Tobacco Documents Online

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Vanguard-a discovery that elimhates the 3 agents cigarettes l/nked to and Heart Diseases: NO Tobacco Tars.-..NO Nicotine, more imporUnt Ar Il C! In the ~ five years l~xhaps you have read articles like: "Cancer by the C,~on", "Csn the Poison in Ci~rerr~es he Av~d~T', "N~ ~ne...~e Smoke~' Enid", ~E~z Ca~ ~-Causin~ ~emi~I Subs~n~ in T~ If ~, you ~ ~ow that t~e is s ~ ~ ~n ~e de~ of ~, h~ ~ ~d ~he i~id~ of lu~ ~. All ~kers, and ~u~rly hm~ ~ok~s, ~ve a ~her mo~li~ ~han non-~ok~ ~ ~en~sm s~ib~ th~ ~ ~e pr~ of ~ba~o ~rs and fine in ci~. Ye~ ~mos~ eve~ ~me one m~i~l author- ky ~blish~ a li~ ~tw~n to~ s~ ~r, or ~n ni~zine and ~rdi~ v~u~ ~) ~iments... another f~ion s~ up and d~ ~he pr~f is no~ ~si~iv~ Bu~ this much ~ ~own for sure: 1. The more you smoke, the ~r~er the probability of your contrac~in~ lung 2. Tob~ ~m ~ve r~uk~ in ~c~ when applied ~ ~n of Shills. 3. Nicofi~ (an albion) is ~ ~bit ~rug. It a~avat~ ~rdiova~ul~r ~ilmen~ (h~ ~fi~). A ~ Canc~-Ca~g A~ent a~u~ ~e ~er of ar~nic in ~bly ~; ~ r~ ~ Y~r ~ recognized as carcinogenic (cancer-e~using) I cork or cellulose.., whether i~'~ a single fllr~er to m~ or a dual filter, or other =ick device~, i~ U~l~ke your present ci~r~reue, Vanguard do anything more than reduce • mere fraction ha~ ab~olumly ~ arsenic. of dangerous substance~ pre~ent in the smoke Fi~ De Not Eliminate Tobacco Tars, of your c~garet-~e. ~qicotfme or Arsenic Three Agents Known To B~ Harmful im No ffl~er on any cigaret~e can protect you Cigarette~ Have Been Taken eomple~ely. Whether that ~ter use~ charcoal Out of Vanguard ! So why rake a chance: Smoke Vanguard and Laboratory Tes~ Prove en~oy pure smoking pleasure un~ainr~d by ~ig~re~ Fatal te Animal~ thee three harmful agents-tobacco ~ but Vanguards Are Not! nicotine and arsenic. The secret of Vanguard (no tobacco tar~ Sixty yo~ug ~lult rat~, evenly divide~l a~ to sex, no nicotine and no arsenic) k "F~ril~" were ~ivi~e~ into ~wo groups. Each ~rroup wa~ i~ in~ravenotmly ~h • f~')~ ~ilu~ion of blended ~ormula of scientifically proce~ed ~ materials (a ~us~er~ion of ~r~pped ~moke natural from Vanguardz ~nd from ~ ~ing ~l~er-zip ci&~ret~e~ Ra~ were obse~wed ~or signs and What's more, Vanguard's amazing fiker ~/mlW~m~ of poi~omng over a period of two dOeS not bare to block ou~ anyzhing. Van- weeks. V~,g,~rd ~ ~light brie~ incr~se followed by g~£rd's tiRer is ~here jtm~ W give you norm~ rs~e of respiration. No o~her signs of clcart, parZicle-free smoke you like. sympton~ o~ poisoning. Le~ling Fil~er Cigarette -- sligh~ brief increase • How does V~ngu~rd ~e? A new, ~ ~ollowed by profound depression and in ~orne in- I clean ~avor. smm~e~ l~-rmanene arrest of re~ph~ion, cysn- ~i~, a~l muscle we~.kness. Onsee of ~ymp~r~ t • Aztd wh~t o~ ir~ aro~a .~ ~t's di~eremL Do~; ~ m@id (within ~ mimne). Anim~l~ th~ f~iled t expe~ a ~tcoo ~x~e./~. Smo~e • pa~k-a wh0~ ~ ,m,,ive died ~urin~ course of injection or wizhim ~ minute of injector, i pack. Give your~lf a chance. Le•dimg Filter Cig&ret~e Vanguard ~ • Remember... it's no~ t;,zt you smoke, i~'~ Do_.._~* ~ Dos.._..~° Mon~ity I w~at you ~rnoke. l.O Z o~ of 10 LO ~one , ~ ~ o.~ of ;0 ~.~ none i • For the first time in your life, smoke ~.o 7 o~ .f ~0 z.o none ~though the to~. effect of cigarette ~,~oke c~n. i • Smoke Vanguard. m~ ke ~m~ exxr~pol~ ~o man, it m~t ~ ~ _~ • moke ~ citrate, contain* ~u~mg W~t~a g~ter ~tential toxicity Z~n ~ *p~l~,~d ~t~O~, ,~rvey, ~ ~ ~ s~ *f V~ar~ with ~ri~s ~en~ ' ~~l~r~A~~w~ ~n. O~a~ Dr~v*. ~aysbere. ~ I~ New Y~r~

Cancer Society Applauds Vanguar : (.finley. ho~pi~ and pa~i~-n~ ~u~erin~ c~nc~r, e~rdio-v~u~af and Brigh~'s d~'~' wired and phon~ ~he manufacturers o~ Van- At that time .Xlr. MeF.ord IL Runyan, Ex~cu- Vsce-Presldent o~ the ~eHc~ Cancer ~- c~ety issu~ ~he fvHowln{ sta~men~: "~e American Cancer S~[ety ~lieves t~at smoking of ci~arett~ ~ ~he chief caur~ ~or ~!arming r~ in ]un~ caner tn Lhe last ~wen~y year~ The Vang,Jz., : ~n h~*.eres:ing reflection of the Public's cone: .... ,'er smoking the familiar tobacco cigarette..~:~,--~pts to produce a smoke are to be ~ ;r~ " ,¢ , ".'ed. However. it will not be possible to mak~ .,,. cstlma~e of the s~fety of +,his or ~ny other .... ~ ",,noking product without extensive observa~:''" ~'~ +.ests.'"

~v~on ~he ~ day, and ~he nex~ ~ch w~s gone Lhe ~nd ~o~ "~ ~b~e ~ ~'~t~ " :~ one ~l~ ~ a~t ~ ~o r~lMe for ~ad-~w~d salty ~ ~u~m~ of w~k. He ~y, ~at ear~n p~ have ~c'n hea~ "in-~,~e~ at~m~t ~ d~ a ~m-~f~t u~ ~ ~h *~elo~t ~e~t~ ~e~ y~ leave v~- Ban~b h~ a~u~M a ~,~re f~t pXant Bay Sho~, N.Y., which once w~ o~r~d by a ~bacco ~n- a r~ for ~ ~n~t~: "~ C~a-Coh te~l Business Week r. YoUr "~an~ar~ £~s far ~vond the various ~e-n~tln~ ~ divulge what it d~ ~n~in." "B~n~b ~on~ an inde~ndent rose.oh agency ¢~ ~rld't to~ ~. r~ t~ pmuct ~mou~n a rat test. zne agen~ ~ven out ~f la ra~- di~ Cr~ ~- ~,,;x.~*~-, ~ ....... ¢ n~,.. sa~ oc va~ ~~ ~i s~ ~), ~£ ~ ~ ~- ,~ ~ of t~ ~t I He "s e to b y V gu d re er u an ar . . ~ Food Fair. Safew~y - ~ck - ~- K~ Ku~ - ht~~-~~'s-Pe~ ~v~-~-Key ~-~ ~ ~ ~ - T~ C~. ~s. Wake~. ~~. ~ ~- ~y~ ~~ ~ ~ o~ ~I ~

January 6, ~966 Dr. W. M. Bright Re: A Process for the Elimination of Carcinogenic Properties of 3:4 - benzo - pyren in Cigarette Tobacco" An application for a German patent on the above process has been registered at the Geman Patent Office, Munich, Germany, under the number B 82 871 IV a/79c. The inventor is Dr. Max Bindlg. He has done research on cancer and is the Chief Hedlcal Doctor of the Medlcal Institute "Perclval- . Pott-Statlon" in Munich, Germany. In the practice of the invention, t~o pounds of an organic substance (unidentified) is added to about 333,000 grams of tobacco for manufacture into cigarettes (rate of application is about 0.3Z). As reported in Tabacologia 18 (No. 9) 25 (1962) aroma of the tobacco (presumably aroma of smoke upon smoking the tobacco) is not affected. It is claimed that the presence of the organic substance in the tobacco prevents the formation of 3,4-benzpyrene (same as 3:4 - benzo - pyren) during smoking. It is conceivable that the above conclusion may have been reached in good faith by the inventor with the analytical method he had available when his experiments were conducted. However, if the experiment and the analysis were repeated by us at this time, it is believed that only a moderate reduction, if any, of 3,4-benzpyrene would be observed. The following factorshave been considered in coming to this conclusion: I. Analytical Metho~ Considerable work has been done both here and in Europe on the development of a reli.able ~nalytical procedure for 3,4-benzpyrene in cigarette smoke. To our knowledge, all methods in use, as late as about six months ago have been extremely cumbersome and time consuming. Host of the methods rec the smoking of about 3,000 cigarettes and in no case less than 100 ci Accuracy of any of the methods was unsatisfactory. For exsmple, analysis may have showed a yield of 3,4-benzpyrene of 3 pg/100 cigarettes on one lot and 1.5 pg/100 cigarettes on a subsequent lot of cigarettes in the same experiment. It is conceivable that in making the analyses for Dr. Biudi~, the analyst might have obtained the value of 1.5 pg/lO0 cigarettes on the control and 0 pg/100 cigarettes on the test, whereas the actual values should have b~en 3 pg and 1.5 pg respectively. Nonetheless, Dr. Bindig could have logically concluded that the 3,4-benzpyrene had been eliminated. In no case have we been able to completely eliminate the 3,4-benzpyrene in our experiments with additives. We contend that many of the exaggerated claims which have been made by various investigators regarding reduction of 3,4-benzpyrene are attributable to unreliable analytical procedures. 2. Types of Additives None of the organic additives has reduced 3,4-benzpyrene in our experiments. Reduction has been achieved with inorganic additives, but never complete elimination. Three types of inorganlc additives are discussed below.

2 Classes of Inorganic Additives (a) Oxidizing Agents Cupric nitrate, potassium nitrate, magnesimnnitrate, aluminum perchlorate and others, have reduced 3,4-benzpyrene and other polycyclic hydrocarbons. However, the nitrates resulted in formation of toxic oxides of nitrogen. These additives are therefore deemed undesirable. (b) Sulfam£c Acid and Anmonlum Sulf~mate Moderate reduction of 3,4-benzpyrene has been achieved by the addition of these materials; however, flavor of smoke is adversely affected. (c) Aluminum Oxide Trihydrate The addition of 25Z by weight of the above reduces 3,4-benzpyrene by about 25Z. Reduction is attributable to lowering of burning temperature. It is believed that formation of 3,4-benzpyrene is one of the fundamental reactions in the smoking process. The prevention of formation of the material would therefore require a very substantial change in the smoking process. It is highly unlikely that this change can be brought about by an organic substance. I have discussed the patent with Dr. Teague,~He w~"~ot able to envisage an organic material that would reduce 3,4-benzpyrene in smoke. Extraction Procedures 3,4-Benzpyrene in smoke has been reduced by extraction of tobacco prior to smoking. The extraction (with hexane, ether, chloroform) removes long-chaln aliphatlc hydrocarbons (C15 through C33), sterols and solanesol, which are believed to be the main precursors of 3,4-benzpyrene. The mechanism of formation of 3,4-benzpyrene fro~ these precursors.ls believed to be a series of cyclizations, dealkylations and dehydrogenations. One would expect that oxidizing agents (i.e. KN03, and others) would affect these reactions. The effect of the anmoni~m sulfamate is obscure although i~could act as a burning retardant. A lowering of the burning temperature would be expected to affect these reactions and it is not surprising therefore to find that al~nina trihydrate reduces 3,4-benzpyrene. However, it is difficult to vis- ualize how an organic substance could affect these reactions. In v~ew of the above, I seriously question the validity of the Bindig patent and do not reconmend that we express any interest in it. Horeover, it should be recognized that the presence of a substantial smount of a foreign organic material in tobacco (0.3~) would likely produce appreciable amounts of new smoke components which might possess undesirable physiological properties.

The cancer researcher and chie£ medkcal do, cot o~ the medical institute "P.ercival-Pott-$tacion" l~unich, Germany has developed a:method which makes . it possible to render benzpyrene~ the cancer producing substance in tobacco,.+ =ed~cal.c'ongress (unknown) and in addition told ~s ~o~e detail~ during an Sn~crview £u Hunich. Accordiu$~y, through chemical and technical method~ possible to el~ninate the cancer producing benzpy~ene. Dr. Biudig . ~old us that a method has been developed in the Hun£ch institute £u ~h£ch ~hey eliminate thi~ danger through structural modification of t~e benzpyrene, the aroma o£ the tobacco £~ in no way ln£1ueneed., 12130/65

M E M 0 R A N D U M This memoraudum relates briefly the past hlstoryoof the ne -' got~atlons which were carried, forward over a period of three~ months between, BARON MAXIMILIAN DE CLARA,Mr. LOUIS BECK and Associates on the one (US) hand" and GLOBE-MONTAN G.m.b.H. on the other (German) hand. These negotiations were exclusively concerned wit.h the purchase . of the world rights (exclusive of West-Germany) for a new German invention registered at the German Paten't Office (Munlch,Germany). under the number B 82 871 IV a / 79. c in respect to " A process for the elimination of the carcinogenic properties of 3:4 benzo pyren in clgarettetobacco." These ne~otlations were successfully concluded on November 18th, 1965: . • ' H~Is~ory: .During Summer of 1965 Baron de Clara was made aware of the' - •existence of the new German process by one of the partners • ..... of GLOBE-MONTAN G.m.b.H. Baron de Clara subsequently in - ' • .i.~. . formed Mr. Louis Beck of the" developments and it was then .. .... :-':. . decided considering the importance of the new Invention ." if it checked out right to open negotiations for the ..... '. purchase of the world rights exclusive of West-Germany.. : • . " A considerable amount of valuable information was sub - .. ~ . sequently forwarded by GLO=~E-.MONTAN~.G,~t~h.H~. ~o~New ~ork which removed practically any doubt.the US-Group m~ght " ~-- ~ have had regaling the valldit~ of the German claims as .... . to the efficiency and economy of the new. process.It was'. .. therefore• ~eclded by the US-Group to..go to Germany to flnal'Ize-the negotiations on the spot. ., US-Group: Mr. Louis Beck,Baron Maximilian de Clara,Mr.D. Thomas, . .,, Mr. Charles Roche and Mr.. D. Halperin. .... . Mr. Louis Beck ~. Mr. Beck is an attorney-at-law with off~ ~t • " " .-. ~ .... ~..515 Madison Avenue,New York City,N.Y.He "~ ~ne . ,. • :-~.~:;..".~.. treasurer of the Democratic Party of the State . '~~ . .~ ~~..~.::. ~..~".: ..",~..:: of New York and a member of the ~esldent's Club, ,.-. -" .~ ~: ".~>~:~..In Washin~ton,D.C.Ee has been highly reco~ended : ..~'... • ". " "-...~. by the Vice-President-of the USA,H.Humphrey,(see ...>....:. ~;.~ letter of Mr. H~phrey to the US-~bassador McGhee . .-...: according to wire information received from the ~' :.'"" :. ~ .... ~a~lin National ~ is In the medl/~ seven . . ~ron,Eaxlmillan,,~e'~ Clar~:. Baron de Clara Is. ~ officer and director " ' ....... """.. ~>.~Ge~n:to~coo deaI'was tha~ of a."Finder"

Mr. Donald G. Thomas : Mr. Thomas has made hls career in business with b~'ILEVER,$he third largest non-US .~ ... corpora$1on in the world.He has been with • said company for 35 years and retired upon • . ~ reachlnl the mandatory retirement age,He ... was Director of Marketing for the Americas ~... fo~ ~:nilever and subsequentlY President of • .: Unllever In~ernatlonal.Mr. Thomas is also " ::presently a pertner of Mr. Beck's in several • ' of Mr. Beck's business enterprises. Mr. ~Charles Roche: Mr. Roche is the Vice-Chalrman of the 'Democratic ~ ,.~.. National Committee and close'ly associated with ;. the Kennedy family.He was Nr.R. Kennedy's room- ~ mate at Harvard. .... ~r".. Da.v,id .Halper~in: ..~ Mr. Halperi.n is an attorney-at-law and a partner'.' . in the law-firm of Halperln'& Rosenwasser of .' " ~15 Nadlson Avenue,New York CItF,N.Y,Mr. Beck. asked Mr. Ha!perln to. accompany him on this trip to draw up the necessary legal papers,lf ' the negotiations should progress favorably. ' During the first trlp.of the US-Group to Germany wewere, able to substantiate mob~ of the German claims and documents.~ne US-Embassy in Bonn,Germany,as.well as ~he German Ministry of Health.officials cooperated" efficiently with us.it was therefore declded'%o draw • .German •Group: Mr.lng. Fink, Prlvat-Dozent Dr. Schoeber and Consul- General h.c. Styler.All ~hree gentlemen are partners in GLOBE-MONTAN G.m,b.H.Globe-Montan G.m.b.H. 's main business activities concern themselves with the de - • velopment and subsequent large-scale industrial ap - ", pllcation" of inventions in the anorganlc and organic- chemical f~elds. ~ • ~" Nr.. Ing...F_Ink: Mr, Fink owns the Gm~ndener China manufacturing plant • (Austria) ,the third largest in Austria and holds participations in other European industrial enterprises, .Prlvat-Dozent_Dr..Sc~h.oeb.e.r: Dr.- Schoeber is a .partner of Mr. Fink's ..... in Globe-Montan G.m.b.H. and other of • • " Mr. Fink's• enterprises.He is also an .". • " associate. Profess'or for Chemistry at the University of Vienna.. .C.o.nsulrOen_eral ~._c. St~,!_er:~ i.~r. Styler is a retlre~ business-man,who " had been in the export-lmport business ' ~ for silk and related materials originating .'~. ~/ from Thailand.He was. the Royal Tha~. Consul ~ ....General in Munich for 18 ye~r.s. . ~ ." • legal papers and proceed with. the purchase of the German invention. ' • Once the pertinent documents had been dra'~ up and the terms agr.eed, o upon,we decided• to return co the USA to.obtaln, additional information ." from the US-Government.lnWshlngton,D.C.We: obliged ourselves to return to Munich,Germany,by the 18th,November,1965,to finalize the ne -.. -"" gotlatlons, " • '; . ~ . i .. ~: :.:~..".'-'o.....~ !..': ,." ..: " " '. ,

2~. Trip to Munic~h,Germauy: . :.. US-Group: Mr.'Louls~ Beck,Baron Maximilian de Clara,Mr.D.G.Thomas, Mr. Charles Roche and Mr. B.Tannenbaum. Mr. Bernard Tannenbaum~ Mr. Tannenba~,~ is an att0rney-at-law and a partner of Mr. Beck's for several years. .He is chairman of one of thepolicy committes of the Democratlc party in the State of New. York. " . German-Group: Mr. Ing. Fink,PrlvatpDozent Dr. Schoeber,Consul - General h.c. Styler,Dr.med M. Bindig and Dr.Bastlan. Dr. med. M. Bindig: Dr. Bindig is the inventor of the new process. Dr. Bastian~ • o~ .i~ • • Junction with some of the major West-German • /~0 ~o~ Universities as well as the world-renowned Max ~.. ~ .Planck Institut on research regarding bloo~ s.ud ~ .~ ; .tumour diseases..~ • ' ~Dr. Bastlan is an~attorney-at-law.He represents the ~o~*~~..~.~ ~.^~' the ~ Bavarian f~ily amongst others ~d enjoys an excellent reputation. For several years he has been working in con - •..~... During the 2.Trip to Germany the purchase ~egotiatlons were finallze@ and upon certain mln~r changes in the initial contract the purchase.. agreement was signed on November 19th,1965,bet~een GLOBE-MONTAN G.m.b.H. and CHEMICAL RESEARCH & DEVELOPMENT CORP. • CHEMICAL RESEARCH & DEVELOP~.~NT CORP. ,a Delaware Corporation,was formrd by the American Groupupon their return •from the l.Trip to Germany.An account was opened for the corporation with the Franklin . National Bank. Management: Mr. Louis Beck,President • ~-~ -~ .... 'Mr. B. Tannenbaum,Vice-.~resident " .'- . ." Mr. D.G. Thomas,Secretary-Treasurer•. ;..!~ The Beck-Tannenbaum-Thomas-Group are the controlling stock-holders.. A certain minority ihterest is represented~by Mr. J.A. Schumacher', " Vice-President of McDonnell& Co.,investment bankers,120 Broadway, .~" New York City,N.Y.TheSchumacher-Group only recently bought into Chemical Research & Development Corp.The remaining equity is o'~ed . by Baron l.~aximilian de'Clara. An understandihg has been~reachedbetween ~ne management of Chemical Research & Development Corp. and Mr. J.A. Schumacher,that McDonnell • . • & Co.would head a syndicate,which might also include Bzown Bros. '. Harrlman,whomMr. Beck is very close to,lf there should be an under - .~. writing.M~. J.A. Schumacher will~also become a director•°f Chemical .! .~. Research .& Development'Cor~. .. . /. . !.... Sb~MARY: Needless ~to say that the potential of the new invention and ~ Its lar~e-sca!e industrial appllcati~n is enormous in view• of the fact that the US-cigarette industry alone, procl~ces "" "~.. - approximately 600 billion clgarett~s alone.It is the intent• oS Chemical Research & Development Corp.' to license the process.against a fee.to the industry worldiwide and it" seems thata fee of US Cents one (I)-per three car~ons " .. ............ ~.~" ~ ............ ." ........................

of cigarettes will be acceptable to the industry. Such a fee in turn should provide a rather substantial income for the stock-holders of Chemical Research & Development Corp., an income which calculated on a net net basis should be in the medium seven figures, if not in the lower eight figures. Our talk with top US-Government officials have shown that the Government will give all its support towards making smoking "safer". The cigarette industry as opposed to former years~is also prepared to collaborate as our recent talks with top officials of the industry. in Richmond, Va. have shown. ~.. In General there seems hardly any doubt in the minds of the people involved in this situation that the endeavours of Chemical Research ~ & Development Corp. will be remunerated rather well but that also a" right step is taken to make smoking "safe~~ and thereby improve the health of ~he public. ..: ' If any further information should.be required please feel free to . .~ contact Mr. J.A. Schumaeher, Vice President~ McDonnell & 120 Broadway, New York City, N.y., RECTOR 2 7800. Re the new German process: The invention of Dr. Bindlg's concerns itself as above briefly described with a method, which eliminates 3:4 benzo-pyren out of cigarette smoke. Through t~e report of ~he US Surgeon General - the so-called TERRY-report -,which appeared ~n Fall of 1964, as well as through the report of the Royal College of Physicians (London, Great Britain) and other Government publications regarding the hazard of smoking, it is withou~ doubt established that 3:4 benzo-pyren is carcinogenic. The el~minatio9 of 3:4 benzo-pyren out of the cigarette .. smoke is therefore of utmost ~mportance to make smokin~ safer.~- .~ ~. In the German urocess an organic compo.undis used, which is sprayed on the tobacco~ As long as tobacco in ~he-course of its processin~ in the plant issprayed anyway no additional equipment has to be added but rather the~organic substance is dissolved.in the normally "used spraying substance.~ The'Cost. for the German substance is very small and only a Very small amount of the substance has to be added to the conventional-spraying fluid, namely: 2 pounds of substance will treat 333,000 cigarettes at a cost of approximately US $3.50.- per 2 pounds of subs tance. Considering the economics and the easinessof application regarding the new German process as well as the overwhelming favorable attitude of the Governments to make smoking "safe~', there can be hardly any doubt chat considering the enormous volume involved in the c%garette industry a highly profitable venture w£11 be built ups.-~..... t~ .

00~ ' e3 e~z~q~/O0"O0~$ - "" sseoo'aa ue~u'6~ - o~oT.'O 'xq o~:~sclo.T. ~o UOT~eue~ouTo:~O-~CT

POST OFFICE BOX 21"7 PA~IS~DE~ ROCKlaND COUN~I'. N. Y. l)ecenber 13, 1966 CJ~ .~..~o~ i~es~rch and Development CorpOration 5.~ ~ls.~n Avenu~ . ::_~. Y(,:~, Nay York IOO22 This letter is a brief sum~ cf the definitive results of our che~,¢al an~ bioloSicel eJq~er|m~r, ts relet~n$ to the spray/us of tobacco ~:h a new £o~ls ~lled "~~1", vhich effectively elt~tes or of the itit~l 8~ ~UliOnl conts~ed herein 8re co~eLe~y do:u~,~nc8 a~ ~alyzes ~r e~rt~nts 8~ presence ~ttaf~tory evidence ~o euppor~ ~r fL~L~8. In both ~e chef, ca! and bioloa|csl tests, ordinary co~rclal ctF, arc~e tobecco u~s used, ~ all condLcton8 vere /den~tcsl ezcepL tbac co~8r/eons ~ m~e of resu~c5 fro~,~ tobacco treated by spray~ it .Jith C~8ol is distinguished fr~ un~reated tobacco. Clsarette8 ~ere ~de ~ith the tobsc¢o a~ ~chsnicslly "s~d" ~der 8t~dards vhich are lnte~tio~l~7 used and acceptod. ~e ~o~b:~llte8 tr~p~ed and filtor~ tu ~eoe e~orl~n~e vss u~ed for ~e eh~cJl ~d b~olos~csl studies. ~ e~srL~nt8l da~ ~8 ~en obtJ~od b~ or~h~ox ~th~8 ~ reliable ~ru~ute~lon. ~ 9~ri~ntal z~lu~t8 cau ~here[ore ~ r~o~ b~ other b~ol~.gical 8~ bi~e~¢81 ~le~r~o torieJ. Chemise! is ~ ~ezd~al [ormu~ition vhich is nou-toz~¢, non-

I~ce~ber 13, 1966 ~rea~nt. Coro~r~ ~d ~ripher~l arterial effects. related to cl~retto ~other /mporc~n.t flndln~ is thsc Chemaol treatment r~ee the ~otal solids ob~ fr~ ~ki~ reprdless of ~o br~ of of cou~ a~d i~rits~ iu ~rials on h~n ~bJects. o

THE LEXING~X)N LEADER Lexington, Ky. Ed. P.5 ]/14/67 BG AHG WSS DSP CS WRL WMB JHS CBW FDR Smoke Gets In You,' Eyes... And Lungs Wednesday marked .the third anni- versary of the Surgeon General's Report on Smoking and Health, the controversial collection of statistics which led to a fed- eral law r, equiring all cigarette packages to state: "Caution: Cigarette smoking may be hazardous to your health." But most Americans still make their jokes about "coffin nails," even though cigarette smoking is extremely harmful to many of our citizens. Many of the peo- ple warned by their doctors about ~,hat smoking will do to them, continue with- out a thought of tomorrow. The Louis Harris public opinion poll, released' the first of this month, showed tha.t only 40 per cent of those questioned were con~ meed that smoking was a ma- jor cause of lung cancer. And although 76 per cent favored the legal caution requirement on cigarette packcges. 57 per cent felt that the warn. ins wvs more than mlequate. Yet. well-trained scientists have found that ~moking is causally related to em. phy~ema, heart disease and cirrhosis of the liver at well as lung cancer. Those persons v'ho should not smoke, who have had warnings from their doctors, should stop now. Also, we should launch a rmtional ef- fort, a serious and meaningful attempt, to prevent youngsters from taking up the Imbit. Fifty years a£o, 42.000 men and $,000 women died of lung cancer. It was a rare disease, then. The tables have shifted and now all forms of cancer make up the nation's second leading cause of death. The National Advlsory Cancer Council has projected thbt ~05,000 people witl die of cancer in the United States during 1967. A grim thought. Since Lexington is the world's .largest hurley tobacco market, it Should be our responsibility to lead the way in develop- ing a safer cigarette and in providing leadership to decrease the-number of deaths which may be Indirectly related to our community's top cash crop. We should not deceive ourselves into offering .economic answers to serious questions of health. We should lead the nation with safer products and should make all people aware of any dangers in using our products.

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4~ECO%~RY EX PER I~{E~ 200 Uh'TREATED CIGARETTES %YITII BENZPYRENE ADDED O

S~veral of ~.~_ny ~.o~%odo for %he doteotlon and isolation of ~benzpy~eno~ ~dch h~ve appe~r~ In the lltoratu~e~ and ~o~- ~ioation~ of tho~e hotbeds have been us~ in our ~l~e. With the ~s~Ible oxc3ption o~ one of these met~do~ z;Dst of the~ o~- fe~/ f~m some defect ~-hioh made them ~ttraotive for ~utlne deten~n~ono of bcgzpyrene. ~ese mot~ds and m~fications had ~en used in the ~urse of a se~es of ~e~ents in ~ch the Identi~cation~ end quanti- fication of bonzpyrene had been sought. ~ther ~an ~ en~erate th~ at ~s ~ze ~ith thei~ successes~ and failures, they ~II be deseX_bed ~t~du the o~eriments pe~onued. 3,4-benzpt~ene of highest purity was purchased from Mann ~esearch Laboratories, Inc. A stock solution was made up ~th concentration of a~ut 20 ~g~/r,~l .ethyl al~hol (95%)~ Fro~ t~8 a 0.i ~ aliquot ~ms ~kon~ ~luted ~ 3.0 ml ~th alcohol s~u~ on the B~c~an DX-2 ~oco~ing ~peotr~pho~me~ in the ~slb?e ~eglon~ 500-~ ~, and the ultra~olet re.on, ~-220 ~ ~e c~mb~d spectra a~e ~ho~,~ in ~g. L A ~m~on of t~s speot~m ~ ~t repo~ted in the literature (E. ~r,,Poly- cyclic gyd~c~ns Vol. 2, p. 135, Academe Press ~b~er~, 19~) sho~m the identity of th~ t~.~o, ~th ~.~th respect ~ ~av~ lengths at I~eh abso~tion oc~l~s~ and ~e ~l,~tive ex~inotion~ at these ~ave!on~hs.

~ 50207 6702

A crook ~-~olution of 3~4-bonzpyrono was r~ade up in order to deter~Ane the range of concentrations ~hlch ~nfon~ ~th the Beo~L~e~ la~. ~ order ~ ~mi~e ~e d~n~er of h~n~in~ pure b~nzpyrone, ~oiG~n~ was e~nated. Znstead~ a ~a~ r~o~t on the tip of a ~at~a was placed in a I0 ~ ~l~ot~o flask~ ~nd the flask ~as fill~d ~th 95% ethyl alcohol ~ ~o mark. ~e absolute c,noentration of benzpy~ene was~dete~nod, speot~- pho~et~cally on the Beckman DK-2. ~e value for the log of ~e m~lar ~tinction ~ofx~clent was ~aken f~m ~ntloy, H.~,, and ~ ~an, J.G., ~no ~alyst, Vol. 83 p. ~2 (1958). In their oal- ~ation~, ~he value for ~ was taken at ~2 m~. ~S fi~e was r~l~lated fo~' 388 m~ since t~s ~ak seom~ to be more r~pre- sent~tlw of the ~neent~tlon of b~,nzpy~ene. ~ou~tion of ab~lute concentration of benz~reno in the s'~ck solution was as renews: 4.465 Literature 4.~ = log 0o38__~5 (optieo.1 density df a 0.1 ml aliquot) C (~-~les/l_iter) 25~.32 (~,oI. ~,~) X liters gr~.mo = 0,385 x 252.32 litez.~ 65706 Concontration of Stock Solution = 3xI~7 - 4.41 ~zr/O.l ~I

V ~I} ~d ~lott~d ve~,~m the ~i~uot~ ~kon (of ~peot~u ~)~ F~ 3~ ~II ~Imt~ ~ om ~ ~trai~h% llme, ~m~ ~ote~'~m~tion bon~p~no c~n~ontr~on~ c~ bs ~on~ ~.~ ~ro~t ~o~a~ ~t 3~ mu~ T~s is e~e~ly valuable in dote~~ ben~one i~ ~o pr~ sense of otho~ ~u~s~ng m~al, x:h~eh is ~ffioult to rezove~ ~inc~ t~s mm, te~al u~y be~ns ~ absorb at wgveleng~, ~hor investi~a~rs have t~ to calculate benzpymone ~noentr~.tions ~ the ~tra~olot ~e~Xon, ~peolfic~ly at ~96 z~, ~#_thout r~u~ success because abse~tion of ~e interfe~mg ~ate~l is ve~ intense in t~s re~on~ The ~olvont of choice ~ the literature is cyelohexano and/ or hex~.ne, In place of these solvents~ we used ne~dlylcyc!o.hoxane bec~use fro~ past e~rperlenoe ~e rotund ~s tu .t~s.~esz oertai~ ~Itlti6~ ~'ll!ch uo~o it a betto~ solvent for pol, ycyolio molec'Ale~. About ~.! )~g~ of s~a~ ~ors ~.tltio~od. be~#e6n me~yl alcoh~l ~d ~o~yl~yelohe~e. ~ter sepa~a~on ~ ing, the ro~due was ~sz~Iv~d in 95% e~yl alcoh.~l and the solution sc~ from ~0-3~ ~, On the b~s .of the optie~l don~ty obt~ne~ ~ud ~e s~n~rS ~o in ~ot~ ~$~, it slstent ~rlth ~r~s published in the li~ra'~re for the t,~o solvents~

iI. .1 .g

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~.~ hm~d~od fil.to~otip cigarettes containing ~ntreated t~er- can tob.~cc~ ~ore ~kod on a 6 p~rt ~.~achinv. ~e clg~rettes ~:ere ~ ~ over~l, 63 ~ of ~ch ~as ~bacc~. ~ ~zarette weigh~ a~ut I g~m ~d ~ ~okod ~ ~t~n i0 ~ of ~o ~Ite~ at a stmnd~ ~ate of one p~f pe~ ~te, of ~'~ seconds duration, and 35 ~. vol~e. ~e ~zoke re,dues were ~eoted on C~b~dge fibo~lass ~Iters ~Ith no m~e ~an 5 residues bein~ ~lleoted on a~ one ~Iter. ~e va~s ~.~nich by-~s~ the filters were t~pped on flasks i~me~sed in d~ ice, ~e r~dues ~ught in these t~ps ~er~ n~t ~ded t~ the filters in t~s e~e~Amont. ~ the ~0 filters u~s ~d~ 0.25 ~al of ~ook solu~on (~ ~gr benzp~en~), ar~ the ~es ~as e~crs~ted once t~th ml ab~o!ute met~l ~coh,l a~ then ~.~th he~e. ~e t~, phase~ ~e~ oe~r~ted. ~ a ~ ~lume of wate~ afar ~ch the o~qu~us alcohol layer wao ~-e~raoted ~th 2~00 ~ met~l~elohe~ne. ~e me~yl~ohe~ fractions were ~ol~ ~od over ~ ~ate and eva~rated ~der va~ao. ~s otep separated ~e ~d~ca~n oom~ds f~ the ~re ~lar n~n-h~c~bon ~bst~uces fo~d ~ ~moke re~c~es~ oar~n fraction is p~epar~ for si~ gel ch~za~grap~,. ~st Investlg~tors have used ~ilica gel in ~ome fo~ or another for the separation of pelycyolio hydr~bone from ali- phatio and s~nller ~lyc~#elie hydroo~rbons. These latter sub~.~ces a~e elutod from the col .~umn~ faster than the fraction containi~ bonzpy.~ne~

On a 25 g, ra~ cillca g, el col~um (Davldcon lb. undo~n~ned aoti~ty) ~'~s plac~d ~,0 )~ benzpyr~n~, The col~ was dovelop~ ~th ~ nl ~thyl~clohe~o~" ~ ml 10% benzene in methylcyclohox~ae and 15 ~ pu~e benzene, ~s ~s~ p~oved to be of lit~e use because of ~or rec~ve~ of st~ndazd (9%), ~d bemuse of the t~e of solvents necessa~ ~ ra~ove ~e st~. from the colu~n. Bensen~; for example, ~ould rezove all of interfe~in~ subst~.nc~s as well as the polycyclie hydrocarbons if ¢Iga .retto residue had been present. Cuzln, J., International Congress of Tobaooo, Brussels, (1958) reporhcd on the use of a modified silica gel colm~m. colu~ contained a. mixture of 5 groz~s of silica gel to I0 grams of sili~io acid. The column ~ms topped with a mixture of i gr.%m silica gel to I gram ciliolo acid. We further modified the syste~ by ~ " ,, ~ep_aoin~ sill,it acid ~i~h Celite 535, a diame~.~ee~s e~th (Jo~m~-H~-nville Co,), an~inert ~up~o~t, In add~tion~ wh~re- as O~zln developed hie column ~th the relatively non-polar solvent n-he~ne~ we dev~Iop.~d ou~o ~dth the faste~ m~ns ~ure of I~ be~ene in ~ethyl~iolohe~ne~ Pallor, M,, ~ebs~ W,, ~d K~m~ H~ Fac~, l-~tt, Osster~.. TaboUret, (spe~al isle), p,l (1965) h~ us~1 10% benzene in oy~ohe~e as their developing mo~a ~th To eu~ column ~a~ added ll.O ug~ st~n~ ~ ~e ~ efa ~ ~l~u~ o£ ~ethylc~clohex~e~ a~d develop~ ~ lO%A~n methyl- ~-c!ohox~n~, ~e first 25 ml c~n~ned ~ stander, 95.,5% was ~o~v~r~ f~iu the ne~ 60 ~ of solvent, ~s then appeared ~ be a catisfact~y column for chro~tograp~hy of the ~?asldue~

The cic~.~c, tto z.o~ldue ~as ch~-ouatogz'.-.:--hcd on an id~ntic:,l so~i~t hho ~ze of ~ho ~)luu~s ~ectcd= ~s ch~ge was nocessar# b~c~uoo o£ th~ pr~sono~ of some da~.k~ rapi~y movJ.nS ~ot~mc~ ~d~ t~as olutod ~.~t~n ~ne ~st ~ ~ ~d prob~bly ovo~'~app~d ~e bon~y~t'~no fraction~ ~.~ daPk pigment o~e off the c~!m~ f~,~ ~-6~ ~I. ~s was follo~ light st~w o~lo~'~ solution t~nlch 80 ~ of solvo~t co~eoted. It ~as ~ocessar~ ~ ~ke a ~dor out of ~o benz~rene f~aotlon f~z~ s~ar~ ~I~~ because it ~;as ~octod ~t benzpyrene~ in the presence of ~'ette rosiduo~ does not behave ~o~y as the pu~e st~nda~,~. ~o ~as al~ ob~o~ by Failer et ~, Spect~pho~ot~c showed no trac~ of bonzpyrsne. ~e ne~:b ~5 ~ of ~-off .~e~ pool~ and e~mp~mtod~ e.n~tho ~o~ that G~llt~ 53~ w~s ~l~c~ idontic~l except that the ~3 ~u~os a sh~,b~n~ in the owrall length of ~e col~, ~At had In the deve!o~e:~t of ~Is z~v~ over ~o last ~ ~ of the first 35 ~ r~ th~,ouGh. ~Is ~m~s fol!o~od by ~e collection of Oml of ole~, pale yel~.ow s~lution~ Bec~mse of the i~tenoe ab=o~tion of ~s s~lutlon~ it for ch~za'~g~.phy on al~Ana~

(~a ~o E-I~ I0~120 mesh, of .~deter~ s~t ~p~ ~ ~la~s ~nt~ne~ ~ gr:as ~nd the ~hi~ ~nt~nod i0 ~Oas of alumina. ~ ea~ ~1%~ ~ plao~ ~,0 ugr of bonzpy=ons, ~o!9~on% of ~ ~l~ms was ~no of ~ho t~.~o 30 gm~ c)l~ns~ ~o s~-~.~ ~an off fzom frao~ons I~-230 ~ e~ ~200 ml, ~ough one col~ ~an ~mo~.;h~ fa~r ~ %ho oZho~, ~o %bl~o of solvon~ noo, soa~ fo~ olu%ion of Xt is no£ ~blo a% ~s ~mo ~ ccitt fo~ %~s ~or ~Iold, Subse~ent ~)l~,~ns of ~la~ ~o ~xmys ~elded a~xt i0~% ~ ~ho basis of these z,o~Its, the bennw~one residue f~ '~ho ~llc~.-co~to 93 col~ was ~~aph~ on a 30 gr~a a!~:-~na ~luom, develo~cntbe~g done, as before~ ~th 10% bon~ene in ,~othyl~,clohez:me, The ~z% I00 ~ of ~Ivent wo~ d'cscz~.~e~, ~o first in~eatlon of the presenoo of bonz-

~ho fir:st ,~d ~,3~ f~.ot~ons did r~t give good ~oo~a ~or bcn~p~no b~o~uso of Into~fo~.ng fiuorosco~co. ~t relatively good ~sc%~ ~ro~ ob~no~ f~m the inten~cte ~raction~. As ~e h~d inc~lc~t~ befog, ch~ma~gr~.p~c~y~ boo,tone in tho presence of ro~due beh~ves ~ome~;hat ~ffe~nt~ than ~ sto.~.z~, T~ may ac~t for ~he app~ent lag in ~ elutlon of b~nzp~ne f:~m ~s colt, s. ~ these s~ot~,a, it was ~l~a~d that a ~,~ ef ~g~ ~.~as is~!a~.,d, ~d allo~.~ug for a m~ re,very of 90%, ~e be~p~cn~ l.ov~i incr~as~ ~ 13.3 )~. S~ce Ii~0 u~r had add~ t~s prop~sen~d a ~~ of 2.3 ~g~ of en~oEenoue py~no, or about I~2 ~/I00 olga~ettes~ ~Is ~a~ falls ~t~n the ~o of 0.9-1.85 }~g~/lO0 clg.~ettes fou:~ ~y out of seven other ~vestiga~rs. ~:o of the r~ai~ng t~ee inves~ga~rs ~ .v~uos of 2,2 and 3,8 ~gr[lO0 eigar~ttes ~o t~ ~ r~Zo of ~18 ~gr. ~s la~ fi~ can ~ ga~,~ n~t only for ob~ou~ roaoon~, but ~.oo b~c~uoe ~ ~er~ msa~Ins f3m~seenc~, a~ therofo~ p~gbably the ~;hole ~ly- oy~c ~dr~carb~n ~sl,

