancer susceptibilities that come from inherited mutations may account for 20% of all cases. couraging evidence to date that the vaccine strategy may work. Berd told of inoculating because the process is so rare in normal future already exists. "After all, we don't 47 melanoma patients with a vaccine made cells. Clinical trials have begun on several cure diseases like diabetes and hyperten of their own tumor cells inactivated by ra compounds that interfere with angiogene sion," says Dr. Lance Liotta, the National diation. Three years later, 60% remained sis. One such compound comes from a fun Cancer Institute's leading metastasis ex- tumor-free, compared with 20% in the un gus that was accidentally discovered in pert."We control them. Why can't we look vaccinated control group. The approach 1989 when it contaminated cultures of en at cancer that way?" works best, apparently, in patients who dothelial cells in Judah Folkman's Harvard By this reasoning, even metastatic have tumors small enough to be surgically laboratory, dramatically curtailing their cancer may eventually be brought to heel. removed but whose disease shows signs of growth. This drug, says Folkman, is aimed Squeezed into a tiny cubicle day after day spread. not at curing cancer but at prolonging the at the National Cancer Institute, Patricia The discovery announced last week period of time colonies of tumor cells Steeg stares at colonies of aggressive that cancer cells rely on the enzyme telo- missed by conventional therapy remain in breast-cancer cells that have shut down merase to stay alive opens up a different at place without spreading. "Suppose we pro the protective nm23 gene. Soon she will tack strategy. The leader of that research long this period of dormancy for 10 years, squirt over these colonies newly identi team, Calvin Harley, has taken a leave from and then another 10 years" muses Folk- fied antitumor compounds. Among them McMaster University to work at Geron man. "Why, now we're beginning to com she hopes to find one, maybe more, that Corp. in Menlo Park, California. The com pete with the normal life span." interferes with metastatic growth, A total pany is trying to craft a drug that will block Indeed, what seems most significant of 14 of these compounds are already sit the action of telomerase, "The cancer cell," about all the new therapies, what joins ting in a freezer in her lab--white crystals explains Harley, "is already very old. If we them together, is not their power, for this that cluster like snowflakes in the bottom can inhibit telomerase, we might cause the has yet to be proved. Rather, it is the seis of test tubes. If these fail to have an ef tumor to die after a few doublings." Even mic shift in strategy they collectively repre fect, Steeg has a list of more than 30 better, the fact that cancer cells produce sent. Increasingly, researchers speak not of others that might. Like many cancer re telomerase and that normal cells (save for slaughtering the cancer cell but of tricking searchers, she conveys, through her own sperm) don't, says Harley, "gives us hope it into dying naturally, perhaps of old age, personal enthusiasm, a sense that an im that we may be able to develop a drug with as other cells do. They also talk of reining in mense psychological barrier has been out senous side effects." the cancer cell, even rehabilitating it, a task breached. No, Steeg has not yet found a The formation of blood vessels in a tu that demands the development of less tox drug that cures cancer or even controls it. mor through angiogenesis is another ic drugs that can be tolerated over a life But, she exclaims, "I'm beginning to like promising target for an anticancer drug-- time, The model for cancer therapy of the the odds " TIME. \FHII.25 199-t 61 L ^x W C