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1. USE ECRM ELEMENT IN 10 PITCH 2. REGULAR MARGINS MAY 8E USED; HOWEVER, TYPING MUST NOT EXTEND BEYOND RED LINES. AST AB-Conlan M.A.R. September 3, 1980 CONFIDENTIAL "Facts" and Citations from "Lung Disease and Smoking," an Industry Position Paper on Chronic Obstructive Pulmonary Disease I. The cause or causes of Chronic Obstructive Pulmonary Disease (COPD) are unknown. (a) Submission of the National Heart and Lung Institute, Hearings of the House Subcommittee on Appropriations--Departments of Labor and Health, Educa- tion, and Welfare~ 93rd Congress, Ist Session', Appropriations for 1974, pp. 291-296 (March 28, 1973). (b) Statement of R. Ringlet, Hearings of the House Subcommittee on Appropriations--Departments of Labor and Health, Education, and Welfare, 94th Congress, Ist Session, Appropriations for 1976, pp. 210-334 (?) (April 10, 1975). (c) S. Robbins and R. Cotran, "Pathologic Basis for Disease," 2d ed. (1979). 2. The origin and pathogenis of COPD are unknown. (a) Statement of J. Ross, Hearings of the Senate Subcommittee on Appropriatlons--Departments of Labor and Health, Education, and Welfare, 95th Congress, Ist Session, Appropriations for 1978, pp. 3374-3382 (April 5, 1977). (b) B. Burrows and M. Lebowitz, "Characteristics of Chronic Bronchitis in a Warm, Dry Region," 112(3) Am. Rev. Respir. Dis. 365-370 (1975). (c) C. Butter, "Capillary Bed in Nonemphysematous Portions of Lungs with Emphysema," 38(3) Lab. Invest. 336 (1978).

1. USE ECRM ELEMENT IN 10 PITCH 2. REGULAR MARGINS MAY BE USED; HOWEVER, TYPING MUST NOT EXTEND BEYOND RED LINES. (d) K. Kilburn, "New Cues [sic] for Emphysemas," 58(5) Am. J. Med. 591-600 (May 1975). 3. Chronic bronchitis and emphysema are virtually in- distinguishable. (Pathologically?, Clinically?, under the current state of medical knowledge?) (a~ United States Department of Health, Educa- tion, and Welfare, Public Health Service, "The Health Consequences of Smoking, A Public Health Service Review: 1967," PHS Pub. No. 1969 (1967) (Revised January 1968). 4. There is no set definition of COPD. (a} C. Fletcher, "Terminology in Chronic Obstructive Lung Diseases," 32 J. Epidemiol Comm. Health 282-288 (1978). The prevalence of emphysema cannot be measured until a definition and methods of measurement can be de- termined. (a) C. Stuart-Harris, "Measurement of the Prevalence of Ephysema [sic]," National Institute of Health, PHS Pub. No. 1699, p. 19 (1968). The incidence of COPD shows a strong family tendency. (a) F. Kueppers, et al., "Familial Prevalence of Chronic Obstructive Pulmonary Disease in a Matched Pair Study," 63(3) Am. J. Med. 336-342 (September 2977). The family doctor inthe incidence of COPD is not yet defined, and the agents for it are unstudied. (a) I. Tager, et al., "Studies of the Familial Aggregation of Chronic Bronchitis and Obstructive Air- ways Disease," 7(I) Int. J. Epidemiol, 55-62 (March 1978).

1. USE ECRM ELEMENT IN 10 PI'[CH 2. REGULAR MARGINS MAY BE USED; HOWEVER, TYPING MUST NOT EXTEND BEYOND RED LINES. COPD is a "constitution based" disease. The link be- tween COPD and lung cancer is independent of smoking. (a) N. Orie, et al., "A Common Familial Com- ponent in Lung Cancer and Chronic Obstructive Pulmonary Disease," II Lancet 523-26 (September 10, 1977). Increased rates of lung dysfunction exist among first degree relatives of COPD and lung cancer patients. (a) B. Cohen, et al., "A Common Familial Com- ponent in Lung Cancer and Chronic Obstructive Pulmonary Disease," II Lancet 523-526 (September 10, 1977). 10. The causes of emphysema are not known. (a) National Institute of Health, "United States Department of Health, Educations, and Welfare, National Institute of Allergy and Infectious Diseases, A Special Report on Emphysema," P.H.S. Pub. No. 1699, p. 19 (1968) Compare n.5(a} supra. (b) National Institute of Health, "Chronic Destructive Lung Diseases: Emphysema & Chronic Bronchitis," DHEW Pub. No. (WIH) 74-614 (1974). 11. Several etiologic and pathogenic factors are involved in the development of emphysema. (a) S. Robbins and R. Cotran, "Pathologic Basis of Disease," 2d ed. {1979). 12. Emphysema is more common in persons who are alpha-l- antitrypsin deficient, a genetic deficiency. (a) C.B. Laurell and S. Erickson, "The Electro- phoretic Alphal - globulin pattern of Serum in AiphaI - antitrypsin Deficiency," 15 Scand. J. Clin. Lab. Invest. 132-140 (1963). 3

