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S POOKU1.1 CANO-HEALTI°I I ] 1 I A RESEARCH PROGRAM TO DECREASE THE RISK OF CANCER AND OTHER DISEASES IN THE TOBACCO SMOKER - ~ -~

tS SMOK.ING AND ~- .- `I A PESEARCH PRGGWM TO DECREASE 'iTE RISK OF CANCER AND OTrfER DISEASES IN THE i0BA0CO 5740KEER . For Consideration-By The - Ad Hoc- Cci.*mittee on Sr.wking and Health of the National Cancer Advisory Board s!AR(1H 1973 - a Prepared wit i the assistance of advisory groups by the Office of the Associate Scientific Director for Program, Division of Cancer Cause and Prevention, National Cancer Institute Bethesda, Maryland 20014 1 ~

- TABLE OF CC;`JTEIv'TS I Page Foreword introduction _ -Proposed Research Plan .1v i Description of Projects ~ 1.Study of Risk Factors a. L3ose Intake 3 b. Genetic and Metabolic Characteristics 4 c. Psychologic Profiles d. Pathologic Concurrences 4 2. Research on Clinical Approaches to Smoke Cessation , S Approaches = ` ical acolo Phan; 3 6 g - ~ . a. Clinical Tri als 6 b. Synthesis of New Drugs Based on Laboratory 6 Evidence c. Bioassay and Evaluation Tests_ of Newly Synthesized_ Lh-ugs d. Organoleptic I+bdifications 6 . Ir.IInunologic Approach - 6 4. Cigarette Mbdifications 7 a. Breeding of Tobacco Varieties b. Tobacco Curing 7 c. Reconstituted Tobaccos 7 d. Processed Tobaccos 8 e. Artificial Smoking Products f. Tobacco Extractions 8 g. Filters - 8 h. Cigarette Manufacturing 8 r . _Chemical Analysis a. Analytical Research ~ 9 rA 6. Bioassay C8 ~ 9 a.- b. Skin Painting Bioassays Inhalation Bioassay in Dogs Cfi 10 10 c. Inhalation Bioassay-in Rodents, Bioassay ~ 10. d. Costs, EAuipment Costs Ciliotoxicity and Cytotoxicity Bioassays 10 7 Bioassay Development 10 ._ 10 a. Inhalation Techniques b Pellet Implanation Technique 11 . c. Transplacental and Teratological Bioassays 11 d. Standardization-- End Points 11

; I Page 8. Metabolic Studies 12 9. ConsuTper Acceptability Studies I2- 10. Evaluatbon Studies 1r 11. Prograri ~lanage:nent and Data Analysis 12 Proposed Organization and Funding - 14 CurreZt Research 1s_ Tobacco Working Group Membership List - 51 Pharmiacologic and Clinical App*osches in Sinoking 53 Working Gro-L. Member_shil, Li,s t I I I I I d I 13

-FOREiVORD During the meeting of February 14, 1973 the Ad Hoc Comittee on Smoking and Health, rf_t..he- National Cancer Rdvisory Board, requested the preparation of research plans for a program in smcking and health, to be-submitted for consideration before the next meeting- of the Committee,-March 25, 1973. This document responds_ to that request. It has been prepared by - Dr. Gio B. Gori, Associate Scientific Director for Program, Division of Cancer Cwwse and Prevention, National Cancer Institute,-after - personal con-sultation on specific topics with corresponding experts of the Tobacco Working Group, the Phar.macologic and Clinical Approaches in Smoking Working Group and other experts, including staff members at the National Cancer Institute,-the National - - Heart and huxig Institute and the Agricultural Research Service, USDA. The proposed plans focus on research for the reduction of risk of disease in smokers, and-do not consider public education efforts. - Traditionally-these have been effectively directed and funded through the National Clearinghouse for Smoking and Health, Center for Disease Control, D17SV, Financial and scientific projections in this -docun:ent reflect estimates and information available at the time of preparation, but may need modification under the inrpact of future evolving research. 111

