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q ,= % rl ( I CANCER PROGRA OBJEC FIVE 1 National Cancel" Plan To Reduce th~ Effectiveness of External Agents in Increasing tne Probablhtles of Development of Cancers in Existing Individuals or in Individuals of Sub- seauent Generatmns. or "To Prevent Cancer i~ Humans by Removing Causative Factors =tom the Environment ot by Reducing Their Effects U.S. Department of ltealtb, Educa,wl., and Wel~re Natio~Tal b~szitutes of Ilealtb / National Cancer Institute t~ ¢o .~. ~l ,~

TArSi E OF' COtITEqTS OBJECT I V_E I ~APTER KEY C~qCER ~ROGRA~ OBJECTIVES P.~IEL HEMBE2S PRE~4BLE I. INTRODUCTION II. RARRATIVE SU~RY OF APPROACHES I. Approach I 2. Approach 2 3. Approach 3 .4. Approach 4 III. COPICLUSI ONS ( PAGE 1i iii iv I-I 2-I 2-I 2-6 2-8 2-13 3-I C,l O~ AKA? OtVAL CANCE*~ pLAN ---- I

C .}~EY C~ICER PDDGRAI4 OBJECTIVES Objective l: Objmctive 2: Objectiv6 3: Objective 4: Objec~ive S: Objective 6: Objective 7: TO Reduce the Effectiveness of External Agents in Increas- ing thb Probabilities of DeveIDpment of Cancers in Zxlstlng lhdividuals or in Individuals Of Subsequent Generations. TO Modify IndivlduaTs {e.g,, by Vaccination) to ~crease the Likeliilood of Cancer DEvelb "on% both in th~ Current Generatie~ and Subseouent Offsbr~ng. TO Prevent Conversions of Cells to these Capable of Farming Cancers C1.e., Block, or Interfere w1:n the Pro×imate Stepj mr Steps, Involved in ~onverslen zo Cells Capable of Forming Cancers>. TO Prevent Tumor Establishment from Cells AlreaDy Capable of Forming Cancers, e.g., Transformed Ceils Cells Consti- Outing Precancerous Tissues aria Cell5 from Pr~marjTumors that LoDge EIsew~ere in ~ne Oo~y in a Metastatic State, Either Active or Dormant. TO Achieve an Accurate Assessment of the Presence, Extent and Probable Course of Cancer Risks in Poaulation Groups {Including Attention ~o Precancerous Lesions) and of Can- cer~ im Individuals Alone [Dlag~osis) aria in Groubs {Detection) ~s an Aid t~ Prevention, Cure or Prognosis. To Cure as Many Patients as Possibl( and to Maintain Maximum Control of the Cancerous Process in Patients noz Cured. TO Restore Patients with Residual Deficits as a Conseauence of Their Disease or Treatment to as Nearly a Norma] Func- tloninc State as Possible. 7~ ~T #~A fi~N~L CANCE~ PLAN

'" C C pAnEL ME ',3ERS Harold P, RUSCH, M.D. - Dhairman Director, McArdle Laboratory for Cancer Research University of Disconsin Nedical School Madison, Wisconsin 53700 Paul KOTIN, M.D. Dean of the Medical School Temple University Medical School 3420 North Broad Street Philadelphia, Pennsylvania 19140 Joseph L. MELNICK, Ph.D. Professor and CDairman, Department of Virology Baylor College of Medicine IDOO Moursand Avenue Houston, Texas 72025 James A. MILDER, Ph. D, Professor of Ontology MoArdle Laboratory for Cancer Research University of Wisconsin Medical School Madison, Wisconsin 53706 Norton NELSON, Ph.D. Director, Institute of Environmental Medicine NYW Medical Center 550 First Avenue New York, New York lODl6 Ernest L. WYNDER, M,D. President, American Dealth Foundation East End Avenue New York, New York lO021 Helen H. BALDWIN, M.S.-Rappor~eur McArdle Laboratory for Cancer Research University of Wisconsin Medical School Madison, Wisconsin 53706 On C~ 6q NA TIONAL CANCCR pLAN -- iI~

PREN'~ LE There i~ enough knowledge presently available which can be applied immediately to prevent the occurrence of cancer in thousands of A~:erican citizens. Some of tile progran,s which lend themselves Pc immediate action are listed in the report of Objective ]. However, the total aim of Ob- jective I cannot be attained merely through the ~pplication of existing information. Inslead it ivill require vastly greater knowledge of fund- amental biology and of basic aspects of the cancer process• Hence, two approaches are required: {a) the exploitation of present leads by the coordinated programs of the National Cancer Plan and {b) the continued support of individual investigators who develop projects and infornlaticn of high scientific value for understanding and ultimately controllinB cancer, Because of the need for improvenent i~ fundamental knowledge, approaches to the major objectives should provid: balanced covenage of (a) basic research, (b) preclinical investigations in animal model systems, and (c) clinical studies in human subjects• The investment In resources should be allocated with a view t~ards balanced support of thes~ three categories of research activity. To achieve fullest exploitation of resources and research capability, an expanded number of scientists, institutions and organizations must be enlisted in the National Cancer Plan, and their efforts must be appro- priately coordinated. This will require major expansion of (a) grants, contracts and other mechanisms of funding; (b) training and recruitn;ent of large numbers and different types of professional personnel, and (c) highly integrated, overall planning and program management• It is urged that immediate steps be taken (a) to increase the training opportunities in cellular and molecular biology and virology, and in cancer biology, virology, immunology, and epidemiology~ and (b) to offer large numbers of Career Cancer Investigatorships to outstanding scien- tists performing laboratory or clinical research. The Career Cancer In- vestigatorships should be awarded for B-year periods with indefinite g- year renewals as long as the investigator remains productive (as determined by a National Review Committee)• To enable maximal utilization of research data and informed decision- r~ making, adequate dissemination of research findings ~sill be required. lhis means improvement in both the communication and the integration of Infomnation. To this end it is essential that the involvement of the scientific ten.unity in the planning and direction of the National Can- cer Program be strengthened, Involvement of the scientific community in the National Cancer Plaa will require continuity and coordination of its participation. TO enhance #.~ the success of the Approaches Planning Sessions, it is recommended that reports of the subsequent Project Area Plannlnq Sessinns be presented t~ the original participants of the Approaches Planning Sessions for further discussion and refinement, in order to provide continuity and coordlna- tion of planning efforts. There is a need for sustained invo]vement of NA TtONAL CANCER ~LA N --