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Xn %he previous oxporim2nt, standard benzpyrene h~d been added to the filters con~niniu~ residue from 200 Un%.~eated cigarettes for the ptu~ose of det~rzining overall recovery of the s~ndard %~mou~h th~ v~-ious steps. The actu~l recov~r~ lay" be$~een 80-90%. Using the upper limit, ~o had estimated that the level of endogenous bonzpyr.ono ~:as e~,o~nd 1.2 ~gr/lO0 cig&rottes. On the basis of ~.his re~ult~ it was decided to extract a ~2~gor n~.,;~e~ of di~arotte residues ~.~%h the hops of obtalninz a fairly acctu~ate determination of bsnzpyrene ~;ith~t ~.~y ad-dition of sb~ndard. In this experims, nt~ therefore, I000 Chcm~so~ tre.a~ed'.ciga- fetters, and 800 untreated, ,mrs smoked on a 20 port machins. The ~-esi6ues .~s before ~,~re collected on Ca~forldgs filters, and. th~ by-pass in dry ice traps. The dry ice trap residues web's analyzed separately from the filter residues in o~@er to see if %~he filters were efficient in trappin~ bsnzp~ene. On the basis of previous results abovs, the untreated cigarettes ~ught to yiel4 about 9.6 ~Zr bonzp~r~ene. ~e f@-~r fractions obtained in G~io ox.po~snt had be~n labo~.ed as foll~-:s ~

Un%~.oatcd F 800 Untreated T 800 Ch.emoso~. I F F ~%o~ for ~ C~rid~e fil%o~o, and T for ~ d~ ice ~aps. In ~oneral, all fern" f~actions ~;ere e~;~ac~d ~ the ~ way, m~d ~e me~Js of pur~ication of the benzp~ene fractions wet6 basica~y the same. H~e~r, some m~ications beca~ necessary ~ order to cope ~.d~a ~ticul~ situations which have arisen. These ~-~i~ be noted ~ tho DRY ICE T~ RESIDUFZ The dr~- ice ~ap residues ~m~e ~titionod bo~;eon me%~l alcohol and mst~l~lohex~e. Since these residues ~-~ere &mall, o~dy 200 ~ of alcohol ~fic~, and about 3x100 ul ms~~l~ ~ here also sufficed. Afar d~nz ov~ s~i~ ~a~, ~d e~o~'a~ion ~der vacuo, the residues ~.~oro c~omato~aphed on 30 g:o_u al~m. co~s. The col~ns ~.~ore de~lo~d ~.~%h I0~ benzene ~ ~!c~loh~an~. ~e f~o% I~ r:~ wore discard. ~ne ne~ 203 ~ collect~d contalued ~ ben~ene fraction. ~ order to ~aro that ~I of ~e ben~p~one ~ms elu~d, the co!~s ~rere developed fun'thor ~i~ 25 ~ of 50~ benzene ~ ~Ic~loho~mne and 25 z~ p~e benz~no. ~ectrophotom~t~-ic ~a~sis of thcse f~actions ga~ no ~ication of th~ presence of a~ bcn~Ten~. Altho~h ~ose

fractionu, c~-p:,,olal~y tho;o obta~_no-~ fr~ ~o b9nzono-rich ~ial~ ~.~oro not p~,ooonb to the oxbon~ ~t th~, ~ould ob- ocur~ co~!otoly ~ b~u~ono ~mt mi~h6 ~m~ boon A positive in~ica6ion of ~ py~onoo of b~n~,one ~ould boon po~s of nbso~tion at ~05 ~d 388 r~, or at Ica~% po~ts of i,~Ioction on ~m c~o. Th~so wore coz~Io'5o~ absent. CA~%~I~3?, PIL~ P~SY/JU!]S Extraction of the treated and untreated filter residues wa~ the s~e, i.e. ~th ~thyl ~lcohel mud motb~rlcyclohe,-mne. Sop-~r~tion e~ ph~es in the ~r~te~ fu~ols ~.mo achi~d by the oI~-~ nddition of ~m~. Tee m~%~vlc~loho~e ph~cos ~.~o~o ~ri~ o~r s~iu~ ~a~, ~d e~po~.at~ under ~cuo. placed on 30 ~ col~ns of ~I~ (Alc~ - ~o H-I~ ~- dot~~ acridly). The col~s ,~ro de~loped wi~h ~ ~ met~Ic~lohox~ in ~-~hich ~he uou~l rnpidly mo~ng d~k rod- br~ pi~.on$ ~ms olut~d. Th~ s~cond fr~c$ion colloc~d I~ m! of I0~ b~nzeno ~ m~t~Ic~loho~ne. O~ a co~u of this oi~o~ ben:~'ene is not eluded in this fraction. ~e ~h~d f~ction collecbod cont~ed 2~ ~ of the s~e sol.n% mixture, a~ ~.~s ~loh ~ color.

pre.~ont in ~e yello:~luh residues. For this p~pos~ the first 20 ~ of fraction #9 t~on off ~e al~dna wore @.;o cqusl p~ and dried un~r nitr~on. To one of ~ ~siduos wa~ added II.0 ~ of st~d bon~ono, ~f~lo %h~ other as a blm~. Th~ss rosiduss ~;ero %~=on up ~ 6 ;~ of alco~ml.and ~hor dilu~ 6~, ~d 54 %~os. At ~e last dilu~ion~ 93% of @~e b~n~ne c~ ~ detoc~d ~d ~ea~ oven thoz~h ~e concen~ntion is a ~ l=~ 0.~( ~r/3.0 ~. ~is c~ be soon in the follo~ ~octr~m~ ~,~en th~ of ~'~cbion #3 veto ~n a~a~s~ pi~zon~ bl~¢, i~ I~s not pos~ible to ~ti~ the io~l of e~o~ez~c~s bon~Trene, ~ho~h ~ the un~o~t~ cigarette rosi~ae bon~-,on~ 4 ~ At ~s po~t, ~o ~e~d m~d ~tre~ residues were puttied f~or, but by dSforen~ CH~O~[~TOGP.~.P~I OF T?~F~a.TED P~SIDU~.~ OH S~YCA OEL-CEL_TTE Fraction #3 fron ~he al~,-~,/n~ col~-m. ~ms p!a~od on a column con~inin.o~ 5 ~ of oilica gel and I0 ~ of oeli~-503. Tee col~u ~ms t~pod ~-;l~h i=! ~ r~O. S~m~dard bon~ne cS~o~2~o~aphcd on o_n idonticnl co!~. ~ne ~o~lopmen~ of co!~u ~.~ done ~th i0~ benzene in cycl~hez~e. sol~nts va~ n~do becau~ it had b~on doto~od pro~ously in the proconce of c~Ichozmne, the ye!l~ pi~nt

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~torfo~.~ ~r~!. This pigment of cycloho)mne first. Ben~rcne is removed ~.~ 10% benzene in cyclohoxano. Re~o~- ~om The ~II~,~ pig~,~n% is remo~O before ben~eno. No attest ~ms ~]o The fraction from %he silica-celiac colu..~n ~:hich contmins benzp~,o'no was c~.o~to~aphed on ~-la~r ~ilica gel plates. ~m ]>Isis ~m~e rondo up acco~ to a ~m~ described by P~.lor o~ al. 2~0 cm of 7 ~a~ silica ~el (Sili~ ~-7 ~hllincr~% Co.) ~ an o'~n o%~r~h%. a p~te ~ one ~0%, alo~ ~iCh ~is ~ms ~o%~ a ~k~o of bon~yrons ~%.h some of .~e )'0~4 pistonS, ~nd rod-brim p~- ~nZ. ~e p!a%e ~7~ dev~lope4 c~cldmx~o fo~, 1.5 ~as ~d~ua%s'because ~;o ool~n~ fronts ,;o~e pr~u6od~ c~lo- p~ ~-~h ~le s~ additions was dovel~2~ ~ I0~ benzon8 in ~lohez~no. ~s p~ hondurans, yoll~ ~ r~-br~ aroas. ~se wo~,e de~cted ~.~ith 'ro~ckli~t."

~no oilic.~-colito frc.ction of thn tr::atod cic, a~'ottou c~n~o~.~to~nF, h~d on a third pl~to ~d.. • dovalopcd ~ I0~ benzene ~ c~lohe:.:ane f~ t~o hours. Ez~n~ation of those plates ~Ior fluorescence in ~o bon~no ~ea. }~o~holoss~ the "bonz- p~rono nro:~" ~.~n~ ~crapcS ~o:.~ ~ho pl~bo, olut~d vlth cyc!oheznno ~icnbio~ of the presence of The benzpyrono fraction from %/~0 first al~,-~h~ col~.un was dried and placed on a oecond, identical ono. pyren,9 ~action ~avo so~,~ irzSication of ~e pro~ence of that su'osbnnco. This fraction ~.~as dric~ nnd prepared for thin-l'.ayor Tn~ bon~.~p~-~eno ~-~c~ion from ~ho cocond al~in~ ~.m~ cb~o:a~to3r-aphod on th~-~r p~'~o ~s do,crib.S fo~ the treated residue. E~c~ion oZ ~hic p!~te ~do~ "~l~:li~ht" sho'aed the pre~onoo of a Blue ~!uorosc~.~ ~t~ial abo~' th~ ~!I~; p~;~ont, ~is m-ca va~ scrap~ fr~ the pla~, clued and dried for paper c~,omato~aphy.

~i1~r p~or of 6 c~ ~id~h ~cr 1.5 ho~ar~ ~m a c~oho;~ - a ~e~o~;, an~ a flue fluorescen% one. BO~ ~'OzO m%a~zed for benzp~.eno ~ec~opho%or,:e%zlca~. The follm~ ~oc%Tt~ is ~% of bon~i~7:one ~'t~ so~e con~a~g ~m%erial s%ill pros#n$. H~;o~r, al~ho~h i% is no~ possible ~e bons~ono 3ovol ~ %his ~ct~mm, nev~E~elcss, all of ~%o i4~nt~ pe~cs of abso~tlon are prescn~. 0n ~s basis th~rof~o %h3 prosezmo of bon~eno ~ t~%%~o=ts4 c~otte residue is defiul%o~

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DETER~[!~ATION OF BY T~ GRI>~ >~THOD

Sewral p~un~ of cigarette tobacco ~:ere placed in a glass J~r. The rol~tlw hu~nldlty of the ~b,~c~ was noa~m~.od ~th a ~liu~ ~ect~-F~g~,z~ete~ equipped ~th a p~bo. ~tor fifteen ~nute~ of eq~llbr~on~ ~ho r~latlw~ hu~dlty ~as rooo~od. ~o ~k~o~ x~as then sprayed ~th chemosol salutlon, ~th th~ aid of a ~int ~r~yer ~po!l~ ~.~th o:.~gon gas, ~ .~zc~ e~ent that the ~o!ativo hu~d~ty was inore~ced by 10-15%. ~garettes z~.de f~m ~is ~baoco h~d o.n average weight of a little zero th~ one gr~.~ ~ overall length of the clgarettos, inc!u~!n~ filtors~ was O0 m~. ~ng ~e actual. ~okiu~, about 55 ~kcd on the n~w ~O p~-t ~ke~. ~ae v~l~ue of ~ho puZf was 35 ~ of ~ set-=rid ~mration once per ~te, ~ae ~g~tte ~ke c~n~ denudate ~-~s o~octed on ~zb~dge ~be~lass filte~ and the by-pas~ in tr~p~ i~ed in dry ice. For ~Is e~~t, ~e ~idue cauzht i~ the d~ ice t~p~ ~.~ss ~t ad~od ~ the C~brldg~ ~ilte~,o, b~use ~.iu the ~.st ~ero has nevs~ b~cn any ~eat~on o~ the p~onco of I© von G, Gr'_,~mo~, Beitzage ~ur Tab~orsohung, Vol. 3~ August 1961 '40 filters (200 cig~rottes) of treated and untreated clga~ettes aze e.~r~c~c:~ ~rlth 3~50 ~, chloroform.

The chlo~fo~,u ic dried.under v~cuo, r.n~ the ~duo tran~for~,od ~ a cep~rato~ ~nnel ~th the aid of c:~l ~ol~s of me'~yl ~,l~h~l ~t~ling 180 3. ~d 20 ~., ~:at~r and ext~ct ~ 200 ~. oyolohe~.ne. 4~ ~d 20 ~i~ 0~i N hydrochlorlc acid and chake again, 5~ l~c~nt the alcohol layer and o~ract ~.~i~ a second 200 ~, tion of ~,olohezme. . 6. ~he ~oI~ ~6Aohe~ne fraotlons ara d~ed: and trar, sfe~r~ to ~ separ~:~#, fu~l ~ a ~tal of 200 ~I, oyoloh~ne, ?, ~Is is back-e~raotod ~th a ~ura of 180 ml, ~et~l al~hol: 20 ~, ~ator#~O ~. 0,I N h~chlo~o a~d. (~ ~to I) 8. ~ c~olohex~ne is ~ashed ~.~th 2~00 ~.. ~mter. (T~s produood ~ze o~l~on). 9. ~ the cyclohezane over sodi~ o~a~ ~d then u~de~ vaCao, i0, ~e residue Is tr~sferr~ ~ a se~ra~ ~nel ~th a of i0~ ~. ~c~he~ane~ and extraot~ ~ 2z~O0 ml. ~t~meth~e~ (el ~te 2) }~ The 200 ~eated resic~e s~emed ~ b~ Ereate~ t~ the 200 1~ G~-~,me~ ~eth~ c~lled for a ~rd I00 ~. ~trmueth~e e~rao~on ~:~ch ~.o not done because it ~d not c~ so in ~e tran~!ation, N~ ~e pa~titlo~ng of 200 ~'oat~ ~.~as sh~r~ ~-~he~,~s ~hat of ~00 t~oated ~s n~t, A o~ght ~u'~on ~as fo~ed. 200 Untreated - 0.25 200 Treat~ - 0.45

Ti~e l~.~,ge Ciffer~nco in ro~!du~ we!zht~ c::nnot bs noo~untod for at this t'In~o, At ~s point, 3.16 ~ of st~_ndard 3,4-bonzpyrene were ~:dded to e~eh ro~;!cuo in order to oi=plify the detection and ~ee~very of both o~genous and endogenous bonzpyreno. For the 200 Untreated sm~ple, a ~0 gr~ c~l~m ~as ~ be used. F~wevor, (of Eote ~) the st~d~ zoved ~ too In it9 p!zce~ a 15 G~ colwm~, pro~r~d aooo~n~ was uscd~ i~e, the ~lica ~s allo~¢~ to ~cnd in a 1.5 hou~,~ (G~,~o~, ne~leobs ~ s~clfy t~me). (cf Notes ~5) Fraction ~l - I~ ~.~I® b~o~ pl~ent~ fast Fraotion ~2 - I00 z~l. prebenzpyrone (Fluo~'e~ees) Fr~etlon ~3 - 125 z.~l. benzpyrene Fx~ction ~- I00 ~. 10% ben3ene/~olohexo.ne Fr.~ehion ~3 is placed in a f~nnol with 125 ml, cyoloh~nno ~nd e~r~etod vith 3.~00 r.~l~ nitro~neth-~noo Th0 nitzoz~ethane is owp?rated~ and hhe ~slduo prepared for paper ch~matog~aphy,

preen--ted ~th d~.~o~ylfo'~:~:,.,~de~ and developed ~.~%~n satu~,atod ~;ith ~z~ylfoi~i~d~ in a osalcd tank~ ~'~[]~ 3 h~urs 15 ~nutet:. (~!vont f~nt ran ~ end of strip), ~ ~n identic~l sh~Ip~ 3.16 )~g~ s~und~ ~;as ~an for ro~ve~ study. ~he strlps %.~o~e so~.rm~d ~th lon~ ~z~,~ ~t~%~olot and ~e b~uc;~ne a~as we1~ ~mW~od ~th p~n~l. ~oss as br~t blue fluor~soont a~.oas~ NOTE - ~oas I & IX ~ere ~oled beoause It is he, eyed th=t ~e~ ar~ ~ho s~o~ but were separated at the sta~g llne by ~Iven~o, (el lbte &) A~as I & II of fraction ';'3 200 Untreated (sili~ ~e.%) ~:;oro put on 8 gr.~us of alu~..in-~ and developed s~th cyo~ehem~ne. Fracti-~n ¢2 wa~ d~,"ie¢l ~dor nitrogen ~,odiss~lwd ~ spectral g~.do oycloh~xa-'ne, and a s.oeotr~ ran from-450-350 ~u on a B~okz---n DX-Z reo~%n3 speotrophot~zo'te~ veraus a oyelohexane blank. (of spoctx'a~ ~), On the ba~Is of t.~Is spsotrma, about Z.87. pyrano ~;ere prosent~ Ca!culathn~ b.~ok on the basis of r~ooverles, etc,, the fln::l r~wI~-~.~as about 3.2 )~sr. ~%%s, however,, shotted

.._J

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an~ ~ ~'no nltrono'~.h.~n~ ex~i-~ctlon ther~ r,:u~t h.~ve bo-~n ~one lo~s ~_nc~ ~a used 2x!09 r~, inoto~d of 3x100, th~n .it h~s b~on up to n~;~, (of i~o~ 6) ~'ao~ion .~I - 12 m~. bro~.m ~E~.~nt -fcst moving F~otion ~-2 - 438 ;~, preber~pyrano - ~l~o~aso~nt F~ac'Lion ~4 - I00 ml, 10% F~otion ~3 ~ms pa~Itlon~d bat:.~o~n ~c~ohemmn~ and nitro- .-s fo~ ~09 Unb~at~d, Th~ nitro~than~ reaction was for p~p~ ~o~togr~phy. ~.~do !~tn~ ~,i fo~" ~ut 3.5 ~ur~ in cyolohex~e satiated ~!th d!~+~h~form,~do. ~h~ a~,o~s ~.~e~'e ma~ko~ off and elu~ ~i~, ~'chy~ alcohol o~y. A s~nd~rd (3.16 ~gr) ~=s al~ x~ on a 6 ~l~ strl~ fo~" ~oc~vo~. (cf Ibto 9) Area I of 200 Ti'e~ted uas eluted "~i%/~ z~thyl alo~lml only.

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Aroa I "t;:,s ~ut on t~ al~a'hm ¢~l~:n of 8 gr.~.ma Rnd dovolopc'l FP~ction ~3 - po~%ben~pyrene - 25 tal. (fluoresces) ,f

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e~lwm~ and developed o~y ~ a~, ~e ratio of ~9 ~l#~ au. was ~o ~o~t and the 5.16 ~g~ ~:as put on a p~c~s~., i~o. oV~ ~r fo~ 1,5 ho'~s. ~is w,~v d~velop~ ~th oyo~.ohe:mno, F~otlon Pa~ pluS ~.;as left off 2 s~e~nd~ Patio, I0 e~!u~~n is of little use bec~.use the standard oom~s off the fi~,st 59 ~I, of cyclohe~no~ ~ Trio eolu,'..~ was d~voloped ~rlth

The ~:~,n~.~.~d :~u~ ~dth 200 Untreated wa~ ent~.oted ~Ith hex~ne ~b~n t,~o m~nu%o~, af%o~ ~ing forayed ~o p:~por :ms ro-o~ract~/~th bonzene - 2~ ~-zaS ~oc~ve~ed~ ~ho c~f~p= ~:cr~ ag~n o~5r~ot~ ~.Ith nothy! ~o~h~! - ano~er ~6% ~=~s ro~vozod f~r a 9% tot~!~ (of spsct~am)

(..,~ L. (.'e t,

50207 673?

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DEC 8

Not included in this report is the che.~'~osol ev~lur, tion ~1~'~," vd~ch Includcr~ lo:~tc~ c~pCrlmcntnl p~'~holo~y and ~n~-liquld phase (O L C) Identification ~nd ~u~,~tlftc~t~on che:~istry. ~h~ O L C ~'~or]~ ~'~ por[or,ued only to ~w~ ~ssur~nce thnt ~,h~lc 3:4 bcnzpyr~nc ~'n~ prccludcd ~n the fo~tion of c~g~rette combu~tion product~ other noxious ~ubst~_~ces ~ere not nco~sly incre~d. Th~s ~sur~ce hns been obt~ined; h~ncc the G L C tracings ~rc not p~r~incnt to thi~ r~rt.

I. Acute To:~Iclty nnd ~issuo ~{ccro.~Is Evaluntlon F, aterlnls and Uethod~ Ordlnnry co:~n~rci.',l clEft'cite tobacco ~'ns used, ~e half of the total batch ~a9 treated by sprnyln~ ~th chemosol under stnnd~rdized conditions. The second half was not so treated. ~hrou~hout# these are Po£orred to (vlth chc~os~l) ~d "u~troatod" (without chc]uosol). Technicians used the oin~l~ cigarette mznually po~ored device for m~ufacture of the cigarettes. Identical b~t separate devlcos ~ore cmploy~ for ~'treated" and "~itreated" tob3.cco. ~llowin~ manufactllre# a total o£ 250#000 clga~ettes ~oro smo~{ed ~n the machine built In this laboratory ~d doscPibed elsowhoro$, The Cnmbrldge ' filter ~nd cold-trap residues ~cr~ ccmblncd ~or 125#000 treated and for 125~000 untreato~ cigarettes. Residues wore worked up In batches ropresentin~ clgsrettes each. '[he following bench Inst~ctlons were follo~ed with each batch: I. Place the filters In a 2 lltor beaker. l~Ith the aid of the large squeeze bottle lab$11ed MoOH, (methyl alcohol), ~ssh down glass delivery tub~s In cold trnps. Ro~ove cold traps and dip for a ~ew seconds In warm water bath. ~ur off Mo3H into b~skor contnlnln~ the tilters. ~inse out the traps ~Ith ~o~o l.~e0~ nnd add to the filters. 3. Add on~ liter of l~[~0] to the filters# ~d allow to soak thoroughly ~t$1 filters dlsintesrnto. ~rgo greed glass pestle Is useful for this p~se. 4. Yho mixture Is ~ured onto a Duc~er funnel contn£nln~ "a fl497 paper. Flltratlo~ Is acc~pllshed by suction ~Ith the aid of water~ ssplrator~ into s 3 liter suction 5. When filtration is c~-~pleto# rc~ove packed pnd~ mid resuspend in another liter of • ~hls Inst~,~ent Is a 40-por~ ~schlno 1~hich ~as ~sed excop~ made that other ¢qulpa~on~ ~'ns c~ployed.

-2- Filter an before. Place both EeB:,i extracts in 3 liter separatory funnel. *Tho ~tumol ~topcock ~ust be lubricated ~vlth a few drop~ of ~'ater only,~ |fold stopper In place with °'0" 7. "~'he filter pad is ,'e-suspended in one liter of cyclohexano. Filter as before, then add thiv extract to the separatory funnel for partition~n~0 The mixture is shaken thorouy, hly. ¢D~ not forget to release pre.~suro by ~nvertiag the funnel and ~lo'.~ly turning the stopcock. Allow the phases to ~eparate. 4 ln~ert through the top~ a long stc~ funnel ~hich should go through the upper cyclohexane layer tats the I~oOB layer, Slowly add about 25-30 ~1. distilled eater. A light bro~ c~ulsion viii appear at the botto~ of the fmmel. 10. Ee~ove the ~mall funnel and insert a long stirring rod ~hich ~ill reach dou, n into this emulsion. Stir gently ~£th a swirling motion. The bro-~n color ~21 $pread ~hrough the solution# but the phases. ~tll separate sharply. ~11o~ to stand for 1/2 - 1 hour. 11. Pour off the tSeO~ layer into a second funnel and the cyclohexano into a round bottom flask of 2 liter capacity, Evaporate the cyclohe~.ane on the rotovap, as follo~,s. ~tth the bath t~mperaturo at about 55° C~ place flask on the end of the rotating gla~s tub~. .$Do not use lubricants of any kind, Turn aspirator on about lml~ ~ay and couple small ball Joint provtougly lubrlcatcd vlth lubr£cant labelled "Bull Joint". Allow vacuum to build up about one minute~ then start motor, Rotate flask Blowly at first to preve£t btmptng~ then ~ore rapidly, Use po~,terstat knob £o~ thi~ purposes 13. Eeanwhile~ the EeO]! fraction is extracted t~lce ~lth 500 ~1. of cyclo- • hexano vithout any addition Of ~atero $If any emulsion for~s at this point~ pour off ~e9~ layer and add 100 mlo cyclohexane to the emulsion. ~his is usually enough to break tt, The subsequent cyclohexmm extracts are dried in the eame flask as the first~ and the sa~e precautions are taken. residue is soluble in ether. Ca~bridge filter~ ~ero replaced after each five cigarettes smoked. Final solubility of total residues ~n ethyl ether ~as accompanied by ~ulfuric acid removal of nicotine. ~othing else vas extracted or othor~ise rc~noved. Ether solution of reslduos were then d£ssolvod in ssame oil (U.S,P°); the ethyl ether ~as blo-.~n off under vacuum and ~ar~ bath.

experinen~s. Exp~ri~ental a~im~is ~or ~hoso studied ~oro C F - I (C~r~;orth) inbred; a~es ~nd average ~i~ht~ ~ith n vlo~ to obs~rvln~ ~ro~th and ~oi~ht-Ealn alterations.

E~ch crollp o~ 150 r.~Ice ¥,'~ro divlded r,s X Control~ sesame ell only inJccted~ 50 nni~als Un~rcatcd cigarette s:.~ol;o roslduos~ ~0 animals Chcmosol-treatod cigarette smoke ronidues~ ~ m~imals O~ initial concern is the "lo~-dosage" experiment ~n vhich the total residues (less nicotine) ~r~m 5 cigarettes daily ~or 10 consecutive days. ~ese mice have bo~n examined daily since the initiation o~ the oxpor!~cnt In Ju:to 1966. No noticeable cha~e9 occ~rod~ nice remained healthy ~tll the 14th. ' day ~,hen approximately I/Sth. o~ the untreated mice were noted to have be~i~lug ulceration at the injection site. The treated nice appeared no~a~ at ~hat ti~e. By the 20th. day I/4th. of untrsated mice had ulcerations of injection sites with doflnlte .loss o~ hair. Treated mice were no~al 5 weeks ~rom the start of ~xporiment. Biopsies el those ulcerated areas m~d subsoquon~ slou~]~s receiving higher concentration~ o~ clgaretto concentrates showed microscopic cba~ges of Intense Infl~atury roactlon with vascular thrombosis ~d necrosi~ el all tissues In the area resultin~ In n slough of the Riop~ie~ o~ multilobulated masses occurring in all three groups sho~od a temporal, pseudocyst ~o~atlon v~!th no ch~acteristlc patholosIcal chanEe. This group ~s no~.~ being ~ollowed for evidence of halibut c~ges at a later date.

On the follo~'ln~ pa.~ l~ ~n e~-ap].e of the e~octs o~ lou-do~e lnJcc~ion of cigarette s:ao'~e rostdu¢~ upon ~rou'th and the ~bilig~, go thrive. ~his particular graph represents a co~parlson bei:woon chon~osol-treatcd clgarettcs and the s~ae brand o£ tobacco wlthout cLer.~osot, The injected ~v.aterlat in each group of mice was the total smoke condensate {less nicot£ne) ~ro:a 5 ci~arettvs, Ten consecutive daily injections were given e~ch animal. I~ is seen that there is a b~dy weight ~rop during ~he in~ection perio~ when ~treated tobacco w~s used. Reversibility Is seen later. The c~oaosol in~ected ~in~al body weight curve approx~,ates that of the sesame oil controls (not shown).

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three A0 25 ci~rotte9 per l~3ection for 10 consecutive ~y~ 50 cignrette~ p~r in3ection for l0 consecutive 100 cigarettes per in~ectlon for 10 consecutive {Sesame oil controls of equal in~ected volu~es ~ero est~blished on ~ll expertment~), At each level paired ~nl~ais ~ere injected ~ith ch~uosol treated tobacco residue~ and w~th untreated cigarette reei~ue~ of the same brand, Observations on these ~lce ~re divSded Snto two type~: lo . ~o~ic mortality Vascular i~pairment ~nd local tissue destruction, A.!. The toxic ~ortality from 25 cigarettes x 10 daily injection an~als ~as ~ero for the sesame oil controls~ the ~ice given che~osol residues~ and those glven untreated residues. B.I. The toxic mortality fro~ 50 cigarettes x I0 d~ly injection animals w~s zero for the sesame oil controls and the mice given chemosol residues, F%~ the third to the fifth week ~ollowlng the first inJection~ ~0 percent of the untreated residue mice died, C.1, Trio toxic mortality ~rom 100 cigarettes x l0 daily injection animals ~as 50 percent from both chemosol residue and ~mtrea~ed residue Sm~mary oz~ tozlc aerial.try: ~emosol treatment o~ tobacco yields a decided decrease in toxic mortali~y In experimental animals ov~r that which results from the residues of smoke from the same~ untreated tobacco. A,2, Vascular lmpa~ent and local tissue destruction from 25 cigarettes x 10 daily injection animals ~as zero in the ~es~o oil controls and the

ehe~no~ol residue In~ectcd raico. '~o uu%,'oat~)d rcsldueo pl'oducud vascular occlusion nnd %issue death n% the in~octlon sl~o In I00 percent of %he nnlmnls st the ~ourtcenth to sixteenth day. B,2 Vascular Inpalr~.on~ end local tlssuo destruction ~ro:. 50 cisarottes x I0 daily in~oc~ion animals %~ns 80 percent in ch~osol residue mlco ~d 100 percent in the untreated ones. C.2 Vascular lmpsin,~ent ~nd local tissue destructio~l fr~ 100 ci~arettes z 10 da~ly in~oction nnir~uls ~ms 100 percent regardless of ch~osol treatment of tobacco. The residues employed contained no nicotine. All of the substances fro~, cigarette smok~ ~'hich may cause vascular occlusion In man are not knozn. ~e type of tissue dest~ction soon ~n all these ~imnls is typically ~d p~uliarly that ~,hich results from arterial occlusion. 8u~m~ary on vascular impai~uent and tissue destruction. ~'he lowest dosage level assayed does not produce arterial occlusion and tissue death if chemosol is added to the cigarette tobacco. This protective effect persists shove the 25 cigarette per injection level. Protcction provided by chemosol s~ainst vascular ~mpsi~uent and tissue destruction is therefore of en.order of magnitude of five ~0 ton-fold. (See photographs 1 through 6 in th~ foiler;lag throe pazes).

i. Chemo~sol treated Residue animal 15 days 25 cigarettes x i0 Untreated Residue animal 15 days 25 cigarettes x l0

Chemosol ~rented Residue 4 _.. 25. cigarottes_x 10 .................. Untreated Residue anl~al~ , 4 ~ee~s ~5 cigarettes x 10

5.Chemoso] treated Residue animals 6 week ~c~ 25 cigarettes x i0 6. Untreated Residue animals 6 weeks 25 cigarettes x i0 $0~07 6753

A fuel adxL~tivo for CIBarotto Tobacco

The ~or,nulatlon now dc~ign,ntcd che;~o~ol contalua har,~le~s which do not a~foct ~etab~lla~ In r, mn or In ani~al~. Che~o~ol i~ non-residual btologlcally. It probably do~s not survive pyroltzat/on tn any form r~re hterestin~ th~ carbon dfoxld~ anO water. The quan~i~tes u~ed ar~ exceedingly small and will not appreclably alter ~h~ wefght ot Specifically~ then~ cheno~ol nay b~ regarded a~ a ~u~l additive for ~obncco, The purpose of such an nddit~ve is to yield ~ altered spectr~n o~ subs%ances in ci[:arotte s:Uok9. ~he foa~lbility of lr, htbiting the fo~mtion of potentially ha~aful ~ub~tance~ like 3:4 benzpyreno was oxperl~ent~lly th~ ten years ago~ (AIvord~ E.',', ~ e~ a~ Brit. J. Cancer 10: 49~-505# ~hie worI¢ "Su~gents a ~nstbtltty ~or ~n~prove~uent by the use of additives or catalyst~"~ and pro:npts recognition of "Evidence that ~ore efficient oxidation could concvivabl~, loxvvr the content of carcino3en~c hydrocarbons'. (p.~# ~nokin~ and ~ealth~ P,H.8. hbltc. I~o. 1103). Th~ foregoing quotations ~rom author~tative sources are not arbitrarily lifted ~ro~ contox~ nor are they unique. Additives have been ~ho~ to reduce ~nzpyrene content of cigarette an~!¢e "tar~" with a ai~ultaneoua reduction tu,~o~-fo~lng powe~ of the tar~. ~9 reverse is al~o true: increaaed bvnzpyrvno ~e acc~panted by increased t~origenic fluality ~n-~moko residuov. (~Tyndvrt and Hoffnan~ D,~ Reduction o~ Tu~origonicity of C~garette.Smoke~ Jour, ~er, ~ed. A~n. 192: 9~ Apr. 12~ ~')mdvr ~d tIoff~nan alv~ ~u~gest that future research programs ~nclufle "bonzpyrono as ].ndicator ~or tu~or-~n~tiat~nff aromatic hy~rocarb~nv". view of thctr work~ thte approach appears ~o~d. ~rthvr retnforc~.~ent of the potential danger t~ fo,~d ~n the gtat~ent that "Benzpyronv ~s one of the

t~'o ~nost ]:vtcnt of the seven carcinogens detected in tobacco s.~olte end it is l)rC~c~',t in z, mch larger quantity thall ~y o~ th9 other carcinogens listed." (p. 57~ ~o~Ing and };o~Ith~ U.S.P.Ii.S. ~bllc. I~o. ii03). The ~orcgolng rtat~nents ~dreasonin~ conatltu'to the logical b~,sls for electing to evaluate fuel additives toy the burning of ordinary "~erlcan" blends of clgarotto ~ObRCco lit curr~nt use. ~ additional sclcnflflc factor Ires influenced profc~nc~ for 3:4 bcnzp~rc, no as th~ principal chenlcnl to prevent In tobacco s~ol~o: the co-c~rcino~onic properties of other substances in szoR~ ~'hich act synerglst£cnlly w].th bonzpyr~nc. (~llhorn# A. : ~carcino~enic Activity Cigarette ~ob~cco Tar~ Cancer R~s. 18~ 5~0-S17, June 1953 and Wynder~ and ]~of~:~nn~ D.~ l~xperlmentnl Tobacco C~rclno~onesls, ~dv~ces Roe. 8= 2d9-453, 19~4). C£gsretto tobaccos fro~ various mnnufacturer~ have been utlll~ed simply because lenders In this field o£ research have found slmllar ta~or-lnduclng properties ~n clgsretto smoRo reslduos regardless of the bread. Eoor% G.~':. end Paul C. Clark# Blolo~Ic~l ~ctivlty ot Rotln~d Tar from ~s o~ Cig~retto~. J. liar. C~cer Inst. 34: ~31-493~ Requlrc~ents of the ~uel additive approach Include some prnctlcel consldora- fleas. ~e first o~ these is cost to the mnnutacturer ~d coaster. ~Ithough cost ~e~ s~ Is beyond the purvlcv ot the studies reported her% is ~o~ bnough in the instance of the ffo~ulation cho~osol~ that ~t c~ readily be sot aside as a barrier to gonor~tl use. The second consideration is possiblo aXtoratlon in the sccoptabtltty o¢ ch~osol trcstod tobacco by hnbituaX cigarette smokers, ih~ trisls provide the only vnlld criteria for this part of the evaluation. In eua~ary it boon fo~d that tl~o rc~uXar-s~oRers of n p~rtlculnr brand find that cho~osol

-6- addilio:~ is not pertinc:~t to the enjoyment or satisfaction derived ~ro~ that brand of cigarette, The third category is t.ho overall irritation frora heavy (throe or more pacl~s daily) ci~aretto s~oktn~. ~cmosol considerably reduces lrritation~ ~sp~cially the pro~uctivc coush ~nduced in r~ny subjects, A fourth practical probl~ stems ~ro~ the intricac~os o~ cigarette manu- vac~uro ~d the difficulty or case of lntro~uct~o~ of a fuo~ ad~tivo as part of thi~ tota~ process, Cheno~ol requires little o~" no equl~ent chan~e ~d no additional steps in manufacture, Virtually evo~ manufact~ror has "flavor dr~" ~tep; ch~o~ol addition can be ~ntroduced at that point, The fifth problem deals v~lth to:~ic factor~ ~nheront in fuel For exe~ple~ metallic ions might require prolonged ~ooding ~d ~nhalat~on ex~rlmentg to cloa~ suspicion o~ tox~city. Chemo~ol cont~ns no such ~nd no other toxic or metallically r~sidual hatter, Reagent gr~de~ naturally- occur~n~ products nnd substances are c~clusivoly us~ tn ~hemoso~, There no ~tential toad!city involved in its use by either m~nufacturor or The sixth practical proble~ is that of the persistence of ~uel additive ef~ect~ on cigsretto tobacco during shipment nnd storage prior to cons~ption, Chemo~l effects persist for n time exceeding normal shelf-life of 90-1~0 days for cig~rettes made and con~cd In the U,S,A, ~el~berately~ less than optima~ or u~u~l storage co~(~itions have been ~ployed in these te~te, A seventh imi~rtm~t proble~ area is tlmt o~ evaluatln~ both general and re~io:~al d~u~o to tissues ~nd the effects upon grov~th rates in exper~ment~~ nnimal~ For this evaluation the total ci~arette smoke condensate is used; only nicotine is r~ovcd - because rodents are hypor~ensttive to nicotine

-7- poJ.so~In[: ~nd ~'.'eul.d l~e killed by nicotine preso~at in s:,~o:~e residues tested In quantities largo enou[{h to be significant. ~eslduos ~ro:a cho;aonol cigarette ~obacco ~.r~ ~trl]=In~ly~ los~ dr.~nglng to living tissue th~n ~troatod tobacco of ~ho s~e blend, Th~s o~foct ~,.nd ~ho protective o~t ul~ gro~th rates pro~ded by chenosol ~III be ex~lIn~ elsev~hero ~n this Chc~osol 19 inexpe/~slvo~ applicable ~'l~hout ~desi1"nblo flavor or taste cha~geg~ productive of less respiratory Irrltatlon~ easily i~corpornted ~a~ufactul'o~ non-toxic~ lon~-lasti~g in effect under ~torsgo Che~o~ol provent~ the for~aatio~ of 3:4 bonzpyreno l~ ci~nrotto smoke. The ~echanisa in physical che:aistry through vhich this ch~go in c~bus~io~ products occur~ Is both beyond tho scopo of interest o~ th~s la~ratory probably - beyond tho techaical cap~eity of any ls~ory currently Eating this problem.

FRC~.[H~<bqZS OF ~ki'flNG, OCTOBER 4, 1953, PAGE Chairman: Dr. Neurath Re~mt sma Present: Dr. Seehofer E%T Mr. v. Bethmann Brlnkmann Dr. LIpp Brlnk~ann ~:r. Salzbrunn GEG Dr. Mueller Reemtsma Dr. Weber Forsch~ngsstelle Dr. Elmenhorst Forschungsstelle Excused: Dr. Barkemeyer E%T Dr. Mal Eilebrecht Mr. Jodl Neuerburg No. 5.5 - Dr. Bindlg Dr. Neurath reports that Dr. Bindlg has not answered to repeated efforts suggesting cooperation In checkln~ his tests. Dr. Bind~g uses a preliminary ~Titten opinion of the "Bundesanstalt fuer Tabakforschung in Forchheim" (Official German Research Institute for Tobacco) as proof of the success of his process to reduce the benzpyrene content of cigarette tobacco. According to Prof. Schmid, the written opinion is solely based on results of prellm~nary tests, thoroush additional tests will be run in order to verify the r~sults. The final report has not been received. The Scientific Commission recommends to obtain eventually an official report from Prof. Schmid of the Forschungsstelle outlining the final results of the tests. In the meantime, we found out that Prof. Schmld is participa~ ng at a meeting of th~ Commission Scientifique (CORESTA) in Rome. Dr. Weber will 41scuss with Prof. Schmid this matter (Dr. Bin~ig) and also the matter '~trosamines." Dr. Eeurath reports in regard to information received, whereby citric acid is identified as the material of Dr. Bindig's research. Strangely enough, Dr. Bindlg does not call it citric acid but oxy-~y~-propsne- tricarboxylic acid. - /

January 31, 1967 COMMENTS ON THE TECHNICAL REPORT ON CHEMOSOL Pa~e 2~ Par. I It is stated that Chemosol does not survive pyrolization in any form ~ more interesting than carbon dioxide and water. Presumably this means that it is an organic compound containing carbon, hydrogen ~ ~d possibly oxygen. On the basis of minutes of the official German Institute for Tobacco, it is believed that the compound being recommended by Dr. Bindig is citric acid. For example, in the minutes of the meeting of t~e Research Institute, held on October 4, 1963, Dr. Neurath reports that the material which has been used in Dr. Bindig's research has been identified as citric acid. Dr. Bindig however referred to is as oxypropanetricarboxylic acid. Interestingly enough, Lorillard has obtained a patent on the use of citric acid to reduce ciliastatic activity of cigarette smoke. At one time we had s~u~ied the effect of addition of fumaric acid to hurley tobacco and definitely established that the sensory strength was greatly decreased by the acid. It is possible that ciliastasis would have been reduced also but the work was done long before the smoking-health problem emerged. WINSTON cigarettes are now being made with two levels of citric acid. Determinations on the two test samples and on controls will be made for nicotine in smoke, solids, aldehydes, HCN, nitrogen oxides, phenols and polycyclies. We will also determine mildness and perhaps ciliastatie activity at the Industrial BIO-TEST Laboratories, Inc. Page 2, Par. 2 The.feasibility of inhibiting the formation of 3,4-Benzpyrene was not satisfactorily demonstrated by Alvord. In the first place, the article by Alvord deals almost exclusively with the depression of formation of 3,4-benzpyrene during the pyrrolysis of cigarette paper. He ran one experiment on tobacco, using 4.25% ammonium sulfamate a~d obtaf-~d a 50% reduc~0n in 3,4-benzpyrene. We

2 repeated this experiment recently on WINSTON tobacco rods at 5% ammonium sulfamate level. The cigarettes did not burn on the regular smoking machine owing to retardation of smoke. Accordingly, addition of ammonium sulfamate rendered the cigarettes unsatisfactory for consumer smoking. It was necessary to smoke the treated cigarettes at the rate of three puffs per minute to maintain burning. Under these conditions there was about a 50% reduction in polycyclics. Dr. Jones reports that the taste of smoke was very seriously adversely affected by the sulfamate treatment. ~a~e 3, Par. 3 According to this paragraph, Chemosol is inexpensive. This statement would lend further support to the view that the material is citric acid. ~age 3, Par..4 Chemosol does not adversely affect quality of smoke in panel tests. experience, addition of organic acids to tobacco had the same effect. In our Page 4, Par. 2 Chemosol reduces irritation; this effect would be expected of citric acid. ~age 47 Par. 4 Chemosol effects persist up to 120 days. In our tests, the effect of fumaric acid on mildness decreased on snorage. We interpreted this as equilibration with bases in tobacco. This, again, suggests that the additiye is an acid. Page 4~ Par. 6 Nicotine was r~moved from cigarette smoke c0ndensat~ for animal tests. This alteration of smoke is believed to be unacceptable if one wishes to extrapolate these data to human data where we are concerned with effect of whole smoke. Page 5~ Par..3 It is stated that Chemosol prevents -the formation Of 3,4-benzpyrene in cigarette smoke. The data which are presented later in this report do not substantiate this statement.

