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PRIVILEGED & CONFIDENTIAL REI~RT The R.J. Reynold's Tobacco Company's Biology Research Division A Program Review 1965-1970 Prepared lot R. F. McDermott, Esq. J. C McElvaln, Esq. C Bordenave, ~sq. Jon.es, Day, .Reavi_s & Pogue _ Metropolitan Square 655 Fifteenth Street, N.W. Washington, D.C. 20005-5701 by Paul E. Brubaker, Ph.D. Principal P. F, Brubaker Associates, Inc. 3 Halstead Road Mendham, N.J_. 07945 201-543-5108 December 15th, 1985

R. F. McDermott, Esq. RJR-BRD Report PRIVILEGED & CONFIDENTIAL 15 December 1985 Sum mary Statements and Conclusion~. This report, presents our analysis of the goals and objectives of the Biological Research Division (BRD) as well as the type of research it performed with special emphasis given to that research which either directly or indirectly was related to Smoking and Health issues and with a view towards providing insight into the establishment of this Division in 1965 and its subsequent closing in 1970.We conclude that the weight of the scientific information contained within the BRD archives will not pose problems in devising defensive legal strategies againsl claims of harm due to defective product design. Specific conclusions from the various research areas are as follows: I. From the Smoke Irritancy research projects. Biological tissues does not recognize tar from various of R JR and Competitor's brands of cigarettes as anything more than a non-specific irritant. Tar from various brands of of R JR and Competitor's cigarettes induces a biological response that is distinctly different from known reactions caused by mineral dusts and,fibers like silica and certain forms of asbestos. Since there was no difference in the irritation response or tars from various brands of cigarettes containing high, medium and low levels of Nicotine, Nicotine is in the gas phase of whole cigarette smoke. Other irritant studies with the gas phase in this series would conclude the same. Menthol and Clyclamin Aldehyde sigt~I'ic~mtly reduce the irritation properties of tar from various brands of R JR and Competitor's brands of cigarettes. Inc.

R. F. McDer mutt, Esq. RJR-BRD Report PRIVILEGED & CONFIDENTIAL 15 December 1985 2. From the Tryptophan Research projects. High levels of Tryptophan, an essential amino acid required for good nutrition, in the diet can increase the level of carcinogenic derivatives of this substance in smokers and during periods when they are not smoking, There is no evidence in the reports that smoking and consumption of high levels of Tryptophan causes cancer in the bladder as had been suggested by Canadian esearch physician in 1964. Diet can affect the metabolism of smokers in a highly variable fashion. The biochemical hypothesis that smoking affected the the metabolism of Tryptophan could not be verified by the BRD research team. 3. From the Polonium research area. Environmental pollution may render tobacco, and other crops for that matter, unfit for use by contamination with radioactive materials that belong to the Radon family of radioactive substances, Polonium-210 and Lead-210. Polonium-2 I0 and Lead-210 are occupational and environmental contaminates that have been known to cause cancer in the same areas of the lungs that have been associated with cigarette smoking for at least 200 years, long before cigarettes went on the market. Efforts to remove Polonium-210 and lead-210 from tobacco below background levels were not successful. Blending, curing and storage bring levels down to where no adverse effects are thought occur. ii, BrulmkeP Associotes. Inc.