< Objective I Preamble such an advisory gPoup OF senior cancer investigators and scientific managers, drawn from the scientific community at large and operating under a.systEm ~.shich provides a gradual rotation of membership. Such an advisory group, having the size and scope of the Approaclles Planning Groups, could be effectively complemented by ad hoc groups of censultants representing a far larger cross-section of the scientific community. H~'~ever, in order to maintain long-range continuity of involvement, it is necessary that the principal advisory group not be replaced by ad hoc groups, whose involvement would be lindted in time and scope. C~ C~ C~ C,I C~ #4A r¢O~'A L CANC£,~ pLA,V V

" C E i , I i F I. INTRODUCTION This program aims to prevent cancer in humans by removing factors frDm the environment which are responsible for the disease or by reducing their effects on humans. It is based upon scientifically sound convictions: l. Environmental factors are of major importance in causin~ cancer in humans. Epidemio]ogical studies in COm~ination with tests ~s have identified factors in environments that are im- portant in the causation and development of human cdncers. 2. [llmination or reduction of hazardous factors from the environ- ment can prevent human cancer. Elimination of these knoun identi- fiab]e f~ctors from the environment is possible and v~ould prevent the development of cancer in persons now living and in their off- spring• ~ 3. Feasible means exist or can be developed to identify and eliminate such factnrs• i,m:ediate steps should be taken to eliminate or greatly reduce from the environment any substance now knovtn to be ~ Carcinogenic to humans or to animals• 4. The introduction of as ,yet unknol:n, man-made carcino~ hazards into the environnlen~ can be controlled. Present-day exposure to nmst of the kr~olIn chemical and radiation carcinogens has resulted directly or indirectly from technological developments of the past hundred years (e.g., dye industry, atonllc fission and fusion, petro- chemical developments). Since the introduction of new products NA TION,~L CANCE f~ pLAN,

• C C ! , ' Objective 1 Introduction continues at an ever increasing pace, the probability of generating new carcinogeric hazards requires greater scrutiny and testing of new industrial processes and products before they are introduced in the environment. lon term su port of carefully designed studies will make possible 5. ~'fl~cdtqon of currently uilknolm factors respon~Ib-l~ hg[[Id~l cancer~b tn~ understaldin_ ~ of hol,i such factors cause can- the reduct on of thelr iT")aCt on exposed persons• Con- tinuing long-term epiaen,ioioglcal studies and a~ are essential to identify othm- factors already in the environment Which present earcinogonic hazdrds to man. ~hese studies must be supplemented by co~iparative studies of the relationship bet.een carcinogenic activity in tests on animals and the threat to man, and by studies of the interaction of multiple environmental and internal factors on humans and in model animal systems, Past ex- perience indicates thet such studies will make possible the elimi- nation of additional carcinogenic h~zards or will provide means '-by which their effect can be minimized. • The following amplification of these convictions underlies the proposed program for prevention of human cancer and justifies the belief that ~e now have sufficient information to act immediatel~ anO prevent a siS- nificant pertlon of human c~icer. om r~ lea T~OIVA L CAhYCEFt pLAN - I-2

C II. NARP~TIVE SUMMARY OF APPROACHES Approach I..The Application of Present Knowledge to Prevent Cancer in Humans ~ Socia] Action. Modern eDidemiological studies indicate clear1: ~naz several human cancers have significant environmental factors in their etiology. In particular, the ca£Jsative l~k hetl,,een smohin~ of cioarrttps ~nd the incidence of lung cancer is unassailable• lhe smokihg of cigarettes plays a causative role in approximately one fourth of tlTe cases of cancer in the American males• in 197D about 5O,oog individuals in the United States died from cancers ~shlch vleuld not have occurred if they had rot smoked cigarettes. For this reason the most effective, action possible today to decrease the incidence of cancer of the lung i~ to reduce to a minimum the inhalation of tobacco smoke. We can anticipate that if cigarette smoking ivere halted today, rather than continuing at its present rate, approximately one half million lives would be saved ~ver f~he next ten yPdrs, For these reasons ~ assign the highest priority to a series of actions designed to reduce the smoking of ciga- rettes by the American public. Additional environmental factors haw been identified ~hich have an undenidble, although smaller, effect on the incidence of cBnrer. There is every reason to act i ~mediately to reduce or eliminate these factors ~.~ from the environment. Che;nicals (polycyclic hydrocarbons) knovm to be carcinogenic tQ man and animals have been identified in the air. Execs-G3 sive exposure to sunlight is knovn to be responsible for most cases of ~in cal}cer. ComposJe~ts of 5mPgmas a ~aterial that collects under the ~ foreskin of uncircuncised Blalesp has been implicated in the etiology of NATIONAL CANCER PLAN -- 2-1 '~1