A RFSC~TZCH -1'RCGRANs 'P3 T~J'iCRLr,Sh TIM RISK OF CA1NCER AN-a CMR DISEASES IN :I-M _ TOBACCO :Z-[OKER IMRODU-L'T'ICN J The use of tobacco poses a dual demand for pub' i.c health action; to - promote pubbic awareness of smoking hazards; and to reduce the risk of-those who continue to smoke, Sy devising protective and preventive measures. -'i`he spirit and- letter of these appro_aches are quite distinct, `a.ndjor valid reasons they _de4°eloped as separate -programs . Public education campaigns have been_ effectively -sponsored by the National Clearinghouse for Smoking and Health, now part of tne- Center for Disease Control }DHE'i, and by the -A-Trierican Cancer Society, the Anerican-Heart Association and other private organizations with public health irrterests. On the other - side-, the coo rciinated- efforts of the A:at rora3 Cancer Institute, ,the-Ns.tionai Heart and Wig Institute and the iJr~:.ted- States Department-of=Agricu?ture,=have been specifically dirocted-- at the identification -of individuals_ -most likely to develop smoking related oancers ar.d diseases, to means of re~cing.their risk, and to the development of cigarettes-that may be inherently less hazardous than those available today. . This presentation deals exclusively with this second approach, and _ does not consider federal research and action in public education, traditionally the province of the National Clearinghouse for Smoking and Health. Markers of individuals-at higher risk may include inborn-characteristics and envirordnental-factors such as genetic defects, physiologic and - patho?ogic_concurrences, nicotine dependency, motivation, occupation, social habit§, smoke intake and smoki.ng mechanics, etc. It is necessary to develop methods for the identificatioz of these markers. Also, pharmacologic and clinical methodologies must be devised to help the Ugh-risk smoker who-should but finds it difficult to quit; these include the study of drugs that aid in smoke cessation or can counteract specific deleterious effects of smoking, and physiologic and motivational research in clinical approaches-to smoke cessat3.on. O ~ C~D ~ Clt QD iv Lri

Retrospective and prospective studies showing a dose-response relationship indicate that a reduEc*ion-uf exposure to tobacco smoke should result in reduced incidence of smoking related cancers and diseases: In fact, during the past-20 years a dramatic reduction in the amount of tar and nicoti ne yields of American comunercial cigarettes-nas-taken place; recent epidemi-ological studies suggest- that a sMoker today-mu3t smoke more of modern cigarettes than he--- - would have o-f cigarettes available 20yeaxs-ag~, in-order-*o develop the same=xisk of disease, and tl'lafsmoking filter cigarettes for 10 years or:~iore significantly decreases the risk-of lung cancer as compared-to snokers -of unfiltered- cigarettes. A1l---this poir.; s to the desirability of filter-cigaretiteS, and other low yield , products- on =the market. Nbreover cigarettes can-be engineered to produce smoke-which,- on -an equal do~e basis, can produce higher or iower carcinogenic response_ arid -other pathologic manifestations iri anima'1s. Choice and-manipula=tion of appropriate tooacco types,-engineering-of the cigarette and -selective -filtration will perait- removal of a considerable portion-of pathogenic smoke components, and-stiii - maintain ccnsumer acceptability. This shouldresult in smoking products which are intrinsically less-injurious to hlman-health, _ over and above the simple reduction of tar and nicotine. - . The health and technological problems connected with tobacco and tobacco smoking are complex and oross a variety of disciplines and interests. For instance, it is to the advantage-af tobacco farmers anci a function of the USDA to foster research on agronomic varieties of tobacco that may result in less haririful-smoking products, as evaluated by agencies with the necessary competence, such as the NCI and the NHLI. The improvement of some cigarette characteristics may possibly result in worsening others; close collaboration of experts in carcinogenesis, cardiovascular and respiratory diseases-and tobacco technology is mandatory to insure that cigarettes become less hazardous for as-mariy as possible of their potential effects in -man. The National Cancer-Insfitute will also coordinate with the National Heart and Lung Institute and other public health agencies in pharmacologic research and clinical application of motivation studies ieading to smoke withdrawal=techni,ques for the high-risk smoker, and in research for the identification of individuals at risk due to-inborn characteristics and environmental factors.