Page 8~ Par. 2 The author states that he used the CF-I mouse (C~.....~rth) inbred. The CF-I mouse is not inbred, but is a random bred mouse sold by Carworth Farms. The CAF-I inbred mouse sold by Carworth was the mouse usually used by Wynder in most of his studies. There is no objection to using the CF-I mouse however, because it is a random bred mouse (Swiss). This strain would also be highly resistant to mammary tumors, yet susceptible to some t~pes of carcinogens. This is not, however, a study on carcinogenesis. The work reported here is simply an assessment of the toxicity of cigarette residues and their apparent reversal by Chemosol; whereas Wynder's work was, of course, concerned with carcinogenesis of smoke residues.~ .~a~e 12~ Par. 2 The author does not mention the volume of sesame oil injected for ten con- secutive days. Neither does he mention the concentration of the residue suspended in the oil. These are most necessary in any description of materials and methods of any scientific paper on toxicity in animals. From viewing the photographs in the paper-~I~~~_-~ the volume injected daily was about 0.5 ml. per day. The results given on page 12 indicate that at the 50 cigarette level the Chemosol plus the residue developed no mortality,' and the residue only produced 60% mor- tality. He does not say how long the oil controls were held, or if they were held for the same period. The I00 cigarette level is obviously a fall'out point (no~ necessarily the threshold). It is assumed from these data (scant as they are) that a'does-response test could be generated with intermediate levels of the residue. These biological data can obviously not be quantitated using the number of ciga- rette residues as the dose. " .............. .page 13 In his results expressing vascular impairment or tissue destruction, the author states that at the 25 cigarette level, the residue alone gave 100% destruc- tion, and no destruction with Chemosol-plus-residue, and 0% destruction for the oil alone. At the 50 cigarette level for which the mice were held for 14 to 16 days, 100% vascular impairment was noted in the residue only, and 80% in the Chemosol-plus-residu~. There appears to be a very narrow limit of does response measured hy this technique. The author also did not mention at the i00 cigarette level if the mice held on the oil, and on the Chemosoi-plus-residue level were held the same length of time that the mice given the residue 0nly were held for.

It is concluded that protection provided by Chemosol against vascular impairment and tissue destruction is of an order of magnitude of five- to ten-fold. Automatically one would use tissue culture experiments rather than in vivo experi- ments for quantitative determinations. It is believed that in vivo experiments are of little value for quantitative determinations. It is believed that the method to determine toxicity of materials would not be acceptable to workers in the field. It is important to note that the animal test described is a test for toxicity. It should be recognized that it is not to be construed as a test for carcinogenicity although the treatment is designed to reduce 3,4-benzpyrene. If one were testing for carcinogenicity by subcutaneous injections, one would not make as frequent injections as are reported here since 3,4-benzpyrene is known to be quite stable and would remain at the site of injection. Experiments in the report include development of analytical procedures for 3,4-benzpyrene and determination of 3,4-benzpyrene in the smoke of treated and untreated cigarettes. In essence, page 24 Shows a calibration curve. The four points fall on a straight line; however, the values which were obtained for the knowns and unknowns fell in the low part of the curve. There could have been serious dis- continuity at the low part of the curve, particularly in the presence of impurities. The extension of the straight line is believed to be an unwarranted extrapolation. .Page 371 Par: I~ Page 3@~ Par. I; Pa~ 39~ Curve at Bottom of Pa~e We can say that the final statement made on page 38 may be correct but the final sentence on page 37, par. i, may not be necessarily " ~ correct because of interfering subs tances • ~ .Page. 44~ Last Peru A total of 5.56 micrograms should have been found in the residue from 200 untreated cigarettes. As can be seen, only 3.2 micrograms were recovered which is~quite an unsatisfactory recovery from these 200 untreated cigarettes.

Pa~e 49~. Par. 2 This is the analysis of the smoke from treated cigarettes. If no 3,4-benz- pyrene had been present then 3.16 micrograms should have been found. However, only 1.7 micrograms were recovered which is about one-half (3.16) of the spiked amount. Obviously, his recoveries are quite unsatisfactory, so how can one regard this as an analytical procedure. Looking at all the data presented in this report, one might conclude that Ehere is a hint that the $,4-benzpyrene content of treated cigarettes is lower. If one were to assume that Chemosol is citric acid, then the addition of an appreciable amount to the tobacco would, change the burning characteristics of the cigarettes. It is conceivable that it would depress the formation of 3,4-benzpyrene to a measurable extent. Even if 3,4-benzpyrene were reduced by 50%, the addition of citric acid could not be exploited commercially since this is not the only alleged carcinogenic factor. It is highly probable that Chemosol would produce a very marked effect on the nicotine content of smoke if it were, indeed, citric acid. A marked reduction af nicotine in smoke however would not be accept~Dle for smoking purposes since a certain minimum of nicotine is needed for physiological effect.

JOHN C. WATTS ouee e! tprt tntatibee COMMITTEE ON WAY8 AND MEAN~ 31 January 1967 M~. Henry Ramm Vice President & Ceneral Counsel R. 3. Reynolds Tobacco Comp--y Winston-Salem, North Carolina ._+ Dear Mr. Rmm: You will remember that I told yon of my own personal experience after s~oking about 100 of the "Chemosol" treated cigarettes when you visited our office several days ago. My background is in engineering and construc- tion and covers a period of approximately 30 years. During this period I have been a very heavy cigarette smoker and had acquired a so-called "morning cough" which was my constant companion. After smoking the treated cigarettes for only one day, I awakened the next morning without the slightest cough ..... and this continued until I had exhausted the supply on hand. For approximately 10 days, I smoked my reg- ular cigarettes (a popular filtered brand) and my cough returned iumediately in its usual form. Two days after you were here, I obtained another supply of the "Chemosol" + treated.cigarettes,- -I have experienced exactly the same result and my cough has completely disappeared. While I have no s~ientific Jus- tification, I knov without doubt that something asso- ciated with the treated cigarettes causes me to+stop coughing during the entire time I smoke nothing else• This is a factual statement on my part that I thought you might like to have - because I have nothing to gain or lose by the success or failure of the "Chemosol" process •

PERRY B. HUDSON. I~. D. February 91 1957 ~!r. Lou~s Beck .;-~ 515 Madison Avenue ~ew ¥or~ N.Y. Dearer, Beck: The ~Imu1 experiments tn t~or production have reached the pelnt at which we ~ow kDow that chemosol treatment of clgare~te tobacco prevents development of ~sllgn~t tu~.|ors when total residues from cigarette smoke are subsequently injected into exp~r~J~cntal a~Imals. ~mattera of this i~por~ance I h~ve sou=hi consultatlon ~ro;= some of the ~orld's author~tles ~ ~or pro~uctlon matlc ~ydrocarbons. Speclflcslly I have included with a personal li~et~e of cxporlencc In tu~or production wl~h Bcnzpyrene ~nd related subslanccs In t~c specific ~nlm~ls utlli~ed ~n my la~ra~ory. Dr. ~s~an D, Haagcnsen Is such a porso~ and his advice has ~en ~ought. ~ofessor Arthur ~rdy Stou~ ~s ~ro~,~bly surglcal patholo~, It t'ould be rldlculou~ for me to c~.~,ent on the enclosed letter authored by these two dlst£n~u~hed ~ed£csl scientists. The photocopy of that letter is given to you In complete confidence that Its contents will bc used discreetly. P~rry ~. l~udson~ M.D. " Pro~oss~r of ~oolo~y Colu~bla University

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CH~OSOL FUEL ADDITIVE -. ORDINARY CIGARETTE TOBACCO BIOLOGICAL TESTING CARCIN~GENF~IS IN MICE l~ce are preferable ~1.~ for large-scale~ long term experiment~. Mice do not m~ontaneous~v develop ~alignaney ~ lime ffl~arco~a. :

Ca~brldgo fil%or r~sldues wore c~b~no~ and the ~ther evil, orated unqer ~cu~. Final}y, cigarette tol,~cco ~:~:,-. rc.s~,~u,m were PHOC~D~ The tech~tique of injection w~ with 25 g,u~s ne~d]es £m- oor~ecutlve days. Anl~]~. w~r~ followed by d~i~y ~x~ml~atlon, bi:~sy of [at~iei~u~ l~sions and tran.~p~ntati~n of conflrr~ ~gn~ncy ~tO t~or-frnc antis. Tno re~ ~ded bore are all ~ ~o e~r~t ~ ~e 19~, ~ a to~l of 300 CF] ~ce gi~n by InJe~gi~ ~ • c~et~ ~ok~ residues p~ day tlmes,~n.. ~e fi~e 3~ ~cludos Sosa,~ oil consols. SESA~ OZL ~NTROI~ There are no t~mors and no ulceration# ~S ~. Arbitrary b~y ~n ~x~]eS o~ ~Is ~ only p~eud~t for~tion~, ~ranu]ation tissue ~ ~0~'~

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A REVIEW OF "TECHNICAL REPORT ON CHEMOSOL - A FUEL ADDITIVE FOR CIGARETTE TOBACCO" The following remarks and questions refer to the unsigned and undated document entitled "Technical-Report on Chemosol - A Fuel Additive for Cigarette Tobacco." Industry scientists representing the six major cigaret£e manufacturers have thoroughly studied the subject report. They have experienced a great deal of difficulty in establishing the validity of the stated conclusions, largely because of the many pertinent and crucial points which have been omitted in the report. From the very beginning many unsubstantiated claims are made. Many of these involve points which could be resolved by well designed experiments which unfortunately were either not performed or are omitted from the report. Consequently, the industry scientists at this point in time can only formulate some general impressions of the work and then submit a list of specific and detailed questions, which if answered will permit a more~.complete evaluation. GKNE RAL IMPRESSIONS i. BIOLOGICAL SECTION: The reported biological experiments appear poorly conceived since the results and their implications do not substantiate conclusions concerning the carcinogenic potency of smoke from treated and untreated b~207 ~779

- 2 - cigarettes. The authors have used, as a means of bio-assay, an injection technique in CF-I mice. As far as we know there has been little, if anything, in the literature concerning the relationship between ulceration at injection sites and benzo-(a)-pyrene (BaP) content of the injected materials. The authors make no statement regarding their injection technique - which in itself could Be critical - in the production of various skin reactions. Incidentally, the use of sesame oil in injection procedures has been criticized severely. .This material is poorly absorbed and is not regarded as suitable carrier. The introduction of "Chemosol - fuel additive" is stated by the investigators to prevent the formation of BaP. Consequently, a relationship between BaP content of the injected materials and the bio-assay results must be established. -No experiments were reported in which BaP in sesame oil was injected into the mice. Further, these studies are based on the precept that a relationship exists between ~e concentration of BaP in cigar@tte smoke condensate and its tumorigenicity. References to the publications of Alvord0 et. al., Wynder, et. al., and the U. S. Surgeon General's Report are given to support this view. More recently, P. Lazar et. al., (Journal of the National Cancer Institute 3__~7(5):573-579, November, 1966) clearly vitiate the hypothesis of a quantitative relationship between BaP and mouse skin activity, including carcinogenicity of smoke condensate. 50207 6780

- 3 - Finally the "Chemosol Report" has been submitted to an independent and reputable biological consultant who has made the following statement: "The biological data consists of observations on local necrosis at the site of administration and systemic toxicity (growth. curves and mortality data). There is no information on carcinogenicity. These tests were done on a residue of the condensate from which it is stated that 'only the nicotine is removed.' I find this hard to believe because they have apparently used a sulfuric acid wash step which will pull out other basic molecules as well as nicotine and might have caused changes in what was left. "The ulceration experiment appears to indicate that the residue from the treated tobacco condensate is less active in this regard than the untreated. I don't know what this means or would show in terms of possible effects on lungs when the treated smoke is inhaled. "The systemic toxicity data are somewhat peculiar in that the treated smoke mortality was not different from the untreated at the I00 cigarette dose (509 mortality in both) but there was a difference (609 mortality in the untreated, none in the treated) at.a 50 cigarette dose. The failure to find a difference at the i00 cigarette level suggests that the difference at the lower level may be an artifact. ~ "Overall, it is clear that the biological work is very preliminary and does not provide an adequate base on which to evaluate the chemosol treatment as promising or not." In summary, it may be stated that the biological experiments performed have in no way demonstrated that there is a difference in the tumorigenic or carcinogenic activity of smoke condensate of treated and untreated cigarettes. The number and kinds Of comparisons were 50207 6781

- 4 - inadequate, the techniques may be inappropriate, and no statistical treatment of the data, as meager as it is, has been offered. CHEMICAL SECTION: It is extremely difficult to appraise the analytical chemical work performed because no two experiments were carried out on identical samples in the same manner. At the start great variation could be expected in the smoke delivery from cigarette to cigarette because the cigarettes were individually fabricated on hand operated machines. No information is givenregarding the quantity of particu- late matter collected on the Cambridge filter or the amount of condensate collected in the cold traps. In a procedure as complex as the fractionation of cigarette smoke condensate - involving repeated extractions, partitions, various forms of chromatography - itis essential that knowledge be had of the amounts of material initially collected as a sample. The techniques used for the isolation of a fraction for ultimate" "spectrophotometric analysis to determine BaP must be carefully controlled and rigidly adhered to, sample after sample, in order to determine reproducibility before any comparison between two supposedly different samples can be made. This principle, funda- mental in analytical chemistry of this type, is entirely lacking in the reported experiments.

- 5 - Questions Concerninq the Biological Aspects of the "Chemosol" Repor~ II. Cigarette Samples: i. What were the sources of the "commercial cigarette tobacco"? Under what conditions of temperature and humidity was this tobacco handled? How much variability in physical properties did these hand-made cigarettes exhibit? o What was the range of physical differences encountered in the cigarettes made on the separate devices? Condensate Samples: i. What time was required to smoke each batch of 500 cigarettes? How was the condensate stored? o How much particulate matter was removed from the total condensate in the methanol partition? How was it proven that after fractionation, sulfuric acid removal of nicotine, etc., nothing else was extracted or otherwise removed? 4. Why was sesame oil chosen as the carrier in these studies?

- 6 - So What was the amount of residue (concentration) finally put into the sesame oil solution? How was the solution stored? III. Animals: i. Why was the CF-I mouse chosen for these studies? What numbers of mice were used (totali in each experi- ment; each kind of treatment, etc.)? Can the fate of each animal in each experiment be reported? If so, give details. What was the seasonal variation (time of year) in growth/weight gain in animals studied, and under which conditions (reference especially to sex differences, etc.)? 4. What numbers of animals of each sex and age were employed in each type of experiment? 5, What. feed, water, cage (housing) conditions were employed? IV. Experimental: i. Were weight gains studies made at each dosage level? Why on the chart relating to weight changes is the data incomplete regarding the control and chemosol groups? Was a statistical technique used to determine the weights at each point given? If so, give details. 50207 678~

Vo - 7 - What volumes of material were injected for A (25 cigarettes), B (50 cigarettes), C (i00 cigarettes)? Were any experiments performed in which the volume injected was held constant/mouse, but concentrations of materials varied? If so, give details. 5. Describe the technique of injection in detail. Results: i. Explain the mortality of mice in Expt. B.I (60~ with 50 cigarettes) and C.I (50% with i00 cigarettes). Has this been repeated? If so, give details. Was any pathology done to determine cause of death? If so, give details. o o o On what basis is the claim made -- "Protection provided by chemosol against vascular impairment and tissue destruc- tion'is therefore of an order of magnitude of five to ten-fold"? Were studies made using any other oils or "carriers"? If so, give details. Were any experiments attempted using pure BaP in Sesame oil? If so, give details, including concentrations. What statistical analysis was made of the results within each group and treatment?. 50207 6785

- 8 - Questions Concerninq the Chemical Aspects of the "Chemosol" Report II. General I. Is information available on the pyrolytic decomposition products of Chemosol and on the biological effects of the material itself or its pyrolytic products? If so, give details. Does the addition of Chemosol to tobacco affect the burning characteristics of the cigarettes or alter the composition of the smoke and is this a function of.the amount of Chemosol added? If so, give details. Is £nformation available on the quantity of smoke on the filter, obtained per cigarette on treated and untreated cigarettes? If so, give details. o Were the smoked Cambridge filter pads stored for a specific period? If so, give details. Describe the 40-port smoker referred to on page 6 in footnote. Were the same smoking parameters employed using this smoking machine, as indicated on page 25, for the 6-port smoker? Recovery Experiment: i. Explain the calculation of .the concentration of benzo(a)pyrene (BP) in the stock solution referred to on page 21.

o - 9 - What are the particular qualities of methyl cyclohexane which make it preferable to hexane or cyclohexane as a solvent for polycyclic aromatic hydrocarbons? What procedures were employed in purification of the solvents used? Is information available on the blank analyses made on the solvents and apparatus including unsmoked Cambridge filter pads? If so, give details. Do the spectra shown on page 30 indicate complete separa- tion of the BP from interfering materials? If so, give details. Are there compounds that show adsorption peaks in the 375-395 mu region which may not have been completely separated from BP by the chromatographic procedure used? If so, give details. ~ Was any correction for spectral background adsorption applied in calculation of the BP found in the recovery experiment? If so, give details. If not, would such a correction have had an effect on the result? 50207 6787

III. - i0 - Experiment with 800 Untreated and 1,000 Treated Residues: Why was no spectrophotometric examination made of the "BP fraction" from chromatography of the treated smoke sample on the second column (silica gelcelite) before thin layer chromatography? (Page 36) Was any test made on preceding and succeeding fractions from this coIumn? If so, give details. Have any determinations been made in which smoke from cigarettes treated with Chemosol and smoke from a control (untreated)sample were analyzed by the exact same procedure? If so, give details. Determination of 3,4-Benzpyrene by the Grimmer Method: i. If Chemosol does not leave a residue and if Chemosol in fact reduces BP, why do the treated cigarettes show 0.2 grams or 1.8 times more residue after nitromethane extraction than the untreated cigarettes? 2. Why was BP added to the samples for analysis My the Grimmer Method? o Was the silica gel used for the chromatography of the untreated sample pre-treated and checked according to the directions of Grimmer? Was the alumina used p~e-treated and checked according to directions? ~020~ 6~88

- ii - o Why was a 25-g. column of regular (untreated) silica gel used for chromatography of the smoke sample from the Chemosol treated cigarettes instead of a silica gel column similar to the one used for the untreated cigarette sample? So Why were the eluates from the silica gel chromatography extracted with nitromethane (an extra step not called for by Grimmer)? o What conclusion can be drawn from this experiment in which the losses were such with both samples that the amount of BP recovered was less than that originally added? 50207 5789

PERRY B. HUDSON, M. D. 117 EAST 71ST BTRIrL'T April 21, 1967 The Honorable John C. Watts House of Representatives Washington, D.C. Dear Congressman Watts: Initially it should be emphasized that the first Chemosol report to you included what were at the time considered to be the salient points in the investigation by January II, 1967. It was not intended to be, and is not, a compendium of all the experimental work and observations. With this letter you are belng brought up to date. In the past, investigations of this sort satisfied only a segment of the institutions and individuals who are working in the field of tobacco smoke toxicity. The methods and equipment employed in making cigarettes, mechanical smoking,condensate handling (collection, storage, etc.), separations protocol, recovery deter- minations, identification techniques and control systems -- these factors still are viewed in various ways by different laboratories. However, the combination of chemical and biological evidence from Chemosol experiments overwhelmingly indicates that cigarettes treated with Chemosol are safer. • The industry scientists are now being given information on the alteration in tumorigenicity provided by the fuel additive, Chemosol. It is unfortunate that these experiments were not given to them before they evaluated the original report. In any event, we have determined differences in the biological effects of smoke from cigarettes treated with and without Chemosol. Secondly, through analytical chemistry, observed differences are explained. All of the biological data on tumor induction were wlthheld from the original report in order to obtain, wi~h discretion, the opinions of experts with great experience and professional stature In this field. The approach used in these experiments dictates the blologlcal importance of the quality, rather than quantity, of smoke condensates. Therefore total gravimetric values for condensates as a particular point have not been extensively investigated with and without Chemosol; no statistically significant comparison has been attempted. Experiments requiring the paintingof rodent skln with tobacco smoke condensates have in recent years received much attention. ~uch experiments are in progress now at the High Tot Laboratories. - 1- 50207 6790

-- 2 April 21, 1967 ~.t~.,.:is ,~.-~.i ..~.':'e.~2ond closely to those of Dr. George Moore, ?ark ~', .,.,.'~"' :i al_.. ]n~;titute, Buff~lo, New. York. Greater ~....;~.:~.e, l,.~.;ew~r, is ~ttached to ~he £~jection experiments. cor~r.~i~av:~s v,~de the High. Tor Laboratories concur tn this A].[ of th~ ,f~brosarcoma ~d~Ced~ in C F-I mice with • +,.WA<e co~densatcs causes death of the anlmls. The :~ ~. l~a~cy in this ~u,~,or.is so g~:~-:that it is the only " "~-,$ us ~i~[ch .has ever s~uccessfu]lY:~een, transplanted from . ~ ~..,~ the C Frl ~;train.. These factors, coupled with the ~, .._,~ i,e~,-.~itio~f,dosages, give ~at.,.Import to observa- ~., ~ ~dw,.C&~.~of t~o=igcn~c [ty b~#the use of Chemosol. :.~,vt :~.u~o~'~.sbo~ in our report are• examples of the - - ~ • addition- to ~-~-,~,~ f~l)_~wZug ,n~~:~ted~ ~o~:,~)~'~t~ i~ection, but Che~sol rag~e, ph s"~.~~a£.W, the answers to it ,,,u~;t b~un4ers~oc~ that the' original experiments % i~ i s ~>oi nt ~ ,~y be c larJ.i",ic4 by .no~.~ t~' M~2,procedures were c.~f~,]o>ed t:o screen against t:h9 ..~t@: po:~s!h~,ty of increased t:,~>:icit~ of s:u~,ke ~c~idues as a.'~6~:.o.,:"u~ecifled and un~o~ ~:,l rotations in the speCi~tw~ of py~e,~l~:~.~eng.-p~oduct$ consequent to the addition of C}.omosoi. Loca~ t.~s[~,e reaction, sk~.n .;~-m.~'ace response, (in ,or~'Ang veh:,cles a;%d w~ ~hout any at ~l.l~[.Sr~th~weight gain cu~es ::d .urvi.~a,l aC -hi# ,doseg¢ - ~-hese. .a~-~.~* ~asures were e~loyed. , s:~.~e~glgarette s~ke ~ ~.~,. les* noxious tban":zesi~u~~-, fgb~%~~ted tobacco. ~e • ,,.:: .~:ive. ageut~ a,-d ~cchan~.sms i~~;~.'d,e differences are T~}e sc, urc~s of co~:~,~iai ci-~.re~.te tobacco were several do,:'e'-.t[c (U.S.A,) ~..alu,~.acLuc~'~ ~.:~'q a[~..~L".~]~ of the Tobacco Institute. 50207 6791

The Honorable John C. Watts - 3 - April 21, 1967 used, and there are no discernible differences in physical character- istics in the finished products. Tobacco weight per cigarette is constant. The time required to smoke each batch of 500 cigarettes has been less than 24 hours in all experiments. Smoking machines operated on a continuous basis will smoke several thousand per 24 hour period. Condensates are immediately extracted and the protocol of separations chemistry initiated. Measurements of the particulate matter removed or retained at each step are not routinely made. Acid washes are not always used; recovery experiments with known amounts of hydrocarbons (e.g. benzpyrene) yield total recovery on the one side and zero on the acid side; surveys for other aromatic hydrocarbons (of varying molecular structure and with different numbers of rings) also yields negative results on the acid side. Sesame oil, lard, croton oil, acetone- these and other carriers have successfully been used for benzpyrene production of experimental tumors; implanted smoke condensates with no carrier or solvent have been used also; sesame oll produces no tumors itself and allows for slow, long-term absorption of condensate with well-documented micropathological changes attributable to the oil alone. The fate ~f every animal in every experiment is determined. At the time of death, regardless of apparent cause, each animal is preserved for complete autopsy with gross and microscopical pathological study. The C F-I mouse was chosen in consultation with colleagues in other institutions and with the advice of scientists at Carworth Farms, a leading producer of strains of animals for particular experimental purposes. The C F-I strain is not the only mouse used, nor are the experiments confined to mice. Both males and females have been used for all experiments; no regard to seasonal factor has been given in weight- gain experiments because of the short duration involved (e.g. 10-day period of injection); however, these mice are kept, not sacrificed, so that long-term results may be obtained. Housing conditions for these animals are identical to those found elsewhere in :the region - (Columbia, N.Y.U., etc.) and found acceptable by leading authorities. Weight gain studies were made only at a dosage level consistent with survival of all animals; to do otherwise would produce artifacts derived from complex metabolic alterations attendant to death from overwhelming toxicity. No statistical technique was either required or employed for weight gain studies used as part of a toxicity survey, considering the results obtained. Volumes of treated and untreated residue injections at each level were identical, as they were for 25, 50 and I00 cigarettes. The

.-'~'~c llonorable John G. Watts - 4 - April 21, 1967 technique of injection is shown in accompanying photographs, as is the "painting" technique. All dying animals receive complete gross and microscopical autopsy evaluations. Microscopical changes found in local tissue destruction of ulcerating lesions from untreated tobacco are the result of arterial occlusion. (This observation was consistently made during toxicity screening.) It does not occur when Chemosol is added to cigarette tobacco. While no extrapolation from this observation to human pathology is made, failure to develop these changes with Chemosol condensates is further evidence of the total safety factor involved. CHEMICAL SECTION: Information is available on the pyrolytic'decomposltlon products of Chemosol. For security reasons this information is withheld. There is no significant biological reaction to these end-products. The appearance, aroma and flavor of cigarette smoke is not noticeably altered by Chemosol, although the composition of the smoke is changed in some ways (e.g. benzpyrene content). The quantity of Chemosol required to produce the desired effect is known. Parameters for standardized smoking have remained unchanged through experiments in which different smoking machines have been used; only the 40-port machine has been used for this work during the past several months. This machine is similar to each of the smaller machines previously used, and except for size is almost identical to the 20-port machine supplied to us by a member of the Tobacco Institute. Experimental smoking is conducted continuously and condensates need not be stored. It is acknowledged that both hexane and cyclohexane are good polycyclic hydrocarbon solvents. Familiarity with methyl cyclohexane prompted, in part, its selection in the High Tot Laboratories. Reagent grade chemicals are used in extraction work and spectral grade for analytical work; further purifications are not routinely required; spectra are run on solvents, however. In the Grinvner method and with modifications in it, "pure" benzpyrene is obtained from the last column. Between 375 - 395 mu the amounts of any substances contaminating the benzpyrene would be insignificant. No spectrophotometric examination is made of the "B P fraction" from chromatography of the treate8 smoke sample on the second column (p.36) because of the large quantity of interfering 6"/93

The Ronorable John C. Watts -5- ~prll 21, 1967 impurity. This has been experimentally demonstrated by adding pure B P and observing how the impurities obscure it for detection. Many experiments have been done In whlch identical procedures were followed for treated and untreated samples of smoke condensate. Consistently negative results for B P in the Chemosol treated samples has prompted the further search as described in the prior report. Multiple malignancies derived from experiments involving hundreds of animals denied protection of Chemosol, against zero in the Chemosol group, provide positive evidence of protection against tumor formation by the use of this fuel additive. More precise instrumentation is available for the final detection of the presence of benzpyrene. However, the amount which could possibly be detected is in a range well within the error inherent in the separations methods. Furthermore, biologically, there is no understandable difference between absolute zero B-P values and those which are practically zero. This information, plus the materlal previously presented to you, answers all of the questions submitted to us, except in those instances in which answers are wlthheld for security reasons. The per- formance of numerous types of chemical experiments and blologlcal studies involving thousands of animals, have resulted in the accumulation of documented evidence beyond that necessary to substantiate the conclusions stressed here. This data is available, and interviews at our laboratory ~_may be the mostexpedient means toward total cl-a~iflcatlon. -. .Very truly yours, Perry B. Hudson, M.D. Professor of Zoology, Co lumbla University President - High Tot Foundation P.S. I am enclosing a copy of information added to the Chemosol Report of January 11, 1967. In addition, there are comnents from the College of Physicians and Surgeons of Columbla University and Baylor University College of Medicine, as well as a few representative samples of the mass of illustrative meterlal on the biological experiments; those evaluated and prepared by Professor Oscar Auerbach are so marked.

~DITIONAL IHFOKI~TION TO BE ADDED TO THE HUDSON KEPOKT FEBRUARY 22, 1957 CHEHOSOL FUEL ADDITIV~ - ORDINARY CIGARETTE TOBACCO BIOLOGICAL TESTING CARCII;OGE~SIS IN MICE BACKCKOUND The Institute of Cancer Research (Columbia University) has one of the longest experiences - 34 years - of continuous interest and experience with carcinogenesis related to aro.~atic hydrocarbons..Publications from r.~at institution prompt the follo~ln8 observations: Hice are preferable aulmals for iarge scale, long term experiments. Mice do not spontaneously develo~.mallgnancy llke ftbrosarcoma. 3, Injection under the skin is the preferred route of carcinogenadministration. 4. Sarcoma develops within from 4-9 ~onths. 5. Some of the mouse fibrosarcoma induced by hydrocarbons is transplantable. HATEKIAL$ &METHODS The oldest and ~ost reliable tumor-~esistant inbred strain of mouse was u~ed - CF1. Young, still-growing animals, both males and females, were chosen. Total cigarette residues.were employed, ordinary "A~erican" blend cigarette tobacco was obtained. O~e half of the particular batch of tobacco was treated with ~he fuel additive Che~sol, ~e other half was not so treated. ~en each batch was ~de into

cigarettes. The clgar~ttes ware smoked on a 40 port machine in the High Tot Laboratories. Technique for smoRing conformed contemporary, Internatlonal standards, The cold-trap and Cambridge £11ter residues were combined in ether, added to Sesame oll and the other evaporated under vacuum. smoke residues were injected. PROCEDURE F£naliy, coral cigarecce tobacco The cechnlque of injection was with 25 gauge needles immediately under the dorsal skin of the .mouse. Injections were repeated at the same I0 consecutive days. Anlmals were ~ollo~ed by da£1y examlna~ion, biopsy of susplctous lesions and transplantation o£ confirmed mallgnancy into ~umor-£ree anlmals,- RESULTS The results recorded here are a11 in the experiment begun June 1966 with a total o£ 300 CFI m£c~ given by injection 5 cigarette smoke residues per day times ten. The figure 300 includes Sesame oll controls. SESAME OIL CONTROLS: There are no tumors and no ulcerations in this group. Arbitrary b~opsy in examples of this group shows only pseudo-cyst ~ormacions, granulation clssue or nothing. UNTEt~TED RESIDUE HIC~: These animals develop fibrosarcoma and lymphosarcoma. The £!brosarcoma varies in differentiation and includes tumors with extreme mlCotlc activ£~y, transplantable. The fibrosarcoma is S0107 6.'/96

CHEMOSOL-T~EATED RESIDUE MICE: These anlmals,develop no malignant tu~ors ~nd no hlcere~lon. Granulation ~issue is found at the si~e of ln~ections. Ei~h~ months have passed since the last injection. Che~osol as a fuel additive for "American" cigarec~es yields total smoke residues which are nonprodue~ive of malignancy in CF1 mice by subcutaneous injection. At ~he same dosage levels and with the same batch of tobacco less Chemosol, smoke residues • induce transplan~sble malignancy in CF1 mice. Amou8 ~he mal~znancies are highly anaplastic fibrosarcomawhieh ~o no~ occur spontaneously iu ~he ~es~ animals used. S0~07 679"~

Speclflcally, opinions have been sought from authoritative sources st Columbia University in ~e~ York and the Texas Medlcal Cen~er in Houston. In addition the nature of tumors produced in response to injection of mice ~Ith ¢isarette tobacco smoke condensates has been evaluated by Professor Oscar Auerbsch, an acknowledged expert lu this s¢lentlflc ares. Hicrophotographs included in ~his repor¢ were ~de in Professo~ Auerbach'~ laboratory from representative mlcros¢opical fields selected by him. On the t~o follo~Ing p~ges are the over~ll evaluatlons from Columbia and from ~he Texas ~edlcal Center.

122 Y.~t 78 Street ~o p~opou~l, to r~v~ the h~rd o~ 3.~ b~r~PT~ f~ cigarette ~v~ by ~ ¢.~vo clear that ~ c~pn~g= of education or ~e use of tobacco in ~y cffc~tlvo ~rco. ~ culy o~r rock, roe Is to d~nlsh the ~ by n~e ~d Z ~d urge that to ~o th~ ~atlable to the ~oMi53 p~nlic. concern for the carc£no~enlc a substitute for prevention, ~o sc~o to ~ to .be the firot practlc~ Otept~rd prevention. bo 0

PART THREE SUP~IARY OF. T~IORIGENE $I S EXTZ RIME,~I aad BIOSTATI STICAL REPORT

O~

(See next page)

Eva~uatlon o£ Results= the anin~als receiving no protection from Chemosoi in :he cigarette tobacco produced a high percentage of ,~...iignanc, anaplastic =umors. The Chemosoi- treated tobacco condensates produced no malignant turaors. The statistical significance of these finding~ therefore a~sumes grca~ i;uportance. To arrive at the abstract significanc~ of these experlr.en~al results, it was necessary to determine ~he mathematical probability of obtaining the same results (within specifiei, acceptable percentile variation) should the experiment be repeated. Such reproducibility of the experiment gives practical significa.nce and value to =he findings. There are several acceptable means of estimating statistical significance of results in biological ex~erimentatlon of this type. We have elected the szringent z~ethod e=:pioying Fibber's Exac= Test. In addition, the competing risks i~vo!ved prompted evaluation under the most pessimistic hypothetical conii=ions consistent with observed facts. The overall probability of .004 indicates that Chemosol cannot be disregarded as the cause of a~ ferentiel in nm]ignant rumor production in ~he ~obacco snake condensa~c~ ~:.is concept i~ corroborated by the blos~a~.~ica! analysis of Herbert Levine, Eead of Bios=atistfcs, >:oncefiore Hospital an& Medical Ce~er, Xew York, whose flnilngs are attached =o ~his report. To assure maximum safety in drawing conclusions, Dr. Levlne had ini~ially assur.ed that Chemosol had no etfect on the failure of Chemosol condensate~ tc produce a ~alignan~y. He failed to prove this negative hypo:he~is despite favoring i~ in each choice ~,rough inter- pretation of results. Therefore, any ether type of anal}~is of =l.e experimental r~sults ~ould clearl5' de~ong~r~te :he positive effect of Chemosol in actually preventing maii~n~ncy.

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', I ~ £AST 2~0Th ~TR~.ET. ~RO,NX. NEW YORK I:,,,;67, T~.LEPHONE: 212/TU 1.1000 June 27, 19~7 Perry B. Hudson, M.D. 117 East 71st Street New York, New York 10021 Dear Dr. Hudson: I have reviewed n~~ preface_ " ........... "~ of .... e:~per~ ........ with Chemosol-treated cigarette tobacco condensa'$e. The study design seems excellent in view of uhe controls that ~:'~'~'~ instituted to avoid specific biases. YLe only ~s~ibl~ co~:.~>lai~..c th_c could a~ise ~.2ould center on the absence of ~he random allocation o~ i'" ..... ~a~e~ z~c. to the thre~ groups. which ~.:are inhzren~!y iesc susc~~cubic than group C ~,ice ~o the development of Lalignanc tc::.cr& upon trea~c:e:~~ ~<,ith tobacco smoke condensate, regardless of whether Chemosol was added. %L~ reverse might also be true, i.e., group C was more at risk than group L. U;-,der ells se~ of circumstances, the observed resu%ts ar~ not likely considerin~ the [:no~:n role of tobacco sn%oke condensate as a ca~*cinogen. Group B should have had some ~u~.ozs if the latter situation was true. and Chemo$ol made no d if feb'ante. ~:~hile the practical si~nifica:.c~ of the experiment i& quite obviou~ tests of sta~isticai signif" -'- ~re TM or'Cot. One ought to .... ~.. ob~,.~no the ou~.~u u~sui'~& upon replicating the ex:~eri- ment under the assumption that ChoL~sol really ~d~ no difference in production of malignant ~umors. i analy~cd the results in ~::o ways zince thare was an elc=~ant of competi:.g risks involved, a concept which i ~,,ill explain belong. In my first approach~ I analyzed the results in terms of the original groups of I00 mice each. U~ing Fisher's Exact %'est, the probability of obtaining the observe/ :-ares of malignant tun:or production (16/100 in group 0 and 0/i00 in Group L)~ under ,~h~ hypothesis that Che.~oso! actually had no effect~ was ca!cula~ed to be .000007, or 7 in a million. In terms of the development of Fibrosar¢omas, the probability was calculated to be approximately 3 in 1,000, o~- .003~. to be exact. As for ~he con,paring risk concept, consider the fact that the A n.ice in group B than died from o~her cau~s might have developed malignant tun~.ors if they had lived longer. To raise this factor ~nto account, I arranged ~he data to provide the most unfavorable possible results for group B and the most favorable possible results for ~[roup C. I assumed ~hat ~he $ mice dying in group B wiZhout evidence of a "__nor had lived longer and deve!op~d tumors w~,~e the 3 ":" dving from other causes in ~rou~ C would haw within a year; ~:~ r~.-~ lived and not developed a t .... ~u. Thus~ group B woui& have a tumor rat~ of ~/I00, while group C'~ ra~ ,,-~ 1O/100. 5020"f 6~21~

- 2 - Using these data and applying Fisher's Exact Test, the probability of obtaining the" assumed results, or results which were more extreme, was calculated to be .00~ with respect to all types of malignant tumors. If only Fibrosarcomas are considered, the calculated probability is .186, which would not be significant if the conventional .05 level is used to indicate statistical significance. The analysis discussed above represents what I was able to do in a limited amount of time. I am sure that the data could be treated in numer- ous ways using different assumptions..However, considering the observed results, other tests of statistical significance are likely to reject the hypothesis that Chemosol had no effect on the production of tumors. Thank you for the opportunity to share your interesting findings. Sincerely yours~ ~erbert S. Levine, Sc.D. Head, B iostat ist ics Department ESL:ss J

.V, rov, l~etl~-m Brir, kn~,rm Dr. ~In~i~ his ¢~ ~l~biu.~ ~il~ o~ chis ~tn~ vere t~lu~ clsl~ of ,he pr~ess. ~'. ~. ~~ ~d ~. LIpp, In a letter of A~Sus~ ?. 19~), ~ve s~s~ed ~ c~c~r~ly ¢es~. ~ the S~, d~loped by ~r~Idt, ~ld ~ tael~ed t~ thO ~e~ Cigarettes in ¢olid ~orm, ~c ~or ~ ~es ~ld ~ used as a solute. Hr. v. ~nd ~. Lipp ~ve a~ ~ 8~ly roll ~ti~ie8 of this C~o~. active ir,~redlen~s are. for ir.stcnce, c|tri¢ acid or o~h~r 50207 6826

F~OH l~J~b'~Z~ OF ~I.~G. OCtObER ~ 19,63~ pA~E 12 Ch~It~nan.* D~. Ne~.~alh Re~Ism~ ~xcused-* Dr. B~rke~y~r ~ Hr. Jo~l Ne~erburg No. 5.5 - Dr. D~-. ~eur=th re~ort~ that Dr. Bir~igh~s not an~vered to repe~t~d efforts ~u~Scs~in~ Coo~ratlon in checkin$ his tests. Dr. ~ndt$ u~es a prelim|nary~|tten oplnlo~ of the "Bun~esan~talt f~er T~bnk~ors~h~ In Fozc~.et~~ (~ficl~1 ~ Re~rch Institute for T~Cco) ~s pr~f o~ t~ s.~cess of his pr~ess ~ red~e the ~zp~ ~t of clgaret~c to~cc~. ~rdln~ to Prof. ~id, t~ ~Itten oplni~ Is solely ~sed or, res~l~s In order The SOle:trifle Cccxalssion recocmends to obtain event~lly ~nofflc;81 repo~ fro~ F~. ~h-.id of t~ Fo=sch~stelle outlinln~ the fl~l r~ults th~ tests. ~ t~ ~tl~ ~ f~d ~t t~ Prof. ~lg i8 ~zticipa~ nS ~etin5 of ~ C~lssl~ ~i~tifiq~ (C~S2A) i~ R~. ~. ~iscu~ ~~th ~of. Sc~Id this ~tter (~. Bindi~) and also t~ ~tte~ ";:itrosa=Ines." Dr. Neura~h report~ in resard to information received, vhereby citric ~cld is identified ~s the ma~erlal of Dr. Bindlgts research. Str~aety enough. Dr. BlnS!~ does not call it citric acid bvt ~ricarbox~lic acid.

f:xcuse(~: Dr. F.~l Eilebr¢ch~ ~:o. 6.~ - Dr. ~ndt~ TOPInio~ of ~he ~.des~nshsl¢ fuer T~bakforsch~s, F~rchhelm • he ~es~l~lt f~er Ta~kfor~b~, Forc~hei~* praised ~. ~Ith • ~i~ opinion. ~Is r~ st~es t~t, mccordi~ ~o the pr~ess ~evelope~ ~y ~. 31ndi~, ~ ¢~arettes s~ a red~ ~,&-ben~p~e cor,~en~ In ~ ~ke. ~rdl~ to t~e ~esult,, ~tres~d ciGsret~s ~ * ~p~e~ c~en~ o~ 2.7~ in t~ ~e, ~ile the ~ke of cig~re¢~es tr~t~ ~c~ding 2csc=rch ~b~r~o~ tested t~e res~tt, In fo~ different tests. ~ results of ~he ~do~.~lt ~ld~t be verified. ~ ~o11~5~8 table viii 8i~ t~ indlvi~1 results. AD~ncles Treated Cisare¢¢es Un¢rea~ed cigarecte~ Opinion of l>~of. Sc~ld Dr. Griper, Univ. Hambur8 Rce~¢s=a C~r~l ~es. Lab. 1.35~g/g conder.s~e 1. lO~/~g/S co.denude ¢,,,I ~D r- (D 0

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~:] . ' i ~ /" ~ ." • ., . . ,,.,..,. . .., .,.. : ,~.~.. ,,.,., , ".,,. ~.. ~ ,:",., ." ,,: -...,, ~.,.'.,., ,,. ,.., ,'.~.. , . 1....., .... , , . , " , ' . . , . ..' ~ ", " ,.. "~-". .'. - ~,~ ",~ ,., " ". •. , • ,,V , " ".::") ~'-" ~ " "-'. , , ' ' " "• , . • ~ .. ":~ .. =j:. ..".'~.~.~.~.'.; ..:..., , ..,/.~. '. '.. .... ~ ~ '-~.=~ ~ -;'~ ,,,;.':, "~..." ,,.., ., . • • ,,, " "..., ",' 'Uo'~'.;.', ~. ',. ",".'~ , ~, , ,'- ,'., , ~ , . . " • " ,,. ' " , "" .. . " " "" '";~"" " " - .... : ;i".:. , .,:k~:~' .. . ": ,L'.' "'" ~.:'~ .'-'.- '~,'-" -' :' ~'-1~".."" "' ' ".,' ,:.-'. ...";. ... ~-/.. ": ;.,,'; • , :',,o',.~\.~-" . .; :: :,i.:.i::,:i~ 70 K~mphurs~ Rochester~ N. Y. .~. ,:~,,~.:'." ,'~ :."(,.". ..... ~~>'.~,~.~,.'.."~. ,'..: ,~.~,,.,... _ ~.... . _ .-,. ' 50207 683tl • . • x...~ Mr. President R. J. Reynolds Tok&oco Co. Winston Salem, North ~rolina

CONFIDENTIAL March 6, 1968 Dr. R. E. Farrar (2) Re: Outsider Idea--Bagasse as a Tobacco Substitute, Frank S. Rogalla, North Bergen, New Jersey Mr, Rogalla has submitted a sample of heavily mentholated sugar beet bagasse to us for evaluation as a tobacco substitute. Hand rolled cigarettes were fabricated from this materlal and smoked by the members of this laboratory. The burning properties of this material were very poor, and the taste and odor of the smoke were quite similar to smoke from cellulose cigarettes. The use of bagasse as a tobacco substitute is covered in U.S. Patent Nos. 328,300, 2,756,021 and 2,809,904. The use of bagasse as a smoking materlal has also been studied by the R. J. Reynolds Research Department, Due to existing patents and to previous studies by the R. J. Reynolds Research Department, it is recommended that no interest be expressed In thls proposal, SOJ:cp S. O. Jones 0

FOLEY, SAMMOND & LARDNI.ER MILWAUKEE ~1 it EI~HON£ E73"0800 February ]3, 1967 PERSONAL AND CONFIDENTIAL Mr. A. If. Galloway, President A. J. Reynolds Tobacco Company Winston-Salem, North Carolina Dear Fir. Calloway: I write at the suggestion of Mr. Neil D. How]and, a Vice President of The Chase Manhattan Bank, New York City, pursuant to a telephone conver- sation which Mr. Win. Grid]ey,.. his/associate at that Bank, had, I beiieve, with Mr. E. C. Peterson, Treasurer of your Company, who mentioned that the sL, bject matter of this letter .lles exclusively with- in your jurisdiction and that this correspondence should, therefore, be addressed to you. Our firm represents, the.~oWner of Letters Patent numbered 3,034,931~ and 3,132,651~.'issued May ].5, 1962 and May ].2, 1964,_ respectively, the former of which relates to the processing of products, for..ismoking and ..the latter to tobacco, in each. case in order..to"accomplish-rapid aging and. elimination or substantially ~reducing. nicotine I confess to writing'~i~:~ ~ome timidity:~e-.. feel yourl/.firm must. beii~i66~d~ted with sugges ti~s .cause I

We,,.'~;~iin'::possession of'. ,ort pre~-~ pared by a nafiiopally known univers:tt~,::orientated research foundation which, followed "the~ procedures ~' "'; suing a mutually . ~; partner, of effe

Idea submitted to Dr. Farrar on 5/8/67 - Joseph E. Rapkin, Esq. Messrs. Foley, Sammond & Lardner First Wisconsin National Bank Building 735 North Water Street Milwaukke, Wisconsin 53202 represents owner of Patents Nos. 3,034,931 and 3,132,651. Mr. Rapkin's Feb. 13, 1967 letter to Mr. Galloway. Mr. Avram's reply dated March 3 re company policy and enclosing standard release forms. Mr. Rapkin's secretary acknowledged receipt on March 6. Mr. Rapkin's March 21 letter saying he will review and discuss release with client. Richard H. Miller of the Foley firm wrote on April 28 re the release - he called Mr. Avram on M~y i requesting changes in the release, Mr. Avram also talked with Mr. Rapkin on 5/1. Mr. Jack M. LeSer, President, International L-K Chemicals, Inc. 2511 North Farwell Avenue, Milwaukee, Wisconsin 53211 wrote Mr. W. S. Smith on April 29, 1967 re their visit together at NATD~ Mr. Rapkin's May 3 letter enclosing release (both copies) with changes initialed by Mr. J. M. Leser, President of client company. Also enclosed report made by the Wisconsin Alumni Research Foundation, indicating the results of their tests. Mr. Avram's May 8 letter acknowledging his May 3 letter and telling Mr. Rapkin that the matter is being referred to our Product Development people and will be in touch with him in about six weeks - bc to Dr. Farrar.