C Narrative of Approaches Objective ] l penile cancers. The continued therapeutic use of hazardous drugs and hormones, and th~ unwitting ingestion of carcinogenic substances in food and water also may contribute to the present incidence of cancer. Certain irldustrial processes and occupations involve exp~sut'e to aqents {chemicals, dusts, or irradiation) kno~,n to cause cancer, In a~l of these situations reductYon of the exposure, elimination of the agent, and/or protection of the persons exposed must bc undertaken to p~event further needless death and suffering. ~. ~evelop Administrative and ke~|slatlvo Pro~raR~. I. Limit tobacco production and use. While outright prohibition of the production and use of cigarettes is probably not prac- ticable, the Federal government must take direct and primary responsibility for a rigorous control programwith sustained surveillance of established standards. The following six actions could greatly reduce the incentives toward and danger ~f smoking, a. Reduce the economic incentives for growing tobacco. b. Extend the limitations on advertlsing, and promotion of tobacco products, especially cigarettes, Equal space requil-ements of all advertising, in parallel with equal- time requirements on radio and televisions, could b~ explored. Control of sales locations {e,g., vending machines), perhaps by licensing, to render cigarettes less available and prominent to susceptible persons. should be considered. Increased taxi~Ig of tobacco products should also be considered. c. prohibit smoking in public areas. The exposure of non- smokers to the side-stream smoke of user's cigarettes represents an unacceptable trespass on individual rights. d. Establish more stringent limits on tar and nicotine con- tent of cigarettes. Standards for the effectiveness Of filters, for low~ nonaddictive levels of nicotine, as well as for maximal levels of "tar" components, are needed to protect present smokers. Continuous monitoring of the product, review and up-grading of the standards, and ex- ¢lusiQn from the market of foreign products which fail to meet the sta~dard~, should be included in the legi~laticn. Proposals considered currently by the Canadian Government should be examined. e, Seek positive financial incentives through tax benefits. Federal medical aids, and other means should be sought for ~On-s~okers. These can be of greatest value if directed toward the younger, IO to 18 year-old, group. While "policing" of smoking habits is impossible, the health costs to the nation of continued cigarette use Justify positive encouragement to stop smoking. Present ~ed~rally-supported encouragement to smoke, such as tax- f~ee. low cost cigarettes available to the Armed Fo~ces Gm @0 G~ ¢m :b

( $ i Objective 1 Narrative of Approoches 2~ 3. and State Department personnel abroad, should be halted. • f. Establish, support, and promote smoking-withdrawal clinics which vzould be available at little or no cost to persons ~lho wish to stop sr~oking (of, A~erican Cancer Socfety model programs ). Control occupational, industrial and hygienic hazards. a. Experience has shown that control of industrial health hazards can be effective. Rev~ Federal legislation (PLgl-gg6)is nou available which if adequately supported and enforced, ~lll be of great aid in this area. Strin- gent, continuous revie%,J of older standards and require- ments is essential. The principle of substitution idth • less hazardous materials and of reducing exposure through containn;ent and personal protective devices is well under- stood in industry; believer, str~ger action o~ these principles is still needed. b. Limitation of elf-borne pollutants. The consistent finding of an excess of lung cancer in urban, as compared to rural residents, and the Ide~)tiflcation of chemicals known to be carcinogenic in smog residues and polluted air is compatible with a contribution of air pollution to lung cancer• For these reasons legislative restriction Df sources of air pollution should be encouraged. c. Ultraviolet irradiation from sunlight is a known cause of sRin cancer• Federal standards for sunlight protective creams are needed. Include all consumer products lna "Pelaney-type" amendment. a. Food• Potential carcinogens in some foods include normal eonstltuonts {bracken fern, methylene dioxyalkylbenzenes, cycasin); fermentation products; natural contaminaDts (aflatoxlns); ~an-~;:ade contaminants (asbestos fibers, hormones, ~DT); Bnd direct additives (nitrites~ which give rise to nitrosamines). Stringent Federal require- ments for better monitoring of foodstuffs at the level of the producer and processor, and more adequate testing of comstitue~ts is needed, Care F~ust be taken to avoid replacing a ;xell-tosted carcinogenic agent by a poorly tested, possibly more hazardous one, b. Household chemicals, i~cluding aerosol sprays, Ibis large, gro~.dng and inadequately regulated group of pos- • sibly carcinogenic agents needs inclusion in legislation designed to test for and ~liminate possible carcinogens, as such materials represent potential hazards to users (inc. persons in occupations not protected by industrial standards: dry cleaners, Co~ineti¢iaTis, homema~orsl etc.)l On C~ ~VA TI~NAL CANCE~ p£~V 2-3

' C C Objective l l~arrative of Approaches O, ¢. Medication and COSRmtiCS. Many drugs, inc]udlng stilbes- trol, arsenic compounds, griseofulvin, isoniazid, chloramphenicol, and chlorinated anesthetics have been implicated as possible carcinogens: Legislative require- ments for adequate pretesting, usage restrictions, sub- stitutions as indicated, and continuous reexamination of standards is essential. 4. Expand legislative r~guirements for pretesting of products and processes for carcinogenicity before they are introduced to the public. Control reguire~lents might be imposed at the time of app]ication for patents. Develo~and Education. RedLrce the use of tobacco. ~Jhile the educational programs already undertaken tD entourage voiuntary reduction of tobacco use have achieved some success, further imaginative efforts are needed, esgecia~ly directed at preventing young (10=IB year-old nonsmokers) from developlng the habit• To this end, an intensive educational campaign utilizing p~er-group dis- approval of the practice should be promulgated. The use and support of media and persons influential l.~ith the age group should be sought• Since many young men stdrt smoking whi|e in the A~ed Forces, tMe active participation of the U.S. At~ed forces in a counteractive Incentive program should he enlisted. Insurance companies should be encouraged to offer lower rates to nonsmokers (and R~nusers of alcohol); in the i~terest ~f public health such companies should be encouraged not to in- vest in the tobacco Industry, 2, Inform th~ medical profession. Certain, identifiable groups hav~ a higher risk of developing cancer, arid should receive special preventive care, in particular, smokers, alcoholics, individuals with defined associated diseases (ulcerative c61itis, xerode~]a pigmentosum, pernicious anemia, etc.), the obese, and uncircumcised males• b. Extend warnings about the hazards of certain therapeutic and diagnostic drugs and procedures vHtb the aim Df limit- ing the exposure from diagnostic and therapeutic x-ray (e.g., improved equipment) and potentially carcinogenic drugs such as griseofulvin. c; Establish educat;onal ~.Iorgshops and clinics to inform the obstetrical profession about the great vulnerability of the fetus to r~diation, drug%, and ho~1on{~s adL~llnistered to the mother and the tragedy of prenatally caused cancer, Through these programs, children l,ho have already experienced preilatal exposure may be identified for follow-up preven- tive care. A nation~;ide effort should be made to enlist NATIONAL CAN~R PLA~/ 2-4