PROPOSED RESEARCH PLAN I I I I I I I Im CtMT- ©N 'I°iE F OLLOrvING -PAGE SUINVARIiES, IMA3OR-RESEAP.c:-: GPTIONS PRCPOSED:= NEXT, DESCRIPTION OF RESF_lkRCH AR.ERS IS OFFERFD Ih3 MDRE D..~'i'AIi., WfITli PRuPO SED BUDGET I:EVELS_ .!NDPRWECTIONS= IN T`riO[JSAN D` OF DOLLARS, - . Tr~.SE FUNDING ES T I~?ATES REPRESENT -'?'~'.- BEST AP_PROXI:-M-ATICNS AT "~i E TIME •`IHIS - DDC[Ba7T= WAS PREPARED: IN TNE FCLLGWING YEARS AND DEPENDING ON E`JDL1rING -R.-FSE.ARC-I OPPDRT[TNI T IES _= MY NM TO BE - RRVISEII. _ FY' 1973 FTGIIRES ItEPRESEtf'I` CIJRFF-vfi APPRCXI]MATED EXTELIMI'h.SIRES. MORE PRECISE DESCRIP-1 ION -bF CURRENT RESEA.~'~ai IS GIVEN AT PAGE -_18 AND FOLLOY'ING. CURREN7 NCI E=- PROJEMONS DO NOT PROVIDE FOR ALL TIiE -INCPtEASED F<.MS PROPOSED IN Tf-IIS DOCIMTT FOR FY' 74, .75 AND 76. - SPECIFIC REOWENAT IONS BY TM- NATIONAL CANCER ADVISORY BOARD W0UTi.D EVENMLY SECURE INCREASED RESCURCES. 1

PROPOSED RESEAR4I PLAN TO DECREASE THE RISK OF SbtOKING RELATED CANCERS A~NC) DI'SEASES ENVIRONNENTTAL CNA,RAC'I'E,RISTICS Occupation, etc. IDfiNTI FICATICIM AND hT+DIFICATI OF INDIVIDUALS AT RISK N up= DEVE3APMFNIT IN'BORN HOST GLaRACY7ERISTICS Genetic, physiologic and pathologic concurrences, etc. BEFiAVIORA.L CHARACTIERISTICS Motivation, smoking mechanics, exposure levels', ftendenGy.' ., ~eS96~0O / WDIPICiITZ(ZI OF 9MQKIW PRODU(.,TS ~ BIOAS'S~t' i PN~TTTr ~ CIwaSTItY PR0IXJCT MODIT'ICATIONS: ' A-gronomxcal, a itiTes, cigarette engineering, reconstituted and artificia1 tobaccos, , 'fractions, £'ilters, etc: BIOAS~.'~AY : Inhalation, s, p nting, cili&-~ toxicity, in vitro studies, etc. lti EVALUATE ° EF'FEGTIVENFSs 01. INTRODUCFD MODIFICATI LESS HAZARDOK~i CI~RE°rTE ~IODk~ ~,._._..._.._.._~..,~

~ fi~ral R.J ~..~1 R..i Y1.~1 ~rJ Irrri L.d r63 Le-A :a mTr..J ~ Thousands of ENollars . Description of Projects pY Ff FY 1973, 1974 1975 ---- --r--- (,100)'* (900) (1s00) 1. STUDY OF RISK FACToRS ' Epideniological Studies,- Will provide evidence on the contribution o environmental actors o in orn an~d`b-eTiavlr al -cFaracteris ti.cs oTie smoker`. T~he program currently fun s hn~Yte d re.sear xn this area, which after three years of activity has accumulated data on a few'tnousand cases. On the basis of this' ' initial return it is calculated that in excess of , 50,000 case's will be neeessary in order to draw , sta~tistically significant concl,usioris ~ Another element of importance is time, namely the validity of the results will be enhanced if the data coll,ected, are reasonably contemporary. ,][t,is desirable, th,ere- foT: 4 data within a sho t e, to collect the necessa~i p eb}~ this res,~ earch period of time. Clues devel , , d will help developing approaches for identification of high-risk individuals, who in turn will be treated or' warned appropr,xately. Currently , identified approaches are as follows: prec~se~tTie~ifc ose intake of smokers.'d'he program is aiwut to fund a research project that may lead to methods for this determination, by measuring smoke components in physiologic flui,ds,of the smoker, stach as nicotine meta- 200 bolites, carbon ihonoxa.de, 'carbon dioxide and others; the possibility'of such determination wi11 have an obvious, impact in tlhe ident3.ficafiori ' 300' 500 of individuals at higher risk and in,a more „ precise detennination, of dose response relation- ship in epidemiological studs:es, 699966 LP0Q a; DOSE INI'AKE' - It is important to determine - . Panenthesis indicates 'subtot;als of each,un.it when, applicable