R. F..D. #' i, box ?44-A Lurey, Vs. - Dec. 17, ~9S4o Your kind and generous letter dated £ec. 14, 1~64~ reached me t?ds A. ;3. and 1 do wan~ ~o thank~ou for ~our interest ~n the matter of ~cotlne removal from the tobacco ~eaf. In answer 1 w~ll sa~ tha~ I have discovered ~ne process ~P~ich ~;'~iI remove #rac- ~Icsl]~ all of the nicotine, accordinE to ~he an£~ses m~6e, and ~he Tobacco ~acturer ~'ho secures the righ~ ~ use t~-ds, ~ new PAVIA~32ED" ~2, ~;ill survive ~le othe%'s will go do~ ~n His~D', E~ntley-Br~ey over TV last evs~ng ~o~ced ~hab the 6over~en~ is enacting C~&aret Labels starting Janu~:~ I, 19~5, end said bheb She labels wi~ be stronger th~ first proposed. Some Tobacco Companies have paid the Gre~t Czar ONE ~JNISZD THOUSAND DOLL~PZ (@I00,000.00) to aid and assist the Tobacco Company to sof~ soap ~he F. T. C. Sometime ago ] wrote the Great Czar, tnd ~_/s enszer to ~ le5ter zas very cold abou~ the removal of nicotine through m~ new discovered process. I doubt very much that he has ever infoz~ed the Tobacco Companies about the removal of nleotlne for fear of loosing ~he Czar position. The~ebster dictionary definite]~ abates that nicotine is po~son and the people of the World are beginning to know it. I, myself, was a victim of tobacco smoke four years ago, which star~ed my research work on the tobacco leaf. The restCLts of~y research ~ork proved satisfactory. ]f nicotine, in the past, had been removed from the tobacco leaf, the Goverz~.'~ent and the ~de61cai Frofe~sion v;ouid not have been in a posit~en to harass the Tobacco Industry, es~eciaily the C~garet ~nnufecturers. I have in ~y po~ze-~sion a boo.~let ent~t!ed " 5itliogre,,P¢" on $: OiiiNG end H£~.ALTH- l~8-!@~S, sent me by U. S. Lepa:'tment of Health, Education, ~nd ;;'elf-are, /uilic Health Service. I enclose herewith, cojy of whet ~cotine contains as ¥;ebster's dlsct~onary. Ykis being looked up by &~any, m;%ny people the world over to ascert,~.fn for themselves just what nlcotine cont~:ins, their findings being very enllghtenlng to them.. Bl~e can not he placed on it. Term#, Su~'geon General of the United States, for ¥.drning the people of ~ne ";,crld the danger of nicotine ~n tobacco. Belng ~gnorant of such danger ] %',as a vic$1m of just such poison. was sorry to hear of ~r. Eeynolds death, which wa~ announted over the TV last: everL%ng and at the same time ~unounced that Er. ~eynold~ had died from emphysema. Such publicity ~o the public over TV throughout the ~,orld ~s a detrluent to the Tobacco Industry. ~ir. Avrem~ I h~ve a C£rtlfied Analyses to sell and if the Eeynolds Tobacco Co:~.p~ny c~res to mr.nuf.~ctu~'e a Tobacco Loaf withnut n~cotine, then ~.e c~:n Jmme.J~..te.ly sU~rt 5020? 69~

---

~~ich~It Is~extracted~s a colorless, oi~, ac,dd transparent liquid ~nd use~, :~ ~ COT] N] C-Acld "- a white ~orless c~stell~ne oub~nce C~ Hc O_ N~ fo~d ;~foods like le~.meat, eggs, whole grain cerceals etc. and prepared syntheticelly by the oxidation of nicotine; it is e member of the vitamin B complex end is used in the treatment of pellagra; a~so c~lled niacin. NICOTIE]~ -A diseased condition caused by the ingestion of nicotine, as from tobacco: nicotine 2oisoniug.

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VITAMIN A AND THE HEALTH OF THE RESPIRATORY TRACT AND THE ORAL CAVITY

TAB____LE OF CONTENTS SUMMARY .... I VITAMIN A AND THE EPITHELIA 5 KERATINIZING METAPLASIA IN THE RESPIRATORY TRACT 9 EPITHELIAL TISSUE: "THE BODY~S FIRST LINE OF DEFENSE" --- 12 PRECANCEROUS DISEASES SKIN DISEASES INVOLVING HYPERKERATINIZATION ..... 19 LEUKOPLAKIA AND MOUTH CANCER AND THE ROLE OF VITAMIN A -- VITAMIN A AND THE FREVENTION OF CANCER ITSELF OTHER EXPLANATIONS INHALATION OF VITAMIN A HYPERVITAMINOSIS A ............ DOSAGE 34 36 37 CONCLUSION TABLE - REFERENCES 44 • ~3

SUMMARY Since shortly after its discovery in 1913, vitamin A has been considered by biochemists and physicians as a nutrient neces- sary for the health of the ephlthelial linings of the respiratory tract. More recently, vitamin A has been shown to be effective in preventing bronchogenlc carcinoma induced in hamsters by benzo(a)pyrene, and in preventing and reversing precancerous tumors, "papillomas," induced on the skin of mice by a similar carcinogen, 7,19-dimethylbenz(a)antracene, called "DMBA." The Council for Tobacco Research-U.S.A. is one group sponsoring re- search into a connection between dietary factors and carcinogenesis. Known since the time of Hippocrates to be needed for the prevention of night blindness, vitamin A is now recognized as hav- ing a more vital role in human health. Its lack leads to the over- production of keratin, a horny substance that makes up skin, feathers, horns, hoofs, and fingernails. This abnormal keratini- zatlon is found in various diseases of the skin, mouth and genito- urinary organs -- as well as the respiratory tract. Leukoplakia, white lesions in the mouth, is one of these diseases. Leukoplakia is also the most common precancerous lesion. The treatments for this disease which if untreated often develops into cancer, are surgery and large doses of vitamin A. The anti-cancer activity of vitamin A has been discussed since the 1920's. The vitamin may prevent or attack cancer and the precancerous states in many ways -- biochemical and mechanical. -I-

Epithelia and mucous membrances, made healthier by the vitamin, have been shown to be less prone to cancer. Abnormal keratini- zation, a stage in the sequence which can lead to many types of cancer, is prevented and reversed by vitamin A. Cilia, the micro- scoplc hair-like projections of the cells lining the bronchi, can be saved from destruct'ion by vitamin A, enabling them to continue their natural mechanical functions: trapping and removing dirt, irritants and carcinogens. The benzene compounds may be detoxi- fled metabolically by large doses of vitamin A. Reporting on his latest findings, confirming earlier findings, Umberto Saffiotti, M.D. of Chicago Medical School, explained his working hypothesis to last April's meeting of the Federation of American Societies for Experimental Biology: Vitamin A and a carcinogen aim at a "common target," a human process now unknown. The carcinogen initiates cancer, while vitamin A prevents cancer. James Olsen, Ph.D., a Rockefeller Foundation researcher, theorized at the same meeting that cells are more susceptible to cancer when they are dividing abnormally; and vitamin A prevents this abnormal cell division. At the American Cancer Society's Science Writers Seminar, last April in Palm Beach, Florida, Ronald Davies, Ph.D., a bio- chemist at Temple University's Skin and Cancer Hospital in Phila- delphia, explained that vitamin A, by speeding up natural skin growth, gives normal healthy epithelial tissue a "competitive advantage" over cancer. --~--

The benefits of vitamin A are not merely local, even though vitamin A has been used for years by dermatologists for various skin diseases. It also acts through the bloodstream when ingested orally or administered intravenously. Getting a biologically active agent into the bloodstream where it acts systemically can be accomplished another way -- by inhalation. Presently adrenalin (epinephrine), a stimulant, and amyl nitrite, for coronaries, are inhaled for their systemic effect. Nitroglycerine tablets, also for heart ailments, are absorbed into the bloodstream when placed under the tongue. Inhaling vitamin A would be akin to administering it intra- venously since the digestive system would be by-passed and the vitamin A would get into the bloodstream by passing through the highly vascular areas of the.tongue, bronchi and windpipe (trachea). A way of transporting the vitamin A for deposit on these blood vessels is via the natural moisture base of tobacco smoke. In addition to exerting some protection against the onset of bronchogenic carcinoma, vitamin A, by keeping the lung's epithe- lial lining healthy, may prevent emphysema. Some researchers have even reported that vitamin A is necessary in the prevention of athlerosclerosis. Normally vitamin A is fat-soluble -- and not water-soluble. But it can be made water-dispersible. Water-dlspersible vitamin A is available at any drug store for sale over the counter.

A device releasing vitamin A into the mainstream of tobacco smoke would assure an adequate supply of vitamin A to the respira- tory tract and bloodstream of smokers.

VITAMIN A AND THE EPITHELIA Hippocrates, probably the. first physician to record the use of vitamin A in treating disease, prescribed "an abundance of liver as a remedy for night blindness." (I) This association between vitamin A (found in liver in high amounts) and vision is well known, however, the nutrient has other roles in human health. James Olsen, Ph.D., a Rockefeller Foundation researcher and noted vitamin A expert, said at the Federation of American Societies for Experimental Biology annual meeting in April, 1967, that even though vitamin A was one of the first vitamins to be discovered, its action was still as mysterious to the researchers as the ac- tion of some of the "newer" vitamins like vitamin E. He, and other vitamin A experts on F.A.S.E.B.'s vitamin A committee, agreed that medical clinicians and researchers have in the past two years de- monstrated renewed interest in vitamins, but especially vitamin A. Vitamin A was apparently discovered in 191B simultaneously by two groups of researchers, McCollum and Davis, and Osbourne and Mendel.(2,B) Among the first signs of a deficiency in the then unnamed food factor were skin diseases, impaired vision and actual damage to the eye. (4) But a more vital role for vitamin A soon became apparent: a role in maintaining the" health and integrity of the protective ephithelial linings of the body, including the linings of the trachea, bronchi and bronchloles of the respiratory tract.

The Heinz Handbook of Nutrition, published for the H.J. Heinz Company and used by the food and drug industries generally, as well as by professional nutritionists, explained this early recognition of the multifaceted role of vitamin A. Soon after vitamin A was discovered as a necessary ingred- ient in the human diet, scientists noted two specific eye diseases caused by a deficiency of the nutrient. One of these diseases involved the drying and roughening of the cornea of the eye, or "xerophthalmia." The other, "keratomalacia," involved a later state of ~he same disease process, characterized by a fluid re- tention (edema), presence of abnormal substances (infiltration), and necrotic softening of the cornea sometimes followed by perfora- tion, the accumulation of pus and inflammation. (6) But in the diagnosis and treatment of patients with the vitamin A deficiency diseases, xerophthalmia and keratomalacia, physicians noted disease symptoms affecting the mouth, throat and lungs. The Heinz Handbook of Nutrition stated on page 147: Early clinicians frequently commented on the dryness of oral, nasal and pharyngeal membranes, hoarseness, husky voice and dry cough in pa- tients with keratomalacia; also the frequency with which respiratory infections, chiefly pneu- monia, were associated with acute phases of the disorders that constituted the primary cause of deathcases, o~6~ntreated or inadequately treated Rather than a nutrient with many independent and unrelated functions, v~tamin A became recognized as a nutrient needed by the one part of the body affected by the vitamin's deficiency -- -6-

the epithelial tissue. This tissue, the epithelium-- coated with a film of mucus when healthy -- lines the organs open to "the outside world," such as the eye, alimentary canal, respira- tory tract and genito-urinary tract. (7,27) As expressed by one researcher, "Aside from its role in growth and vision, the vitamin is important in maintenance of epithelial structures othe than the eye." (8) This importance is described in The Heinz Handbook of Nutrition on page 74: Vitamin A is essential for the integrity of epithelial tissues and normal growth of epithelial cells. Deficiency of vitamin A results in atrophy of the normal epithelial cells. Deficiency of vitamin A results in atrophy of the normal epithelial cell layer followed by proliferation of the basal cells and metaplasia to a stratified, keratlnized epithelium. In mucous membrances, secretory function is deranged and eventually obliterated. These changes may occur in the mouth, the respiratory tract, the urinary tract, the female genital tract, the prostate and seminal vesicles, and in the eyes and paraocular glands. In non-secretory, protective epithelium, vitamin A deficiency results in hyperkeratinization. Hyperkeratinization is the excess of keratin in epithelial tissue where some keratin is normal and necessary -- such as the skin. Analogous to hyperkeratinization of the skin is the pro- duction of keratin where keratin is neither normal nor necessary under normal conditions. This occurs in the mucous membrane epithelia of the respiratory tract and the urogenital (genito- urinary) system and manifests itself as keratinizing metaplasia. -7-

Either too much keratin or keratin where it shouldn't be is the common denominator of most vitamin A deficiency diseases. The unwanted keratlnlzlng or hyperkeratlnlzing process is a mor- bid change in epithelial tissue and can be reversed by ample doses of vitamin A. Many of the diseases involving keratinization or hyper- keratinization are precancerous diseases and modern scientists have considered the keratinization process significant in the search for links in a chain of pathological events that end up as cancer. Not only does lack of vitamin A cause the over-production of keratin, the nutrient, when administered, can reverse this disease process and establish equilibrium with the right amount of keratin being produced. (9) Vitamin A also protects against abnormal changes in the cells, called "keratinizing metaplasia." As The Heinz Handbook of Nutrition continued on page 209: The basic pathology of avitaminosis A (vitamin A deficiency) is hyperkeratlnization of the skin at large and keratinizing metaplasia in the linings of the respiratory, gastrointestinal, and genito- urinary tracts and endocrine, salivary, sebaceous and lacrimal glands. -8-

KERATINIZING METAPLASIA IN THE RESPIRATORY TRACT The respiratory tract is particularly dependent on vitamin A, as those early clinicians discovered while treating keratomalacia of the eye. In discussing vitamin A deficiencies, pioneer nutrl- tionist James S. McLester, M.D., wrote on page 305 of Nutrition and Diet in Health and Disease: Diseases of the respiratory tract are common. The mucosa of all parts of the tract becomes keratinized, but even before this has occurred, there are, no doubt, profound disturbances of function. Because of the readiness with which accumulations of keratinized cells become in- fected, this metaplasia of the epithelium of the respiratory tract and communicating cavities may lead not only to colds and bronchitis but also to sinusitis, otitis media, bronchiectasis and pneu- monia. This, no doubt, explains the frequency and high mortality of pneumonia in in~ants who suffer from vitamin A deficiency. (10) Keratin and keratinizatlon must be discussed whenever the pathology of vitamin A deficiency or "hypovitaminosis A," is con- sidered. Vitamin A deficiency causes the replacement of many different single layered epithelia by a stratified "keratinizing metaplasia." This is explained in detail in Some Aspects of Vitamin A Metabolism by J.S. Lowe and R.A. Morton, Volume XV in the series, Vitamins and Hormones: Atrophy of the epithelium concerned, .reparative proliferation Of the basal cells, and growth and differentiation of the new products into strati- fied keratinizing tissue. Regardless of the original function and structure of the region, this replacement epithelium is identical in all locations and comparable in all its layers with epidermis. -9-

When the vitamin A deficiency is brought to an end% the epithelium of each region returns $o normal both in morphology and function. (177 In Volume of of The Vit~amins: Chemistry, Physiology and Pathology, edited by W.H. Sebrell, Jr., M.D. of Columbia and current chairman of the Food and Nutrition Board of the National Academy of Science's National Research Council, and nutrition expert Robert S. Harris, the effect vitamin A deficiency has on the respiratory tract is explained on page III: Keratinizing metaplasia of the entire respiratory tract~ nares (nostrils) to bronchioles, occurs early. Cough is an early symptom in infants. Atrophy of the epithelium and-loss of ciliary action even before replacement by keratinizing epithelium favor bacterial invasion, and hence lobular pneumoni@ h~s been a frequent immediate cause of death. In the early days after its discovery, vitamin A was called the "anti-infective vitamin." Reason for ~this reputa- tion was the nutrient's role in maintaining healthy epithelia in and around the respiratory tract. On page 76 of the l~th edition of Nutrition in Health and Disease, Lenna F. Cooper, Sc.D., wrote: When vitamin A is deficient, the membranes lining the nose, the throat and other air passages, the alimentary canal and the genito-urinary tracts show changes in the epithelial cells known as keratinization. Wherever these tissue changes occur, the natural mechanism for protection against bacteria or other foreign substances is impaired, and the tissue may easily become infected. Clinical observations show that normal mucous membranes lining nose, throat, -i0-

sinuses and ear passages are the best defense aEainst infections and that adequate vitamin A is an important factor in maintaining the normal functions of these membranes. From these findinEs came the term anti-infective. This was not reallM Justified, because the function of this vitamin is really the mainte- nance of normal epithelial cells that. naturally afford the best phys$olQEic protection aEainst bacterial invasion. (ii) Keratinization of the respiratory tract due to a vitamin A deficiency can become so clinically acute that such serious lung disorders as blockages of small air passages, the bronchioles, and lung collapse (atelectasis) have resulted. (12,25) -Ii-

EPITHELIAL TISSUE: "THE BODY'S FIRST LINE OF DEFENSE" In describing the epithelial lining of the respiratory tract, in the countless articles on vitamin A, the experts keep using the phrase "the body's first line of defense." This "first line of defense" is protected by vitamin A. (18,19,20,29) For example, Paul Gyorgy, M.D., world-renowned nutritionist and professor at the University of Pennsylvania School of Medicine in Philadelphia, called vitamin A "the epithelium-protecting vitamin." (21) It protects by preventing the replacement of normal cells with a stratified epithelium. (23,30) L. Jean Bogert, Ph.D., summed up the many ways vitamin A is necessary for the epithelial health on pages 264 and 265 of his book, Nutrition and Physical Fitness: One of the chief functions of vitamin A is to maintain the health of epithelial tissues, namely the skin and membranes that line all passages which open to the exterior of the • body. When deprived of an adequate supply of vitamin A, these tissues undergo changes that lead to a peculiar type of horny degeneration called keratinization. Damage to the mucous type membranes that line the mouth, throat, nose and respiratory passages is one of the earlier effects of vitamin A lack. In addition to general de- terioration of the cells, these membranes lack their normal secretions, and there is loss of the little filaments called cilia, which, by constant movement, aid in keeping the membrane surface clean. Probably vitamin A shares with other vita- mins in promoting health of tissues and is 'anti- infective' chiefly in the sense that it~helps to keep healthy the lining membranes that are the 'first llne of defense' to prevent entrance of bacteria into the body. If there has been previous -12-

deficiency of this vitamin, the diet, extra doses of it, will be helpful in rebuilding stores of it in the liver and restorin= damaged epithelial tissues to health.'T22) Some researchers have even reported that vitamin A may prevent the onset of athlerosclerosis. (86) -I3- 0

PRECANCEROUS DISEASES Other diseases involving areas of the body other than the respiratory tract respond to vitamin A therapy. They, too, should be discussed because some of these diseases are precancerous. Also, all involve keratlnization of the epithelia: that process which can result from a vitamin A deficiency and which under certain conditions can be reversed by vitamin~ A. The presence of keratin is used by pathologists when, by microscopic inspection of tumor tissue, especially from the lung, they seek to determine if the specimen is or is not malignant. Metaplasia (changes in cells) may indicate a "malignant transfor- mation," but to diagnose epidermoid bronchogenlc carcinoma (squamous cell carcinoma) microscopic study reveals keratinized cells. "The outstanding feature" of epidermoid bronchogenic carcinoma (squamous cell carcinoma), one text writer said, "is the presence of keratinized cells." (26) Keratin flakes are observed when breast carcinoma is examined under magnification. (32) "Keratinization is freely present, and numerous masses of dead horn, surrounded by large foreign-body giant cells, occupy the stroma (structure) in ovarian carcinoma." (34) In addition to the wealth of scientific literature on vitamin A and the prevention and reversing of abnormal keratinization and on vitamin A and the prevention and treatment of specific diseases involving abnormal keratlnization, such as leukoplak~a, the most common precancerous lesion, there are articles and textual -14-

references to a more direct association between vitamin A and cancer. But since most of the literature shows vitamin A's ef- fect on the precancerous state, the sequence from normal, healthy tissue to malignant tissue is germane. In a discussion of this sequence the terms "neoplasm," "precancerous" and "premalIEnant" are used. Stedman~s Medical Dictionary, (B3) on pages 1214 and 1215, defined "precancerous," "premalignant" and "precancer": A lesion from which a malignant neoplasm is presumed to develop in a significant number of cases. (Emphasis ~rovided) And "neoplasm", on page 1006, as: ... new growths not only in the sense of the rates of reproduction of cells, but also from the point of view that the process of neoplasia may result in types of cells that are vastly different from those in the normal tissue of origin. For example, neoplastic cells are fre- quently invasive, and may even grow when trans- planted into other species. On the basis of cytologic and histologic, or the clinical course, or both, considerations (neoplasm) may be sig- nificantly classified as malignant or ben__~ (and also intermediate forms) . . ._ (emphasis theirs) Admittedly, some of the lesions that make up the American Cancer Society's seven danger signs may never become malignant, but enough do to warrant concern when noted. Although experts still do not know the exact nature of carcinogenesis, they generally agree that cancer does not appear instantly but only after cellular changes. At a precancerous stage this progression can often be reversed by vitamin A. (35) -15-

Early detection and treatment can and, in fact, does prevent cancer. According tothe United Nations World Health Organization, (36) "(1)t would seem ...that the majority of human cancer is potenti- ally preventable." The report of a W.H.O. expert committee stated that one way to "control" cancer is the recognition, diagnosis and treatment of the "precancerous state." On page 7 the committee says: The idea of a "precancerous state" came originally from dermatology - that a correlation exists between certain abnormalities or lesions of the skin and the subsequent appearance of a local cancer. It seemed reasonable to infer that the prior skin condition, while not itself neoplastic, predisposed the affected tissue to subsequent cancerous transformation. The diagnosis of the precancerous state is valuable because the immediate treating and curing of the precancerous state will often prevent the development of cancer. On page 9: The therapy of precancerous lesions forms a corner- stone of cancer prevention. Such therapy should be undertaken as soon as possible after diagnosis, should be adequate, and should be subjected to rigid follow-up. The training of the medical pro- fession in this subject is, perhaps, one of the more important current practical aspects of cancer prevention. It is most urgent that such training as is now practised in certain countries should be made world-wide. Squamous cell epithelloma, a form of squamous cell carcinoma, follows diseases involving the excessive keratin production .(37,42) The incidence is frequent enough to warrant this note on page 159 of The Practitioner's Illustrated Dermatologist by Howard Behrman -16-

of New York Medical College and Theodore A. Labow, M.D. of Columbia | Presbyterian Medical Center: Squamous cell carcinoma may be preceded by leukoplakia, senile (actinic) keratoses, and scarred or ulcerated lesions of many varying origins including radiodermatitis. These lesions grow much more rapidly than basal cell epitheliomas and often metasta- size. The degree of malignancy, however, varies from lesion to lesion. Studies, cited in the Surgeon Generalls report, Smoking and Health, show that the epithelium of the tracheobronchial tree of cigaret smokers undergoes changes similar to the changes caused by a deficiency in vitamin A. These changes are (a) loss of cilia, (b) basal cell hyperplasia and (c) the presence of atypical cells. (38) Some studies have indicated that the cilia of non- smokers remains healthier than the cilia of smokers.(BS) And vitamin A maintains the health and integrity of the cilla.(35'28) Concluding the discussion on the changes in the ciliated c~lls attributed to smoke, the report stated that these lesions are premalignant. (38) Back in 1937, Edwin J. Simons, M.D., in his book ~rimary Carcinoma of the Lung, wrote about the sequence from a normal respiratory trsct to one with cancer-like growths. On Page 91: According to the information at hand, the effect on the bronchial mucous membrane of the diet, and especially that of a diet contaluing little or no vitamin A, has not been fully determined. Wohlbach and Howe kept white mice on a diet without vitamin A and found metaplastic changes in the uro- genital epithelium. Also, the bronchial epithelium -17-

began a marked transition involving the basal cells and even changed itself in isolated areas to Keratin-like squamous epithelium. In many places there were small islands of such nature that the epithelial changes in the air pa~a~es in many instances resembled the growth, of. real ignant tumors. (Emphasis provided) (~) - -18-

SKIN DISEASES INVOLVING HYPERKERATINIZATION The dreadful road to cancer has milestones, warning signs and exit ramps. Sign posts along this road include observable cellulam changes and the precancerous lesions or diseases. The cellular chan~es, hyperplasla and metaplasia with loss of the cilia part of the cell, have been discussed. Much can be learned throughdermatology about the precan- cerous state and vitamin A's influence on this state. Epithelia is present in the skin and so is keratin. But too much keratin, hyperkeratinization, is an early stage in carcinogenesis. The build-up of keratin growths is the disease "keratosis." (See Table A) ,! Keratosis can be "senile, a geriatric problem, "actinic" -- caused by sunlight, or "arsenical" and all are Precancerous. (40,41) Another type of keratosis, seborrheic keratosis, is not precan- cerous. (40) Vitamin A has been shown to prevent and reverse keratosis. 35,43) Howard Behrman, M.D. and Theodore A. Labow, M.D., wrote on page 157 of The Practitioner's Illustrated Dermatology: Senile keratoses (actinic keratoses) are pre- malignant lesions of the skin which, fortunately, usually remain in situ for a long period of time. Susceptible individuals who have had excessive sun exposure over the years have an increased ten- dency to these growths. Senile keratoses are single or multiple well-demarcated f]at, or eley~d~ gray- bland lesions with a dry warty surface. ~"w; -19-

Pointing.out that senile or actinic keratosls is precan- cerous, Gordon C. Sauer, M.D., a professor of dermatology at the University of Kansas School of Medicine, warned on page 229 of the Manual of Skin Diseases: Lesion begins as a faint red, slightly scaly patch that enlarges peripherally and deeply over many years. A sudden spurt of growth would indicate a change to a squamous cell carcinoma. Individual lesions may merge and grow into a tiny horn sticking out of the face or neck. (40) On page 230, Sauer warned: To rule out cancer, e~very cutaneous horn should be sent with intact base for histopathologic examination. The incidence of squamous cell carcinomatous change in the base of a cutaneous horn is appreciable. (40) (Emphasis theirs) An etiological factor in carcinogenesis, particularly of the facial skin and llp cancer, is excessive sunlight. First indication of this development is the. build-up of keratin in the exposed area, or "hyperkeratos~s." (45) Hyperkeratlnizatlon alone is not cancer, but pathologists who notice hyperkeratini- zation are advised to take another biopsy. A renewed biopsy taken "sufficiently deep from the border of the lesion" may re- veal cancer cells. (46) Cancer of the larynx, the voice organ which houses the vocal cords, starts with metaplasla, or abnormal cellular change. Then abnormal corniflcation of the epithelial layer takes place. -20-

Excessive keratin forms on the surface of the epithelium. Kera- tosls then develops in the subepithelial layer. A recent text, Management of the Patient with Cancer,, stated on page 403: When changes of a malignant nature occur in the cells near the basement epithelium, it is re- ferred to as "carcinoma in situ" ... In some cases keratosis may undergo carcinoma if situ changes prior to invasion, while in others the malignant invasion o@~u~s without any observable intermediate stage. (7) Smoking and chewing tobacco is related to cancer of the oral cavity according to cancer experts, Lauren V. Ackerman, M.D., and Juan A. Del Regato, M.D. (49) But here, unlike the tracheo- bronchial tree, in the area of the lips, tongue, mouth, nostrils and gums, the phases in the development of cancer from various causes can be observed. As A~kerman~and Del Eegato pointed out, there are other factors influencing the development of oral cancer -- one is poor nutrition. Women, in the Scandinavian countries par- ticularly, have Suffered from sideropenia, or Plummer-Vinson syndrome, a deficiency in iron and vitamins generally. "The disease is probably due to a dietary deficiency and should be considered a true precancerous condition." (49) A precancerous Condition preceding cancer of the mouth and tongue. (49) -21-

LEUKOPLAKIA AND MOUTH CANCER AND THE ROLE OF VITAMIN A The most common precancerous lesion in man is a disease that involves keratinizatlon of mucous membranes -- leukoplakia. (50) Literally meaning "white patches," this disease is characterized by small, raised, white patches on the tongue, llps, inside the cheeks and on the roof of the mouth when it affects the oral cavitM, and in the Eenito-urinary tract, especially the vulva. . The most common precancerous lesion in man is also a disease that can be prevented and treated with vitamin A. In fact, aside from surgery~ the only positive therapy generally recommended for leukoplakia is vitamin A. (51,52,53,72) ~The Practltioner's Illustrated Dermatology advised on page 151: Leukoplakia is a p~emalignant lesion of the mucous membrane. Therapy: . . . Patients with leuko- ~l~k~a of the mucous membranes of the mouth must not smoke! Vitamin A buccal tablets (r~62c), 75,000 to 150,000 units d~i~ ~or several months may be helpful . . 3 (Emphasis theirs) Also recommended in the same book are high-protein and high-vitamin diets. -22- The evidence of vitamin A deficiency in the mouth is keratl- nization and leukoplakia The epithelial cells become atrophied ~ Repair is attempted by proliferation of basal cells and the new cells form into stratified epithelium. (54) As Differential Diagnosis

D1a~nosls of Mouth Diseases explained on page 133: The patient may complain of difficulty with vision at night, dryness of the skin, hoarse- ness and a dry cough. As far as the oral cavity is concerned, ~¥~ess of the mouth is the chief complaint. The resulting leukoplakia is cften a harbinger of carcinoma.(73) The Surgeon General's report Smoking and Health, claimed research data suggested that there is a strong clinical impres- sion llnkin~ the occurrence of leukoplakla in the mouth with the use of tobacco in its various forms. According to the report, oral carcinomas frequently develop at the exact s~te of an earlier leukoplakia lesion. (55) On page 203 the report concluded: Althou~h these results do not warrant any conclusions by themselves, they are consistent with the suggestion that oral cancer is fre- quently preceded by characteristic premalig- nant chan~es and that these have a relationship to the use of tobacco. Apparently excessive smoking rather than merely smoking is a factor in the cause of leukoplakia. And the disease is seen in patients who do not smoke. (56) One of the strongest calls for earlier detection and treatment of this number one precancerous lesion and its more severe mani- festations, leukokeratosls, came from Ashton L. Welsh, M.D. -23-

" lie adde~t t',~at tL: Io.;~ or' all 'JV cigarcU.e a.dver[[~[n~: "wouL:>'~ b~ the end of the public, but it v. oukt bc a s.~',ere eco~om~c .blow at p~c:~nt." ]n the loag run, he in- "No'.,: thMg~ come a]on,~ .... Tni~ i~n't co?or sets, pcc@e who use cok~r heavily to sc'][ I~at}" con'~e into the picture . . like l)r. Frz~nk Star, ton, p~csMc:4 of thc ('I3S ¢orporction: Acco.,lh~g to Fred ]"r[endly, folr,-~c.r !,:c~dcnt of C ~ S No~,s, I)r. Stnnton, a ~onsnlc.ker, is actively interested In h~5 b:.ok '5)~ e to Ci~'cum:,t:,nc~5 Our C:o.nt~o~/'.SD).~jri(ndly wrote "In the i'nonths preceding tim Stu'geoi~ Gener;l's report [J9~I] Stanton insisted that CBS had to begin formulating a policy, tits plan v,'a~ that well in. advance we should announce that on a specified future d~te we would . eliminate all cigarette advertising, for '.which, I was once told, CBS receb.'cd proximately ~70 niillion annually. StaMen' . believed 'that this amount-almo:;t half a tolal'of over [then] 15900~000 cigarette dollars spen~ in broadcasting each year~ coukl be repl~,ced by vther advertising Mr. Yriendlv ~oes" en to say tkat'Dc~ Stantoa lost that ~ound bu~ adds the{ "i~e is a relentless adversary when he has decided O[~ ~ ('OU!'/0 Of ~(+[]O11, and if the gov~iiMllell~ doe;n't order it first, I predict that eveMu- ally Stanlc, u's name will be assoclat(d with the limitalion m" rejection of cigarette ycrlising ¢,t~ lelevlsion." I)r. StanIo~ at~d C}IS re.fused tO cleny or confirm Mr. F~iondly's allegati:n on groun:Is thzd thoy had inadc 1~o comment On his book since its publication. Seventh io m~ elght-part tc~ies o,~ '£V clgareltc adventist;,2. Nell: ~m }'CC com- ~'u~in:: and ~ ferccr.s~ on, v.hat is likely to I~:qq~cn 1o l,rt,:~dcnst ci~;;,rclte aJs in the C> O

In Leukoplakia~ Leukokeratosis and Cancer in the Mouth, he said that the continuation of keratinization "progresses until a hardened, horny layer is produced." Unless checMed, this sequence proceeds to malignant dyskeratosis (self-destructive proliferation and changes in the cells). (56) The "field" is then "prepared" for malignant changes by an increase in size of the epithelial layer, as well as an increase in size of each of its component elements. (56)

VITAMIN A AND THE PREVENTIO_N ,,OF CANC.ER ITSELF The most definite findings to date on the antl-cancer effect of vitamin A came from Umberto Saffiotti, M.D., a research patho- logist at Chicago Medical School. Saffiottl, listed as one of the authorities in the Surgeon General's report, was the first researcher to demonstrate satisfactorily that benzo(a)pyrene could cause bron- chogenic carcinoma. He did this by feeding into the tracheas of Syrian Golden hamsters iron particles coated with the carcinogen. After passing through the bronchi, bronchiole and alveolar, the carcinogen was diffused through the parenchyma of the lung where it attacked the bronchi from the "rear" -- from the sides of the cylindrical bronchi away from the inner side protected by cilia. Saffiotti announced his f~st findings showing that vitamin A prevented bronchogenlc carcinoma at the Ninth International Cancer Congress in Tokyo in October, 1966.(57,87) He announced that he duplicated the results of his early experiments when he addressed a meeting, of the Federation of American Societies in experimental biology in April, 1967 in Chicago. (58,59) In his latest experiment, fifty-seven hamsters were given benzo(a)pyrene alone. Fifty-nlne were given benzo(a)pyrene plus 5 mg. (5,000 International Units) of vitamin A palmitate adminis- tered twice weekly in oral doses. Of the 57 annals receiving only the carcinogen, 30 developed 42 squamous tumors in the bronchi and 27 developed 51 papillomas (tiny precancerous growths) of the forestomach. -25-

Of the 59 animals receiving the carcinogen plus vitamin A, only 13 developed squamous tumors in the bronchi and only 16 developed 25 papillomas of the.forestomach. The number of animals, adminis- tered the carcinogen plus vitamin A, with squamous metaplasia, was 17. Ten exhibited this metaplasia with no tumors. The number of animals who were administered the carcinogen alone was Ii, and every one with squamous metaplasia also had tumors. Saffiotti explained that the vitamin A prevented the squamous metaplasia initiated by the carcinogen from becoming squamous cell carcinoma. His working hypothesls: Vitamin A and a carcinogen aim at a "common target" -- a human process now unknown. The carcinogen initi- ates cancer, while vitamin A prevents cancer. Saffiotti is not alone in investigating a direct connection between vitamin A and the prevention of carcinogenesis. George Wolf, Dr. Phil. of Massachusetts Institute of Technology, an internationally recognized expert on vitamin A metabolism, told a press conference at the December, 1966 meeting of the American Association for the Advancement that his work on vitamin A's role in the production of mucus and the retardation of keratin formation supported Safflotti's findings. (60) The precancerous conditions first became recognized by the dermatologists,(36) and dermatologists are investigating vitamin A's effect on precancerous conditions. Ronald Davies, Ph.D., a biochemist at Temple University's Skin and Cancer Hospital in Philadelphia, in April, 1967, told the American Cancer Society,s Science Writers -26-

Seminar in Palm Beach and reported in the February, 1967, issue of Cancer Research that vitamin A prevented and actually reversed the formation of papillomas, tiny benigh but potentially precancerous skin tumors. (43) These tumors were first induced on the skin of hairless Rhino mice by applications of the carcinogen 7,12- dimethylbenz(a)antracene (DM~A). According to Davies, vitamin A accelerates the normal process of skin growth thereby encouraging healthy skin. This gives normal, healthy tissue a "competitive advantage" over cancer. (43) Davies~ insisted that vitamin A has this anti-tumor effect even if the subject shows no classical signs of vitamin A deficiency. In 1963, B.K.S. DiJkstra, M.D., a Holland physician, reported that, of 330 patients with bronchogenic carcinoma between 50 and 65 years of age, a curiously high number was born in March and to a lesser extent February -- a time of the year in the era before modern preservation techniques o-- when most pregnant women in Holland were poorly nourished. (62) With no fresh vegetables for them or fresh forage for dairy cows, the vitamin A content of their bodies was low. He stressed the importance of vitamin A in the development of cells such as those in the lining of the bronchi and suggested that vitamin A deficiency is an important factor in the later de- velopment of pulmonary diseases. He reported that more often than not, lung cancer patients have first suffered from other disease of the lung -- caused by poor resistance -- such as pneumonia, tuberculosis or asthma. DiJkstra concluded, "The lack of vitamin A could be an important fa6tor in the development of carcinogenesis." -27-