R. F. McDermott, Esq. RJR-BRD Report PRIVILEGED & CONFIDENTIAL 15 December 1985 3.0 From Dr. Johnson's Chronic Smoking Series. This work used worst-case levels of cigarette smoke exposure as is evidenced from the smoking machine studies where a I to I 0 dilution of smoke from RJR brands delivered 10 times as much tar as a human smoking one cigarette. Alternative means of exposure that involved inserting tubes in the throat or nasal passages and delivery smoke directly into the lungs by-passing key nerve endings that regulate breathing rate and affects how much tar would be delivered to the lungs is also a worst-case exposure method that nullifies extrapolating meaningful results to the human smoker. The human counter-part would be a smoker with a tracheotomy smoking through the surgical opening in his throat. Exposure to whole cigarette smoke under these worst case exposure conditions appeared to cause a tranquilizing affect thought by Dr. Johnson to result from stimulation of the vagus nerve. This nerve acts to sedate the body by reducing heart rate and stimulating digestive tract and salivary glands. This explains why the rabbits in these studies and Dr. Colucci's work did not lose weight and why some of the animals died of heart attacks. At times Dr. Johnson observed a 65% reduction in heart rate of some of his animals. Hyperplasia or increased size and number of cells in the respiratory airways observed in these animals is consistent with a non-specific irritant effect and not necessarily a signal of tu mot for marion. In fact, no cancer or cancer-type growth was reported in any of the animals that were exposed to worst-ease smoking conditions for more than half their lifetime. III, ) Brubakor Associatos. Inc.

R. F. McDer mutt, Esq. RJR-BRD Report PR I V I LEGED & CONF| DENT l AL 15 December 1985 Dr. Johnson felt that under these worst case exposure conditions it would take smoking 4 to 6 WINSTON 85 mm filter kings for 6 to 7 months to produce emphysema-like changes in the lungs of rabbits. However, no studies were ever performed using a positive control where actual emphysema is produced so that comparisons could be made to verify that his observation were right. Therefore, it is uncertain as to whether or not emphysema had been induced. The same conclusion applies to Dr. Colucci and Dr.Simmons work. 4.0 From the Colucci Chronic Smoking Studies. Working just over 90 day exposure periods, half the exposure period Dr. Johnson thought needed to produce lung damage, Dr. Colucci demonstrated significant changes in the capacity of the lungs of rabbits to manufacture fat; fat the lungs need to maintain a normal healthy function. Although he, and later Dr. Simmons speculates that these changes could have grave metabolic consequences, no pathology of the lungs of these animals was ever confirmed. These changes could only be linked to emphysema on purely a theoretical basis and were never confirmed in fact by further studies. Therefore, this work is a best preliminary in nature. Smoking reduced the capacity of the lungs of some of Dr. Colucci's rabbits to make fat from Palmitic Acid, a smoke constituent like the vitamin Nicotinic Acid that has nutritional value. One use of Palmitic Acid is to make the kinds a fat that go into making membranes; i.e. the phospholipids. One way to think of cancer is uncontrolled cell growth. Cancer would require phospholipds to make new cell membranes. Since smoking caused a reduction in phospholipids in the lung, therefore, it theoretically also reduced the capacity of these organs in these animals to develop cancer. iV. Brubaker Associates. Inc.

R. F. McDer mort, Esq. RJR-BRD Report PRI V ILEGED & CONFID]~NTI AL 15 December 1985 5.0. From the Dr. Simmons Work on Surfactant. Damage to the film that lines the deep interior surfaces of lung, a.k.a, surfactant, was thought to arise from direct action of inhaled gases and irritants on the film itself, from interference with the synthesis of the film by cells in the wails of the lungs, or by interference with those factors that are involved with its removal, factors needed to make sure just the right amount is maintained for normal healthy conditions. These changes were thought to be involved in giving rise to emphysema. Dr. Simmons did not demonstrate that worse case chronic smoking caused such effects. 6.0. On the Closing of BRD Operations. We are also not convinced after all of the research we reviewed in the Smoking and Health area that BRD was closed because of unfavorable results from their smoking and health research activities. Simply stated, the Smoking and Health research program had not fully matured and was only in its infancy when the doors closed. We found no evidence in the reports that we reviewed, including those of BRD's scientific directors and managers, that results of the. smoking and health was causing problems. On the contrary, our impressions of the Smoking and Health research program was one of an optimistic tone stimulated by the prospect of finally placing the biology of smoking on sound scientific grounds. Our review of the work they performed in this area, we feel, justifies their optimism and even offers new and exciting evidence suggesting that smoking may not be a primary carcinogen. We refer to the smoke irritancy research effort. V. Br-ubak:or ~a~a~ocia~.o~. Ir~o.