1. USE ECRM ELEMENT IN 10 PITCH 2. REGULAR MARGINS MAY BE USED: HOWEVER, TY'PING MUST NOT EXTEND BEYOND RED LINES. (b) I. Reintoft, "Alpha ~-Antitrypsin Deficiency: Experience from an Autopsy Material," 85(5) Acta Pathol Microbiol. Scand. 649-655 (1977). 13. Aipha l-antitrypsin deficient persons develop emphysema 14. 15. 16. 17. earlier in life than persons without this deficiency. (a) C. Larsson, H. Dirksen, G. Sundstrom and S. Eriksson, "Lung Function Studies in Assymptomatic In- dividuals with Moderately (PI SZ) and Severely (PI Z) Reduced Levels of Alpha l-Antitrypsin," 57(6) Scand. Respir. Dis. 267-80 (19V6). (b) R.S. Rankin, "Extensive Bullous Emphysema a Young Woman," JAMA 236 (18:2107-08 1976). Alpha l-antitrypsin deficient persons develop emphysema. at rates irrespective of the amount they smoke. (a) R.S. Rankin, supra, n. 13(b) Alpha 1-antitrypsln deficient persons develop emphysema irrespective of whether they smoke. (a) P. Dunand, G.J.A. Cropp and E. Middleton, "Severe Obstructive Lung Disease in a 14 year old Girl with Alpha-2-Antitrypsin Deficiency," 57(6) J. Allergy Clin. Immunal. 615-622 (1976). The protease-antiprotease theory of causation, of emphysema received wide publicity. (a) "The Pathogenisis [sic] of Pulmonary Emphysema" I The Lancet 8171 (April 5, 1980). (b) M. Clark and M. Gosnell, "Clues to the of Emphysema," Newsweek (April 14, 1980). Cause Ozone and other substances may inactivate lung anti- proteases enabling proteases to destroy lung tissue. 4

1. USE ECRM ELEMENT IN 10 PITCH 2. REGULAR MARGINS MAY BE USED; HOWEVER. TYPING MUST NOT EXTEND BEYOND RED LINES. (a) J.E. Gadek, G.A. Fells and R.G. Crystal, "Cigarette Smoking Induces Functional Anti~protease Deficiency in the Lower Respiratory Tract of Humans," 206 Science 1315-16 (December 1979). (b) A Janoff, H. Carp, D.K. Lee and R.T. Drew, "Cigarette Smoke Inhalation Decreases A I Antitrypsin Ac£ivity in Rat Lung," 206 Science 1313-14 (December 1979). 18. Most smokers suffer no substantial obstructive damage 19. 20. to their lungs. (a) C. Fletcher, et al., "The Natural History of Chronic Bronchitis and Emphysema: An Eight-Year Study of Early Chronic Obstructive Lung Disease in Working Men in London," (1976). The protease-antl-protease theory does not explain why more whites have emphysema than blacks. (a) R. E. Murphy, et al., "Is Emphysema a Disease Predominantly of the White Male? Preliminary Report," 181 (8) JAMA 726-27 (1962). The protease-anti-protease theory autopsies show the population, infants. cannot explain why emphysematlc lesions in all segments of including children and even premature (a) A. Hislop and L. Reid, "New Pathological Findings in Emphysema of Childhood: I. Polyalvealar Lobe with Emphysema," 25 Thoraz 682 (1970). (b) A. Hislop and L. Reid, "New Pathological Findings in Emphysema of Childhood: 2. Overinflation of Normal Lobe," 26(2) Thorax 190-94 (1971). (c) D. S. Holsclaw, "Pediatric Pulmonary Disease: An Overview," 6(7) Pediatr. Ann. 10-11, 14-17 (1977). 5