One of the earliest references to an anti-cancer function of vitamin A was the work of Errs. FuJumka and Masaki in Japan in 1925. (61) They noticed that rats fed a vitamin A-deflcient diet developed cancer while rats given vitamin A d~d not. The most enthusiastic report on vitamin A's antl-cancer action probably comes from the U.S.S.R. N.N. Petrov of the U.S.S.R. Academy of Medical Sciences' Institute of Oncology wrote in A G~nera~ Guide to Research and its Treatment: Cancer: ...vitamin A deficiency which led in some experiments to hyperplasia and proliferative lesions of the epi- thelium. The addition of vitamin A to the carcinogenic hydrocarbon benzpyr@~e.retarded the induction of malignant growths. (~7) The Council for Tobacco Research-U.S.A. is also interested in the effects of diet on carcinogenesis. Clarence Cook Little, D.Sc., on page 64, of his ~965-1966 report to the industry, listed as a grantee of funds: Frederick A. French, A.B., director of Cancer Chemotherapy Research, Mount Zion Hospital and Medical Center, San Francisco. The project title: Carcinogenicity, cocarcinogenicity and anti- carcinogenicity of dietary factors in relation to pulmonary tumors. Possible interrelation- ship of tobacco bases and dietary factors. Chemical studies_9B.pyridine bases incSuding niacin analogs. ( -28-

OTttER EXPLANATIONS Not only does a deficiency of vitamin A cause a transforma- tion from mucus-lined epithelia to keratinlzed stratified epithelia, but the deficiency also causes, as part of the process, a disap- pearance in cilia. Cilia are the microscopic halr-like projec- tions of cells lining the lung's air passages. These cilia perform the necessary functions of trapping and moving from the lung- inhaled foreign substances including dirt, irritants and potential carcinogens. Vitamin A can restore the cilia as part of its activity in reversing the keratinization process. (71) How the cilia cleanse is explained on page 267 of Smo_~ and Health:(66) The cleansing mechanism of the mammalian respiratory system is dependent upon the efficient, integrated functioning of a complex system. From the nose to the terminal bronchloles, a mucous layer in which impacted particles and dissolved materials reside is propelled over the surface and removed from the res- piratory tract by the rapid, systemic, and purposeful beat of the cilia. The Surgeon General's report claimed on Pages 267 and 268 that tobacco tars and smoke inhibit this ciliary motility: There seems to be little or no doubt that cigarettes smoke is capable of producing significant functional alterations of ciliary activity in vitro. Such alte- rations could interfere markedly with the self- cleansir~ ~^~o~o~ of ~h~ ~-~O~V tract. The report admitted that the results of the test tube studies with human and animal lung tissue cannot be extrapolated to apply to man, but stated that autopsies have revealed shorter -29-

cllla and less.clllated cells in smokers than In non-smokers. Vitamin A's effect on the cilia and the cilla's function was explained as early as 1936 by Sir Robert McCarrlson, M.D., Sc.D., considered the father of nutritional sciences, on page ~5 of his book Nutriti.pn a~d H~alth: Let me draw.your attention to the kind of change that is brought about in eplthellumby lack of this vita- min. This membrane is covered by tall epithelial cells, each of which has a fringe of cilia. A func- tion of these cells is to secrete mucus which not only traps bacteria but permits the oilla to perform their movements -- this they can do only when the membrane they fringe is moist and the moisture contains calcium, The function of the cilia is, by their rapld movements in waves, to propel bacteria or foreign particles, as of dust, towards the exterior of the body, whence in normal circumstances, they are ejected. It has been estimated that the cilia move at the rate of about 600 times a minute. Now when the food Is deficient in vitamin A~ the cil a s o o .a _ hE ce Is em- selves l'ose their s~'cretory ~haract~r~" becom~r~horny or kerati~zed~as it is ~alled. ~ure ~p yourselve~ w~at this means~ no longer Is-this tra~plr~, thi~ pro- pelling of harmfu!.partlcies~ whetherof dust or bac- - in the teria~ or both~ possible ~reas sosf~ected. Unless the deficiency be very grave, it is" only at certain places that these chan~es occur. Where they do occur, the local defenses are broken down and bacteria are free to implant themselves in the soil thus made ready for them and to invade the tissues. And it is a curious fact that, in these circumstances, bacteria that may otherwise exist as harmless saprophytes, often take on pathogenic properties and become disease- producing. Mark how serious a view the body takes of these events; at once it sehds u~ ~efe~se forces in ~he fbrm of round ~ells t~ man the b~each~, and these ~ay ~cc~_u~'ate to such an extent ~s actually ad~noid-l~'outgr0wths." (Emphasis provlded~ Cilia then, kept healthy with Vitamin A, can also trap and propel carcinogens. Carcinogens in the concentrations found in our environment, -30-

are not enough to cause bronchogenic carcinoma. Cell changes from other causes -- and non-functioning cilia in the bronchi -- plus these carcinogens apparently combine, with other factors, to cause lung cancer. (169) One of these other causes of cell chan- ges and an inhibitor of ciliary function is Vitamin A defi- ciency. (28,68) As the W.H.O. report continued on page II: Multiple etiological factors are at work. In this instance the existence of polycyclic aromatic hydro- carbons in both tobacco tars and polluted atmos- pheres, is well established. However, levels are so low that other factors would seem to be required to induce the tumors. From a cursory observation of the pathogenesis It is apparent that the co- existence of squamos metaplasia and exposure tB carcinogen would be likely to increase the locali- zation in such a lung. Again, the paralysis of ciliary action would predispose to this hazard. In terms of cancer prevention it is impossible to rule out the possibility that these non-speclfic links in the chain of pathogenesis may be vital. (69) Mucus -- perhaps overlooked by cancer researchers, is also involved in vitamin A's anti-cancer or anti-neoplastic activity. And certainly, mucus is important in the natural cleansing of the lungs of smokers and non-smokers. (68) The healthy epithelial lining of the respiratory tract is coated with some mucus. How- ever, the epithelia of the vitamin-A deficient subject's respira- ./ tory tract, instead of being covered with a mucous membrane, becomes keratinized. The role of mucus is currently being Investigated by the Council for Tobacco Research -- USA. (63) -31-

The Report o£ the Advisory Committee to the Surgeon General, Smokln/~ and Health polnts out the need for Investigation lnto mucus and Indications of mucus chan~es caused by tobacco smoke. However, much is known of the relationship between vitamin A and mucus. With particular reference to the findin~ of Saffiqtti,(58) George Wolf, Dr. Phil. of the Massachusetts Institute of Technology, and a recognized expert on vitamin A metabollsm,at the December, 1966, meeting of the American Association for the Advancement of Science said that his findings supported Saffiotti's. Vitamin A stimulates the production of the mucus, while the deficiency stimu- lates the production of keratin and reduces the production of mucus. (60) Mucus, secreted by the mucus producing cells stimulated by vitamin A, may itself have some anti-cancereffect. According to Sm.9~ing and Health, the healthy oral mucosa appears to be resis- tant in general to cancer induction, even when highly active car- cinogens, such as benzo(a)pyrene, are applied. (38) Vitamin A might perform its anti-cancer duties by encouragin~ another "mechanical" function, involving not only the saliva but the cilia as well. As the repo~ stated: Mechanical factors, such as secretion of saliva, interfere with the retention of carcinogenic agents. As mucus acts both mechanically and biochemlcally, so also does saliva. The report continued: ~ Saliva may also play a chemicalrole in modifying the action of carcinogenic agents-on the oral cavity and pharynx. (38) -3z-

Vitamin A will prevent the dryness that precedes the precancerous mouth lesion, leukoplakia. There is yet another possible explanation for the anti- cancer activity of vitamin A. Researchers at the Dunn Nutritional Laboratory of the University of Cambridge in England reported that two benzene ring compounds, sodium benzoate and bromobenzene "became harmless" when given in conjunction with large doses of vitamin A. (55) On page 61 in the Symposium~ of Nutrition., Thomas A. Moore, Ph.D., one of the world's leading experts on vitamin A, explains : (R)ats given llb~'-doses of vitamin A were able to resist metabolic stresses which proved fatal to animals receivln~ only bare minimum necessary for growth. ~70~ Metabolic processes~ including the Krebs cycle, are being investigated for their relationship to carcinogenesis. (89) Even though the two poisons in the Cambridge study are not the same compounds as the benzene carcinogens similar to benz(a)pyrene, this metabolic "detoxifylng" effect of vitamin A should not be overlooked as a possible explanation for part of vitamin A anti- cancer activity. -33-

INHALATION OF VITAMIN A Breathing vitamins? Although novel, this concept is neither ridiculous nor unscientific. Since vitamin A acts sys- temically to prevent lung cancer, inhaling the tiny particles of the nutrient puts them in the blood stream quicker than if they were swallowed. The many blood vessels in the tracheobronchlal tree "pick up" the vitamin after the first puff. Vitamin A is then.carried to the bronchi, the site of bronchogenlc carcinoma -- for added local or topical benefit. Swallowing herbs and plants to relieve sickness is as old as the art of medicine itself. But, breathing the smoke from burn- ing stramonium leaves is an ancient folk remedy for asthma that is used even today. "Inhalation therapy," this different way to administer medication, has profound application in treatinE the modern patient. (74,75) Antibiotics are inhaled for both their systemic and local effects against infections. Warmed salt and glycols aerosols are used to treat lung diseases and to diagnose cancer of thelung. Enzymes, chemicals produced by body organs to assist in metabolizing food, have more recently been inhaled by those suf- fering from excess mucus in the lung. "Mucolytic agents," such as the enzymes trypsin and pancreatic dornase have helped patients suffering from bronchiectasls, atelectasls, chronic bronchitis and other bronchopulmonary diseases. Epinephrine (adrenalin), a stimulant, and amyl nitrite, for

coronaries are Inhaled by patients for their systemic effect. A nitroglycerin tablet, also for the heart, is absorbed into the bloodstream when placed under the tongue. Even the smoker who does not inhale would benefit from Vitamin A in the mainstream of tobacco smoke. The tongue, for- ward parts .of the throat and nasal passaEes contain blood ves- sels capable of "picking up" and transportinE the vitamin through- out the bloodstream. Inhalation of vitamin A provides a conveni- ent and effective way of benefiting fTom the anti-keratinizing and anti-cancer effects of vitamin A. -35-

HYFERVITAMINOS IS A The intensity of the warnings of vitamin A toxicity is greater than the published data on the subject. Hypervitamin- osls A does occur frequently in children when their mothers give them concentrated vitamin A liquid or vitamin A and D, not accord- ing to instructions -- by dropper -- but in the same large table- spoon dosages by which their mother used to measure cod liver oli (7~) Adult Eskimos and explorers who consumed Polar bear ~ liver, loaded with vitamin A, also became intoxicated by vitamin A.(7~) But according to William H. Stimson, M.D., the medical director and chief of the U.S. Public Health Service Hospital in Seattle, Washington, only six cases of vitamin A intoxication in adults have been reported. (7~) Fifty thousand l.U.'s are considered toxic, but the dosages in the cases of adult intoxication have generally been in the hundred thousands and millions of International Units. (7~) Furthermore, unlike other vitamins, such as vitamin B-I and vitamin D, there are no data indicatlnghumans are allergic or hypersensitive to vitamin A. (75) -36-

DOSAGE Whenever vitamins and diseases are discussed, questions arise: Does the vitamin have this effect only because the sub- Ject is deficient in the vitamln;, that is, does the vitamin have a physiological effect? Does the vitamin have this effect even if the subject is consuming and utilizing enough of the vitamin; that is, does the vitamin have a pharmacological effect? Cer- tainly the "need" for vitamins was first recognized when their absence from the diet of man and other animals produced certain symptoms. But no one will doubt that some vitamins produce ef- fects in the body not related to fulfilling a nutritional defi- ciency. In fact, ten per cent of all U.S. sales of pharmaceuti- cals in 1963 (87) were sales of vitamins prescribed by physicians -- not sold over the counter. How many of these prescriptions were to fulfill nutritional deficiencies and how many were to treat diseases in patients who were not deficient in the vitamin pres- cribed is not known. -Vitamin A prescribed therapeutically -- and not to supply a nutritional requirement -- for ache, leu- koplakia and hyperkeratinization or k~ratinization diseases in dosages of iO0,000 I.U. 's and up. (90,91) Saffiotti's findings to date have not answered these questions. But Saffiotti did use doses that, while they were not toxic, were substantially larger than doses which would be needed to correct a vitamin A deficiency state in the Syrian Golden hamsters. And Davies reported that vitamin A would even pre.vent and reverse tiny precancerous skin tumors in hairless Rhino mice who were consuming -37-

adequate amounts of vitamin A. He made it clear to the Science Writers' Seminar, sponsored in April, 1967, by the American Cancer Society, that vitamin A had a pharmacological, as well as a phy- slological effect, in preventin£ and reversln~ papillomas. The distinction between the physiological and the pharmacological ef- fects of vitamins may be merely arbitrary for practical purposes. The minimum daily human requirement of vitamin A, according to the Food and Nutrition Board of the National Academy of Sciences National Research Council, is 5,000 International Units. But more is recommended by such nutrition experts as Henry C. Sherman, Ph.D., D.Sc. and Caroline Sherman Lanford, Ph.D. of Columbia University. On page 290 in their textbook, Essentials of Nutrition, they wrote: In view of the facts mentioned in the preceding para- graphs, the question, how much vitamin A value is re- quired in human nutrition?, logically raises a fur- ther question. Requ~d for what: for the maintenance of passable health that each individual is potentially able to attain? ...Human requirement should, mean not only what is needed for the prevention of specific die- tary symptoms, but further what is needed to permit a human population to realize fully the potentialities of its hereditary birthright. ~78) Because observations upon the human popUlation reveal more frequent slight deficiencies in vitamin A, they wrote on page 292: ...(T)he actual requirements (are) higher than hitherto supposed .... (I)n case of vitamin A there is a wide zone of beneficial increase between the minimal-adequa~e~nd the long run optimal level of intakes. Sherman took issue with the N.R.C. recommendation. in his textbook, Chemistry of Food and Nutrition: On page 468 -38-

From 6,000 to 12,000 I.U. daily is scientifically more logical to provide' both for individual varia- tions in requirement and for the maintenance o£ such a bodily reserve as has been found to b@ favorable to higher health and longer life. (79) On page 467, he discussed longevity and vitamin A." ...Vitamin A is one of the outstanding nutrients of which stepwise increased intakes induce correspond- ingly higher health and longer life up to intake le- vels about four times that of minimal adequacy. There is no doubt that in these experiments the addi- tion of extra vitamin A to a diet which already con- tained "enough of everything" did positively and constructively build higher health and longer llfe. And we need have no doubt that this same thing may often occur with people....The increase in the average length of normal adult life in these experiments was I0.~ per cent with males and 12.1 per cent with females. If one finds doubt about some questions of relation of vitamin A to disease, one can still be confident that it clearly promotes positive health. The discoverer of another important vitamin, panothenic acid, a B vitamin, Roger ~. Williams, Ph.D., said "There are people (perhaps i0 per cent or less) who have requirements much higher than the general population." For this reason, he recommended vitamin A supplements "at levels higher than ...recommended." (80) Fredrick J. Stare, M.D., Ph.D., professor of nutrition at the Harvard School of Public Health, said, "The diets of teen-age girls are inclined to be low not only in iron, but also in vitamins A and C and the mineral calcium." (81) A World War II survey of dietary habits of industrial plant workers conducted by the Committee on the Nutrition of Industrial Workers of the National Academy of Science's National Research Council revealed that, although "only 15per cent of the workers

had diets low in vitamin A, nearly every worker had vitamin A lesions (avitaminosis A) in the conJunctiva as shown by the biomicroscope." And so using the "accepted" standards of the National Research Council, symptoms of vitamin A deficiency appeared in many workers who,.according to these standards, were on diets not deficient in vitamin A. (82) Sixteen per cent of American families in 1955, according to the U.S. Department of Agriculture (92) were consuming less than two-thirds of the recommended National Research Council (NRC) Allowances. But American dietary habits have changed and are changing. In the period from 1910 to 1957, the per capita civil- ian vitamin A consumption in the U.S. "before cooking losses" peaked in 1944 to 130 per cent of the vitamin A consumption for the 1909 to 1913 base period. The averages dropped sharply during the period from 19~4 to 1957 (approximately the time this book was written).(83) Cooper and associates in 1958 expanded on the issue of nutri- tional deficiencies in this country in the 13th Edition of Nutrition in Health and Disease: The United States s~ill has mild nutritional deficiencies, especially among people of low income and limited edu- cation. Often these deficiencies are termed subclinical because they are not the frank deficiency diseases found in underdeveloped countries. Surveys made (in the U.S.) during World War II showed that large numbers of people were not eating foods to provide the nutrients recom- mended for optimum health. (83) Although many diets are inadequate "evidence of serious malnutrition may not be conspicuous." "However, poor diet pre- disposes a propDrtion of such groups to the possibility of physical -40-

ills or defectsresulting from habitual malnutrition. (83) Torben K. With and Umprey Milford of Oxford University in London pointed out a difference between this "minimal requirement" and an "optimal requirement" considerably hi~her. (85) In their book, Absorption, ~et.abolism and Storage qf Vitamin A and Carotene,• they ~explained the way the body absorbs vitamin A after intravenous administration. Intravenous inJec- tlons of vitamin A "showed a distinct rise in the blood sample taken 15 minutes after the injection (from the other arm), but the values reached essentially the initial level with one hour, and the rise subsided completely wlth24 hours." (84) Vitamin A propionate may be the most suitable form of the vitamin. It is available in liquid, water-dispersible form from Vitamins, Inc. of Chicago, lllinols. But vltamin~A acid may be more suitable. Vitamin A, or retlnol, is virtually tasteless, assume the-taste of its base. but does O~ 0 r~

C ONCLUSI ON Vitamin A is recognized as a nutrient necessary for health and integrity of the epithelial linings of the oral cavity and the respiratory tract. Vitamin A can prevent and reverse pre- cancerous conditions in humans. Vitamin A has prevented bronchogenic carcinoma in experimental animals. -42-

TABLE A - PRECANCEROUS STAGES INVOLVING KERATINIZATION DISEASE AREA AFFECTED STAGES BEFORE. CANCER REMARKS Leukoplakia and Leukokeratosis Mouth Vulva Urogenital Tract Vitamin A deficiency Leukoplakia Leukokerat os is Vitamin A Surgery Leukoplakia is the most common pre- cancerous lesion. Keratoses:" senile actinic arsenical Cutaneous horn Skin Lip 01d age, sunlight or arsenic exposure Possible cutaneous horn Neck Face Ears Keratosis Lesions merge to form horn Electrosurgery Surgery Topical applica- tion of anti- cancer drugs Vitamin,A Surgery Keratosis and Leukoplakia fre- quently precede squa- mous cell epitheliomas, a type of squamous cell carcinoma. Squamous cell carcinoma often occurs at base of horn. Papillomas Skin Vitamin A deficiency Carcinogenic exposure Keratosis Vitamin A Papillomas are tiny precancerous skin tumors. Keratinizing Metaplasla in the respiratory tract Tongue Mouth Nostrils S inuse s Bronchi Vitamin A deficiency Keratinizing.meta- plasia Loss of cilia Sometimes bronchitis, sinusitis, pneu- monia ~ ~ lun~ collaDs.e. • Vitamin A One of the first clinical signs of vitamin A deficiency noticed. Keratinizing Metaplasia and cornification of the vagina Vagina 01d age or Vitamin A deficiency or both Keratlnizin~ meta- plasia Cornification of the v,a~in~ ~ Estrogens Vitamin A Use in mice as an assay to determine extent of vitamin A deficiency.

REFERENCES o McCollum, E. et al: The Newer Knowledge of Nutrition, 5 ed., New York, Macmlllan, 1939, PP. 290, 308 McCollum, E., Davis, M.z The Necessity of Certain Liplds in the Diet during Growth, J. Biological Chemistry, 15z 167- 175 (1913); The first medical article on vitamin A published in Milestones In Nutritions, Volume Joslyn, M.) Westport, Avl Publishing, 1964 Follis, R., Jr.: Deficiency Diseases, Springfield, Thomas, 1958, p. Wohl, M. Goodhart, R. 9 ed.,: Modern Nutrition in Health and Disease: Dietotherapy, Philadelphla, Lea & Febiger, 1964, pp. 349-353 5- 3., P. 128 o The Heinz Handbook of Nutrition, New York, Published for H.J. Heinz Co. by Blaklston Division of McGraw-Hill, 1959, pp. I~-147 7. 4., p. 353 8. 4., p. 353 i0. II. 12. 13. lb. 15. 16. Parnell, J. Sherman, B.: Effect of Vitamin A on Keratinizatlon in the A-deficient Rat, Fundamentals of Keratinization, Washington, A.A.A.S., 1962, pp, 113-115 McLester, J.: Nutrition and Diet in Health and Disease, 5 ed., Philadelphia, Saunders, 1949, p. 305 Cooper, L. et al: Nutrition in Health and Disease, 14 ed., Philadelphia, Lippincott, 1963, p. 176 Sebrell, W., Jr., Harris R. (ed.): The Vitamins: Chemistry, Physiology and Patholog~v, Volume i, New York, Academic Press, 1954, pp. Io8-110 I., p. 314 3., P- 128 9., P. 118 12., pp. 138-141; 145-14~

i?. Lowe, J. Morton, R.: Some Aspects of Vitamin A Met abolism, Volume XV of Vitamins and Hormones (Harris, R. et al ed.), New York, Academic Press, 1957, P. 117 18. Sherman, H.: The Science of Nutrition, New York, Columbia U. Press, 1943, p. 7~, 75 21. 22. 25. 28. n. p. 76 Thomas, G.: Dietary of Health and Disease, 3 ed., Philadelphia, 1940, pp. 27-32 Gyorgy, P. 9 ed): Vitamin Methods, New York, Academic Press, 1951, pp. 5"(, 91, 92 Boger, L.: Nutrition and Physical Fitness, 5 ed., Philadelphia, Saunders, 1950, pp. 264, 265 Johnson, H. : Bridges' Dietetics for the Clinician, 5 ed., . Philadelphia, Lea & Febiger, 1949, p. 54 Aydelotte, M.: Vitamin A Deficiency in Chickens, British J. Nutrition 17:205-213 (1963) Goldsmith, G.: Nutritional Diagnosis, Springfield, Thomas, 1959, p. 99 Rosenblatt, M. Lisa, J.: Cancer of the Lung: Pathology, Diasnosis and Treatment, New York, Oxford University Press, 195b, pp. 209-213 Salmon, M. : Food Fact for Teenagers, Springfield, Thomas, 1965, p. 43 McCarrison, R., Sinclair, H.: Nutrition and Health London, Faber e Faber, 1936,. pp. 45, ~6 Hawley, E., Mauer-Mast, E.; The Fundamentals of Nutrition, Springfield, Thomas, 1943, pp. 245, 249 30. Rosenthal, H. et al: Stem's Applied Dietetics, 3 ed., Baltimore, 1949, p. 224 31. Liebow, A.: Tumors of the Lower Respiratory Tract, Washington, Armed Forces Institute of Pathology, 1952 32. 33. 34. Nicholson, G.: Studies on Tumor Formation, London, Butterworth, 1950, p. 146 Stedman's Medical Dictionary, 20 ed., Baltimore, Wil.liams & Wilkins, 1961, pp. 1214, 1215, 1006 32., p. 146 et seq. -45°

35. B6. B7. $8. S9. Eddy, W. : Vitaminology; The Chemistry and Function of the Vitamins, Baltimore, Williams & Wilkins, 1949, pp. 4-6, IO Prevention of Cancer, Technical Report Service No. 276, Geneva, World Health O~Eanizatlon-Unlted Nations, 1964, pp. 4-9 Behrman, H., Labow, T. : The Practitioner's Illustrated Dermatology, New York, Grune-Stratton, 1965, p. 159 Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service, Washington, U.S. Department of Health, Education and Welfare, 1965, pp. 167-173 Simons, E.: Primary Carcinoma of the LunE, Chicago, Book Publishing, 1937, P. 91 Sauer, 0.: Manual of Skin Disease, 2 ed., Philadelphia, Lippincott, 1966, p. 229 et seq. 37., p. i~7 40., p. 40 Davies, R.: Effect of Vitamin A on 7~12-Dimethylbenz(a) anthracene-induced, Papillomas in Rhino Mouse Skin, Cancer Research: 27, Part I, 237-241 (February, 1967); and American Cancer Society's Science Writers' Seminar, Palm Beach, Florida, March, 1967 37., p. 157 Ackerman, L., Del Regato, J.: Cancer: DiaE~osis, Treatment and Prognosis, 3 ed., St. Louis, Mosby, 1962, p. 262 et seq. 45., pp. 266, 316 Nealon, T., Jr.: Management of the Patient with Cancer, Philadelphia, Saunders, 1965, P. 402 et seq. 48. 45., p. 258 pp. e60, ~85 Sharp, G. et al: Oral Cancer and Tumors of the Jaws, New York, Blakiston Division of McGraw-Hill, 1956, Pp. 32-34, 66, ii0, 180, 181, 208 51. 52. 53' 50., pp. 66-68, 210 45., p. 1055 37., P. 151 -46-

54. Differential Diagnosis of Mouth Diseases, New York, Columbia University. School of Dental and Oral Surgery - 0ral Diagnosis Staff, 1943, p. 133 et seq. 59. 60. 61. 62. 63. 66. 38., p. 203 et seq. Welsh, A.: Leukoplakla, Leukokeratosls and Cancer in the Mouth, Springfield, Thomas, 1955, PP. 15 & 29 et seq. (Publication No. 267, Amerlcan Lecture Series, Amerlcan Lectures in Dermatology) - - New Scientist, No. 367 Saffiotti, U. et ai: Further Studies on Inhibition by Vitamin A of Respiratory Tract Carcinogenesis, Federation Proceedings[ Federation of American Societies for Experimental Biology 20: 692 (March-April, 1967) Saffiotti, U. et al: Cancer, in print Wolf, G., Nutrition Reviews 20:161 (1962) Hoffman, F.: Cancer and Diet, Baltimore, Williams & Wilkins, 1937, pp. 234 et seq. 95 et seq. DiJkstra, B~, Origin of Carcinoma of the Bronchus, J. National Cancer Institute 31:511-519 (1963) Little, C.: Report of the Scientific Director: 1965-66, New York, Council for Tobacco Research - U.S.A., 1967, p. 63 63., p. 64 Govan, A. et al: Changes in the Epithelium of the Cervical Uteri: A Study by a~Panel of Pathologists. engaged in the Survey of.Carcinoma in situ carried out by the Royal College of Obstetricians and Gynaecologists, J. Obstetrics & Gynae- cology of the British Commonwealth 73:884-896 (Dec., 1966). 38., p. 267 et seq. 67. Petrov, N.: A General Guide to Research and Its Treatment: Cancer, Leningrad, Rukovodstvo Pc Obschschei OnkoloEi~, 1961; London, Pergamon Press, 1962: New York, Macmillan, 1902 68. Proudfit, F., Robinson, C.: Nutrition andDiet Therapy, i0 ed., New York, Macmillan, 1950, p. 339 69. 36., p. Ii 70. Moore, T.: Article in Symposium on Nutrition (Herriott, R., ed ), Cambridge, University of Cambridge, 1953, p. 60 et seq ~ O

71. Sherman, H., Lanford, C.: Essentials of Nutrition, 4 ed., New York, Macmillan, 1957, P. 285 72. Bernier, J.: A Manual for the Differential Diagnosis of 0ral Lesions, St. Louis, Mosby, 1942, p. 38 et seq. 73. 74. 75. 76. 77. 78. Thoma, K., Robinson, H.: Oral and Dental Diagnosis, Philadelphia, Saunders, 1955, PP. 163, 282,~ 310, 312 Stimson, W.: Vitamin A Intoxication in Adults: Report of a Case w~th a Summary of the Literature, New England J. Med. 265. 369-373,(Aug. 24, 1961) Wolf, G. : American Association for the Advancement of Science Annual Meeting, Washington, Dec., 1966, un- published comments Barach, A.: Symposium Inhalation Therapy: Historical Back- ground, J. Anesthesiologist 23. 407-421 (July-Aug., 1962) Kanig, J.: Pharmaceutical Aerosols, J. Pharmaceutical Sciences 52:513-535 (June, 1963) 71., p. 290 79. Sherman, H.": ChemlstrM of Food and Nutrition, 8 ed., New York, Macmillan, 1952, p. 468 et seq. 80. Williams, R.: Nutrition in a Nutshell, New York, Doubleday, 1962, p. 129 81. Stare, F.: Eating for Good Health, New York, Doubleday, 1964, 174 82. Glllet, L.: Nutrition in Public Health, Philadelphia, Saunders, 1947, pp. 91, 92 83. Cooper, L. et al: Nutrition in Health and Disease, Philadelphia, Lipplncott, 1958, pp. 9, 244 84. 85. With, T., Milford, H.: Absorption, Metabolism and Storage of Vitamin A and Carotene, London, Oxford University Press and Copenhagen, Einar Hunksgaard, 1940, p. 77 84., p. 156 et seq. ,/ 86. 87. Proceeding of the Sixth International Congress of Nutrition, Edinburgh, Aug. 9-15, 1963, Edinburgh & London, E. & S. Livingstone Ltd., 1964 Prescription Drug Industry Fact" Book, Washington, Pharmaceutical Manufacturers Association, 1965-1966, pp. 12 and 13 -48-

90. 91. 9e. Medical World News, February 3, 1967, P. 9 Bergel, F.: Chemistry of Enzymes in Cancer, Springfield, Thomas, 1961, PI~. 2B-25, 38-I;B, 56 eB., pp. 295,~21, 1;22 35., PP. 26, 27 Agricultural Handbook No. 62 and Supplement for 1956, Washington, U.S. Department of Agriculture, .1957, pP. 11,12 -49- r~ o o o

p. o Dr. S. O. Jones Re: Outsider Idea (Ol-ll) U.S. Patent No. 2,770,241 - TOBACCO S~KE FILTER AND METHOd, Joseph Winkler, Queens, N. Y., ~ssi9nor to A~..erican Collo Corporation, New York, N. Y. This patent pertains to the use of polyurethane foam as a cig- arette filter material. %he o~eneral claim in this patent is that polyurethane.being hydrophobic re~noves high molecular weight, water insoluble components from smoke such as polycyclic polyphenols and polycyclic nitrogen compounds. The author states that all of the filters presently on the Inarket are hydrophilic, which r~akes them effective in tl:e re~vai of water-soluble smoke components but in- efficient in the removal of water insoluble smoke components. The c~.ai..m.s include filters made from open cell po3yurethane foam and co||~bination filters consisting of open cell polyurethane foan~ and hydrophilic substances such as cellulosic n~aterials, silica gel ,.etc. In order to evaluate this patent, a sample of P-9100 Polyether Uretha~e Foam was obtained from the General Foam Corporation, 640 Vest 134th Street, ~ew York, N. Yo Cigarettes were prepared in the followin9 manrer: The cellulose acetate filter was removed from regular WINSTON (85-mm.) cigarettes and replaced w~th approximately 95 mg. of P-910O polyether urethane foam. These cigarettes along w~th regular WIRSTONS and WINSTONS with the fi)ter removed were submitted to U~e Analytical Division for analyses. The results of these analyses are as follows: ~.;INSTON Regular t41NSTON Tob. Rod Anal_y_si__s_ v~thout filter WINSTON with Urethane filter Av. Draft (in.H?O) 1.66 3.31 3.28 Puffs per Cigt. 8.95 9.08 9.43 Wet TPM, mg./cigt. 42.1 23.2 28.3 Corrected TPM, mg./cigt. 3~.4 19.1 22.0 Ni cotine 1.73 1.07 .1.31

without filter ~: ~ ..'~ STOI~ Ana l_~.ys~i~ HCN, ~9./cigt. 369 302 215 Oxides of Nitrogen, ~g./cigt. 268 270 273 Acrelein, pg./cigt. I14.5 l?S.l 122.7 Acetone, ug./clgt. 440 440 482 Acetaldehyde, ug./cigt. 728 770 If2 Formaldehyde, ug./cigt. 43.6 48.1 55.0 Phenols, ~,g./cigt. I00 36 20 Polycyclic I~drocarbons Results ~,ot received from Analytical £;! .~;S FO.~. Tc.b. Rod with Urethane filter Division. Seve.-'al significant differences were observed in the analytical data from the smoke of unfiltered I~INSTON cigarettes v;hen compared to data obtained from the smoke of cellulose acetate filter and polyether urethane foa,~ filter cigarettes. These differences a~e recorded in the following table. Pe_.rc__e_n_t..~R.e_d__u._c.t_i_o_.n_.lq__h_-~D__C_o.~_,}Ea.~ed to Unfi I to-red Ciqarcttes WINSTON Tob. rod Ar~!~~ ~]..~_~_EI NSTO~N with Urethane Fi I te r Corrected TPM 41 32 Ricotine 38 24 HCN 18 42 Phenols 64 80 The analytical data obtained from the s~;~oke analyses recorded in this ~,emorandun: neither prove nor disprove patent claims that the hydrophobic urethane foam re~noves pnlycycl ic polypheno!s and polycyclic nitrogcn containing compounds along wi~h other water insoluble compounds from cIgarett~ smoke. It would seem that the results of polycycllc

aromdLic h~d~ocai~bon deter~inatlons would be . ~port~..n.t, si.n.ce tF~is type of compound is both polycyc'lic and h~/dr(~p:~obic; but tF, ese determinations will not be forthco,ming for fo~,r or five weeks. A check with the Analytical Divisinn indicates that they have no ~,ethods for the d~.terminations of any of the polycyclic polyphenols or poly- cyclic nitrogen compounds, and it is believed that the develop~e:.t of these determinations would involve a great length of time and effort. An evaluation oF the analytical data received to date does indicate that although the polyurethane foam when used in quantities so as to produce the same pressure drop as that of a WINSTON cellulose acetate filter is slightly less effective in tar and nicotine removal (9 and 14% respectively), it is considerably more effective in the re- moval of HCN and phenols (24% and 16% respectively). Since this data does indicate that polyether urethane foam compares favorably with cellulose acetate in tar and nicotine removal from smoke, is substantially more effective in th? removal of HCN and phenol~ and the p~l~cyclic aromatic hydrocarbon determinations have not been completed, it is reconlnended that these analyses be repeated For veri- fication and that the decision to show interest in this invention be delayed until these results can be obtained. LCC:js CC: Mr. R. H. Cundiff ~r, D, P. Johnson Lawrence C. Cook

Deeeuber 31, 1970. Dr. Xra sLnser, Amoricanl~edLcat &soocLstLon, $3$Horth Dearborn Dear Dr. Thank you for your letter of Docoubor 28 ln vhlch :l~u enclosed suemsries-of fifteen (1~ sr~ts rettrenent age sad an ret/~Ltt8 frou uty ~y. 14re H. C, Roemer ~LU succeed me as Oonaral Counsel. ~[ thiu~ you she are mes~.o, that I h@.vo been doslKnatod ~aLrmsn of the Council ":b~r Tobacco Resosreh end tn that capacity I v111 undoubtedly eout~nuomy contacts with you. ~ do not knovvhothoryouha~o boon sending 8uu~arlos of stunts to the ~FR .but ia the interest of eiose ilaibon if you h8~o not • ~ou~d appreciate your sonding them to mo as Chatmn. : ~;hile ! will mslntaln my hose in Wluston-Ssleu where my address Is 714 OaktavnAvonue, Zip Code 27104, I w111 spend consldorsb1~ t~ in the offlcos of the ~unelt for Tobacco Research in Ne~York. Hy home telephone number Is 723-2553. extend to you uy best wishes for the ~sseYeer. Sincerely yours,

MAURICE H SEEVERS, M.D., Ph.D., Ann Arbo¢. Mich. Chairma~ RICHARD J. BING. M.D. STUART BONDURANT, M.D., AIl~ny, New Yo~ EARL EVANS, JR., Ph.D., Chica~o, ill t~:)l~t:'RT J. HASTERI.tK, M.D., PAUL KO'I'IN, M.D. -~ Sto~y Brook, New York ~UL S. LARSON, Ph.D., Richmond, Va. RICHARD D. I~MIhK~TON, Ph.D., Houston, Texas IRA SINGER, Ph.D., AMERICAN MEDICAL ASSOCIATION ,535 NORTH DEARBORN STREET • CHICAGO, ILLINOIS 60610 • PHONE (312) 527-1500 • TWX 910-221-0300 \ December 28, 1970 Hr. H. H. Ramm Vice President and General Counsel R. J. Reynolds Tobacco Company Ninston-Salem, North Carollna 27102 Dear M~. Ramm: Enclosed are sunmmries of 15 grants which have been approved by the Committee for Research on Tobacco and Health since its last meeting on October 24, 1970. Sincerely yours, ira/~S~~ger sk enclosures 0

X, ll~h Fudenbarg~ M. D. i.,. llugh Fudenberg, M.D. was' awarded a grant for a per~.od of three years beginnin~ }lay I~ 1971 with a total budget of $143,687.00. The first year budget was approved for $49,839.00. to

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Education s_ud Resc?~rch Found.ation TITLE OF P.~OJECT: Th~ Effect of Nicotine and Catecholamines on the Microcirculatlon of the Cat with Special Reference to Red Cell Velocity snd Capillary Diameter. ~aus Hellberg~ M. D.~ ~incip~ Investigator .. ~min Rickat~t~ M. D.~ co-mn~esomg~,~o~ T. Morit% ~.D. Huntington Memorial Eospital~ I00 Congress Street~ Pasadena, California 91105 9.~vcr~mcn~ o~.~p~vo~ o~,~c~es ;upporfin9 r~seo~c~, on~crc ~o~w~r~e~ to in~'esfig~tors w'ao ~q,J~;t such b,~ormotlon. Your s,j~ory ~s to ~e work ,~i! consist of the study of nicotine ~d related compo~ds on the. coronao- ~croeirc~ion of the beating ~ud the ~rested heart. The heart 9f cats be use~: aud ~sus~ization ~ll be acco~olished through tr~sill~ination: high speed cin~matogr,?~hy mud frame to frsme mn~ysis of red cell mordent. A te~ of workers from the C~ifornia Institute of Technolo~ ~d the Jet ~op~sion LzBonato~ ~_ll act as technicsl advisers. SIGMATURE OF PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL (m~.~ical, g,cduate, etc.} USC School•of Medicine Klaus Hellberg, M.D. was awarded a grant for a period of two years b~ginning November I, 1970 with a total budget of $61,500.00. The first year budget was approved fo~ $30,750.00.

~,T~ o~ ~o~cr:,,Cardlovascular Function ~d Elect~oca~dlographlc Changes In Smokers and. Non-Smoker's in Response to Mammal Treadmill Exercise." Principal Investigator: Paul L..McHenry, M.D. Assistant Professor . Department of Medicine Indiana University School of"Medlcine Indianapolis, Indiana Co-Investlgator: John W..Jordan, M.D. Instructor, Department of Medicine Indiana University School of Medicine Indlana~olls, Indiana , . ..... . ~AM--" ^~O A~o~zss o~ ~NSWTUVm.." Kranner~: institute Of Ca~dlology Indiana University School of Medicine Indi~na~. Indiada .. ~ '~ The-maximal treadmill exercise responses , ~en 25. and 55 years of age will be. studled differences between cigarette smokers and non-~ between, the two groups are: i. Duration of maxlmal exercise. 2. Maximal heart rate• 3. Systolic blood pressure during maxlnu 4. Incidence of arrhythm/as ddring maxi~ 5. Differences in the computer quantlta! slope and depression in response t¢ approximately 900 clinically normal males. to determine if there are any significant ~mokers. The parameters to be =ompared exercise testing. sl exercise testing. ed c~anges in the ST segment" maxlmal exercise.. PRINCIPAL IN VESTIC, ATOII PROFES:~tONAL SCHOOL • (r,=8;c.l, ~,oau~;,, -.,c.) /22.,(~. ' Paul L. McHenry, M.D. was awarded a ~rant for a period of three years ~eginningFebruary I, 19711with a total budget of $30,400.00. The first year budget was approvd~ for ~9~550.00. 0 0

Department of Pharmacology .. unCvers~ty, of Conuect~cut..Health Ceuter ~iversity~ of. Connedttcut Health Center : " "also occurs ~ the g~tro~ntestinal tract ~nd in the ad=~al medulla~have not been clErlfied.. ~e res~r~ ai~ consist of t~e de.te~.i~tion of the optim~ conditions for the rele~e of the ~tracellular a~ne~ .followed by the elucldat¢on of the ~taSollc requireme,ts for this process an~ the stud~ o~ the nicot~ic receptor . that triggers the exocytosls. By dete~ng" the metabolic requirements for the release process and the structure and f~c~ion of the nicotine receptor site, it ~y be possible ~o desl~ c~po~ds that ihhibit am~e release thus preventing some :.of the physloloEical effects of nicotine. ~ • Herbert Fe!senfeld, Ph.D.; two years >eginning November I, 1970 with a total budget The first • ar's budget was approved for $13,805.00. 0 f.,,.

~:~TJ~CO;:P,O;ZCT:~ Central:~autonomio .and reflex.actions of tobacco smoke and the interactions of some constituents (nicotine, carbon monoxide and oxides of i~nltroqen;~ ;t~ a~roach through a ~erfused ~n .~onard~rocita,...Ph.D.~.,.~ Dept. of Pha~acolo~ -Prlnc~pal Investigatory, Assoc. Pha~acology ..... Di~e ~'~arr~ngton, Dept. o.~.Pharmacolo~ .- Research Assistant ,,~,~o,~s~o~,),s%~))~,(, Albany ~ledical College, 47 New Scotland Avenue, ~.-,".- -.- - Albany, New York 12208 ~'.i.. : : ." "~'-. vascularly isolated, perfused, in-si~u cat brain -)reparation ~aving reflex ~nd/or tonic neural control over. the h~art ~d peripheral circulation, as ~reviously described by us (Barrett, J~P., Ingenito, A.J. and Procita, L. ; -~. Phnrmacol. Exp..TheraF. 170: 199-~0~ (1959) will be used to investigate the effects of cigarette smoke and various constituents of cigarette smoke {e.g. nicotine,-carbon monoxide and th~ oxides of nitrogen) o~ the control of c~rdiovascular f~ction by th~ brain. ~The drugs or gases will be added either alone or ~n various co~Inations, in solution, to the blood in th~ extr~cor- poreal perfusion circuit or to th~ o~genator in the circuit, while ~onitoring systemic arterial ~ressure, heart r~te. ~nd brain p~rfusion p~'e~sure. smo~e and so~e of its constituent gase~ will also be a~inistered via the lung of the ~ni~al in the same preparatio~ ~o dete~ine to wh~t the extent the p~ri pher~l actions of these agents differ from. their centrally-induced actions ~-~what effects might ~sult from the interactions of central and peripheral ments. "Th~ preparation will also ~ii~.~ ~n analysis of the ~et~olic charac- teristics of th~ 9effused b~i~ ~der ~he i~fluence o~ various s~oke consti- tuents. The m~abo!ic characteristics to be studied includ~ o~gen ~d ~pta~e ~d CO2 ~nd l~c~a~e production. Also, the vascularly isolated c~bral circUlation'will allow a~ ana!ysi~ of the effects of the~ constituents, dividually or in ~o~ination, c~ the perfu~ion characteristics (e.g. and flow) of the cer~brel va~cul~tur~.~ Leonard Procita, Ph.D. was a~arded a grant for a period of three years beginning November I, 1970 with a total budge.t of $49,800.00. The first year budgef was approved for $15,875.00.