,.J f t' Objective 1 Narrative of Approaches She proFPssion in preventing penile cancer through circumci~ioR of nov:born males. 3. Infom Occupational Groups. a. Inform and encourage manage~lent tO reduce the exposure of .employees and the public to carcinogenic agents. Explana- tion of the scientific and economic basis for legislative • controls, and the responsibilities and benefits these impose, ~hould be provided. b. Inform labor, through their unions, of self-protective practices, lhese group~ should be warled of the cocarci- nogenicity of combined environmental factors ~.9. additive effect of smoking for a worker in the asbestos industry . c, Infon~ farmers regarding safer use of agri-chemicals and aerosols, a~id the hazard of excessive sunlight, Create a~aremes~ of farmer's strategic po~itio~ in preventing release of environmental carcinogenic agents into air, water and food. 4, Inform Congress dnd the general public. The value of pre- Ventive measures and the d~ngers of uncontrolled dissemination of carcinogenic agents through the envirom~ent urge the main- ten,nee of an ongoing program designed to inform Congress and the public about actual ilazards, tile need for and natul'e of pro- posea and presert legislation, t~e findings of researcrh and the identification of conditions B00 factors reducing ano lncreaslng %he likelihood of developH~g cancer. C~ Ca ~IATIONAL CANCE[f pLAN -- 2~5

( Objective I Rarrative of Approache% .i B, Approach 2+ The Immediate ~!pllcatimn of Technology to Prevention of Cancerin Hu1~lans: ~ment of ~Pications~ ~l vet an~67~ ?or ~-~i- C~rc~ A Not all of the known or suspected carcinogens in the environ~:ent can be ~liminated by the prpgrams described In Approach 1, For some, control Is i~9ossihle~ for others, control methods are at present un- available; for some, son:e control methods are inadequate or present great social or economic cost• For these problems, the aid of engi- neering, chemical, and pharmaceutical industries should be enlisted to devise control devices or substitutes for hazardous processes and products. I. Less hazardous cigarettes and other smoking products• Significant progress has been made already in altering and trapping the oxidation products of cigarettes and rendering them safer. ContimJed intensive efforts in this direction, based upon sound analytical and bioassay procedures {see Approach 3) should be sought. ~. Less hazardous industrial processes and products. '-" The operations of the petrochemical iadustrles, dye industries, and mining (esp. radioactive) industries present special hazards to workers and nearby r~sidents. Employees must be Safeguarded by protective devices and procedures. Ubenever practicabl~, the development of alternatives and substitutes should be encouraged through tax incentives. 3, Less hazardous usage of fossil fuels and alternate energy sources, a. Efforts to limit air-borne pollutants probably can best be carried out in cooperation with those ~ork- ing outside of the area of cancer research. The foll~ving pertinent problems were identified by th~ 1971 Committee on Biological Effects on Atmospheric Pollutants Divlsion of Medical Sciences, t{ational Research Council of the National Academy of Science pg xxix, {I) "Close scrutiny should be directed to deterioration effects of aut~mobil~ control devices and the use of diesel-fueled vehicles under overloaded conditions. C#) Research into the effects of fuel COaTpOSl- tions and of advanced emission control ~OVJC~S should b~ cD~tiDuDd, Polycyclic organic matter emi~slons from aircraft should be assessed, (B) (a) gV C~ G1 -6 NA TIO~VA {. CANCER pLA~

( ( j , q _._~ective I Harrative of Approaches 4, 5. r~ (41 SuhstltuCion of ~Iternate fuels or more efficient co~bustio~) processes a~d discon- tinuance of codl-refuse stora9e practices seeln to be appropriate m~thods for the resLriction of coal~regulated polycyclic orgatdc matter emissions, (5) Emiss{on associated with coke production requires additiondl research on control procedures and source analysis." b. Explore the desirability of substituting alternate ener!]y sources (~*ater, solar, nuclear) for fossil fuels. Encourage the inventim~, production, a~d ma~s m~rketing of highly-protective, Iono-lasting creams to protect the skin egalns~ exposure ~o sunlight, Enlist aid of ~harmaceutical industry In keeplng recor~ and follow-up studies regarding any n~w medication (open records Of doclors {~Ingj atld DaCients receiving, such medication ~o be maoe available ~f needed), ~ZA ~'/Otj~l. C~CER F= A IV 2-7 Oh C~

( i , Objective 1 Narrative of Approaches 3, Approach 3, Detectlon and 14entification of External Cardnoqenic Epidemioloqical studies, particularly with migrant groups indicate thRt several important human cancers have significant ~nvironmental factors in their etiology• Environmental chemicals, both man-made and of natucal occurrence, al-e principal suspects among tdese. Already a number of diverse organic and inorganic chemical car- cinogens fnr the bu~2an have been identified. Zpidemiolocical grounds indicate that additional important environmental chemicals exist that play a determinin~ role in the etio]opy of important bunyan cancers of high incidence, such as cancers of the lungs, colon, stomach, and breast, lhere is a]so reason to suspect that several environment factors, not carcinogenic in themselves may act in con- cert tQ produce human cancers, The likelihood that viruses also contribute to the etiology of human cancers merits continued investi- gation. The detection and identification of any such agent will facilitate rational approaches to YtS elimlnatlon or reduction in the human environment. A major and sustained effort over •several decades {~he 15 to 25 year latent period for development of human cancers requires this time Scale) by epidemiologists, clinicians, add ]aboratory workers in viral and chemical carcinoQenesls will be required. Simultaneously, improved analytical methods and assays should be developed to test the hypothese~ engendered by the epidemio- logical studies• The detection and identification in the environment of agents carcinogenic for humans is of prime importance to the goal of preventing human cancers• A. Zpi~emiological Studies. |.. Establish teams :o~prised of foreign-based and {].S. epidemiologigts, clinicians, and laboratory investigators• of chemical a~d viral carcinogenesis. These te~m effor~, supported by long-term comn)itments of adequate funds and persDn~el, should be directed t~ard comparative studies of the incidence of cance~ an~ understanding of the as- sociated etiologic parameters. The importance of encourag- ing and devising means for maximal cooperation.and exchange of information ~vitMn the team is of the greatest impor- tance. New personnel and training programs will probably be needed. ~. Cigarette smoking. Investigate the effect of modified ~obacco products and smohlng flahits on the incidence of l~ng cancer• Follo,~ the recommendations for reseal-ch by the Cor~ittee on Rio~ogical Effect~ of Atmospheric Pollu- tants Division of Kedical Sciences, National Research £oul)cil of the l~atio~a] Academy of Science (1971}. "Much 9renter documentation of cigaTette smoking is badly needed, lhe exclusion of this major etiologic fa~tor in disease from the 1970 census is unfortunate• Valid esti- mates of cigarette consumption in major community areas, both urban and rural, in relation to lung cancer and other major disease entities are not easily available .... " .. (pg xxxlv.) ~#A~IONAL'~A?ICERp~.AM • Z-8 GI "4

