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Microbiological Associates 5221 RIVER ROAD • BETHESDA, MARYLAND 20016 TELEPHONE: (301) 654-3400 January 27, 1982 Dr. Sheldon C. Sommers Scientific Director The Council for Tobacco Research-U.S.A., Ii0 East 59th Street New York, NY 10022 Dear Charlie, This is a synopsis of MA's "Mini-NCl" contract efforts. I. Numbers of contracts A total of I0 contracts and i grant were awarded to MA during the period from February 1970 to December 1981. The bulk of monies were spent during 1976-1981, and amounted to approximately $6 million. The scope of these contracts included: a. Genotoxic effects of cigarette smoke related materials in short term in vivo and in vitro assays. The endpoints monitored included bacterial mutagenesis, bacterial DNA repair, mammalian muta- genesis, mammalian DNA repair, mammalian transformation, and mammalian cytogenetics. b. Biochemical responses to cigarette smoke and cigarette smoke related materials and chemicals. c. Development and characterization of both the subcutaneous and intratracheal model systems for induction of both sarcomas and car- cinomas in the inbred strains of mice. d. Genetic control of carcinogen induced sarcomas and ~ulmonary carcinomas in the inbred strains of mice. e. Genetic regulation of certain factors thought to play a .role in susceptibility to chemical carcinogenesis. These include up- take and distribution of chemicals, me:abolism, DNA binding, DNA repair, virus expression, promotion, and immunocompetence. f. The role of one of these factors in determining cancer susceptibility in humans, (i.e., capacity for carcinogen m~tabolism). g. The use of the model systems for lung cancer to assess the potential carcinogenic effects of life-time daily exposure to whole smoke. h The development and characterization of cigarette smoke • and chemical aerosol generating equipment. Equipment was also developed to monitor, control, and document smoke and aerosol exposures•

Dr. Sheldon C. So~=e~s January 27, 1982 ~~ ~ Page 2 i. The development and characterization of an animal exposure system whereby "nose-only" exposure to the test aerosol was effected. The exposure system allows for the unique situation where the biological effects of different test aerosols can be compared under conditions where 90% of the particulate deposition is in the respiratory tract. 2. Personnel A total of 21 professionals have been directly associated with these CTR contracts. Because of the nature of the workscope,.the technical backgound of these professionals included virology, ~mmunology, cell biology, biochemistry, and chemistry. The principal investigators on these cohtracts were Drs. Richard E. Kourl, Carol J. Henry, Carrie E. Whltmlre, Aaron Freeman, and Jhong Rhim. Co-principal investigators at MA have included: Ken K. Kanagalingam, Ph.D. Kin-Kai Hwang, Ph.D. Marshall Dinowitz, Sc.D. Donald Putman, Ph.D. Ronald Lubet, Ph.D. Rodger D. Curren, Ph.D. William Hall, D.V.M., Ph.D. Leonard Billups, D.V.M. Leonard M. Schechtman, Ph.D. llarold E. Radtke, Ph.D. Kunjuraman Nayar, Ph.D. Bharat Bo6shan, Ph.D. Charles Demoise, Ph.D. Ronald Salerno, Ph.D. Bernard Sass, D.V.M. Richard Imblum, Ph.D. Support staff have included up to 25 technicians, laboratory aides, animal caretakers, washroom, and office personnel at any one time. The development and characterizations of the inhalation equipment required close collaboration with the staff of the Analytical Chemistry Division, Oak Ridge National Laboratory (O~), Oak Ridge, Tennessee, and Process and Instruments Corporation (P&I), Brooklyn, New york and included: Oak Ridbe P&I # Michael Guerin, Ph.D. Joseph Greenspan, Ph.D. Tom Gayle, B.S. Leroy Florant, B.S. James Stokely, Ph.D. Robert Holmberg, Ph.D. John ~aton, Ph.D. * Jack Moneyhun, B.S. The scientific scope of the contracts resulted in technical 'collaboraticr with individuals from a total of 25 other research instutions, as listed below: L. Alfred, Ph.D. M. Arnot, Ph.D. "W. Benedict, M.D. T. Bremner, Ph.D. Charles Drew Medical Center, Los Angeles, California M.D. Anderson Hospital and Tumor Institute, Houston, Texas Children's Hospital, Los Angeles, California Howard University, Washington, D.C. o o