COMMITIEE FOR RESEARCH 'IOBkCCO AI~ID HEAL'Ill AMERICAN MEDICAL ASSOCIATION 535 NORTH DEARBORN STREET • CHICAGO, ILLINOIS 60610 • PHONE (312) 527.1500 • TWX 910-221-0300 MAURICE H. SEEVERS, M.D., Ph.D., A/~n Arbor,.M~ch. Chairman RICHARD J. BING, M.D. P'a~Oena. Ca~if. STUART BONDURANT, M.D., ~bany. N~ Y~k ~ EVANS, JR., Ph.D., ~, IlL ~ERT J. ~TERLIK, MD., ~la. ~lif. P~L KOIIN, MD. R~a¢h T~n~s Park, N C, M~IN KU~HNER. MD., ~ Br~ N~ Y~k UL S ~N, ~.D., ~, RI~ D. REMINGTON, ~.D., ~. Texas ~A SINGER, ~.D., Hr. W. T. Hoyt Executive Director The Council for ii0 East 59th 'eet New York, New December 16, 1970 Research-U.S.A. 10022 Dear Tom: Enclosed on Should to send the actions taken by the Committee for Research and Health at its last meeting on October 24, 1970. require any further information, I will be happy to you. " y yours, Ira S: ,,nger / sk enc. ~0 0 0 0

AMERICAN MEDICAL ASSOCIATION 535 NORTH DEARBORN STREET • CHICAGO, ILLINOIS 60610 • PHONE (312) 527-1500 * TWX 910-221.0300 ~N TO|A~O ANO MAURICE H. $EEVERS, M.D., Ph.D., ~ ~;, Mich. C~i~m~ RICHARD J. ~NG, Pas~a, Cal if. ~L EVANS, JR., Chi~, IlL ~RT J. H~RLIK, M.D., P~L KOTIN, Re~ch Triable P~k, N.C. ~RViN KU~HNER, M.D.. N~ Y~k, N~ York P~L S. ~, Ph.D., Ricked, Va. RIC~RD 0. ~INGT~. Ph.D., H~s~, Texas I~ ~NGER, ~.D., ~ ~etary July 29, 1970 Hr. H. H. Ramm Vice President a9~l General Counsel R. J. Re.ynolds ~Yobacco Company Winston Salem,~orth Carolina 27102 Dear Mr. Ram~: Enclosed are summaries of nine grants which have been approved by the Committee for Research on Tobacco and Health since its last meeting on May 8, 1970. Sincerely,, yours, Ira Singer ~ sk enclosures o

Htcotlutc P~ecepCors in M~cle Me~brane: A Stuoy of D~seusitlzation ~.me~ #.po,~ee, mdeH;cieI~*ItsolPR~OPALiNVESTIGATORS ~4ALLOTHERPROFES~CHAL PERSONNEL l~o~er~ ~. VoI1e, ~=o£essor. Depar~e.~ of ~baz~acolog7 5~m C. Hanc~:k, &s~t~an~ Professor, Depart~en~ o~ Pharmacology SUMMARY OF PROPOSED ~/ORK - (200 ~rd~ e: I,s,.) - b d~, Science • hree psra~eters of .mscle activity viii be studled: depolsrizaLion by plcotinlc dru~s, conduction blockade and trensalsslon blockade by nicotine and related d:ugs. i~ ~polari~tio~. A d~e ~es~e cu~e describing de~l~rizaCion of frog sertorius ~cle fibers by nicotine rill be co~truct~. ~en this has be~ accoqplish~ a ~tudy be ~e of a f~ly of ~se-r~e ¢u~ shying the effect of ~e first dose of ~cotlne ~ de~lar~z~tion ~used by the seco~ dose of ~Ine. ~lysls of ~he I~ly o[ curves vlth ~he v1~ of ~e~tn£ng shlf~s ~o ~he rlih~ a~ changes £n ~~ should s~gges~ ~he ~t~e of ~e recepVor l~¢tlva~ion proces~. Sl~lar cu~es d~crlblng ~bocurarlne-nlcoc£ in~erac~lon v11] be co.trucked. b. ~nduc~ion. ~e cela~onshlp be~een depolarlza~1on prcduc~ by nlc~Ine blockade of conduc~£on ~ ~perfec~. In s~e nu~cles, ~he ra~e of recovery ~o~ block paral]eled ~he ra~e of re~la~Iza~ion. In o~her muscles, ~he block of coud~c~lon las~ed by & ~o 8 mlnu~es :he re~uro of ~he =e~brane potential ~o no~l values. A s~udy ~11 be ~de of the relationship between depolarlzaclon b7 u~co~Ine k~ co~duc~on blockade fr~ sever~1 s~andpoin~s. c. Tra~Isslon. I£ ~£11 be lm~r~anC ~o study ~he depo~arlzl~ and ac~i~s of ~co~£~ on J~¢£1o~1 ~ra~alsslon, Tradlclonal ps:~e~e:s of cra~sslon the frog ~ur~cular J~c~ion (end-place potentlY, mln£a~ure ~euC1~l, etc.) ~11 be s~udied. ''SOb~rt ~i V0IIe,~Ph.D. was with a total budget of $27,429.00 beglnnlng August year was approved for $12,591.00. PROFESS~NAL SCHO0 ~ (mtd|ce|~ Sm~lvot e. a~arded a Sr.~t for a period of ~wo yea~s 1, 1970. The first

I~.l.~-~O~o s-v. o,o~ HOT|CF- (~F RE.SV.~RCW( PROJECT ~'~ ~o. " ~* ..... ~.~,~/ ....... ~ $CI~C~ ~FO~ON ~CHARGE ~";~/I " NOT OO~ PUB~ICATIOH'O~~:'~ IMITHSONIAN" INITITUTION .- " ",':~ r ~:~:~, ........ ~ ~ucation" ~d Research Fo~dation ~ .... 0 ...... ~tzo~a~Zc.~R1ectz~hyslol glcal and Phamcological Evaluati~~ o~ Posslble Interactions ~.: ~- ~e~n Th~ya~te and Ni~otlue in ~llan Auton~Ic r "~" ~ ~'~t~ ~'t~'~dl~i~lel titl;I el PRIHCIP~~ ~VESTI~TORS'~d ALL O~ER PROFE~LpERS~E~" ~ged ..... .~u~.a.oaoo~(.ovn.sn~u~: ~dical ~olle~e of Virginia VZrginla C~onweal~h U~iversi~y ~~ ' ........ ~ " Dept. o~ ~a~colo~ Health Sciences Divlsi~n ~ ........ " ~ ~V Box 726 Ricked, ~RY OF P~S[D ~RK - (~ ~.ds o. less.) - ~ ~0 Sc;~ce I.~ot;~ Exch~9, ~o.ies of ~.k in ~..ss o...x~,ed ~.h .. ~ve~l ~d p~ ~cios sWanS ~s*o~. ~d o~e fo~rd~ ~vts~rs ~ ,' - ~ ~t~sos. - " ~ o~se:va~Lon ~ha~ ~he £h/ocya~e blo~ level~ elevated fr~ 100-3~. has ~en ~horou~hly d~en~ed. Values Ln non-smo~e:s range from 0.31-2.55 ~%. The major aspectof the current investigation is to determine if there is a relatlonshlp between the thlocyanate anion in concentra- tlons found in smokers and the action of nicotine in autonomic ganglla.: Such a zelatlonshlp is based on the ability of anions to modulate activity of excltable cells. Adam D. Winters, III, Ph.D. was awarded a grant for"a period of three years b~ginniug November I, 1970 with a total budget of $27,699.00. The first year budget was approved for $17,306.00.

NOTICE OF RESEARCH PROJECT $CIF~qCE |NFORMATION F~CHANGE |MeTNSONIAN INSTITUTION Giw nan,as, d~m~-#~, m4 efflcio8 ott|es d PR~OP~ INVESTiGATO~ ~ ALL OTHER P~FE~L PER~EL ~ged ~ &e ~i~i. ~or~e M. ~ss, ~.D., ~ai~an, Dl"~sl~n of Pathology, ?resby~eri~-S~. L~k.e~s Hospital; R~ben Eisens~eln, M.D.~ Attending Pathologist, Presby~er~-St. Luke's Hospital; Jo~ P. Ayer, M.D., A~t~d/n8 Pathologist, P~sbycerlan-S~. Luke's :~spltal; ~c~rd A. Sco~t~ H.D., Inspector fn Paeho1~y~ ~fvers~cy of I11/no~s; ~ald g, ~en=~ A.D,, ~sistan¢ Professcr ofPachology~ ~Iv~rs~ty of 1111nols. P~AM£ AND ADORSSS OF IItSTl'rtiTION: Presoyterian-S~. Luke's ~ospi~al, 1753 W. Congress Parkway, Chicago, Ill£nols 60612 We have sho~u |:ha~: rabbits on a regimen consis~ins o£ a 500 mS.Z cholesterol d£e~, a ~e~a~e dosage of ~c~n D ~d daily in, actions of nicotine develop a ~e~e arterial disease of~en c~licated by ~hr~o~r~ert~is. ~e ~ose og ~h£s research te co ~e~ihe ~he rela~l~ influence of ~he ~o11~ gac~ors: (1) b~e~lip~c h~ercholes~erol- ~ie; (2) nico~ine-in~ced response of pla~a f~e fa~y nclds ~d ~he~r. ¢~poslt~o~; (3) factors resp~sible for nicotine activation of vi~in O £n the /udu¢~/~ of drter~al calc£f~cs~i~ and (~) factors resp~sible for a~te~iCls ~th or vLCh~C chr~bosts c~ItcaCln~ ~co~Ine-~tu D induced ar~erlal c~Iclfica~lon in h~ereholes~erol~c ~als. S~ prosress has been :ade In ~valusclon of the influence o~ e~ch of ~he able factors ~o ~hac ~he ulc~a~e obJecc1~ is ~o dete~Ine h~ ~his disease can be pre~ed by ~cabollc Interference dlr~c~ es~eclally ~ard ~nct1~s of ~e liver, sdr~al ~d clrcula~nS vssoaet~ve a~e~c.. I~ qINCIPAL INVESTIGATC~ .... PROFESS~ONALSC}IO~uuIv. Of Ill. SchooJ of Hedi¢£ne (.edicel, ~k~te, ~eorg~ M. Hass, M.D. was awarded'a gra~ fo~' a p~riod of ehree years beginning February 1, 1970 with a ~otal budge~ of $73,680.00. The first year of this grant was approved for $23,760.00. o

NOT FOR PUBLICATION OR PUBLICATION REFERENCE NOTICE OF RESEARCH PROJECT SCIENCE INFORIVlATION EXCHANGE SM|TH$ON IA N INSTITUTION AGENCY NO, SUPPORTING AGENCY: AM/ Education and Resea_-ch Foundation TITLE OF PROJECT: "A Study of the Sites and Mechanisms of Action of Nicotine in th..e .,Central Ne~y~Ajs System" Give names, deparlments, and official titles of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the proiect. Peter Lomax, Associate Professor - Department of Pllarmacology, School of Medicine, UCLA Donald J. Jenden, Professor - Department of Pharmacology, School of Medicine, UCLA NAME AND ADDRESS OF INSTITUTION: University of California at Los Angeles, School of Medicine, Department of Pharmacology, Los Angeles, California 90024 ~:ARY OF PROPOSED WORK - (200 words or less.) - In the Science Information Exchange summaries of work in progress ore exchanged with mont and private agencies supporting research, and ore forwarded to investigators who request such information. Your summary is to be used .or these purposes. Many actions of nicotine on the central nervous system (CNS) have been de- scribed and, as with peripheral nervous mechanisms, both excitatory and i~hibitory responses have been reported. Direct application of nicotine to different brain structures in conscious animals has rarely been employed and confident relation- ships between the action of the drug and specific areas of the CNS have not been fully established. Cholinoceptive neurons have been identified in several sites in the CNS and many effects have been described following injection of cholino- mimetic agents directly into the brain or the ventricles. The terms nicotinic and muscarinic are well understood as applied to peripheral actions of acetKIcholine but their relevance to central cholinergic responses is not clear. The purpose of the present study is to investigate central cholinergic responses to determine the effect of nicotine at the same sites. Both the direct effects of the drugs and the effects on endogenous .acetylcholine will be investigated. Other CNS mediated responses to nicotine will also be studied. ,This research will utilize methods developed in our laboratories. Microapplication of drugs to specific brain areas in conscious unrestrained animals and estimation of brain amines by gas chromatography provide a new approach and should prove {o be powerful tools. SIGNATURE OF ~ ,~ PRINCIPAL INVESTIGATOR ' ~ , " Peter Lomax PROFESSIONAL SCHOOL (medical, graduate, etc.) School of Medicine: Dept. n~" Pharm~- cology. eter omax, M.D. was awarded a grant for a period of two years beginning July 1, 19"70 with a total budget of $44,147.00. The first year budget was approved for $21,613.00. . r~

|T~,I[ OF pIIIOJI[¢T: A~A Education and Research Foundation '~he ~-££e~t o~ ~noking and/or ~a~£ei~ on ~unds~en~al Electrophysiolo~ical Properties o~ Cardiac Tissues" AND ~t ODRCJ$ OP INSTITUTION: University. of Chic~o - 950. East.. 5g~h Street. - Chica~o~ Illinois.._ 60637 ;~k~R7 OF PROPO~gD WORK - A .study of the precise el~ctrophysiologic e££ects o~ nicotine and ca££eine 1) The isolated Purkinje giber and rabbit atrial AV node preparation. 23~ ~ anesthetized open che~t dog. awake ~rained dog with chronically implanted electrodes. These investigations are stimlated by the need to know r~he relationship o£ rJwse t~o pharmacological agents to cardiac arrhyt~nia. ExcitabilitT, re£ractoriness, vulnerability, ccr~uc~ion and autcmaticity viii be studied at a variety of concen~ratious usir~ nicotine and cag£eine alone or in ¢oncer*... A~ both, these agents have a pm£cund ef£ect on ccntractilitT and in particular on .the mobility o£ calcitm ixon within the cell, the possibility that changes in excitabtlit7 may be mediated in small part by a calcit~ e££ect may be investigats~. Previous aSten~ion ~o these problems has been mainly in anesthetized preparations or in animals rendered arrhyt]~¢ by sce~_ pharmao cologicni or surgical intervention. The precise relationship o£ caf£eine and nicotine to a cardiac arrhytImia is as yet undelineated, even at a time when restricti~ or withdrawal of smokin$ and co~£ee drinking is £requentlv advised in therapy. SIGNATURE OF PI~NCIPAL INVE}IIGATOR , PROFESSIONAL SCHOOl. ..... Rode , ..................... rick .W:-Ch£1-ders M.D. was awarded 8 grane for a period of L-~o years beginning June 1, 1970 with a eocal budget o£ $&9,992.00, The £ir$C year budgee was approved for $2&,996.00,

NOT FOR PUBLICATION OR PUBLICATION REFERENCE NOTICE OF RESEARCH PROJECT S~IKNCK INFOBMATION EXC~ANG~ SMITHSONIAN INSTITU T|ON SUPPORTING AGENCY': AMA Education and Research Foundation, TITLE OF PROJECT: The Effect of Tobacco Smoke on the Upper Respiratory. Tract with Special Reference to.the Effect on Cilia ~ve homes, depar~ents, ~d olficiol titles of PRINCIPAL INVESTIGATORS ond ALL OTHER PROFESSIONAL PERSONNEL engoged ~ ~e project. Professor Tore Dalhamn ~. Institute of Hygiene University of Uppsala Sweden NAME AND ADDRESS OF INSTITUTION: Temporary address: Institute of Hygiene, Box 17007, 104 62 Stockholm 17. Sweden SU~/VIARY OF PROPOSED WORK - (200 words or IBss.) - In Ne $¢iBnce |nfo~otion Exch~ge summori,s ol work in progress ore ex~mg~d ~th. ~vcrnm~t and p~vote og~cies sup~rting reseorch, and ore fo~arded to investigators who retest sum in|o~moti~. Your summory is to be used ~r ~ese pu~oses. The effect of single chemical substances on tracheal ciliary activity in vitro The action of various substances has been described in earlier studies• It therefore appears, advisable to continue the experiments along twolines, one being the effect of single substances and the other of these substances in compounds corresponding to the occurrence of the relevant components in tobacco smoke. The absorption of ci.~arette smoke in the nasal cavlt~ . In most long-term exposures reported, the animals.inhaled the smoke through the nose. It is, however, imperative to obtain at least an approximate conception of how much of the smoke is absorbed in the nasal cavity. Not until .an adequate assessment of the absorption in the nasal cavity is obtained can we embarE upon comprehensive experiments using long-term exposure. :~h_e~fect of the smoke on tracheal ciliarZ activitz in different animal species A large-scaled investigation of the effects of the smoke on ciTiary activity in different animals (cat, guinea pig, hen, pig etc.) in vivo and in vitro may lead-to some standardiza- tion of experimental techniques, i4oreover~were '~o~n that in vitro technique is comparable with in vivo procedure, much work could be avoided. SIGNATURE OF ., ,~. .... PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL Professor ofHygiene, University of (,,dl¢ol, g,o~,, ,to.). U ppsa I a, ":Sw_ eO~n Tore Dalhamn'~ M.D. was awarded a grant for a period, of three years with a tqtal bu'dget of $55,800.00 beginning November i, 1970. The first year budget was approved for $16,000.00. -

~'~ $1-SlE-?BA; RrV. e-64 NOT FOR PUBLICATION OR PUBLICATION REFERENCI:" NOTICE". OF RESEARCH PROJECT SCIENCE INFORMATION EXCHANGE |,MITHSONIAN INSTITUTION lll~ NO, ~, AGENCY NO. SUPPORTING AGENCY: AHA Education and Research Foundation TITLE OF PROJECT: Goblet Cell Hetaplasia and Exposure to Cigarette Smoke: • Systems and Human Studies Animal Model Give homes, deportments, ond of|iciol title, of PRINCIPAl.. iNVESTIGATORS end ALL OTHER PROFESSIONAL PERSONNEL engoged on the proiect. Kaye H. Kilburn, M.D. Triggvi Asmundsson, M.D. Associate Professor of Medicine Instructor of Medicine Dept. of Internal Medicine Dept. of Internal Medicine Phillip C~ Pratt, M.D. Associate Professor of Pathology Dept. of Pathology NAME AND ADDRESS OF INSTITUTION: Duke University, Durham, North Carolina 27706 SUMMARY OF PROPOSED WORK - (200 words or less.) -. In the Science In|ormotion Ex¢~onge summori~s o~ work in pr~gre,$ ore exc~on9~ wi,h. 9ovemm~l ond privote ogencles supporting reseorche end ore torworded to investigotor$ who request such Iniormoti~. Your summory Is to ~ u$oo , ~r these purposes. L The two aims of this investigation are (I) to develop and compare animal models for the induction and persistence of goblet cell metaplasia.(chronic bronchitis) using cigarette smoke and other agents particularly viruses and (2) to quantify goblet cell me£~plasia in autopsied'human subjects' bronchial trees and relate it to cigarette smoking.history, dis- tribution of centrilobular emphysema, clinical history of chronic bronchitis, the Reid index and causes of death and degree of exPiratory obstruction to air flow. The animal model which will consist of young and oldVmale rats will be subjected, in groups of 24, to unfiltered cigarette smoke from 20 cigarettes per day in a 1.25 cu ft chamber for 8 hours 5 days a week for thirty exposure days. After this lesion is thoroughly standardized, similar animals will be exposed to influenza or similar respiratory viruses at the end of the smoke exposure period. Because of the resistance of rats to respiratory viruses, hamsters or ferrets may be utilized. The effect of dehydration, starvation, vitamin A deficiency.and estrogens will be evaluated in subsequent series of animals. Perhaps most Importantly the effects of papain lung damage (centrilobular emphysema) on development and persistence of goblet cell metaplasia will be examined. There is evidence to suggest that emphysema predisposes the lung to bronchitis ip human subjects. Sagittal sections of human lungs obtained at autopsy will be studied to q~ .tify the goblet cell metaplasia and relate it to the distribution and severity of centri- lobular emphysema. The lungs will be studied after fixation at l~ cm inflatiop ,sure with normal buffered formalin solution. Both histochemical and ultrastructural stui ~ ill supple- ment the histology. Suitable ~amples will be taken so that Reid indices can be .culated. Particular attention will be paid to signs of airway obliterationand to the relationships between centrilobular emphysema and goblet cell metaplasia inspecific lobules within segments of the upper and lower lobes of each lung. The relationship of pigment deposition to the lesions of emphysema and bronchitis will be studied. SIGNATURE OF PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL (meal,col, 9roduote, etc.). ~_ 'K-~ye-~-~T.~Kilburn, M.D. was awarded a grant for a period of two years beginning August I, 1970 with a total budget of $80,000.00. The first year was approved for $40,000.00.

NOT FOR PUBLICATION OR PUBLICATION REFERENCE SUPPORTING AGENCY: NOTICE OF RESEARCH PROJECT SCIENCE INFORMATION EXCHANGE SMITH$ONIAN INSTITUTION AMA Education and Resea~ch Foundation TITLe o~ PRO~ECr: The effects of nicotine on neuroendocrine reproductive and rabbits. -" mechanlsms.in female rats Give names, deportments, and official litles of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the project. Dr. Charles H. Sawyer Professor of Anatomy UCLA Medical School and Brain Research Institute NAME AND ADDRESS OF INSTITUTION: UCLA School of Medicine, Los Angeles, California 90024 SUt~ARY OF PROPOSED WORK - (200 words or less.) - In the Science Information Exchange summaries of work in progress are exchanged with 9ovcrnmcnt andprivole agencies supporting reseor~hs ondore forwordedto investigotorswho request such information. Your summary is to be used ~t thcse purposes. The study proposes to investigate basic neuroendocrine mechanisms involved in re- productive processes and the effects of nicotine on these phenomena: the synthesis and release of pituitary gonadotrophins, ovulation, luteal maintenance and secretion of progesterone, pregnancy, parturition, lactation, milk ejection, the onset of puberty, and the electrical activity of the brain related to several of these processes. Methods will include radioimmuno- assay of pituitary lutelnizing hormone, follicle stimulating hormone, and prolactln; thin layer aI1d gas-liquld chromatographic techniques for assaying progestins~ surgical, microscopic~and hlstologlcal methods of assessing ovulation and luteal development; and stereotaxic, electro- phalographic, and polygraphic and mlcroelectrode systems of recording cortical and sub- cortical electrical activity of the brain. Thus the project will probe at some depth the basic reproductive mechanisms in females of two representative mammalian species and test the effects of nicotine at each stage in the cyclic processes. SIGNATURE OF PRINCIPAL IRVESTIGATOR PROFESSIONAL SCHOOL (medical, grad,rote, etc.} ..... Medlcai ~nn]_ Professor Charles H. Sawyer was awarded a grant for a period of three years beginning May I, 1970 with a total budget of $65,056.68. The first year budget was approved at $19,650.00. ~0 0

SI.-SIE~78A; REV. a-G4 • • COT FOR PUBLICATION OR J PUBLICATION REFERENCE SUPPORTING AGENCY: NOTICE OF RESEARCH PROJECT SCIENCE INFOR~IATION EXCHANGE SMITHSONIAN INSTITUTION A~ Education and Research Foundation li SlE NO. ~', AGENCY NO. TITLE OF PROJECT: Effects of Nicotine on Cellular Endocytie and Seereto~V Mechanisms Give names, deportments, and official titles of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the project. Sorell L. Schwartz, Ph.D. Associate Professor Department of Pha~naeology NAME AND ADDRESS OF INSTITUTION: Georgetown University, Schools of Medicine and Dentistry. 3900 Reservoir Road, N.W. Washington, D.C. 20007 SUh'A~ARY OF PROPOSED WORK - (200 words or less.) - In the Science Information Exchange summaries of work in progress are exchanged with government and private agencies supporting research, and are forwarded to investigators who request such information. Your summary is to be used ~r Ihese purposes. Endocytie and exoeytie processes are common to a large portion, if not all, of cells from protozoan to mammalian origin. The end6cytie process which encompasses pinoeytosis and phagoeytosis and the exocytic p~oeess which includes cellular secretion are potential sites for the action of a varlet%, of drugs. The effects of nicotine and other agents will be studied on cultured mouse peritoneal maerophages. For the study of the exoeytie proeess, cells will be clotured in presence of sucrose. This results in the formation of pinoeytie vesicles whieh eon~)ine with lysosomal organelles to give vacuoles containing the sucrose and lysosomal enzymes. The cells with then be exposed to various agents such as nicotine, aeetyleholine, ATP, etc. and the release of sucrose and lysosomal enzymes for~ the cell followed. For study of the endoeytie process, sucrose- laden cells will be exposed to invertase. In the nozvnal situation, invertase is taken into the cell via pinocytosis and the pinocytie vesicles combine with the sucrose containing vacuoles. This eom~ination results in the digestion of the sucrose, the passage of the metabolites through the vacuolar membrane, loss of osmotically obligated ware6 from the vacuole, and a disappearance of the vacuoles. In studying this p~ocess, sucrose- laden cells will be exposed to invertase in the presence of agents such as nicotine and the number of vacuoles in the cell counted as well as the measurement loss of radioactivity which originated from isotopicslly labelled sucrose. The inter relationships of such ions as Ca++, K+, Na+ etc. will also be studied. PRINCIPAL INVESTIGATOR .,.=gv _¢~ _ PROFESSIONAL SCHOOL./ (medical, graduate, etc.) ~ec~eaJ.=.___Dental a~d ~_~-q~u~Le . Sorell L. Schwartz, Ph.D. was awarded a grant for a period of two years beginning February i, 1970 with a total budget of $57,850.00. The first year budget was approved for $29,974.00.

51oSr~c.*?SA; REV. 6-e4 NOT FOR PUBLI~AT|ON OR PUBLICATION REFERENCE SUPPORTING AGENCY: NOTICE OF RESEARCH PROJECT SCIENCE INFORMATION EXCHANGE SMITH$ONIAN INSTITUTION AMA Education and Research Foundation AGENCV TITLE OF PROJECT: EFFECTS OF NICOTINE ON THE GASTRIC ~IUCOSAL CIRCULATION Givenomes, deportments, ondofficialtitlesofPRIHCiPALINVESTIGATORSondALL OTHER PROFESSIONAL PERSONNEkengogedontheproiect. Eugene D. Jacobson, M.D., Principal Investigator, Professor and Chairman, Department of Physiology and Biophysics Daniel Hodgins, Ph.D., Co-Investigator, Assistant Professor~ Dept. of Biochemistry and Molecular Biology Harvey Ulano, Ph.D., Research Assistant, Department of Physiology and Biophysics NAME AND ADORES5 OF INSTITUTION: University of Oklahoma Medical Center, 800 N~ 13th Street Oljl@hom~ City~ Oklahoma 73104 SUMMARY OF PROPOSED WORK - (200 words or less.) - tn the Science Informatiol~ Exchange summaries of work in progress ore exchanged with government ondprivate agencies supporting resecrch~ ondare forwarded to investigators who request such information. Your summoryis to beuse~ ~ ~hese purposes. Smoking of tobacco is associated with an increased incidence of peptic ulcer formation but not with an augmented gastric secretory response. The present study is directed toward investigating changes in gastric mucosal blood flow and gastric mucosal cyclic ~IP formation during shJmulation with gastric secretagogues as influenced by nicotine. Conscious dogs provided with gastric fistulas will be used to permit measurement of gastric acid production, gastric clearance of aminopyrine and mucosal biopsies for measurement of tissue adenyl cyclase, phosphodiesterase and 3'5' adenosine monophosphate. Since ulcer formation can occur in the absence of excess acid production but with mucosal ischemia, the finding that nicotine decreases aminopyrine clearance, activity of adenyl cyclase and cyclic AMP formation would provide a mechanism for ulcer formation in men who smoke. SIGNATURE OF ~" PRINCIPAL iNVESTIGATOR'-,'.- PROFESSIONAL SCHOOL''' Eugene Do Jacobson, M.D. was awarded a grant for a period of two years b~ginning February i, 1970 with a total budget of.$.45,798.00. The first year budget was approved for $22,618.00.

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~aola $. ~lmiras, H.D. P~.D., Pro~essor o~ l~ysiolo&y, Department of ~hysiolog~v-Ansto~y boherty B. Hudson, PI~.D., Assistant ~ese~rch Physiologist, Department of Physlolo~y-Anato~y Theony V~lea~, Ph.D., As~/~an~ Research P~stolo~is~, ~rC~enC o~ ~hyslolo~y-Ana~o~ PRINCIPAL INVE STIGA TOR P~OF ESBO~L SO4OOL Graduate Dr. Paola S. Tlmiraa was awarded a grant for a period of three years b~ginnlng February I, 1970 wi~h a ~otal budget of $91,680.00. The fl~s~ year budget was approved for $28,449.00.

The romolut£om t~s rote~red to Rotoren~o Ceem~ttoo G ~d~Lc~ Sam IIL~cm~ •lter~to dolojAto ~rem ~&en~v~11o0 msppo~ted the rog~lut£o~ o:¢opt £or poJ~t 3 :Ln the r~oolvo £or~:Lns to ¢l~otto raCOOn ~4nd~tod th~ prop~£oty o£ A)IA Urban U. ,ver~eXe0 Boste~ --- ~loo oppooed te the tern Atom. lt°n ~emS to ren~late ~ny sejment ot ~ociety ~n ren;~rd to taxes. D.I. VJ~d, Jr., ~om, JI.C. -0 PoLut t J~ the resolve Ls ~ ~o. Po~t J ~d ~ s~A~ -- ~Ldlos ~o ~Jor ~ o£ the oc~ of to~e~ t~S. ~s~om ~SO ~o ~d to ~ors o£ ~to Cede eot~o ~oro ~s me mo~ to cZ~o ~t ~ ~ cl~ottes ~o ~ ~ly ~ ~ ~st o~tos. Po~t~lm ~ ~ the C~c~ ~et~ ~ ~ ~ve ~eh ~ Ue ~ t~cco ~ ve ~o ~t~ey. Zt ve~ a~t t~cco~ ~ to~cce ec~ -- ~y £o~p ~tr~os are ~ ~K lots o£ to~cco £o: tho~ ~ ~e ~ ~S lomo £=~ ~o We sb~d st:on• t~:~ce ~ the ~e o£ to~cco ~ not A Dr. hLnon(?) ot Orolon (not l£ste4 as • dolelito) -- 8upperted the renolutLOno Zt nooks to ntrons • hoslth hasardt PUBLIC RELATIONS COUNSEL P. O. BOX 523 " )3 LINCOLN ROAD • GI~F...AT NECK, N.Y. ].]02] • (2).2) 895-7445

Robert K. Bl~o, ~reemv~lle, NAeb. -- the :o£ere~ea to ms~s£dAes a=d taxee should be doAoted becauo theTOre me e£ ro©euseadatAoa~ to ~hat hal~s te I~e~lo who aa~keo .... B. D£11em o£ ~n ~eles, a ~ 0£ ~e ~£~e e~tt~, ~ste the ~ daT |~ |) At v~ ~oamAb2e .to learn the J~ moz~J~, a:d t~ts Jm£emastJ~m m ~tted to the t~too O~ Dec. a, rhea the Ibw~so e£ ~eXeB~tom reeemve~ed0 re- £ere~¢e ¢oe~tttee G0e report ~m adopted ~Atho~t d~oli:Les. |. ~he report e£ the AMA-4~/ ~LaLsea Ce~sAttee e£ the ~e met at the ~ t~ as d~d c~ttoo G, ~ot~o, ~: ~ ~tteo M~~ ~ ~t ~ov~. Xt ~ ~to: 1~~ the ~- ~~1~ ~o~oct ~s ~s~s~ st ~e ~ot~, v~tb doctors a~ t~t It k ~N. ~voF, ¢~ttoe ~ ~ended the p:o~ect0 ~ eddttA~ to the other £ivo ~tm mtA~ ~ ca:o ~ c~ttee ~°s :o~ ~c ~ £~ s ~to ~ ~o ~:o e£ Delo~tos ~t ~e=~t Dote ~e University o£ Chtca~, ~s ~ ~ d~octo: o£ ~o divlsl~ o~ sc~t~£~c actAvAt~os ~ v~11 as~ ~t cm ~ttor et J~ ~ t~t ~te. ~"~~ I R ATI N ~ PUBL C EL 0 S COUNSE P. O. BOX 523 * ].3 LINCOLN ROAD ~* GREAT NECK, N.Y. ].],02]. * (212) ~eleZe 0 0

AMERICAN MEDICAL ASSOCIATION IIOUSE OF DELEGATES Introduced by: Section on Preventive Medicine Henry A. Holle, M. D., Delegate Resolutlon: 17 Subject: Smoking and Health Referred to: Reference Committee G (H. J. Smith, M. D., Chairman) 1 2 3 ? 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 26 ~ 28 29 30 31 ., 32 33 37 38 Whereas, The Surgeon General's Report on Smoking issued in January 1964 has been followed by increasing evidence confirming the causal relatlonshlp between smoking and lung cancer, heart disease and emphysema as well as shortening of llfe expectancy, and the lack of significant change in cig- arette consumption by the American publlc in the intervening years is of great concern to many physicians and other persons; and Whereas, The followlng factors appear to be responsible prlmarily for "the failure of clga~ette.consumptlon to show any appreclable, decline since publication of the Surgeo~ General's definitive reports: (I) The expendlture'of vast sums of money.by the tobacco industry on radio and television advertising to create a favorable image of the cigarette smoker; (2) Current f~deral regulatlons fall to'emphaslze signifi- cantly the grave hazards associated with cigarette smoking; therefore be it Resolved, That, in view of the above, and because of speclal concern for the one and a half million adolescents who start smoking each year, the American Medlcal Association strongly endorse establishment of a natlon-wide prevention program encompassing the fpllowlng: (I) Discontinuance of radio and television advertising of cigarettes; (2) Discontinuance of federal subsidies to tobacco growers; (3) Substantial increases in federal, state and local taxes on cigarettes; (4) Expansion of health education programs publlclzlng the dangers to health from smoking; and be it further Resolved, That the American Medical Association strongly support the warnings issued by the Surgeon General on the dangers of tobacco and en- dorse the efforts of the Federhl Communications Commission and the Federal Trade Co~mlssion to react to these warnings. PaSt ~ous'e Actlon:A-69:270-271; C-68:181; A-68:69; C-67:211; A-67:101; A-64:37-3B; A-63:34-35

SUPPORTING AGENCY: : ,. AMA Education and Research Found~ti~~ . ~ ~'rlTl.E OF PROJECT: " Respiratory Tract Retention-of Vapor Phase Constituents of Cigarette Smoke Give name,, depottments~ and oflliclol title, o| PRINCIPAL INVESTIGATORS and ALi~ OTHER PROFESSIONAL. PERSONNEL en~oged on the proioct. John L. Egle,Jr., Ph.D. Assistant Professor of Pharmacology NA"E AND ADDRESS OF INSTITUTION: Medical College of Virginia Department o£ Pharmacology .~Ichmond, Virginia SUGARY OF PROPOSED WORK - (200 wo~ds or less.) - In the Sc;*nce Info~otton Exchange summer;e, o~ work in progress ore ex~eng~d with. ~vernm~t and private agencies supporting research, ~nd are fo~erded to |nvestigotors who retest such in|onn~ti~. Youe ,ummow is to ge used ~t these purposes. ' Over 50 compounds are knovn to occur in the vapor phase of cigarette smoke at a concentration of one microgram or more~ per AOml puff. ~t is proposed that the respiratory tract retention be studied in experimental animals for some Of these compounds'which are pre~en~ in ~elatively high concentrations or are considered to be noxious substances. Examples of'such compounds would be acetaldehyde~ hydrogen cyanide, acrolein, proplonaldehyde formaldehyde, acetone and hydrogen sulfide. The amount of each of the substances retained by the respiratory tract would be determined. Such factors as the respiratory rate~ tldal volume and concentration inhaled would be varied to observe their effect. Comparisons would be made o£ slngle breath retention to that retained in experiments of several minutes duration. In .both cases efforts would be made 6o determine the most critical factor co~trolllng uptake. AnQther major aim is to determine the amount tak6n up by different segments of the respiratory tract. Since these substances are brought into contact with the respiratory tract during smoking, it would seem desirable to know as much-as'posslble about total retention as well as fractional retentions by subdivisions of the respiratory tract. PRINCIPAL INVESTIGATOR .... ~ . ~ ,( .4 I {me~¢o~0PRO~SS~OSA~,e~u~,e.SC~OOLe,¢.} Schoo! of.. G~adu~t ~ S t.u~le.s Dr. John Egle, Jr. was awarded a grant for a period off three, ears beginning November I. 19~9 with a Co~al budget o~ $46~006.00. The ~Irst year budget was approved for $~7~I~4.00.

"00"6~9'ffI~ ~o~ paAoxdd~ ~ ~ ~T) e~t~ "00"~00'ZC~ ~o ~B~pnq poAo~dd~ u~ qaTzS 696I 'I a~qmaAoR SuIuuT~aq

Dr. Kober~"L. Vo11~ (Ph.D.) vas awarded a grant for a period of C~o yeaYs beg~nninK February I, 1970 v£~b a total budsec of • $25,213.00. The £1rs~ year budse~ was a[,proved for 11

I ' NOT FOR PUBLICATION OR PU BI.ICA TI(~N R(F~RE:NCE SUPPORTING AGIrNCY: : TITLE OF PROJECT: .. NOTICE OF RESEARCH PROJECT • SCIENCE INFORMATION EXCHANGE SMITNSONIAN INSTITUTION .~ AMA Education and Research Foundation Effect of Cigarette Smoke and Related Pollutants on the.Clearance of P~rt]c]~ from ~-_h~ T.unq_ Give homes, deportments, end offtciel titles of PRINCIPAL INVESTIGATORS end ALL OTHER PROFESSIONAl.. PERSONNEL engeged on the proiect. Roy E. Albert, M.D., Professor, Department of Environmental Medicine Horton T.ippmann, Ph.D., Assistant Professor, Department of : Env:Lronmenta 1 Medicine NAME AND ADDRESS OF INSTITUTION: New York University Medical Center 550 F~rst Avenue SUMMARY OF PROPOSED WORK - (~0 ~,~ o, ~e,,.) - In the S~¢e I~o~ti~n~¢~=~e~ ,~mori~, o~ ~rk in prpgre,, o,, exc~eng,~ with, ~vemm~l end privote o9~cies sup~rling teseorch, end ere Jo~orded to investlgotors who ~eque~t such inio~ti~. You~ lu~o~ is to ~ use4 w ~ese T~is 9=og~a~ deals ~¢~h an tnves~tga~ton .o£ ~e e~£ec~s of Rtga~e~e s~o~e and nela~ed 9ollu~an~s dn ~=on~htal ~le~ance. The ~tudy involves the determination of bronchial clearance in h~ans and do~eys by serial measurements of the rates-of disappearance from the lung of inhaled gala emitting radioactive monodisperse particles. The purpose of ~,e study is to ~haracterize in hu~s and miniature do~eys: El) the normal kinetics of bronchial clearance; (2) the nature, severity and frequency of clearance abnormalities in cigarette smokers and individuals with fra~ bronchial disease; (3) the natur~ and severity of bronchial clearance abno~alities An the dopey following acute and chronic exposures to whole cigarette smoke and its major components. SIGNATURE OF PRINCIPAL INVESTIGATOR__ ': PROFESSIONAL SCHOOL (medicel, 9,o(luote, etc.) po~£_~raduate Medical •school Roy E. Albert, M.D. was awarded a gr.ant for a period o.f three years beglnnifig February I, 1.970 with a total budget of $313,690.00. The first year was approved for $123,080.00. .

NOT FOR PUBLICATION OR PUBLiCATiON REFERENCE SUPPORTING A GE:N'CY : TITLE: OF PROJECT: SCIENCE INFOR~IA~ON EXCHANGE SM|TNSONIAN iNSTITUTION • GENCY NO. ANA Education and Research Foundation Nicotine'', aggressivity and environment-A laboratory study on the effects of nicotine in conflict situations. Give names, deportments, and official titles of PRINCIPAL INVESTIGATORS Qnd ,~LL OTHER PROFESSIONAL PERSONNEL engaged on the project. Daniel Bovet, Principal investigator; Filomena Bovet-Nitti, Co-investigator .AIq[:' ANO AOORI~'S$ OF iNSTITUTION: 1, via Reno, 00198 Rome, ITaly Laboratorio P sicobiologia e P sicofarmacologia, Consiglio Nazionale Ricerche SUMMARY OF PROPOSED WORK - (200 words or less.) - In the Science Information Exchange summaries of work in progress ore exchQnged with ~povernmentand privale agencies research, end ore r these Purposes. supporting forwarded to investigators who request such information. Your summary is to be used Analysisof the effects of nicotine and tobacco alkaloids on several patterns o~' emotive behavior such as anxiety (freezing) submissive behavior and aggressivit~'. St.udy of the ection of nicotine in several conditions (acute adminsitration, chronic administration, early stages of development) and comparison of its effects with that of psychotropic drugs such as neuroleptics, tranquillizers, ataractic and CNS stimulants. Special attention will be given to the effects of nicotine in conflict situations such as those observed in coexisting colonies of different species of animals or in cross-fostering animals belonging, to digferent species. PRINCIPAL INVESTIGATOR --(-D~-d =, Bayer) PROFESSIONAL SCHOOL (~,~o~, ~,o~,oi,, .to.) National Research Council) Pro~essor Dani~l Bovet was awarded a grant for a period of three years with a budget of $89,700.00, beginning November I,. 1969. The first year budget was approved for $29,900.00.

TH E AM E RICAN M E DI.CAL..ASSOCIATION 535 North Dearborn Street, Chicago. Illinois 60610 * * Area Code 312 OCTOBER, 1969 • FOR YOUR HEALTH'S SAKE . o . • A/~IERICAN MEDICAL ' "" ..... . .~ .. , • . .... ~...... : :.- . .. .. :SOME FACTS A~UT SMO~NG:A~ HEALTH " .:. .. According to recent estlmates.Amerlcans ~moke about500".":-,~;:~:~ ' hi.ion cigarettes, the equivalent of about Z,777 cigarettes a year ~or everF man~ woman, and child in,the countrF or over seven cigare~es ..... :,. .,. per day. The estimate is the result of a stead7 increase up to ~ecent :",..' years. The ~merican Medical ~ssoCiatlon's House of Delegates, con- ce~ned with the health hazards of smoking~ hav~ initiated an education- ~ program on the subject, directed especially to the young. THIS IS DUE TO THE FACT.THAT THE SMOKING HABIT usually begins in the early teens. By the IZth grade in highschool "many children are heavy smokers. Several studies in A~nerican secondary schools indicate that about one of every four .boys smokes cigarettes, and one of every eight girls. The boys also are heavier smokers. This ratio follows through in adult life. Exact figures fluctuate, but it has been estimated that about 60 per cent of ~erican men smoke as contrasted with 30 per cent of American women. SINCE 1939, NUMEROUS SCIENTIFIC STUDIES have been con- ducted to determine whether smoking is a health hazard. The trend of the evidence has been consistent and has permitted sound evalua- tlon of the health risk. Based on evidence derived from human popula- tion studies, clinical and autopsy studies, and animal exPerimenta. tion, the smoking of cigarettes does constitute a definite hazard to health.