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4 Objective 1 ~ [laG,ive of Approaches I B. A hypotDetical "exposure-experience" profile derived from multifactorial analysis might specify sex, age, weight, mdrit~] status~ therapy regimes, nutritional patterns~ and residence experience. If the 2G-year tumor incidence of a large number of persons matcbing such a profile could De compared Ivith GrOUpS differing in single areas of the profile, some better insight into the complex causes of cancer in humans might be "'Gained. , 6. Study the occurrence of cancer in occupational Groups. 7. Conduct epideniological studies usinG congenital malfor- mations as a concordant for cancer. 8. Hormones (inc. hormonal oral contraceptives) These sub- stances need study in regard to incidence of breast, cervical and prostate cancer on a v$orld-tvide basis. 9. Diet. Further epidemioloGical studies in ~onnection with laboratory investigations are needed on nutritional pattelms and cancer incidence. lO. Drugs. Patterns of cancer incidence and drug therapies ~rit expanded study. 11. lo~-level radiation and its relationship to human cancer incidence needs intense, world-v#ide, comparative study. beve]o~ and Improve Bioassa~s for Carcinohens Relevant to HunI~IIS, Present bioassays for viral and chemical carcinogens and suspected carcinoGenS ar~ inadequate in many respects. Re- producibility, sensitivity, and speed of assay period need to be increased (see IDa8 report of the Discussion Group on Chemical Carcinogenesis of the l~ational Advisory Cancer Council, Appendix I page 20). In particLJlar, reIevanc~ of in vitr~ bioassays to human carcinogenesis must constantly ~e-sought und improved: the criteria of neoplastic change, accessibility of the carcinogen, and its conversion to an active fern, present important difficulties to be overcone. The follD~vin9 five syste~Ls offer promise for bioassays, 1. Host-B~diated assay systems. lhese relatively rapid assays for mutRgenicity and cell C/~ transformation in vitro $~ou]d employ both hm;;an and test . animal tissues to effect the metaholic conversion of the ~w~ chemicals under test to active forms ~hich have mutagenic C,~ or transforming activity in I110 test cell. Host-mea~ate~ assays may leID to reveal False ~ositive and false nega- ~ tire results am~n~ the resu)~s of the ~hole aniF~al Loses NA TfONAL C~4NCER PI.AA .2-I0

( Objective 1 C ~arrative of Approaches e=J for carcinogenirity, and provide priorities for life- ti~le testing of suspected CdrCino~e~s. Transfomation in cell cultures, induced by chemical as well as viral test substalces, should be explored fur- ther• Succes~ in such a syste~ may depend in part on improvement of culture teclmiques aired at d) 9rovting ~ormal an~ prir~y cells on ~ large scale, ~nd b) gr~- ing populations fron single~ isolated cells (cloning). Detection of cell-surface antigens. Cell tran~form~tion by viruses in experimental cell cul- tures is accompanied by induction of surface antigens• These antigens, which are labile dnd complex~ as yet are inadequately characterized. Nevertbeless, quantitative and qualitative analysis of Such cell surface antigens may provide a useful assBy method, as well as providing a method fo- d~tecting ~iral invol~e~ent i~ huma~ can- eers (see D, 2}. Detecting viral activity through specific biochemical characterization of tumor cells. a. lransfonnation of cells by oncogenic R~A vir.ses In- volves the induction of new enzymes, particularly reverse transcriptase. An assay system evincing viral infectiQn could be based upon the detection of such enzymes in the human tissues or in cell cul- tures. If it is learned that reverse tra~scriptase is virus-specific, the enzyme might serve to ideRt- ify viruses in human tisst~es, eve~ in the abse~c~ of virus particles (section D, 2}. b. Dotectino cell messenger RNA complementary to tile DNA product of viral reverse transcriptase by hy- bridization migbt serve as a method of determining vir~l etialogy in human tumor tissue and as' evidence of transfon;~ation in bioassay systems (see D, 2). h~rov~d a~4 additional lo~g-te~m, ~h~le anim~l assay. ~b~se p~oced~r~s n~ ~o~sish of life-tim~ tests of high levels of chemicals administered by various routes to short-lived m~T~als, beuAte their relatively high cost and other deficiencies, these tests are required until . C2~ reliable, rdpid, bro:d spectrum tesPs for carcinogenic- Ity tests in whole animals sbould be unde~.Iritten for • the entire survival period. In the past, valuable data was often lost when animals were hilled because of economic Bnd Space considzrations. Centralized animal ~ maintenance colonies might be considered for this pur- ~,~ pose ~l . ,, . . 2. 3. 4. NA "[#ONA h CANC£R {~LA@ -- 2-11