R. F. McDermott, Esq. R JR-BRD Report PRIVIL~ED & CONFIDENTIAL 15 D~cember 1985 Based on our analysis, we have found that the BRD was first and foremost a research and development operation. The research it performed was primarily concerned with screening chemicals isolated from tobacco for commercial applications in the speciality chemical markets or the pharmaceutical industry. Its' other focal points were fermentation research and providing quality control testing services for various RJR internal operating units as well as R JR affiliated companies. These support services range from water quality testing to tobacco beetle control, a program that continued through the entire BRD operational period. Although Smoking and Health research activities was a major reason why this unit was created, it never appears to have gone beyond 30% of BRD's research activities. Until 1966, the Smoking and Health research within this Division was largely a reactionary one. The attempts to confirm the biochemical hypothesis that smoking could cause bladder cancer by changing the way the body handles one of its essential nutrients is an example of this type of research. Recognizing the need to place the biology of smoking on firm scientific ground they set out to study the effects of chronic smoking on the lungs in various experimental animals. This was a carefully planned and well orchestrated research effort, exemplified by the work of Dr. Colucci beginning in 1967. In so far as causation is concerned, BRD did not plan or carry out any research designed to determine if smoking would cause cancer in the lungs or any other organ for that matter. We feel confident in making the same statement about chronic, pulmonary diseases like emphysema. In fact, as we mentioned, we have uncovered evidence, crude though it may be, which we feel draws a biological distinction between the mechanisms of tobacco tar and mineral dusts like silica and asbestos act in the body. Specifically, cigarette smoke tar appears to induce a non-specific irritant type of reaction in tissues much in the same way as other known chemical irritants behave. Excessive and. prolonged smoking or continued exposure to poor air quality either in the workplace or outdoors will cause non-specific irritation of lungs. vi. Bs-ul~ak er Annociates, Inc.

R. F. McDermott, Esq. RJR-.BRD Report P RI V I LEGED & CON FI DENT I AL 15 December 1985 Based on the biology we have reviewed, the body does not appear to recognize cigarette tar condensate as a foreign body to be attack with a full scale inflammatory reaction involving immune neutralization and rejection. Mineral dusts apparently due. Tt~erefore, we suggest that breathing mineral dusts predisposes the lungs to more harmful effects than normally would occur from breathing non-specific irritants like tobacco smoke. In other words, the cart is before the horse, should this evidence prove to be valid with further research. It suggests that on the issues of synergy and causation, separating asbestos effects from those of smoking can be done on a scientifically valid basis since they appear to interact with tissues by lwo entirely distinct mechanisms. The BRD approach to Smoking and Health emphasized at the outset was to select methods that would simulate the exposure conditions of the human smoker. The Physiology Section began by developing a smoking machine in 1967. After several pilot studies were tried and the smoking machine failed, alternative methods of exposure were used. These methods involved inserting a thin plastic tube in the throat of rats and inserting a tube in the nose of rabbits and delivering measured amounts of smoke directly into the animals lungs. While it has some distinct advantages in that you could be sure the smoke went into the lungs. It had some disadvantages as well since it by-passed the nose and sinus areas of the upper respiratory tract; areas equipped with nerves that govern breathing rate and therefore particle deposition. It also tends to compromise the use of information developed from such procedures. Nevertheless, the procedures and operations of BRD were similar to those used in o~.her laboratories at that time and are far better than painting smoke condensate on the skin of mice and inferring what might happen in the lungs. Other summary statements and comments can be found in various sections of the text. vii. B~ubaker A~oc|ate~. Inc.