SKILLED RESEARCH PERSONNEL HAVE CONDUCTED studies that prove tobacco smoking, particularly c.l~arette smoking, is associ- ated with a shortened life expectanc7. Cigaretts smoking is regarded as an important factor in the develop~nent of cancer of the lun~ and cancer of the larynx, and is believed to be related to cancer of the bladder, esophafius, and oral cavity, l~lale cigarette smokers are said to have a higher death rate from coronary heart disease than non- .smoking males. Cigarette smoking is regarded as the most important of the causes of chronic bronchitis'in the United States. A relationship does exist between pulmonar~ emphysema and cigarette smoking, but it is not established that this relationship is causal. The majority of. .physicians and researchers believe these observations to be correct and say, "Don't smoke! If you don't, smoke, don't start." AN INDIVIDUAL I~L£Y. TRY TO~ REACH A SOLUTION about his own smoking by studying the evidence, making a rational decision, and acting on it. Accordingly, let~ us review some of the evidence that has accumulated Irorn the i, esearch of many ..investigators .during the last~wo decades, • SINCE SMOKING HASMARKED PHYSIOLOGICAL EFFECTS~•~" perhaps we should ask what is smoke? . ... " Smok~, a "productof combustion~ ~Is a mixture of gases, various vaporized chemicals, and millions.of minute particles of ash and other solids. These are drawn into the mouth ~during smoking and into the lungs by inhalation. The smoke includes some vaporized nicotine, a- toxic subs'~ance found in tobacco, although much of it is changed by heat. It contains tars and other..products from the partial burning and distillation of the tobacco. A SMOKER GETS MORE NICOTINE and tar if'he smokes a cigarette to the end. A significant amount of carbon monoxide is also produced. It is picked up by the red ,corpuscles of the blood, which • normally carry oxygen. The more heavily they are loaded with carbon monoxide, the less is their oxygen-carrying capacity. SMOKING CAN AFFECT THE RESPIRATORY SYSTEM. As smoke is drawn into the breathing passages and the air sacs of the lungs, the gases and particles in the smoke settle onto the surround- ing membranes. One point of special impact is ~vherever a large air- way branches into t~vo smaller ones. This sort of location is where most lung cancers begin. PATHOLOGISTS AND PHYSICIANS SKILLED IN THE MICROS- COPIC anatomy of disease--consistentl7 find that the lining mem- branes become damaged and are less effective .in removing the toxic and irritating chemicals introduced by the inhalation of smoke.

PATHOLOOISTS ALSO HAVE FOUND THAT SI~OKII~G" not ordy thickens the lining membranes of the air passages and obstructs them with secretions but also stimulates a contraction of the muscles in the'air passage walls which narrows them and further reduces air flow. There is considerable evidence that a single cigarette will mark- edly reduce the air flow of even an experienced smoker. Potentially harmful particles are deposited into the air sacs, the point where emphysema develops. Recent pathological studies in humans suggest an association of these changes found in smokers and development of this disabling lung disease. SMOKE ALSO AFFECTS THE MEMBRANES llning the larynx or voice box. A pathologist identifies a smoker's larynx by the thicker, often swollen vocal cords~ The changes in the voice box are similar to those that occur in the air passages and in the lungs. These irrita- tions cause swelling, and increased secretion and result in "smoker's cough,' ' SMOKING AFFECTS THE CIRCULATORY SYSTEIVI--the heart and blood vessels. Nicotine, if injected or taken In tobacco smoke,., stimulates that part of the nervous system that controls the heart, blood vessels~ and other internal organs th.at function almost auto- -~... rnatically. 1~Iore s'mokers die from coronary heart disease than do nons rook ers. AMONG OTHER. EFFECTS OF SMOKING are those of an ap- .:" parent tobacco a11ergy in some senitive'persons, and aggravation of .... peptic ulcors. Patients with these conditions are genera11y advised not to smoke. SMOKING IS DIR.ECTLY ASSOCIATED WITH ACCIDENTAL • DEATHS from fires in the home. A study of death certificates by the " National Safety Council led to an estimate of 1,000 deaths EACH YEAR in fires caused by smoking. About 900 of these deaths occurred in the home; many of them when people smoked in bed. l~ore than an average ... of two fatal conflagrations per da7~ wholly preventable! " .. WHILE ALL TOBACCO SMOKING is ~belleved to affect.health and life expectancy, cigarette smoking appears to have a much greater effect than cigar or pipe smoking. Among the possibl.e explanations are that cigar and pipe smokers often do not inhale, and the tempera- ture at which the tobacco burns is different. • FILTERS AND DENICOTINIZATION OF TOBACCO or ciga- rettes are alleged to reduce the hazards. However, denicotinization has no eHect on the kind or amount of tar in the smoke, and filters can only reduce, not eliminate, the hazards. THA~ SMOKING IS RELATED TO PSYCHOLOGICAL AND SO- CIAL SITUATIONS is well known, not only 'in the reasons people give

for smoking, but also in o~her~ obvious reasons which the' don*t give; Young people, often start smoking in imitation of older people who smoke or as an expression of a subconscious wish to be like them. O.Ider children and youth want to be accepted by their friends and associates. Often friends dress alike, talk alikeB and have other be- havior in Common. Smoking may be part of this attempt to conform. • Not smoking could also be part of a group p.attern, . AS A MEANS OF RELAXATION, the mechanical aspects of. smoking are recognized. Under tension or during an awkward Iu11 in activity, smokers probably do relax by taking out a package of cigarettes, choosing one, getting matches, lighting the cigaretteB and handling it. SOME AUTHORITIES SUGGEST THAT A CIGARETTE repre- " sents a reward that a smoker can offer himself whenever he wishes, or ~that the act of smoking represents a means of self-expression. In young people, it may represent freedom to do as one pleases, or be a reaction against adult authority. Others believe that pet)ple smoke "because of the need for oral activity to fulfill an unsatisfied suckling RECENT STUDIES HAVE SHOWN ~THAT YOUNGSTERS whose parents smoke will also tend to smoke. If older brothers and sisters smoke, the younger ones are more likely to become smokers. •l~luch research remains to be do~e before an understanding is reached regarding the factors in smoking that produce satisfaction and often lead to habituation. WHAT DO AUTHORITIES SAY ABOUT SMOKING? Physicians, s~ientists, and many other health agencies have studied the relation- ship of smoking to health and most are in general.accord. The most extensive examination of smoking was published inl January, 1964, by the Advisory Committee to the Surgeon General of the U.S. Public Health Service. The committee reported: "Cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smdking far outweighs all other factors. The data for women, though less extensive, point in the same direction," THE DANGERS IN SMOKING~ ESPECIALLY HEAVY SMOK- ING OF CIGARETTES, are recognized all over the world. Statements on the subject have been issued not only by the U.S. Public Health Set- • vice, but also by the Royal College of Physicians in Great Britain and a special committee of the World Health Organization. THE AMERICAN MEDICAL ASSOCIATION STATED officially at. its Annual Convention in 1704: "The American Medical Association • is on record and does recognize a significant relationship between cigarette smoking .and the incidence of lung cancer and certain other diseases, and that cigarette smoking is a serious health hazard."

THE HOUSE OF DELEGATES OF THE AMERICAN MEDICAL ASSOCIATION has. officially endorsed the actions of the Joint Coral rnittee on Health Problems in Education of the National Education Associa.tion and the American Medical Association. This Committee, recognizing that "...the specific components oftobacco exerting harm- ful effects on the human organism have not yet been defined and the exact pathological and physiological actions of these components have not been determined, nor the psychology of smoking full7 understood, recommended authoritative~ research...in smoking such as that being conducted by the AlvtA and others." THE JOINT COMMITTEE ALSO RESOLVED "That schools, physicians, health departments and other community agencies operate in an aggressive program designed to discourage children from starting, the smoking habit and to influence youth who are smok- ing to discontinue the habit." THE AMERICAN IMEDICAL ASSOCIATION has not confined itself to mere endorsement. It has never allowed tobacco advertising in its health magazine, TODAY'S HEALTH, since its establishment in 1925, and it banned tobacco advertising from its Journal for physicians and its exhibits at scientific meetings in 1954, long before the statis- tics had accumulated to their present overwhelming mass and rendered the hazards of 'smoking so apparent. It is sponsoring clinical and sci- entific research, as well as an educational program on a continuing basis to call to the attention of the public, particularly young people, the known evidence against smoking. WHAT CAN BE DONE ABOUT SMOKING? Manufacturers are trying to reduce the hazards of smoking by modifying tobacco, reduc- ing nicotine content, and filtering the tars. The long-range eHects of these efforts are not now know/,_ and cannot, in the_ nature of things, become known for some years to come. Cancer often waits Z0 years 6r more to become manifest after the irritation that provoked it, and by the same token, years must pass before the effectiveness of a pro- gram of prevention can be demonstrated. RESEARCH HAS BEEN INITIATED TO FIND AND ISOLATE or refine l~armful substances so that those who smol~e may continue to smoke safel7. Thus far, the results have been discouraging. As part of its concern with this problem, the American Aiedical Association is sponsoring a large-scale'study to determine mechanisms by, which human ailrnents may be caused or aggravated by smoking, in order to • define more accurately the role of tobacco in health and disease. WHILE TO SMOKE OR NOT TO SMOKE is a matter of individ- ual choice, most authorities now agree that never to smoke is prefer- able. Further, they would agree that significant evidence is accumu- lating which, indicates the desirability for the heavy smoker to stop smoking or cut down to the point of moderation.

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535 NORTH DEARBORN STREET • CHICAGO, ILLINOIS 60610 • PHONE (312) 527.1500 • TWX 910-221.0300 CO..,T~E ,0, nE~.~C, ~, ~ ~ ON TOBACCO AND HF..ALTII MAURICE H. SEEVERS, M.D., Ph.D., Ann A~bo~, M~ch. Chairman RICHARD J. BING, M.D., Deboit, Mich. ROBERT J. NASTERLIK, M.D., Chicago, IlL JOHN B. HICKAM, M.D., Indianapolis, Ind. PAUL KOTIN, M.D.. Research Triangle Pa~k, N.C. PAUL S. LARSON, Ph.O., Richmond, Va. IRA SINGER, Ph.O., Secretary August 25, 1969 Mr. H. H. Ramm Vice President R. J. Reynolds Winston-Salem, Dear Mr. Ramm: and General Counsel Tobacco Company North Carolina 27102 Enclosed are summaries of eleven grants which have been approved by the Committee for Research onTobacco and Health since its last meeting on May 23, 1969. Sincerely yours, Ira Singer ~ sk enclosures

~OTICE OF RESEARCH" PROJECT SCIENCE lNFORMA310N EXCIIANGE /U~A ~'~iucation and Resuarch ~ ...... " "- 'tlTL[OF pRO~ECT; Studies on blood elot[ing and fihrino]ysis during chronic smoking., Chr~stos ~. fioschos, H,D,, AssLsLan~ Pzo~ssor o~ Hedlcl~, Dep~r=men~ o~ HedicLn~ Allen ~. Wetsse~ H.~.~ Assistant P~o~esso~ o£ Hedtctne, Depar~m~n~ o~ Red~c~ne Hoha~ad I. Khan, H.D., Fellow in Hedic~ne, Department of Hedlcine Henry A. Olde~rtel, Research Associate in Hedicine~ Department of Hedtciae ~A=t*~O~rSSOFmS¥~TUtmO~: New Jersey College of Hedicine 24 ~Idw/n Avenue JeroeK Clt£~ New JerseLQ~304 s~ok/n~ on the heart and mechanism o~ action, It is p~cposed to examine £roops of dogs changes o~ the clott/n~ and ~tb~tnolyttc mechanism across th~ heart and "in the systemic circulation at various stages oZ a chronic smoking ~e anl~al~ will be subdtvtded into g~oups with peclods o~ smokin~ varying ~ro~ these to ]2 mo~ths arid at yearly intervals the~ea[/e~. Studies z'elated ~o clotL~,~ and fib~inolysis wt11 be carried out prior to and aL the end oI each experimental period and the results will be c~pared with control animals. The ef[ect~ o~ local ~natomical ~hanBes in c~binatton with chronic s,nokin~ will also be examined t~ a separate group oZ dogs placed on a high lipid diet. In anochec g¢oup o~ non-nicotine eftect, if any, o~ chronic smoking upon clo/t/n~ and fibrinolysis wil! be. ex~tned by administer/ng nicotine in amouots corresponding to those rece).~eo by regular smoking, Thus the Froblem 3f formatidn o~ thrombus in the coronary artery and whether a chronic smoker ts more prone to this process ~y be analyzed in. the proposed experiments with ;: total budget of $'q'~ 220 00 beginning Au~,ust 1 1969 ' . .s _~<1,097 yc.ar buoget ~,n appro.~,c,d for $~'; . The fir~ ~.

SCi~J~Cl~ EXCH~.I~GE /~, FAu¢~.t~on ~ Rese~ch Foundation. ;h0 Effeq~..,~..~aternal S~oklng on ~eonatal Davtd E Copher, . Assfstant Professo~ Oepar~ent of 0bstetrtcs ~nd Gynecology Indiana Un|verstty Hedtcal Center "Thts stud~ Is destgned to tnvestlg~te the sp~tt~ ~elatfonshtp of m~tqrnal smok1.~ on fe~l g~o~v~h and develo~en~, 'and neonatal health. Pertod~c testing o~ the tnves~g~tton~l subjects throughout pregnancy ~ done utllfztng resttng dat~ compared to stress sltu6tlons, Stress s~tuattons Involving ~th the ~other and the fetus ~ttll ~ caused by sttn~ulattng the mother ~1th various concentratlons of oxygen tn ~sp~ed gases, !. ~dd~tlon, a carefu~ survey of the matern~] envt~nt ~fll be completed on e~ch subject tn order to pair the stHdy samples, Fetal heart rate changes throughout pregnancy ~11 ~ utfllze~ ~s a stgnal .o~ fet~l status. The ~.ner of .oonat~l adaptton to extrautertne life ~11 be documented b~ changing acid-base status a~d oxygen cons~ptlng. Follo~-up of the ~lated tnfants Hf11 be conducted unttl the dge of three years. -- David E. Cophor, M.D: ~aS awarde-~a grant for a period o£ three years begiuni~g Augudt 1, 1969 w£th a total budget o£ $76,080.00., The approved budget £or the flrs~ year was $33,840.00. SIGNATURE OF P~INCIPAL iNVESTiGATOR, PROFESSIONAL SCHOOL

~.Education and Research Foundation ::~":' : Some Structural Aspects of N~eotine G!v~ome,s~, clep~lmenls~,~l e~clel titles el PRINCIPAL INVESTI~ORS end ALL OTHER PROFE~I~AL PERSO~EL engogtd on the p~oiec~. ~'" Cha~es H. Jarboe~ Ph.D. Associate Professor • ~.--. D~artment of Pharmacolb~ NAM£ AND ADDRESS OF INSTITUTIOII: University of Louisville, School. o.f Medicine. I01 W._Chestnut ~ARY OF PRO~SED WORK - (~ ~,ds o, less.) - In the Science Inlomofi~. It ~s the a~. of this s~dy to explore the activity of Marious n~eotine dePivativ~s at the ne~o~se~ar j~ctlon. The classes of co~o~ds to be .. s~die~ are: U his ~e~ylnicotinim diiodi@scontaining a variety of s@.st}.tutents ~n .the ~ position of the benzene 2/ mono b~zyl ~ s~sti~ted) methyl ~Icotine wiO, benzyl groups ~n both the pyr~dine - 3Z .~xed bi~ ~I quaternary ~oni~ s~ts of nicotine. Ne ~ish to explore the aff£n£ty ~A2, o£ the~e ~ub~anee~ o~ the £~og ~eetus ~om~ ~e~a~a~on a~ee~ta~n~g the ~o~tanee of~ ste~e ~ ~t the ~e~o~a~ ~et~on. SIGNATZJRE OF PRINCIPAL INVESTIGATOR PROFESSIONAl. SCHOOL (me~icol, g,aduote, etc.) School of Medicine Charles H. Jarboe, Ph.D. was awarded a grant • beginnihg August i, 1969 with a total budget year budget was.approved ~t $11,640.00. for a period of two years of $23,760.00. The firs! 0

• ,-e,,-T*~, ,~v.*-,* . . NOTICE: OF. R~SE;ARCH PROJECT I,~= ~o. * I u o o I " ~ ' ~o~cv ~. ~o~T~o~o~c~ ~ ~ ~ucat~on ~d ~ese~ch, Foundation ~,~ o~ ~o~c~-,- ~e e~ects o~ ~Co~tne ~ other ~u~no~c~y sc~Ive d~ on be~or o~ ~ce Give'earn,s! .d,pef~me, ts, e,d offlclol titles e| PRIHCIPAL IHVESTIGATO~ ond AL~ OTHER PROFE~I~AL PERS~HEL en~ged ~ the -,.. ~ce ~.. ~b ~ ~. o~ ~slolo~ ~£eeeo~ .... NA~£ ARD ADDRESS OF .RSTITUT,OI:: Uaiversity 'of Californial School of Y~dicine~ ~rt~nt ~RY OF PROPOSED ~'ORK - (~ ~ ~ le~s.) - I. the Scieace Info~mofi~ Exch~ge~o~e~ ~f ~rk in ~o~es~ o,e ex~ge~ ~h ~ve~l ~ p~ve~e eg~cies suppling ~eorch. ~d o~e fo~rded to invesiigo~s ~ teques~ s~ inf~ti~. You~ su~e~ J: ~ ~ used ~ ~e~ ~o~,.- " .. , .: ~he geDeral aim'of this york i~s to study wlde-ranging behavioral effects of nlcotine~ &ImethylpheDylpiperazinium, hexamethonium, tetrabenazine, benzquinsmide, and norepinephrine in mice that have been Immunosympathectomized as compared with suitable control groups, • Inclt~li~g mice with adrenal dem~dullation. The drugs have been selected because of their actions on autonomic ganglia or their ability to deplete catecholamlnes in an attempt to identify factors that contribute to behavior~ differences already o~served between immunosym~athectomized and intact mice. The ex~rimental animals have been found to b~ less disturbed than intact animals by situations that contain a negative or av~rslve comlx)nent. A variety of tasks hav~ been studied, some of which involve le.arni~g while others do ~ot, "and some of which are rewarding ra~her than punishing. A number of these tests will be utilized in the present research., Because of the necessity for dlffereht types of ~ntact control groups, the Opl~rtunlty will also be provided to evaluate the behevioral effects of the drugs, in ~orm~. 1 animals in a variety of situation{. The major portlonof the work will be done with the ssme strain already used, vlz., Webster Swiss, but coml~rative data will be collected ~rom a more feral form as well, ~uch as Peromyscus. PRINCIPAL. INVESTIGATOR -- ' - - .. PROFESSIONAL SCHOOL. (meclico|, 9mdu~le~ etC.) ~dICS). Bernice M. Wenzel, Ph.D. was awarded a.grant beginnfng August I, 1969 with a tot~l budget first year budget was approved at $15,726.00. for a peqlod of two years of $32,929.00. The

NOTICE OF kF.$F.ARC}; PROJE:CT SCIENCE INFORMATION EXCHANGE .I ,~. ~ucatJon and Re~e~-ch Foundation TIT~ O~ P~O~ECT; Accelerated Carcinogen Te~;.,g , G,v+ ...... as, depo,lmenl*, "~d o~ficiol ,,,le" ol PRINCiP~ INV[S;IGAIORS ~.d AL~ OTHER PROFE~iCqAL Homb~rg~r, F:cddy bi.D., Prcsidc;~ a=~ircctor Todd, Neff B. P~.~., Research Aesociate VanDc:~en, Come!Is G. Ph, D., Rev-~rch Associate This is an effort to shorten tumor induction time ia carcinogen" testing by using th~ method of transplantation of multiple-pooled carcinogen injection sites into ~resb secondary hosts, deve.loped by the principal investigator (C~ncer Res. This method will be ap.plied to a recently discovered inbred line (BIO i5, 16) of Syrian hamsters which are "super-sens'itive" to subcutaneot~s carcinogens (DMBA ha's a latent time of from three to twelve weeks with a n~ean o~ eight we~ks~ compared to a mcan latent time of seventeen wecks Jn r~ndombred hamsters). Known "pure chemical carcinogens will be used to stands.rdizc the method which then wi!l b~ s.pplied to ~nvironrnental carcinogens. PROF ~SSIOHAL ~7,tGG~ ' (medic*d, |,e~k~ete, el¢.),,, Freddy ~o~burger, ~.V. was awa~ded~-grm~t for a perl~d of one year beginning August I, 1969 wlth a budget of $23,621.00. 4;) o

SUPPORTING AGENCY: AMA Education and Research Foundation TITLE OF" PROJECT: Acut~ Effects of Tobacco on the Auditory and Vestibular Apparatus Give names, deportments, and of|iciol titles o| PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the p,oiect, Martin Spector, M.D. Clinical Assoc. Prof. Otorhlnology, Te(nple Mad. School Chief of Otolaryngology, Kensington Hospital Carol Kozlakiewicz, ElectronyStagmography technician and clerk Mrs. Betty Weiss, M. A., Audiologist NAIVE AND ADDRESS OF iNSTITUTION: Kensington Hospital 136 W. Diamond St., Phila. ,..Pa~ 1912.~ SUMMARY OF PROPOSED WORK - (200 words o, less.) - |n the Science Information Exchange summor|.es el_ wo,k in progress ore exchanged with rnment and privole e~encies supporlin9 research, end ore forwarded to investigators who requesl such Inlormotion. Your sun~ory is to be used )r these purposes. One hundred subjects will be studied for the immediate effects of cigarette smoking on audition to see if smoking causes immediate spontaneous, posltfonal, or gaze nystagmus by electronystagmography, as well as verticalnystagmus. Then the same subjects will be studied after fifteen minutes to check on dissipation of effects. This test will be repeated afte~ a week. The statistics will be studied to see if heavy smokers differ in their acute responses from non-smokers, or occasional smokers. Martin Spector,.M.D. beginnii~g August i, PRINCIPAL INVESTIGATOR ... _I [ t/.lk £',J\ ~_~: _ PROF ESSIONAL SCHOOL (medi=o|, graduate, e,c.) Temple M edical S chool ' "p~fL~d :of was awarded a grant for a one 1969 with a bu}dget of $8,911.00. "-':~:-~".~ ~c 1:~ JU[; 19 9 year

Leonard Zahn ~nd Assoclates~ :Inc. ~ubJect.. American l~ical Associat~ton ~Meeting, July 13-17, 1969 I, House of Delegates -- Activities on ~moPAng, A. The three anti-smoking resolutions (copies of which were obtained early • ~nday, July 13) were referred to the House*s Reference Committee 0, which held hearings on these and other proposals beginning Monday morning~ July i~. The resolutions had been introduced by delegations from Arizona, Oregon and Wis- consin. Committee chairman Clarence S. Livlngood commented: "This is an old subject.= Delegate Daniel Te Cloud of Phoenix said his state's resolution ha~ been introduced at the request of the Arizona Hedlcal Association. "Though the AMA has taken action against smoking through statements and resolutions# we Would llke to see more of an anti-~oking effort in regard to television and advertis- ing and especially in the high schools. We want to see a good education program.z" Delegate Ernest T. Livingstone of Portland, supporting the Arizona and Wis- ¢onsin resolutions, said the Oregon proposal was offered to change the situation ~here the HEN Department was campaigning against smoking while the Department of Agriculture "doe s the opposite." He gave the committee copies of what he said was correspondence with Oregon's Congressional delegation. The comnittee's report, to the House of Delegates was made Tuesday m~i~ting, July 15, and was adopted after two changes in the section referring to the anti- smoking resolutions. . Delegate John" C. Quertemous of Kentucky proposed that the three underlined words in the follo~ng paragraph be changed to "the incongruity of"." Resolved~ that~ through appropriate channels# the American Medical Association indicate to the Congress of the United ttate~ its oppositiou~ ~ the expenditure of tax dollars to promote the production and sale of tobacco while at the same time spending other tax dollars to discourage cigarette smoking because of its hazard to health." California delegate Alfred J. Murrieta, referring to 196~, questioned ~is sentence: "In the same year the House of Delegates 'commended the establishment of the research program (on snoklng and health) that is being carried out by the American Medical Association Education and Research Foundation." Dr. M41ford Rouse said the AMA-ERF does not do any tobacco-health research but is only a "conduit" through which funds are channeled, to scientists. The sentence was deleted. B. The AMA-ERF Liaison Committee to tho 'House of Delegates reported that tobacco end health research, funded by the tobacco industry, "is necessary and of value" though public relations of a "positive nature have not been derived by either the AMA or the .AMA-ERF by the latter~s association with the tobacco industry."

Leonard Zahn and Associates, Inc. The Liaison Committee recommended every physician and the public at large be informed by the AMA of the relationship of AMA-ERF to the tobacco research project and that the program be continued. Reference Committee E of the House of Delegates concurred in its report ~nd the delegates adopted the report without discussion. Anti-Smoking Papers. Three papers dealing directly with smoking were on the program~ A. "Termination of smoking by a single treatment" -- Herbert Spiegel, a psychiatrist at Columbia University College of Physicians ~nd ~urgeons. As predicted, this paper attracted considerable press attention. Jim Spauldiug, science editor of the Milwaukee Journal, commented~ "It was cute and easy to write." Further, a press conference for Spiegel was held Monday morning, July 15, a day in ~hich the House of Delegat.es was" not in session. A copy of his paper was obtained. Splegel's one-shot, self-hypnosis session for smokers is based on whnt he called the "positive" approach: s~oking is a poison for your body# you need your body to llve~ you owe your body this respect and protection. B. ~k~at about smoking?" --Daniel Horn, USPHS. A copy of his paper also was obtained. Horn's presentationwas pretty~uch a rehash.of what he has been saying for a longwhile. He said that since the turn of the century, the effects of smoking have wiped out all beneficial results related to increased life ex- pectancy. Life expectancy for males has increased only fouryears, not the expected eight years. Cigarette smoking is declining in this country "on an absolute basis. The reduction of smoking is increasing." Horn personally delivered copies of his paper to the scientific press room at the Coliseum. He appeared to be trying to promote a press conference for him- self. The "sameness" of Hornts paper was pointed out to the man in charge of the press room and he agreed a press conference would not be of any value to the writers present. C. "Cigarette smoking and the serum activity of enzymes associated with atherosclerosls" -- CTR grantee Alfred Kershbaum et al. Delivery of this paper was cancelled because of Kershbaum's recent unexpected death. 0 0

Leonard Zahn and Associates, Inc. 3. Other Papers. "The ~nterdisciplinary approach to the rehabilitation of the emphysenmtous patient" ~- Dr. Irving Kass, University of Nebraska, Omaha. Kass noted that three factors are responsible for the increased incidence of chronic obstructive lung disease in the U.S.: smoking, air pollution, and ~overty. All patients at his universitytsRegional Chest Center are encouraged to stop smoking. However, he added, behavioral scientists at the center have found that some. patients ~to have smoked for many years cannot function adequately ~hen cigarettes are prohibited. Dr. Yredrick J. Stare, a CTR'grar, tee, spke on "Calories, cholesterol and alcohol." He noted that "smoking, lethargy, high blood pressure, obesity, and a host of genetic factors are all involved in heart disease along with cholesterol." Several physicians, speaking at a session on "Chronic Pulmonary Insufficiency and Problems of Air Pollution," appeared at a press conference. Dr. fan Higgins, University of PAchlgan, Ann Arbor, noted that cigarette s~oking "is almost certain~v a more important cause of chronic respiratory disease, lung cancer and heart disease than is air pollution." (His actual paper was on e~fects of sulfur oxides and particulates.) Dr. John R, Goldsmith, California Public Health Department, Berkeley, said that cigarette smoking is a major contributor to chronic respiratory in- sufficiency. Ozone can interfere with pulmonary function and nitrogen dioxide, in long-term experiments with anima~ls, has produced a condition resembling emphysema. (His paper was on the health implications of automobile pollution, with emphasis on lead anti-knock compounds in gasoline.) John A. Zapp, Ph.D., ~ilmington, Vel. (he is associated with a research instituted funded by du Pont). Zapp said that from a scientific point of view, the evidence about air pollution and health "is not yet firm." There could be a problem in the future, if the present composition of pollution continues and increases in intensity. Heavier levels of air pollution impose stresses on people and "if they're not in good health~ the results could be disastrous." Dr. Stephen Ayres, St. Vincent's Hospital, New York, noted that manydoctors are unaware of the air pollution-disease relationship. Respiratory infections can result from air pollutants or "inhaled particles such as cigarette smoke."

Leonard ZahnandAssoctatesx Inc. 4. New~ President. Dr° Halter C° Bornemeier of Chicago was elected president-elect of the AY~o He will take office in June l~O° Dr° Gerald Donnan of New York is the current president. Bor~emeier has been speaker of the AMA's House of Delegates for t~e last three years. He is a surgeon and has been a~irector of the National Tubercu- losis and Respirator~ Disease Association. 0

A/.~RICAN ~/DICi~L ASSOCIATION HOUSE OF DELEGATES (A-69) 1 6 ? "Io z6 i? "18 z9 ~0 ~8 ~9 Report of Refez'ence Committee E Presented by: George W. Slagle, M. D., Cha:.rman Mr. Spea/:er and Members of the House of Delegates: Reference Committee E gave careful consideration to the several items referred to it and submits the following report. (i) REPORT E OF THE BOARD OF TRUSTEES - N~.; USES OF OLD DRUGS Report E of the Board of Trustees informs the House of Delegates of the action taken as directed ~j Resolution 14 (C-68). The ~.~% was directed to discuss with the Federal Food and I~'ug Administration the legal implications of physician use of drugs for purposes not approved by the FDA for inclusion in official labeling, such as package inserts. Your Reference Committee is pleased to note that a meeting has been held ~ith the FDA Geneyal Counsel and a member of the FDA Bureau of ~.~dicine. A report on the statements made by the FDA representatives ~s published in the February 17, 1969 issue of J~ and pertinent ex- cerpts are appended to Report E. The report of the discussion should answer many of the questions that prompted introduction of Resolution Soeaker, your Reference Co~_mittee recom:.mnds accewtance of the House of Delegates. ~'~ (2) Rr~ORT BB OF THE BOARD OF TRUSTEES - BLOOD DONERS Report BB of the Board of Trustees calls to the attention of the House the need foy mo~e volunteer blood donors and requests the con- currence of the House in three recommendations submitted by the Committee on Blood to encourage volunteer donations. The United States Post Office would be urged to give favorable consideration to the issuance of a commemorative stamp calling attention to the need for more volunteer blood donors; designation by Congress of Jsnuary, 1970 as National Blood Donor [bnth ~muld be encouraged; state medical assoclatious would be encouraged to promote actively state legislation to permit persons 18 years of aze or older to donate blood without parental per- mission or authorization. J,Ir. Speaker, your Reference Committee recommends adoption of BeDort BB of the ~oard of Trustees ~v the House of Delegates. (3) REFORT OF TILE A!.IA-ERF; RE~0RT OF THE A~.IA-ERF LIAISON CO~.IITTEE OF THE HOUSE; ~{D SUPPLEMEq~ARY REPORT OF THE A~-ERF LIAISON COI,~tITTEE These three Reports rela~Ing to the programs of the A~.~-ERF were considered tocether. The Report of the President of the AMA-ERF on

Ref. Co~m. E- P,~.Se 2 6 7 8 9 10 ll 14 16 19 ~6 5o the current status of the Foundation's programs :ms informative. The first repo:'t of ~ ~ ~n~; ~/.~V~-E~iF Liaison Cor~dttee of the House on its study of these proz~'~us deserves the carefal attention of all the Delegates. Your Reference Committee recommends that these reports be accented bl,: the House. The Supp!euentary Report of the A],~A-ERF Liaison Committee contains five recom~,~endations for House action based upon the careful conslde~-atlon and study the Committee has given to the purposes and programs of the Foundation. Your Reference Co~tmittee concurs in these reco~:~endations ~Ith the addition of one change requested by the Liaison Committee. On page l, line ~2, the Liaison Cor.~ittee has requested that the phrase, "because of fiscal considerations," be inserted followinc the phrase, "at the present time". ~.[nen the /U~'~%-ERF Student Loan Procram ~as discussed by witnesses appearing before the Reference Co~a~ittee, information was presented in- dicatinG that a number of medical students may face serious financial problems if mo~-e funds cannot be made available at lo~: interest rates through student loan programs. Further, financial assistauce needs to be made available if prospective students unable to afford the expense of a medical education are to be recruited. Your Reference Committee was informed that the A2.5',-ERF Board of Dissectors has appointed a special committee as recommended by the A/~Dk-ERF Liaison Committee me study these problems and recozt~.end solutions to alleviate the crisis faced by financially distressed medical students. Your Reference Committee concurs in the Liaison Committee's emphasis on the importance of info~ing the profession a~ the public of the role the ~,~-L"~F serves in co:~junctlon ~ith the Tobacco Research Project. The A/~-ERF Liaison Co~nittee has pointed out that the Foundation serves only as a conduit for funds contributed to support basic research on the re- lationship of tobacco to health. The Foundation, through the Comzaittee for Research on Tobacco and Health, has established a project-review committee for the grantinz of funds fez institutionally-sponsored, basic research and conducts none of this research activity itself. Your Reference Committee feels that this activity of the ~.~-ERF is comple- menta~ to the objectives of the Association "to promote the science and art of nedlcine and the betterment of public health". ~. Speaker, your Reference Committee reco~.ends adoption of the Supplementary Reoort of the PJ~Sk-ERF Liaison Com~ittee of th4 House ~ith the requested chan~e..oq3~_a~xe_~__li_ne___~ REPORT A OF THE JUDICIAL COUNCIL - REVI~'~ OF ETHICAL CONSIDE~&TIO~ REL~ING TO CL~;ICAL LABOPJ~TORIES Report A of the Judicial Council, containir4z a review of policy positions adopted by the House of Delegates, prior opinions of the Judicial Council and a comprehensive analysis of current issues relating to the delivery of laboratory services, provides a valuable source docu- ment for the House of Delegates.

C Report of Reference C~mittee G Presented by: Clarence S. LivJ.ngood~ M. D., Chai~.nnan ~ p-~ 1 Mr. Speaker and ~bers of the House of Delegates: 3 6 8 9 13 lh 16 1B 1.9 ~3 31 33 35 3? 39 (1) REPORT I OF THE BOARD OF TRUSTEES - SCHOOL AND COLLEGE PHYSICAL EDUCATION Report I of the Board of Trustees would reaffirm a resolution on physical education programs in schools and colleges which was adopted by the House of Delegates in 1960. This resolution urges medical societies to do everything possible to encourage effective physlcal education for all students in schools and colleges. By effective physical education is meant regular instructional periods involving a wide varietyof physical activities designed to catch ~e interest and meet the needs of all pupils -- the under- developeS, the physically average~ and the physically gifted. In 1960 when this resolution was adopted, the American Medical Associa- tion did not have a C~aittee on Exercise and Physical Fitness as it now does. Accordingly, this Co~uittee believes that reaffirmation now~ ~en the interest in physical fitness is accelerating, would strengthen the Committee's posi- tion in trying to implement one of its major objectives -- to improvethe physical fitness of our youth. The Committee, through meetings and conferences, has close working relationships with other agencies interested in physical fitness and believes that~ through its own channels and those of these other agencies~ more could be done to implement the intent of this resolution than was possible upon its original adoption. The Boar~ of Trustees agrees with the Con~ittee on Exercise and Physical Fitness, that reaffi~aation at this Convention would have a fine potential for implementing the Committee's objectives with respect to the physical fitness of youth. _Mr. Speaker, your Reference Committee reco~ends adoption of Report I oft he Board of Trustees. RESOLUTION h - PPJ~SERVATION AND EXPA/~SION OF HOSPITAL SCHOOLS OF NURSING RESOLUTION 35 - LICENSED PRACTICAL NURSES AND DIPL~.~ BIrRSI NG PRCGRA~ RESOLUTICN ~9 - PATIE~IT CARE IN HCSPITAES RESOSUTION 75 - RECRUITMENT FOR }~RSES AND PARA/,~DICAL PERSONNEL At virtually every recent Convention -- annual and clinical -- the House of Delegates has considered resolutions and taken positive action with

3 5 6 7 8 9 I0 ii 13 17 19 3~ ~ 35 Ref. Ccam. 0 - Page 2 respect t6 the availebilit:, cf nurses and nursing ~er~Ices. In te~s of this bachgroun~ Resolutions !~, BS, ~, ~nd 75 were considered together. In 1967, the House of Delegates of the American Medical Association reaffirmed its support "of all forms of nursing education including bacca- laureate, diploma, associate and practical nurse education puogr~ms;" and commended "hospitals that conduct diploma schools of nursing for the great contribution belngmade by these schools to the health needs of the nation." In 1968, the House urged increased subsidies to hospital nursing. schools, encouraged state and local medical societies to seek local "sources of financial support for hospital nursing schools" and urged concerted action by/~4A and other appropriate agencies "to encourage increased enrollment in hospital nursing schools". Your Reference Committee believ~ that the testimony given at the Reference Committee hearings ~as directed toward the same objectivesthat the House action of 1968 sought to achieve. It was also indicated that the obher resolutions on this subject have similar ~oals. Accordingly, your Reference Committee recommends reaffirmation and s~ren~thenlng of AMA's ~osi~icn in this area throu~ a substitute resolution as fol~ows~ i~ lieu of Resolutions !~,.. Resolve~, That the American Medical Association reaffirms its support of all forms of nursin~ education includlnc bacca- laureate, diploma, associate, and practical nurse education programs, and be it further Besolved, ~nat the American Medical Assoc~atlon encourage the continuation of federal subsidies to schools of nursin~ education, and be it further ~esolve~, That the American Medical Assoclaticn talm appro- priate action in consultation ~ith the professional and vocational nurses' associations, American Hospital Associa- tion and other concerne~ groups to increase the enrollment in diploma sohools and practical nurse education programs, and be it further Resolve~, That appropriate steps be taken by the American Medical Association to encourage recruitment into the health professions, cf health-oriented personnel released from the armed services, that the cooperation of allied health professions and vocations be soug~,t in this effort, and that such action be referreS to the Board of Trustees and its Council on Health Manpower for implementation.

Ref. Ccmm. G - Page 3 °1 6 8 9 10 (3) RESOLUTION 14 - ANTI-CIG~LRZI~fE SMOK..IIG RESOI/;TI£L" 39 - CIG~2~ETTE SMOI(ING RESOLUTION 72 - SMOKING AND HEALTH: FEDERAL SUBSIDY AND tIVERTISIi~G As early as 196h, the House of Delegates of the American Medical Association pas~ed a resolution which "recognized a significant relation- ship between cigarette smoking and lung cancer and certain .other diseases," indicated that ':cigarette smoking is a serious health hazard...," and stipulated that, "programs be developed to disseminate ... health education material on the hazards of smoking to all age groups through all available mean0 of communication." 13 ~-- I- the same year the House of Delegate~ commended the es£abllshme~t~ 15 ~ of the research pr~ram (on smokin~ and health) that is being carried ~t ~ 16 b~ the ~erican Medical AssoclatlonE~ation and Re~~~at~.~~ I~ Since 19~, the House of Delegates has periodically ~ken subsequent actions 18 19 ~3 ~5 to broaden and strengthen its position with respect to smoking and health. This culminated with the adoption of Resolution 13 (C-68) on smoking and health at'the Clinical Convention in Miami in 1968. Your Reference Committee believes that Resolution 13 reflects both the intent of the current Resolutionslh~ 39, and 7~, and the testimony presented on the subject at this Convention. Accordingly your Reference Comr.ittee recommends that ~is position as set forth in Resolution 1~~ be reaffirmed ~ith one a~ditional resolve in lieu of Resolutions 14, ~9, and 72, as foll~,s: ~8 ~9 30 3~ 3~ 33 3~ 35 36 37 39 Resolved, That the American Medical Assooiation again urge Itsmem~ers to play a major role against cigarette smokiu~ by personal example and by advice regarding the health hazards of smoking; and be it further' Resolved, That the American Medical Association discourage ~moking by means of publi~ pronouncements and educational programs; and be it further Resolved, That the American Medical Association take a stFon~ ~tand against amoking by every means at its command; and be it further Resolved, That, through appropriate channels, the American ~2 Eedlcal Association indicate to the Congress of the United es ~tg'o~p~~ the e'.~enditure of taX dollars ~o 4~ /promot~e the p~oduction and sale of tobacco while at the same ~5 / time spending other tax dollars to discourage cigarette smok- ~6 ~ Ing because of its hazard to health. ~ /" Mr. Speaker, Your_Reference Committee r~commends th, _adopti~ Pf hgi ~esolut~pn_!~ as amend~. . _. ~ .... ~ ' • -# 0

AMERICAN ~{EDICAL ASSOCIAq~ION 535 NORTH DEARBORN STREET • CHICAGO, ILLINOIS 60610 ° PHONE (312) 527-1500 • TWX 910-221-0300 COMMITTEE FOR RESEARCH ON TOBACCO AND HEALTH MAURICE H. SEEVERS, M.D., Ph.D., Ann Arbor, Mich. Chairman RICHARD J. BING, M.D., Detroit, Mich. ROBERT J. HASTERLIK, M.D., Chicago, II1. JOHN B. HICKAM, Indianapolis° Ind. PAUL KOTIN, M.D., Research Triangle Park, N.C. PAUL S. LARSON, Ph.D., Richmond, Va. IRA SINGER, Ph.D., Sec{etafy February 4, 1969 Mr. H. H. Ramm Vice President and General Counsel R. J. Reynolds Tobacco Company Winston-Salem, North Carolina 27102 Dear Mr. Ramm: Enclosed are summaries of fifteen grants which have been approved by the Committee for Research on Tobacco and Health since its last meeting on December 2, 1968. Sincerely yours, sk enclosures

SUPPORTIHOAGENCYr AldAF_.ducation and Research Fo~nda~.~..o.n : . .Effecfs of N|cof.lne and Smoking on Blood Vessels Oi?~ nome~ ~po,lmtntt. e~d elficlel titlt= o| PRINCIPAL INVESTIGATORS m~d ALL OTHER PROFESSIONAL PERSONNEL enOoge¢l o~ the project. 3:~^;:~: Bevan, .Pharmeco I ogy, Professor O~=/A;~.~e de rgaa, r~d ~herma co I ogy, Ass I C.~..:~Su~~PhaFmacOIogy, Assls#.Res.Pharmacologls# . NAM( AND•ADDRESS OF INSTITUTIONt Unlverslfy of California,- 405-.tlllgard Ave., Los Angeles, California 90024. SU~4A~ OF PROPOSED WORK - (200 ~rds e, 13 ~s.) ~ In ~e Sc|~nFe In~ot;~ Exc~ge =ummorles of ~,k ;n progress ore ex¢~on0~ w;~h. ~enm~l ~d privole ~¢;e~ $~p~'ling research, ~d om tor~r~ed to investigators w~ ~eques! ~ Informot;~. Tour summery ~s to be us~ • '~de of Acfl~n of Nlcoflne on ~he S~mpafhe~l~ P~s~gan~llonlc Adrenerflc Neuron~ : Ne propose ~o ex~end our curren~ sfu~les on ~he mechanisms whereby, nlcoflne and nl¢oflne-Ilke compounds ac~ on sympathetic edrenerglc neuroeffecfor ~rans- mission In blood vessels. Nlcoflne can release noreplnephrlne (NE) from She adrenerglc nerve plexus in vascular $lssue. The main me.chan|sm for lnac~Iva- lion of NE released from fhe. nerve ~ermlnais Is a re-up~ake Into ~he neurones. The purpose of our proposed s~udy Is fo (I) elucidate fhe'mode of acflon of nlcoflne in releasing endogenous NE and (2) ~he effectof nicotine and relafed drugs on ~he up~ake-of NE. T~ese sfudles ~II! be carried ou~ on . isolafed blood, vessel preparations. Several experimental approaches will be used faking ~dvan~age of Isotopic, elec~rophy~lologlcal and classlca; pharmaco- logical fechnlques. The Silo and Origin of fhe NIco÷ln~-lnduced Vasocons+rl~or Response In lntacf Animal There ~s general agreemen~ ~ha~ smoking can cause an increase In pressure and ~o~al pe~iphera| resistance, ~nd ~ha~ nl~o~Ine probably accou~s for ~hese effects. A-I~hough I~ has been sho~n ÷ha~ nicotine h~s ac~lons ~any si~es- In ~he body, and ~he consequenc~ of e~ch action Is kno~, cular.s;~e or s.l~es affected by ~he amounts of nlcofine absorbed durln9 smokin< and ~hlch are responsible for ~he circulatory changes Is no~.esfab'llshed. series of sfudles ~lll be inl~laSed ~o de~ermlne ~he Shresho!d and response characteristics of the alkalolds a'~ these various po~en'~lal slfes of action ~o elucidate Shls problem. PROFESSIONAL SCHOOL 3~hn B~Van, ~,D. was awarded a grant .for a period of three years beginning August I, 1968 with a total budget of $161,600. The first year budBet was approved for $49,690.00.