Dr. Sheldon C. Som~ers January 27, 1982~ Page 3 M.D. Burke, Ph.D. D. Busbee, Ph.D. E. Cantrell, Ph.D. A. Conney, Ph.D. W. Essman, M.D., Ph.D. H.-R. Glair, Ph.D. J. Gielen, Ph.D. H. Gurgis, Ph.D. H. Herscowitz, Ph.D. R.J. Huebner, M.D. D. Jerina, Ph.D. W. Levin, Ph.D. R. Lerner, M.D. J. Levy, M.D. R. Levy. M.D. H. Lynch, M.D. D. Mattison, M.D. University of Aberdeen, Aberdeen, Scotland North Texas State University, Denton, Texas North Texas State University, Denton, Texas Hoffman-La Roche, Inc., Nutley, New Jersey Queens College, New York, New York University of }~inz, Malnz, West Germany University of Leige, Leige, Belgium University of California, Irvine, Irvine, California Georgetown University, Washington, D.C. National Cancer Institute, National Institutes of Health, Bethesda, Maryland National Institutes of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland Hoffman-La Roche, Inc., Nutley, New Jersey Scripps Clinic and Research Foundation, La Jolla, California University of California, San Francisco, San Francisco, California Scripps C~inic and Research Foundation, La Jolla, California Creighton University, Omaha, Nebraska National Institute of Child Health and Human Development, National l:~stitutes of Health, Bethesda, Maryland

Dr. Sheldon C. So~/mers January 27, 1982~ Page 4 R. Mayar, Ph.D. T. McLemore, M.D., Ph.D. D. Nebert, M.D, F. Oesch, Ph.D. R.A. Prough, Ph.D. R. Rasmussen, Ph.D. P. Thomas, Ph.D. I. Wang, Ph.D. A. Wood, Ph.D. N. Wray, M.D. Texas A&M University, College Station, Texas University of Texas Medical Center - San Antonio, San Antonio, Texas National Institute of Child Health and Human Development, National Institutes of Health, Bethe~da, Maryland University of Mainz, Malnz, West Germany University of Texas Health Sciences Center, Dallas, Texas University of California, Irvin Irvine, California Hoffman-La Roche, Inc., Nutley, New Jersey University of South Carolina Medical School, Charleston, South Carolina Hoffman-La Roche, Inc., Nutley, New Jersey VA Hospital, Houston, Houston, Texas 3. Facilities Between 8,000-10,000 square feet of dedicated space at }~ was renovated to CTR specifications to include smoke generation rooms, animal exposure rooms, animal rooms, and laboratories for biochemistry, chemistry, tissue culture, virology, and immunology. An animal colony was maintained for an average of &,000 animals/year, with a cap@city for 8,000-10,000 animals at any one time. 4. Equipment One of the major directions of these contracts was the develop- ment, characterization, and documentation for smoke generation and animal exposure equipment. This resulted in the final design and construction of a) two State-of-the-Art Smoke Exposure Machines (SEM) series II, SEM IIB and C, b) a SEM II sham exposure machine, c) a modified Walton smoke exposure machine, d) smoke or aerosol monitoring, control and documentation system, e) animal expose, re units permitting "nose-only" ~ exposure of up to 480 animals at one time to the same aerosol, f) animal~'~ containment trays permitting rapid loading and unloading of animals for ~ "nose-only" aerosol exposure, a~d g) flow sensors to monitor and control ~ rates of aerosol flow. ~ ~o~

Dr. Sheldon C. Som~ers January 27, 1982 ~ ~ Page 5 5. Publications and Presentations Staff associated with these projects have been invited participants to approxiamtely i0 international symposia and have presented approximately 60 lectures at a variety of academic and scientific forums. Approximately 50 peer-reviewed publications have been generated with an additional 15 in various stages of completion. We hope this brief (!) summary is helpfBl. Please call if we can be of further assistance. Sincerely, Richard E. Kouri, Ph.D. Scientific Director Carol J. Henry, Ph.D. Assistant Director of Research REK;CJH/ph