R. F. McDermott, Esq. RJR-BRD Report PRIVILEGED & CONFIDENTIAL 15 December 1985 Contents. 1.0. Purpose of Report ............................................................................................... 2.0. Scope .................................................................................................... .................... 3.0. Bladder Cancer ................................................................................................. 3. I. Introduction ............................................................................................ 3.2. Origins of the Tryptophan Studies ................................................ 3.3. The Tryptohan Tresearch ................................................................. 3.4. ResuIIs .................................................................................................... ... 3.5. Summary Statements ......................................................................... 4.0. Polonium in Tobacco ...................................................................................... 4. I. Introduction (Radon) .......................................................................... 4.2. Exposure & Effects ............................................................................... 4.3. Research Program ................................................................................ 4.4. Sum mary Statements ......................................................................... 5.0. Smoke Mildness Studies and Cancer ...................................................... 5.1. Introduction ............................................................................................ 5.2. Method Development & Performance .......................................... 5.3. Summary Statements .......................................................................... 6,0, 7,0, Introduction .................................................................................................... ...... 1.0 3.0 3.0 8.0 9.0 I 1.0 13.0 14.0 20.0 22.0 22.0 26.0 29.0 30.0 32.0 32.0 35.0 43.0 5.4. Commentary ............................................................................................ 48.0 The chronic Smoking Series ........................................................................ 53.0 6. I. Orienlation ................................................................................................ 54.0 6.2. Ciliastasis and the Chronic Smoking Studies .............................. 60.0 ~).3. Ciliastasis Projects and Interpretation ......................................... 63.0 .4. Summary Statements and Comments ............................................ 67.0 The E~arlySmoking Studies .......................................................................... 73.0 7.1. The Smoking Machine ......................................................................... 73.0 7.2. Smoking Machine Studies and Comments .................................. 74.0 7.3. _The Thiocyanate Studies .................................................................... 78.0 7.4. The Colucci Studies of the Biochemistry Section ..................... 79.0 7.5. Overview of the Colucci Studies ..................................................... 79.0 7.6. Colucci Design Features and Background .................................... 86.0 The Colucci Fate Studies ................................................................................ 107.0 8.1. Palmitic Acid and Lipogenesis ........................................................ 109.0 The Chronic Smoking Studies ..................................................................... 111.0 9. I. Orientation ................................................................................................ 112.0 9.2. Palmitic Acid Distribution Studies .................................................. I 13.0 9.3. Chronic Lipogenesis Studies and Analysis .................................. 118.0 9.4. Surfactant Studies and Analysis ...................................................... 124.0 9.5. Summary Statements and Comments ............................................. 130.0 ao B~ubskor ksmocimtot, imc.

R. F. McDermott, Esq. RJR-BRD Report PRIVILEGED,& CONFIDENTIAL 15 December 1985 I 0.0. Operations ............................................. ............................................................ 133.0 10. I. Orientation .............................................................................................. 134.0 10.2. Historical Perspectives ...................................................................... 139.0 10.2.1. Summary Statements ........................................................ 140.0 10.3. Early Research Objectives ................................................................. ! 41.0 10.4. Smoking and Health Studies ........................................................... 142.0 10.6 Reasons for BRD's Proposed Expansion ....................................... 142.0 10.7. Why BRD was Created ....................................................................... 143.0 10.8. BRD Staffing Plans ................................................................................ 145.0 10.9. Why BRD was Closed ............................................................................ 140.0 Appendices 1.0. projecl Re_quest ........................................................................................... 2.0. Index to Tryptophan Studies ............................................................... 5.0 3.0. Index to Chronic Smoking Studies ..................................................... to.0 4.0. Index to Colucci & Bumgarner Chronic Lipid Studies ................ 5.0. Index to Colucci & Simmons Chronic Lipid Studies .................... 22.0 6.0. Histroical RJR R&D Program .................................................................. 31.0 7.0. BRD Personnel Profile .............................................................................. 32.0 8.0. BRD Research Objectives ........................................................................ 9.0. Personnel Expansion Profile .................................................................. 36.0 bo Brubsker Asse©iste=. I=¢.