( Objective 1 Harrative of Approaches C, g, Devise and ~)rove Anir'al Hodels of Hurrah Cancer In&Jcible yb~emica], Viral and Radiation CarciTloqens and Cotrbina- tions "[hereof. For too fe~t human cancers do we have adequate animal models. IChile animal models using chemical carcinogens exist for leukemia and cancer of the breast, liver, colon, bladder, esophagus and lung, most of these are deficient in some regards and need improvement. Even more critical is the absence of any aMmal model for tuN'ors of the stomach, pancreas, and uterus• Animal models are ~eeded for screen- ing for human carcinogens, for studies of factors that could alter the incidence of specific human cancers, and in the basic goal of understanding and eradicating the causes of human cancers, lhe uses of good model systems can be il- lustrated by the studies of skin carcinogenesis in the mouse, where considerable progress has been made in under- standing tbe Stages and mechanisms of carcinogenesis. Models for other organ systems in which staging and modifying factors in carclnogenicity can be studied are greatly needed. Improved Methods for Analysis of Chemical and Viral Carcinogenic Aqents, 1. Better analytic procedures for carcinogenic agents in the environment and in human tissues are needed be pro- vide measures of total exposure to potential human carcinogens• Requirements for a "carcinogen free" or minimally carcinogenic environment (Approach I, 2) must rely ugon rapid, sensiLive monitoring and surveil- lance techniques. The success of epidomiologic studies also must rest on actual measures of the environmental exposure encountered by groups under exanffnation. Improved analytical methods for detection of the carcin- ogenic agents in the host tissues and body fluids are needed for studies directed toward interference with the host-carcinogen interaction• The specific proce- dures most needed will depend upon the demands of the projects undertaken to accomplish Approaches l, 2, and 4. 2. Isolation and identification of candidate viruses, sub- viral particles, and virus-specific antigens in human tumor tissue. A cooperative, wide-ranging program between clinicians • and virMagists should be undertaken to screen many types of human tumors for presence of viral particles. Adequate supporting bioassays and suitable controls will be needed. In addition to studies directed toward C,~ leuhemias, lymphornas ~ aild sarcomas, greater efforts should be made l~lth epithelial tissue and carcinomas. Some of the bioassay apDroaches described in sec- tion Ill, C have relevance as methods for identifica£ion of viFuses, NATtOIVAL CANCER PLA(¢ -- 2-12

. % C C flhiectivQ ] Narrative of gpproaches 4. Approach 4, ModlModi~fhe Host Response to External Carcinoijenic Agents in hlodol and Human Systems. A. Inten~ Study of the Mechanisms ef Action of [xtcrnal Chemical Studies on the metdhoIic activation and inactivation of carcinogens and on physiologlc factors that alter carcinoge~fic processes sug- gest ~so approaches that should be explored for" their possible usefulness in the prevention or interruption of cile.Rical carcino- genesi~ in humans. I. Alteration of the metabolism of chcrliCal carci1~og~ns. The majority of chemical carcinogens require metabolic con- version to active carcinogenic forms in the host. Likewise, chemica] carcinogens are metabolically inactivated to dif- ferent degrees by various routes in the best. If one could . increase the deactivation or reduce the activation of chemica] carcinogens, the production of cancer by these agents would be reduced. It has been found that the netubolic processes'of carcinogen activation and deactivation are catalyzed by microsomal oxidases within the cell. The level of such oxidases can be increased by inducers of these enzyles or rpduced by il~hibitors mr by low protein diets. In several experimentdl models the effects of th~se agents on the activation and deactivation of specific chemical carcinogens reduced the tumor response. Caution must be emphasized in these approaches to the i~hl- bition of chemical carcinogens, since closely related oxidases are involved in the activation and deactivation of differPnt chemical carcinogens and desirable net effects on one chemical carcinogen might result in the opposite effects on th~ metabo- lism of another chemical carcinogen. Nevertheless, it is important to continue studies in anir~al models on altering the metabolism of chemical carcinogens by these means so as to lower their effectiveness. 2, Trapping of ultimate carcinogens. the electrophiiic nature of the active forms of chemical car- cinogens predicts that by administering nueleophiles which would react with the carcinogenic electrophiles and thus pro- • vent their attack on i~,~ortant infon,'alional molecules such as nucleic acids and proteins, this might inhibit che-.ical carol- • nogenesis. Several nucIPapF~iles might be used in this l#ay, some of which occur as constituents of hemal diets. At present the trapping of carclno ~nlc electrophiles in umans does not appear tc be a [tactical nreventive [roceuure~ )ut because of future ~ossibilities t~ese studies should be intensified us~r9 chemica carclnogens in lmportant animal Blodels of human cancer. p4A TIO~.'AL CAJVCE,~ pf.A~ 2-13 Gm -5 ..~

Objective l Itarratlve of Approaches .L B. Intensify S~u~Z of ttechanisms of Action of Viral Carcinoaenic Ae~. CDnslderahlc success has recently been gained in understandinq the initial events in some models of viral oncogenesis: never- theIess, much greater understandinq of the consenuences of cell- virus interaction in ~olecular and immunoloqical terms are needed before methods of interrupting the carcinogenic nrocess in humans can be devised. • C. intensify Study of Mechanisms of Action of Radiation-lnducod Carcinoge~ic ~ents. D. Intensify the Study of Yechanisms of Action of Carcinonens~ Cofactors, and other Combinations. As vet, understanding of the mechanisms by which slnale, well- .defined carch~ogens act o~ the host target is limited. Never- theless, ~t appears that the time has come to undertake the much more complicated tests of multifactorial carcinogenesis. Theories of interaction or synergism betv,een radiation and chemical carcinogens; bet~een chemical and viral carcinogens, between chemical and radiation factors, and betl~een these combinations on the host, merit testing. In view ef the difficulty of these studies, it cannot Be anticipated that propress will b~ very rapid, l:owever, the strong likelihood that human camcer is indeed the product of such multiple evenbs and interactions should encourage a start. Study General and Snecifie Resistance to Exterra! Carcinogenic Ae~s ] nc 1Lid ~ nq~odl C~2~fa c to r s. In the study of resistance, it is necessary to analyze the process of carcinoQenesis into stages. Different factors ~nitiate carcino~enesis~ promote initiated cells to progress toward tumor formation, and modify or inhibit the action of tumorigenic agents. Experimental studies Of all the~c types of activities and interactions are needed. For example, in the develogment gf skin cancer in mice tv!o stages hav~ be~n identified. The first, initiation, is ~f short duration, irreversible, alld specific. It is followed by a promoting ~eriod, which is of long duration, reversible and brought about by a wide variety of non-specific chemical and physical i~fiu~nces, ter~:ed cn- carcinogens. It appears likely that tobacco smoke carei~oaenosis in humans follows a similar pattern of irreversihle initiation and reversible, long lasting nrom~tion. The modifying effects Df envil'onml~ntal changes, and the possibility of manipulating these f~ctors and enh~ncin~ resistance ~ou]d seem t~ be greatest durin~ this S~co~d interval. Preventative measures couid thu~ be based on altering as many modifyin~ factors as ~ossible with the net goal of reducing certain types of cancer. 1. C~ it~munological systems. The functioning of the i~munolo!~ical ~] system, following the first exposure to a carcino(len, needs investigation. The possibilities of enhancini~ resistance ~ ~VA T~O~I~L CANCC,R pL,~ ~z 2-14 i.