1. USE ECRM ELEMENT IN 10 PITCH 2. REGULAR MARGINS MAY BE USED; HOWEVER, TYPING MUST NOT EXTEND BEYOND RED LINES. 21. 22. (d) H. H. Kilburn, et al., "Genetic and Bio- chemical Clues for Emphysema: Complications for Early Diagnosis," 10(0) Prog. Resp. Res. 31-48 (1976). (e) J. Kleinerman and D. B. Rice, "A Postmortem Epidemiologic Study of Emphysema and Bronchitis in Young Males," 663 Am. J. Paetr. 55A-56A (1972). (f) K. K. Pump, "Fenestrae in the Alveolar Mem- brane of the Human Lung," 65 Chest 444 (April 1974). (g) J. L. Watts, et al. "Chronic Pulmonary Dis- ease in Neonates After Artificial Ventrilation: Distri- bution of Ventrilation and Pulmonary Interstitial Em- physema," 60(3) Pediatriacs (September 1977). Some smokers develop early lung changes. These changes have been studied, but their meaning remains unknown. (a) A. F. Gelb and E. Klein, "Clinical Signi- ficance of Pulmonary Function Tests: The volume of Isoflow and Increase in Maximal Flow at 50 Percent Force4 Vital Capacity During Helium - Oxygen Breathing as Tests of Small Airway Dysfunction," 71(3) Chest 396-99 (1977). (b) D. A. Soloman, "Are Clinical Significance of Pulmonary Function Tests Helpful in the Detection of Early Airflow Obstruction?" 74(5) Chest 567-69 (1978). (c) E. McFaden and R. Ingram, "Peripheral Airway Obstruction," 235(3) JAMA 259-60 (January 19, 1976). "Although these abnormalities [See n. 21.] can be found in some smokers, it is not at all clear whether chronic obstructive lung disease will eventually develop in these people. Long-term follow-up studies will be necessary to establish this point. (a) E. McFaden, supra n.21c.

2 R[GULAR ~,IARGINSMAY BE USED, itQV, EVER,IYPING MUST NQq E;,I-rENDBEYOND RED LINES. 23. Some reports say that lung function decreases faster 24. 25. in smokers. (a) L. Iirnell and J. Diviloog, "Bronchial Asthma and Chronic Bronchitis in a Swedish Urban and Rural Population with Special Reference to Prevelance, Respiratory Function and Sociomedical Condition," Scand. J. of Resp. Dis. Supplementum No. 66 (1968). (b) G. K. Slueis-Cremer and H. S. Sichel, "Ventilatory Function in Males in a Witwatersrand Town. Comparison between Smokers and Non-Smokers." 98(2) American Review of Resp. Diseases 229-39 (August 1968). (c) United States Department of Health, Education and Welfare, Public Health Service, "The Health Conse- quences of Smoking, 1969 Supglement to the 1967 Public Health Service Review," (1969). (d) J. Shelhamer, H. Menkes, B. Cohen, M. Meyers, S. Permutt, E. Diamond and M. Tockman, "Smoking and Decline in Pulmonary Function-Male-Female Differences," 121(4) Am. Rev. Respir. Dis. (Ann. Meeting Suppl.) (April 1980), part 2). Scientists do not know whether the subtle changes in lung function reported in some smokers are related to lung disease. (a) J. A. Dosman, et al., "Sensitivity of Vari- ables Derived from Single Breath Nitrogen Test in Smokers," 77:2 Chest (February 1980, Supplement). (b) R. J. Knudsen, D. B. Armet and M.D. Lebowitz~ "Reevaluation of Tests of Small Airways Function" 77:2 Chest (February 1980, Supplement). Other factors such as hormones and genes may have more to do with lung function changes than smoking. (a) C. E. Rossiter and H. Weil, "Ethnic Differenc~ in Lung Function: Evidence ofr Proportional Differences, 3(I) Int. J. of Epid. (1974). s

Differences in (b) C. C. Seltzer, et. al., " Pulmonary Function Related to Smoking Habits and Race," 110(5) Amer. Rev. Resp. Dis. 598-608 (1974). (c) J. Shelhamer, supra n. 23d. 26. Much research is necessary. (a) "Smoking and Health, General," (1979). a Report of the Surgeon • ET 8