" : C C Objective I Narrative of Approaches 2. ASA T/ONAL CA~CE~ PLAN -- 3, 4, 5, 6, • .:..,- i:-.!..•- throuq]7 these m~aT~s should be explored• The relative balance of cellular i~r;munity versus tur~!or~enhancino humeral anti- bodies ~rlts study• Normones. Further elucidation of the role Of hormone~ in the carcinogenic ~rocess is needed. Certain model studies have indicated both pronlotin~ and protective effects of different ho~loiles under dificrent experill~ental conditions and i11 hunlans, Caloric restriction or excess. Further studies on the role of calorlc restriction and excess on burial• follnation are ~eeded. At present the role of caloric restriction in lowering tile effectiveness Df chemical carcinogens i~ nob understood at the cellular or n]olecular level. Research on this process should incl[~de irlv~stigations on the effect of restriction On the imrT]unoIogic system and On the fo1~atio~ of gnz~11es that d~toxify carc;nogens. Combination£ of caloric restriction, Caloric excess, ~nd r~striction of snecific dietary components also need to be studied for their effectiveness in inhibiting chemical carcinogenesis. Specific animal models of human cancers ~,rould be very useful, Other nutritional factors. Experimental and epidemiological evidence sbo~zs that dietary factors enhance or inhibit carci~ogenesis, not necessarily by ])ei~g carcinogenic, but by affecting the influel~ce of a carcinogen on a given target cell• Additional studies on the role of nutritional factors on cancer fomatien are heeded. For example, metabolites of tryptophan may be involved in the fonnation of so,~e cancers, nutritional deficiencies may modify the mucous-producing epitheliu,~ of the cervix reducing resis- tance~ and excessive intake of fat influences the lipid-soluble hon~;ones and their receptors. Ceil-growth inhibitors. Phenomena such as wounding and irritation speed cell growth Bad also accelerate carcinogenesis in animal model systems. Reducing irritation or slo~ing ceil growth would be expected to have the opposite effect and agents ~.Iith these effects could be considered for preve:~tCve therapy if active in sensitive animal models. :m The bases of resistance among humans exposed to high levels of carcinogens• Th~ majority of people ~Ibo smok~, even larqe nu:~bers of ciga-~ reties, do not develop cancer. The inmluno]ogical system, the lack or presence of viruses, and the level of various ~ enzymes that activate or inacLivate carcinogens should be investigated on various bUlllan tissues including the placenta. 2-15

( Objective 1 Narrative of Approaches Comparative studies ia animal models on the same parameters should also be done on sensitive and resistant strains of tile same species. F. Studios to Identify Persons With a lliah Risk of Cancer by ~estin~ their Cells for Susceptibility to Onto enic Viruses. In such studies, c~l} cultures derived from individual humans would be tested for sensitivity to trBnfonnation by kno~,'n onco- genie viruses. Individuals whose ceils were sensitive would be considered under "high risk" in comparison to those $~11ose Col}s were resistant. G. Studies to Eliminate Candidate Cancer Viruses from iliRh Risk Groups. Experiments v$ith Nerpes type 2 virus, a possib%e etiological agent '~n cervical cancer, indicate that it nldy he eli~in~ted by treating virus-infected cells ~:ith neutral red or proflavin. After uptoke, the treated tissue ~s ill~minated and, as a result of the photo- dynamic effect, the viruses are killed, High risk groups (e.g., prostitutes} could be treated with the agentand follow-up studies maoe to detormine th~ effect of eliminating ~i~e viru! or ~ne in- cidence of ca~icer. I¢.4}rlO~VY&L CANCCI~ pLAJV 2-16 0

I / Ill. CO~CLUS IO!iS The effDrts to eliminate carcinogenic hazards from the environment and to identify and subsequently ~liminate, as yet undetected carcinoo~nlc factorsh ark of crucial im~tedlate importance in tbe preventiDn of cancer. In addition, we must Intensify o~r effcrLs to understand how carcinogenic substances act i~ the best. On}y ~brough s~cb u~derstan@i~g wf~] it be- com~ possible to prevent the disease in b~mans expDsed to agents which ~ause c~nceP, There is conceptual and scientific unity inherent in the entire program, which has been divided for operational purposes into approaches, Success ~n acbievlng olle approach depends upon essential approach elements de- fined in that category and i~ other categories as well. The e~tire plan #epends on a close interral~Lionshfp among the many apgroache~, eleme~ts and projects that comprise the objectives and should reflect a continuum of information at all stages of the plan. :b 3-~

.4 T q , c NATIO:IAL CNICER PL~ CONFERENCE PROJECT AREAS SESSI08 NOV, 29 - DEC, 2 O~jective One APPROACH 1 Charles g. Kensler, Ph.D..- Chairman St. Vice President & Director of kife Sciences Division • Arthur 0. Little, Inc. 35 Acorn Park Cambridge, Massachusetts 02140 Richard R, Bates, M,D. Branch O~ief, Experimental Pathology NCI. 91#g, 37, Room 3A09 BllI, Bethesda, llaryland 20014 Fred G. Beck, Ph,D. Director, Orchard Park Laboratories Boswell Park Memorial Institute P.O. Box 312 Orchard Park, New York 14127 W. Bay Bryan, Ph.D. Scientific Coordinator for Viral Oncology RCI, Fedl, Bldg., Room 4600 NID~ OetOesda, Maryland 20014 • Walter E. Heston, Ph.D. Chief, Laboratory of Biology RCI, Bldg, 37, Room Z[24 RIM, Bethesda, Maryland 20014 R, Walter Schlesinger, M.D, Professor & Chairman, Dept. of Microbiology Rutg~rs Medical School College of f,~odicine and Dentistry P.O. Box 2100 BewBrunswick, New Jerscy 00903 Bela Toth, D.V.M. Associate Professor of Pathology Bniversity of Nebraska College of Medicine 42 Be~.,,ey Avenue Omaha, Hebraska 68105 APPROACH Z Marvin Z~len, Ph.D.- Chairman Professor of Statistics SUI~Y at Buffalo 4230 Ridge Lea Road ~lherst, New York 14226 Rosv,,ell K. Boutwell, Ph.D, Professor of Ontology McArdle Laboratory for Cancer Research University of Wisconsin Medical School Madison, Wisconsin 83706 l~win O,J, Bross, Ph.D. Director of Biostatistics Roswell Park Memorial Institute 666 Elm Street Buffalo, New York 14203 RoBert d. Bryan, Ph,D. Associate ProFessor of Pathology USC School of Nedicine 2025 Zonal Avenue Los Angeles, California 90033 dos~ph A, DiPaolo, Ph.D. Head, Cytogenics & Cytology Section, Biology Branch I~CI~ Bldg• 37, Room 2A13 RIH, Bethesda, 14aryland 20014 Frank J. Dixon, M.D. Chairman, DopE. of Experlm~ntal Pathology Scripps Clinic & Research Foundation 476 Prospect Street La 3olla, California 92037 William F. Forbes, Ph.D. Professor of Statistics ~ ~ University of Waterloo Waterloo, Ontario, Canada C~ C.q *VA~IO~'At. C#INCE~ PLAN B-ll . iI ,. i :

I" ( APPROACH 2 (continlJed) L. Saxon'Graham, Ph.D. professor of Sociology S~Y at Buffalo 4224 RidB~ Lea R~ad Amherst. New YerL 14226 ]ngegerd Rellstrorl, M.D. Research Associate Professor of Microbiology University of Washington H~dical Sch~o1 Seattle~ WashiBgton 98195 Mr. Nathan Hantel Senior ~akhematical Statistician NCI, Fedl. Bldg., Room 5C12 RIH, Bethesda, Maryland 20014 Walter Troll, Ph.D, Professor of Environmental Medicine NYU Medical School RNS Bldg., Room 601 550 First Avenue ~ew York, New York 10016 Elizabeth (. Weisburger, Ph.D, Scientist )irector NCI, Bldg• 37, Room 3B27 "~ill, Bethesda, Ma~land 20D~4 ( Ob'ective One APPROACH fz ~, ! John H. WefsSurger, Ph.D. - Chair~n Bead of Carcinogen Screening Section, Experimental Patholo~ Branch N~I~ 51dg. 37. Room 3~BB NIH, Bethesda, Naryland 2gOl4 A11an }{, Conney, Ph.D. Director, Dept. of Biochemistry DruB ~letabolism Noffmarn LaRoche Inc, Nutley, Ne~ Jersey 07110 Nans L. FaTX, Ph.D. Associate Director for Programs National Institute of Environmental Health Sciences P.O. Box 12233 ResearcN Triangle Park, North Carolina 27709 Barry V. Gelboin, Ph.D, Supervisor Research Chemist.Chemistry Branch, Cdrclnogen Etiolo!~v NCI, Bldg, 37, Room 3E24 NIR, BetBesda~ Marylaad 20014 Dietricl K. }{offmann, Ph.D. Chief of Diw~i)n of Envlronmenta] B~cinoDenosls American l{ealth Foundation 2 East End Avenue New York, New York I0021 Benjamin L. VanDuuren Sc.'D, Professor of Environmental Medicine N~U ~edical ~ntDr 550 FirsL Avenue Ne~ Yorh, New York 10016 om ~J :J c~ t/A TIOiVAL CANCE FC pLAN -- B-12 ~°

( ( Objective One APPROACF{ 4 Edwin N..bennette, M.D. & Ph.D. - Ehai rman C~ief, Viral & Rickettsial Diseas~ Labor~tory California Stat~ Dept. of Public Realth 2151 Berkeley Ray BerKeley, California ~A704 Hollis G. Boren, M,D. Chief, Pulmonary Disease Section 51100 West National Avenue ~il~a~ke~, Wisconsin 5~193 Gig B. ~ori, Ph.D. Associate Scientific Director for Programs, Etiolo~ Branch ~CI, RldR. 31, R~em ll~g~ ~IH, Bethesda, Maryland 2R014 Daniel ~orn, Ph.D. Director, National Clearinghouse for Smoking ~d R~/t~ 5600 Fishers Lane, RO~m 11A56 Rockville, Maryland 20852 Robert M, McAllister, M,D. Professor ~f Pe~iat~'ics Children's Hospital of Los Angeles P.O.Box 54700, Terminal Amnex Los Angeles, California 90054 William ~. Payee, Sc.D. Deputy Director Rational Institute of Environmental Health Sciences P.O. Box 12233 Research ~Tiang~e PaTk, Rorbh Carolina 27709 John B. $torer, M.D. Scientific Director For Pathology and |~D1ogy, Biology 9ivisi~n Oak Ridge Nationa] Laboratory P.O, Box Y Oak Ridge, Tennessee 38730 APPROACU/~ Gerald R. Wogan, Dh.D, - Chaiman Professor of Food Toxicology Dept. of Nutrition and Food Science, Room 56-217 Massachusetts Institutm of Technology Cambridge, Massachusetts 02139 Robert E. Eckardt, H.D. & Ph.9". Director of l,ledical Research Division Psso Research & Engineering Co. P.O. Box 45 Linden, New Jersey 07g36 Raymond V. Gi]den, Ph.D. Vice President of Research Flow Laboratories, Inc. 1710 Chapman Avenue Rockvil~e, Maryland Z0852 professor Sidney Laskin Research Associate Professor, & Pirector of Laboratory of l~ha~ atio~ Toxi coi ogy NYU P;edlcal Center Dept. of Environmental Hedicine 550 First Avenue New York, New York lODI6 Mr. Clifton R. Read Senior Edi Lot-Consul tant American Cancer Society 2]9 East 42nd Street Rev~ Yo~k, Re,~ York 10917 Irving R. Tabersha,v, M.D. Professor of Occupatlohal Medicine School ef Public Heal~h 19E~ Ear~ Wa~re~ Ra1~ University of Call fornia Berkeley, California 94720 Gm ~a C~ CA NA TtO~C ~ L CA~ICE R PLA N -- 8-13