~,:~mr,.s Ao,..CV, N~ ~ducatton ~nd Research. Found~tion -~~,Clas~'r~L~es~i~l~Phamacology and ~he B~olog~cal Disposition o~ ~ 4epo,~s, ~ ~fficiol titles ~f PRIHCIPAL INVESTIGATORS ~nd ALL OTHER PROFESSI~AL PERSONNEL ,ngo~ed ~ the p, olect, -Tetsuo Oka, H.D,, Pon~-Doc~oral ~ell~ " ::~Susan Sc~eige, H.S.; Laboratory" Techuologis~ " , - ~niv~i~y o~ MichiEau Medical School we~.t ~d p~;vo~e ~cles s~;ng ;oseorc% ~a o~o ~contrac~lle activity og the /le~ and colon o~ unanesthe~/zed do~s ~nd ~nkeys us~n~ str~iuzeze forc~ ~ransducers. The ~fects, o~ n~co~/ne rill be determined ~nd the si~ and mechanism(s) og nicotine ection v~ll be identigied by use ~ sele~t/ve and excretion o~ nicotine in the Car/C. ~lug, Jr,, Ph'D., M.D~ was awarded a grant for a period ef two years beginning February I, 1969 with a total budget, of $77,428.00. The first year budget was approved for $41,306.00.

NOT FOR PU+LICATIOm OR +P~RTING AGENCY: HOTICE OF RESEARCH PROJI'C'I' • SClF~CP. NPORY~ON BXCIIAKGg IMITN$ONIAN INST ITUYION A~A Educa¢~on a~d Research Fo~da¢ion ++~.Nicotine on cardiac transmem~rane potentlals ;,~ aDs.s, 4.portent,, +aA ~lli-.i.I ,II!.,'o1PRINOPAL INVESTiGATOrS o.~_AL~ OTHE~R PROFESSIONAL PERSONNEL ."~o0eA oa ,h+ ~,oi*ct. ~s/stant Professor • + + " " ~epar tment of AND ADDRESS OF INSTITUTIOH~ ~nLve:s~y o~ Connec~Lcu~, S~o~s,~Connec~tcu~ +,UMMARY OF PROPOSED WORK - (200 ~,d+ o, I.*ss.| .- In I.h* Sc;.en.ce 19fo,mofio~ Exch.onge s~nmories ~f '~,k in ptog,elt ore exc~o~ged with ~ovemmen! ~ p~;vole eg~cie/s~llng ~eseor~. ~d ore Io~orded to i~vesl;golo~s w~ ~e~ell lu~ In~om+oH~. You~ su~o~y Is ~ ~e ~s~ . '~"+ ~ objective o~ this zesearch p~o&ram Is the dete~imatlon of the reactivity Of Indi,/idual heart cells to nicotine and ~elated pha~acolo~Ic agents. ~croelecttode stl~Zatln& an~ recording techniques ~11 be used to monitor the alte~atlo~s In the electr~physlologlcal activity o~ slngle ~eattc+lls cause~ by nicotine. In vle~ o[ the functlonal dlffe~emces ~!splaye~ by pac~aket, con~uctlng~ and contvactlmg cells vlthln the hea=t~ this" s~udy ~iII necessarily include ~ comparative examination of th~ ~esponses. o~ these cell t~es to the al~a13Id. ~e indirect (neural) am~ dl~ect cardiac actions o[ ~Icotlme rill be stu~le~ In tvo mays: I.) 5y the use of drugs that interfere wi~h the " activity o~ the paras~pathetlc am~ sympathetic divisions of the autonomic nervous system, ~d 2.) by the use of cultured heart, cells. Since heart cells can be g~o~ as monola3"~r cultures ~evol~ of neural elements, ~rug-lm~uced effects c~n omly arise ~rom an action ~ myoca~dlal:cells. Both pscePa~er and non-pacemaker, cells vii1 be studied for reactivity to nicotine. ~icotine-lnduced chanEes Iv the electrical activity of functlonally distinct heart cells ~11 permit a dete~inatlon .of the mechanisms involved In It~ actions on the heart as yell as provide-some insight into the cellular mode o£ action of this agent. PRINCIPAL INVESTIGATOR_ 7 / U.LC~AJ.4 ,J /I 0,~/.~'+ c+.. ~ROFESSIONAL SCHOOL Unl,~erslty o.f Connecti'/c/u/~ Achilles J. Pappano, Jr., Ph.D. was awarded a grant for a period of two years beginning February I, 1969with a total budget of $36,165.00. The first year budget was approved for $19,890.00. ' 0 I%%%

NO~ FOR PUBLICATION OR PUBLICATION REFERENCE NOTICE OF RESEARCH PROJEO'I" SCIENCE INFORMATION EXCHANGI,'. SMITHSONIAN INSTITUTION tA'~tNCV SUPPORTING AGENCY: A~A F~ucation and Research Foundati, on , . TITLE OF PROJECT: Study on Mortality on. Twins in Relation to Smoking Habits. Give .crees, deportments, end ofiiclol titles of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIGqAL PERSONNEL engogecl on the prelect, Re_~sponsible inves~.i~ator: Lars Friberg, M.D., PPo~essor Co-lnves~i~tors: Rune Ceder15~, Ph.D., Associate P.ro~essor, Blrgltta Floderus, B.A., Research Assistant, NAM£ AND ADDRESS OF' INSTITUTION: • Institute o~ Hygiene, Karolinska Institute, $7104 01 Stockholm 60, Sweden SUN~ARY OF PROPOSED WORK - (200 ~rds o~ less.) - In ~he Sc;ence Information Exchange ~merle~ ~J ~k in progress ¢~e exc~on@ed whh govern~cnl end privets ogencle~ supporting reseorch, end ere Iorworded to lnvestigotort who request suck Informotlon. Your surety is to be used lOt these purposes. In 1959-61 the Institute o# Hygiene at the Karolinska Institute, Stockho!m camp{led a register comprising al] twins (same sex) born .in Sweden between 1886-1925 (about II,000 pairs). • ~ Mortality rate in smokers and non-smokers since 1960 will be studied. ' The analysis will be per?armed according to the same principles as in the earlier epidemiological studies on morbidity, as reporteW by Rune CederlS?. Thus the mortality will b'e determined separately amon~ smokers and non-smokers by selecting one twin gram each pair. The smokers and non-smokers in.thls ser~e~-~re as hetero~enous in ~enetlc and environmental gactoms as smokers and nOn-smokers in general. A second analysis evaluates mortality among smokers and non-smokers in smoking discordant twin ~airs. The latter analysis is likely to reduce diggerences in prevalence due to variables associated with smoking hat are not controlled in.the girst typQ o? analys~s. PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOlp1 " • (medical, graduate, etc.) .~ . . - Stockhol~n D~. Lars Fribe~g, M.D. was awarded a .gran~ for a period of one year beginning February 1, 1969 wlth'~ budget of ~3,30Q.00. c>

NOTIO~ OF RESEARCH PROJECT SCIENCE )NFOfit£tATIO,"! F, XCHANGE $MII HSONIAN INSTITUYION ~ FAucation ~nd_~es~ _a~.¢h. Foundat;ton

- s~.,,'~s~,s ~cv s.s~ . ' NOTIC~ OF RESEARCH PROJECT .~ssz ~o. * { ~- " " ~ '~~~"~ ....... SCIENCE INFORMA~O~ EXCHANGE .N{cotinc and Cardiac Failure ve harness, depo;Imtnts, o~cl ~,||iciol titles o| PRINCIPAL INVESTIGATORS end ALL OTHER PROFE~I(~IAL PERSONNEL cngoged ~n the p,o]ech Arthur L, Bassett, Ph. D,, Assistant Professor of Pharmacology Brian F. Hoffman, M. D,, Professor and Chairman, Department of Pharmacology AND ADDRE;$$ OF INST|TUTIOk~: College of Physicians and Surgeons of ~olumbia University 630 "~Vest 168th Street, N.ew York. New ~/'ork.10.032 " ] ~e objec~ve of ~e proposed research is to determine, by using nicotine in studies on ~e electrical and mechanlc~l characteristics of isolated mammalian heart mu~le, mechanisms responsible for changes in contractility and, in particular, the mechanisms responsible for the decreased contractility that occurs during heart failure. Preparations of cat papillary musc~ and dog atrial trabeculae will 5e obtained from normal hearts and from hearts in failure Induced by chronic pulmon~.ry artery con- striction. Portious of normal and ~iseased human myocard[um will be obtained from hmnzns undergoing open heart surgery. Several concentrations of nicotine will be added to ~e perfusate for both normal a~d fai]ed ~nimal and human myocardial preparztions. ~e length-tensiqn and force-velocity relations for these preparations will be obtained to determine if nicotine differentially affects force development by normal and failed myocar~um. ~e 1shah-tension relation and diastolic compliance wiD be examined in similarly perfused preparations during controlled s~quentizl changes in len~h; these len~h change~ will include excessive ~mounts of stretch so that optimal len~h can be deterr.~ined. These da~ will permit a comp~risou of the ~ffects of nicotine on diastolic compliance ~nd optimal !ength for normal ,~uscles ~nd may indicate if nicotine influences c~rdiac output by altering the pressure- volume relationship for the intact heart by ~ctious ~ddit~onal or separzte from its positive inotropic action, " The ~ctions of nicotine will be determined on ~ftercontr~ctions induced by cardiac ~lycosides, czlcium, low temperature and cstecholzmines normal ~nd failed muscles. Simultaneous monitorin~ of electrical and mechanical activity will a!low an analysis of whether nicotine ~cts on transmembrane potentials or mechanical "threshold' potentials. These 3~t~ may indicate i~ c~rdi~c zfter- - contractions can be affected by direct mobilization o~ intracellular calcium ~nd if aftercontr~ctions may arise from different mechanisms. PRINCIPAL INVES~IGA10R ~ ~ PR0~ESS=0~L SCHOOL College of Physicians & Surgeons A~thu~-'~i Bassett, Ph.D. was aw~rded.a grant for a period of two years beginning February I, 1969 with a total budge~ of $25,052.00. The first year budget was approved at $12,726.00.

SCIENCE INFORMA'~ON EXCHANGE |i~ITH|ON IAN iHSTiTUTtON • . ~n~, Unlver~ity of ~onnec~icut P ROF [ S~ION..~ ....... ~d~ard ~. 'He~der~n~'Ph.~D. ~as ~'~rded a grant for ~a period o~ t~o years beglnniug February 1, 1969"~i~h a ~o~al budge~ o~1,2~.00. The ~irs~ year bud~e~ ~as approved a~ ~20,30~.00.

NOTICI[ OF RESEARCH PROJECT |*~,~o. SCIENO~ INFOEMATION EXCHANGE A~A E~ueation ~nd Research Foundat.~.on The Actions of Nicotine on. ~on and Drug Hovements in Brain Slices ¢e n~ts, depe~lment|, ~d officJeJ 1;tje8 of PRINCIPAL INVESTIGATORS end ALL OTHER PROFESSt~AL PERSONN£L en0oge~ ~ t~e pro],ct, Dr. George ~. ~eiss - Depart~en~ o~ Pharmacology - Associate Professor .... 0~ ..................... Hedic~l College of Virginia, ~Icb~o~d, Vir~ta 23219 • ~he a£ms of th£s project are to delineate (a) the actions o~ nico~Ine upon ionic ~vements ~n ~he central nervous system ~CNS), ~b) the dtstrtbu~ion of n~c~t~ne in the CNS. and (c) the e££eetso~ n~co~n~ on uptake and re~ease relevant agents (eg. sero~on~n) ~n r~e C~S. Systems to be emp]oy~d ~nit£nlly are ~ bra~n slice preparations ~om 6 d~erent specific bra~n areas -- ~he cortex, the caudate nucleus, ~he hypothalamus and the reticular £orma~lon. Experiments vtll be deslgned to y£eld ~nformation concerning the relationship o~ sctZon to £on~c movements (~a22, K~2, Ca~5) and concentra££ons as ~1! actions o~ serotonln and, possibly, oth~ragents. '~ is antlclpated that an understanding o~ e~ects o£ ~lcotine upon the ~i~dl~ dist~tbution ~od movements o~ auch blologlca11~ active ami~es as se~otonl~ would p~ovtde valuabte inst~h~ ~sslble ~echanisms o~ act/o~ o~ ~tcot[~e ~ ~h~ C~S. ~ addition, characterization o£ the ~st~i~tto,~ and ~vements o£ ~co~i~e in different C~S a~eas ~oul~ t~ic~e the e~ects o~ a~a~o~tcal di~£e~ences upo~ access of ntcott~e to ce~lula~ sites o~ ~ctto~. S~GNATURE OF ~ ~ • ' (~.~cet, ~,e~ete, e,c.) Grad~a te " George ~-~" We~-Ph,D. '~as a~arded a g~--for ~a' p~r"i~ of three years beginning February I, 1969 with a total budget of $47,577.00. The ~irst year budget ~ms approved at $1.9,157.00.

HOT FOR PUBLtCA'T|ON OR PUBLICATION NO IC SCIENCE INFORMATION EXCHANGE SMITHSONIAN INSTITUTION SUPPORTtNG AGENCY: A)4A Education ~nd Research Foundation TITLE OF PROJECT: The Effect of Cigarette Smoke on Cultured lluman Per.,ipheral Blood Lymphocytes. 'Give homes, deportments, end ofliclol titles of PRINCIPAL INVESTIGATORS ond_ALL OTHER PROFESSIONAL PERSONNEL engogec~ on the project. Herbert Save1, M. D. Assistant ~Professor of Medicine "~A.E ANO^D~RESS6~ I,STITUT'O': The University of Vermont, College of Medicine, Burlington, Vermont 05401 SU~,~ARY OF PROPOSED WORK - (~0 ~rds or less.) - In the Science'lnfo~mot;on Exchon~e s~mories o~ ~k in pr£gress ore exc~ong~d with. government ohd privote ogencles supporting reseo~ch~ end o~e fo~orded to investigotors who request such Informoti~. ~our su~ow is to ~e use~ , these purposes. The over-all aim of the research is to determine the role played by immune mechanisms of the lymphocyte type in the complex rel@tlonshlp between cigarette smoking and chronic bronchitis. First will be determined the direct toxic effect of cigarette smbke upon peripheral blood lymphocytes frOm normal Indlvf~uals, non-smokers, patients with chronic bronchitis and patients with bronchogenlc carcinoma. The effect of cigarette smoke on lymphocyte Cransformatlon.will also be determined, both non-speclflc prollferatlon ,induced by phytohemagglutlnln and specific immune transformation induced by antigens such as bacteria and viruses. In addition to studying t~e direct toxic effects of cigarette smoke on lymphocyte transformatlon, an attempt Will be made to determine the incidence of lymphocyte hypersensitivity to cigarette smoke; that is, whether or not lymphocytes can be stimulated into blastlc transformation following exposure to cigarette smoke in vitro. Thus, the effect of cigarette smoke upon peripheral lymphocyte viabillty and stimulation in various clinical settings will be studied• PROFESStONAL SCHOOL (medicol, graduate, etc.) Unlverslty'of Vermont Colle~ of Medicine Herbert Savel, M.D.. was awarded a grant for a period of two years beginning May I, 1969 wlth. a total budget of $35,868.00.. The first year budget was approved at $17,170.00.

~,v~, Educat, ion and TITLE OF PRO.;ECT~ Rese~r'ch Founded.on.. _ Effects of Nicotine" on Cellular Secretory Mechanisms Sorell L. Schwartz, Ph.D. Associate Profes.,or Department of Pharr~acology Georgetown Untver~l~, Schools of Medicine and Secretion is a f~damentsl process tha~ occurs-ln.a l~rge ~rie~ of cells :tom protoz~n to mammalian origin. A ~rie~ of drags affect the secreto~ process, and amon~ them is nico~e. The secretogo~e effects of nicotine have ~en noted in ~ humber of cc~} t~s includi~ ~ose from chromaffin tissue, ~lfvary glands, the perterior pltuita~ ~nd the mucus secreting cells of the trachea. In order to study the mechanism of ~e secretogo~e activi~ of nicoth~e, ~n approach ~vJll be used ~sed on the'concept .- that secretion occurs by a pr.~cess of reverse pinoc~osls. Mouse mononuclear phagoc~e~ will be cul~red and e~sed to a non-met~oli~blc isotopic s~smncc capable of inducing pinocytosis. ~e substance of choice will be determined from a ~u~er of agents ~ble of inducing pinoc~osis, e.g., E~'A and its chelates and cotloidal .gold, ..By the use of time lapse cinemicrography, the ~fluenc8 of nicotine on both the piuocytic and reverse pinocytic processes will ~ mo~tored. Centrl~gal, electropHore~c,' chro~tograpMc techniques will ~' utilized to study'the biochemical ~re of pinosomes, secretory products, and alteration of the molecular arrangement of plasma and pinosome me,fanes. If such a model is success~I for study~g ~everse pinoc~osis, then a ~her de~crlption of cellular secreto~ processes may result. PRINCIPAL ~NVESTIGATOR PROFESSIONAL SCHOOL Sorell L, Schwartz, Ph.D. was awarde.d a grant ~or a perlod-of, one year Begtnutng February I, 1969 wLth a budget of~ $35,308.00. 50207 71 98

.I i April 3, 1970 FROM Medical News Report, a newsletter published by Bing Blasingame, reports in its March 30 issue that y Harold Margulies, MD, has been named acting director of Regional Medical Programs in HEW. This makes him, among many other things, Dr. Horn's boss. I would urge whatever steps you can take to learn what Dr. Margulies' attitudes about smoking and healthmight be. Directory information states that he graduated in 1942 from the University of Tenn. College of Medicine at ~ -Memphis, that he is 52, board certified in internal medicine, a former secretary of the AMA Council of American College of Physicians.

February 27, 1970. William W. Shlnn, Esq., Shook, Hardy, Ottman, Mitchell & Bacon, 915 Grand Avenue, Kansas City, Missouri. 64105. Dear Bill: Enclosed are summaries of eight grants which have been recently approved by the American Medical Association Committee for Research on Tobacco and Health and which were sent to me by Dr. Singer under date of February 25. S inc erely, H. H. Ramm, Vice President and General Counsel. 5020? 7200

time they are 18 years old, He h alarmed that about one million teens start amoklng for every million in the older age group~ who glve it PHS figures that teer~ager~ are spending $10 mil- lion • week on cigarettes, while the leading manu- facturers of cigarettes are buying IV advertising at the rate of $15 million a month. (Sen. War,en Magnuson, Democrat of Washington, recently pro- posed • bill seeking free time on TV for public service education about smoking and health Thls~ he told the Senate, would help combat the influence of cigarette advertising ) According to Doctor Horn, one of our blggest problems with teen-age smoking is changing the attitudes of many parents: some parents, particu- larly those who amoke themselves, feel .too late to do enything. " ~ But done, - to [or cultural, of which k ,roportlon.s to fit the He ~ays the most Import•hi concloslon is almple to determine: ~oki~ is harmful ~ ~e~ert ~cause It may cau~ ~em future di~bl~ity and ~rly ~ath. According to ~tor ~orn, =verf par- ent must im~ to the child ~¢ res~nslbifity his or ~r heahh. Addes~nts ~ould ~ aware that what ~¢y ~ can make a difleren~ ~ ~Ir hea~ as well ~s ~ o~rs who may ~l~te ~m. In ¢lementar~ and high ~s a~ over ~untry, kctures, pamphlets, and ~lms a~ut the dangers of smoking are ~ing pre~nted by the ~edcan ~n~r ~lety, ~e National ~ngre~ ~or Parents an~ ~eachers, ~e ~ublic Hea~ vi~, and o~rs. ~n after ~ ~rgeon re~ on Smokin~ and Health, ~ U.S. Bureau called a ~fer¢~¢ O~ ~n-~er# in W~h- in~ton to plan ways ~ i~ormy~ ~opl¢ l~ut ~lat~fi ~doptcd a XcDlulI~ ~a~rmIq~ ~icy ~ardi~ ~ lh~ ~hh an~ ~lled for ~orouS ~ntln~atlo0 of i~ ~asures for ~r- reCt{~ aetna; ~nt;~ ~ ~it *AMA re~gnlzed '~nd ,~at{n~, w ~nlz~~ ~leter;~, effects ~r~ra~ ~gardipg emokln~ and ~lthY -. ~n~ and Pre~l~nt .J~on have sppioved an act ~lrlng ~alth wainln~ ~'dlgarette ~.'~p narwhal agencies ha~ ~e0 ~tabl~d '~¢ ~ ~ i~okt~ pr6~e~: Sta~¢ and ~al Inter- i~e~y ~U~;ls Oh ~i~' aM ~alth havei/own "~a~dty ~r~hOu( ~e e~n,6. ~," :,. '. " • ~I#~ .~6 hp~hed by'lch~, ~mmunlty, or In- &~n&nl q~y~ t~ real a~wei~0 t~ problem ~ ~ ~ U.~. ~lldren', "~ut¢~u and ~ "tidal "~6ngh~ fo~ ~ing add Health haw pU~is~d ~lpful hlnlg f~ ~en~ ~ho want ko d~ra~e ~elr Children fr~ im~k~. NOt all "~.~U~shom ~n ~ appl e~ to' four" eMId for ~ children, none 'of them will ~ effective. But, ~nsi~rlng the lm~rtant ~ahh threat, th~ I~ons from ~ pamphlets may ~ wor~ a try: ~1 ¢ ~ exa~ple. If y~ smoke, ~y to st0~. - ]f ~ ba~ ~d and hlled, ~ frank with your . ehil~r¢~ a~ut ~at. T~II lh¢~ ~I you whh you : ~OM't~ ~at :~u h6~ ~kt ~eywltl ~ver ~et , ~k~d.*' 'And kt ~m k~ O} ~r ~at .smoki~ ~ay have .u~zrlly your life. Find an example In "Ot~, t~. ~ou~kch-ytar- ~d Imo~¢r limmy ~., for Cxamp1¢~ worshiped hlgh ~1 track liar. Jimmy'l later ~Inted out that t~ athlete w~ ~ ~osmoker. that

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THE TOBACCO INSTITUTE, INC. WASHINGTON, D. C. 20006 Wl LLIA.M K LOE:InF£R. ,,J R. VICE PNKIIDENT-PUEtlC R[I*ATION" December 3, 1968 MEMORANDUM To: From| Mr, Philip Grant Mr. Frederick ~ Haas Mr. Cyril F. ~etsko Mr. H, H, Ra~m Mr, Paul D./~mith Mr, Addlso~ Yeaman ~obacco I~.,, tt~ute/ Staff Mr, Wllllam llo~pfer~ Jr, Mr, John V, Blalock Mr, James Bowling Hr. Dan E. Provost. Ill Mr. Robert Spansler Mr. Richard Stiunette Mr. Charles B. Wade, Jr. The enclosures will help to clarify for you the smoking and health publicity which you may have noted this week from the American Medical Association meeting now in progress in M~ami Beach. The documents are a copy of a resolution offered by the Pennsylvania Group and a copy of the report to the House of Delegates, by the Reference (Resolutions) Committee. Resolutions 29 and 36 were tabled in the Co~mittee. The former, from Michigan, would have placed the American Medical Association on record in favor of prohibition of television cigarett~ advertising. The latter,, from Indiana, would have attempted to persuade doctors to give up smoking, to try to make patients quit smoking, etc. We anticipate that the House of Delegates will have given routine approval to the Committee Report today. Leonard Zahn, of Hill & Knowlton.and Jack M~lls, of the Institute Staff, are in Miami Beach and are keeping us informed. nJg O

AMERICAN MEDICAL ASSOCIATION 535 NORTH DEARBORN STREET • CHICAGO, ILLINOIS 60610 • PHONE (312) 527-1500 • TWX 910-221-0300 coomm11~E Fen HKSF.AnCN TOB,~CCO &NO IOFJII,TN MAURICE H. SEEVERS, M.D., Ph.D., Aan ~MX, Mich. RICHARD J. BING, M.O., D~oit, Mich. ROBERT J. HASTFRLIK, M.D., Chica~O, IlL JOHN B. HICKAM, M.D., h~ia~apolls, IN:L PAUL KOTIN, M.O., Remch Tllan~le Pink, N.C. PAUL $..LARSON, Ph.D., RIchalond, iRA SINGER, Ph.D., August 9, 1968 Vlce~ Presldfand Gene~_al Counsel R..~. Reym~Ids Tobacco Company Wins~-Salem, North Carolina Dear 1~. Ramm: Enclosed are summaries of ten grants which have been approved by the Coum~ttee for Research on Tobacco and Health since its last meeting on June 18, 1968. Sincerely yours, sk enclosures

NOTICE OF RESEARCH PROJECT SCIENCE iNFOP,~;A'I"ION ~.XC,,AN.GE SMITH$ONIAN INSTiTUTiON Education ar.d Research Foundation SI "-: NO. ~ AG E:N CY ~0. ~ITLE OF PROjF.CT: ~'ha se T: Pulmonary Patho-physiology in Cigarette Smoking Development of Apparatus and Replicate Studies in Normal Subjects Give names, deportments, one[ official titles of PRiNCiPAL iNVESTiGATORS and ALL OTHER PROFE$S~GNAL PERSOXNEL. engaged on the project. Samuel T. Giammona, M.D. Associate Professor Department of Pediatrics University of Miami School of Medicine Edward M. Smith, Sc.D. Assistant Professor Department of Radiology University of Miami School of Medicine NAME ANO ADDRESS OF iNSTITUTiON: University of Miami, School of Medicine ..... 1600 N.W, .iQth ~venu@,..Mi~mi, Florida 33136 SUV~ARY OF PROPOSEO WORK - (200 words or less.) - In the Science lnformatio~ Exchange summa,ies of ~,k in progress ere excSonge~ with ~overn~nt and privote agencies supporting research, and ore |o~arded to investigators who request such information. Your sugary is to be used • those purposes. The specific objectives of the present research are to investigate the diffusing capacity, dynamic regional distribution of ventilation, .regional ventilation-perfusion relationship, exercise toleraice and the reactivity of the pulmonary capilla~y bed in young smokers. In this first phase of the study completion and development of a ~ew 14 cry~tal array for collection of the ventilatiQn-perfusion data will be carried out. The incorporation of a body plethysmograph, into the pulmonary function studies for functional residual capacity and airway resistance will be completed. Ten normal subjects will be studied repeatedly during this first year to evaluation the replicability of the study and the range of variation in normal non-smokers. 'It will be essential to document the reproducibility of the studies and"the range of variability in normal~ subjects by carrying out replicate studies during this developmental phase. Data from this initial study will be used to design the experimental approach for studying groups of smokers. PROFESSIONAL SCHOOL University of_ Miami (medlcal, g,oduo,e, etc.) School. of Med~ ci ~ Samuel T. Giammona, M.D. was awarded a grant for a period of one year with a b6dget of $56,839.00. The project will beginon August I, 1968. 50207 721 2

NOTICE OF RI~SEARCH PROJECT $Ci£NCg INFORMAl]ON EXCHANGE |IdlTH$O~IAN IN STI,~ TIOK "~'O*T,.GA~.CV: .~ Education and Research Fou~d~tlon rkZ OF PRO.~mCT: Effect of Nicotine and Other Tobacco C~nstituents on. Qo2 and Electrophy31ologlcal Properties o~ the Mam~allan Neart • e ~e$, ~por~t~, ~d ~ff;clel lltlts of PRINOPAL INVESTIGA~OR~ ~ ALL OTHER PROFESS~AL PERS~EI. ~ged ~ ~* ~o~ec~. I) Kalman Greenspan, Ph.D., Dept. of Medicine, Associate Professor 2) Suzanne B. K~oebel~ M.D., Dept. of Hedlcine, Assistant Professor AND ADDR£SS OF INSTITUTIOH: ICzannert Institute of Cardlology 960Locke Street, Indianapolls, Indiana ~ae aim of the project is to study the effects of tobacco constlt~ents • (nicotine, carbon monoxlde, cyanide, thLocyanate, and arsenious oxide), upon (1) the electrophyslologlcal and contractile properties o~ the mammalian myocardlum and i~s specialized conducting tissue, and (2) the oxygen metabolls~ of the various tissues of the heart, The asents..a~ known to have bo~h an inhibitory a~ a stimulating effect on the heart. ~ ~Ho~ve=, ~he mechanl~(s) whereby these changes in metabolism and/or elec~ophyslologlcal propectles induced by these agencs~ ~uch as oicotlne, remains obscuce,, ~ attempt ~iII be mad~ to corcelace changes In metabollsz ~¢h the ~ction potential 8enecated by the cardiac ce1~.s. -. PROFE$SiOHAk ~HOOLindiaua Universit. School of Medicine Kalman G~ee~span, Ph.D. was awarded a grant £o~ a period o£ th~oe years beginning August 1, ~968 with a totsl budget ~£ $49,320.00. The approved budget £o~ the £¢~st yea= is $~5,840.00.

PUILICATION SUPPONi"IN G NOTICE 0F RESEARCH PROJECT SC[F~Cg INFORMATION r.XCHANGF. SMITHSONIAN INSTITUTION Education and Research Foundation TITL[ OF PROJECT: ....... ~,~~ehavioral Effects:of Nicotine Absorption in Utero deporlmt~t$, ond olflc;ul tides of PRINCIPAL INVESTIGATORS and ALL OTHER PROF£~i~AL PERS~EL ~ged . . .. ~ " .... :~ . Y - -.~~Pe~Lnatal S~ud~es. ~/ef Investigator. " " C.-Martin, Ph.D., Posc-Doc~oral Fell~, Center for Study of Aging and Development, and ~boratory of Pertnata~ Studies~ Co-Investigator. AND ADORES¢ OF INSTITUTiO~: Duke University Medical Center Durham, North Carolina 27706 SI.~.(ARY OF PROPOSED WORK - (260 ,,m~s or !ess.) - In ~e ~i~. In~of;~ Ex~g. swm,~;es ©! ~,,k in progre;s ore *x~Osd ~mm~l ~d pfiNle ~¢i05 lUp~nI re$lor~, ~d ore Iorward~ ~ ~vesli~tors w~ legist ~ in~ti~. Your su~o~ • ~tco~tne ¢nJecte~ o~ tnges=ed d~tlv at ~he 1~ level of 5 ~g/k~ leads ~o con~!stve episodes ~¢¢h ¢empo~a=y~, constriction of placen~al vesseIs in ~he .preg~an~ ~a¢ and ¢o the p~oduc¢ton o~ ~de~e~gh~ and u~der-develope4 ~oung a~er long ~elayed 8estaet~ as p~tously repo~¢ed by us. ~ls s~udy involves alterations in neuronal ultras~ruc~ure In brains o~ ~ an ~say of behavto= of the young ~o dete~t~e ~hethe~ nicotine treatment p~oduces steady s~ate and lea~tng ~e~tct~s as s=vere as, similar to, or dtf~ere~ ~r~ ~he ef£ec~s o~ chronic bu~ transient tn~rau~erfne hypoxia. ,Tnrse g[o~Es of young are involved: (I) Offspring of mothers getting chronic doses of nicotlue during p~egnancy and weaning; (2) Offspring of mothers subjected to I~ oxygen tensions daily during pregnancy; (3) a control untreated group of pou~g of s~ilar age. Beba~oral testing involves Skl~er boxes, Mlller-Hower boxes, and activity wheels to test effect of treatments upon:, (I) Spontaneous activity; (2) zesponses to and dlfferentlatlonb~l~een one or mote stimull; (3) sustained performance once le~ed; (4) pezseve~a~tendencies ~hen tested by interchanging cor~ec~ with previously incorrect st~u!l. -- ~Ro Frederi~ Becket, beginnlngAugust I, . ;i;i.~approved budget for SIGNATURE OF PRiNCiPAL INVESTIGATOR PROFESSIONAL SCHOOL Ph.D. was awarded a grant for a period 1968 with a total budget of $74,923.00. the first year'is $39,981.00. of two years The 5020~ "T2%~

NOTICE OF RESEARCH PROJECT 5CIF.~CE INFO~UATION EXCHAN.Gg |MITHSON IAN INSTITUTION AMA Education and Research Foundation TITLE OF PROJECT: - ..... ~' " - " - ~P~.roperties ~nd ~ocation of Nicotine-sensitive Neurones. Give n~me*; ~kpmlmenls, end ofliciel titles el PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIOHAL PERSONNEL ,n~god ~ the ~:~ ~.: .~, ,~/:1: ,~ .~ "~::" ..,. ,, ,'.: :~I';¢~Dav~d~A~-B~o~;.~,Ph; D. ,,L~ture~:..~n:~-~Ph~c oleo, (Pri.ncipal Investi gator) ," ~. A ~eseareh assLs%an% ¢o be ap~oLn~ed. NAMI AND A~RISS OF INSTITUTION: SUUMARY OF PROPOSED WORK - (200 w~rds o, less.) - i~ He Sc;~ce information Exchange ~;*s of ~,k in p~re;s ore ,x~ged e~ pu~se~ ~he VL:~* locatLon of nLcotLne-se~sitive ~eurones, ~d to identify such neurones ~ study their properties. The experiment~ ~pproaches :~ll-~be:~[firstly, to ascertain ~-~aether nicotine-sensitive neurones speclflc~ly ~c~ate ~y radloactively-labelled subst~ce which may then be used to label the neurones; snd secon~y, to identify such labelled neuroneg by autoradiography. Preliminary experiments ~ll . be ~dert~en using the superior cervical s~pathetic aud nodose ganglia as ex~ples of discrete pop~atio~s of nicotine-responsive and ~responsive nerve cells respectively. Ultimately, it is hoped to identify nicotine- responsive neurones in the central nervous system, ~d thereby provide further info~ation regarding the mech~ism of action of nicotine on the centr~ nervous system. - SIGNA'PJRE OF PRINCIPAL INVESTIGATOR. PROF ESSIOI';.AL SCHOOL (m,~dicol, g,oduol¢, *tc.I St. Barthol ome;.~' s Hosni t-~l David A. Brown, Ph.D. was awarded a grant for a period of three years beginning February I, 1969 with a total budget of $47,470., The approved budget,s, for the first year is $24,760.

NOTICE OF RESEARCH PROJECT ~,e,,o. * SCIE~CF. INFORMATIO~ EXCHANGE S~ITHI~HIAN INSTITUTION ~v ~ NO. AMA Education and Research Foundation (:-.~.~ ~-~r~,- ...... :: Effect of, chronic nicotine admlnls~ration on cholest.erol and steroid :~.~,~+:~, .... . hormone metabolls~. :~IVo.n~meN~ deF~Iments, ~nd olfici,,l l;tles ot PRINGPAL INVESTI~TORS ~d ALL OTHER PROFESSI~AL PERSONNEL ~ged ~ ~, ~iect. Do~laS'Anderson, B,S;. Ralph ~illimus, B.S. ::.~: ..:-~:'~ ,~.. - Researc~ Assistant - Research Assis~tant AND ADORESS OF INSTITUTION: Wayne State University School o~" Medicine, 1~00 Chrysler Freeway, Detroit, Michigan 48207 .~INAARY OF PROPOSED WORK - (~)0 words o. less.) - In the Sc;enc, In/~n~ot;o, E~c~g, s~o,ies of ~.k in r.o~.ess are .x~ge~ + ~1 ~d p~vote ~cies ~,;~ ~leo~. ~d om io~,d ~ bVllfigo~i ~ ll+llsl ~ ;nitric. Your s~o~ . " "~e~ ~ " "~;~, ,~.~ ~:, ~e ~se of this s~u~y Is to ex~e ~he mech~i~ of th~ nic~e induced ~,~Suc~ion" of cholesterol t~over fo~~ c~onlc nicolas ~is~ra~ion _* 8.:. ~. P~ac. & ~. ~erap. 161:~7-5~, i~8). ~e stay ~ii be carried out . ~eX ~s ~i~ed ~o a control ~o~ ~ ~ e~r~n~a~ ~o~. ~e e~er~en~al ~ogs ~ receive O.~ ~ nicotine per ~ b~y weigh~ (~ico~e 2 ~/~ O.~ N~CI), ~Jec~ed subc~eouslv ~ t~es a : An atte~pb will be made to identify the reactions in cholesterol synthesis ~hat ~ght be affected by chronic nicotine ~dministratlon. For this purpose we will examine the effect of chronic nicotine administration upon hepatic activity o~G-hydroxy-O- methyloglutary! reductase and upon the incorporation oi mewlonic-2-C acid into cholesterol. Experiments ~I~I also he carried o~ to exa~Ine the e~fect of chronic nicotine =&n~nlstratlon upon the turnover rate of steroid hormones. For this study ~e ~a~Ine the.~f~ect of chronic nicotine adm~nlstrstion upon a) the ~hcor~ora~on of .cetate-loC± into steroid hormones, ~) the ~ncorpora~on of c~olesterolo~-C steroid hormonesl~and c) the biologica~hhalf-life of exogenous steroid hormones (aldo~tero~e-4-C , hydrocortisone-4oCA , etc.). PRINCIPAL INVESTIGATOR S £gm~dur Cudb~a~aso., Ph.D / PRO~ESSIONA~SCHOOL Na~e State ~ni~ersity School o~ (medicol. 9,oduo~e, etc.) Medtc i,e S~Smundur ~u~Oj~rna~on~ 'P~:D. w~s ~w~rded a ~r~n~ ~o~ a period o~ three year~ be~innin~ ~u~us~ 1, 1~8 wi~h a ~o~1 bud~ec o~ ~8~,238.00. The epproved bud~ec ~or She ~i~s~ yea~ is $2~,117.00. ,

NOTICE: OF RE:SI='ARCH P~OJE:CT $CIF~C~ INFORMATION F.XCHA~GE ~ulIPORI'IIq@ AG[NCY: ~ F~ucation and Research Foundation "a ~u~y o't ~ne ~ctions of ~.:~cotine and Yo~cco S~oke • iT~( OF PROJ[¢T: Cerebral Autonomic Areas ~'~ich Influence ~eripheral -~-~ ............ " Ca~iovascula~ Function." Sve amet, ~m~l=, ~ olli¢i=l llft,= ot PRINOPAL INVESVIGAVOR~ =d ALL OVHER PROFE~I~AL PERSONNEL ~.. .... Le ~hazd.. Procita,, Ph;D; ,. Assoc. Prof.. Dept, ~ Pharmacology.. i'~2Alphonse 3. Ingenito, Ph.D., Assxstant Prof. Dept. Pharmacology. ::~ James P. Barrett, Ph.D., Research Associate, Dept. Pharmacology. ...¢ ,.OAOo.zSSOF'"S"xu*'o": Albany ],~edical College of Union University ::' The Proposed research applies a technique which allows for the in situ :;pe~fusion o~ the cat 5rain enclosed in a'controlled chemical enviro~ent ~but. chemically separated from the remainder of the body except for the ~:~ neural ~onnections. This technique permits us to secure a more complete separatzon of the central ~rom the peripheral actions o£ drugs which may pzoducealterations in an othelwrise stable hemodynamic situation. Hssentiallv the preparation comprises an extra-corporeally perfused brais with neuro~enic ~ontrol over the peripheral circulation of the body_ and an e~tra-corporeally perfused hind limb. This experimental approach permzts us to speci~ically investigate the actions of nicotine and tobacco smoke, when perfused through the brain, on the blood pressure and peripheral resistance in the periphery thus giving us some insight into. the central autonomic actions of these agents, if they exist. At the same time we can also determine the actiohs of the nicotine and tobacco smoke on the pressure-£1ow relationships in the cerebral circulation and also in the circulation of the hind-limb when these are perfused through the latter PRINCIPAL INVESTIGATOR - PROFESSIONAL SCHOOL " Leonard Procita, Ph.D. was awarded a grant for a period of two years beginnfng August I, 1968. The total budget is $25,0Q0 with an approved, first year budget of $]1,875.00.

NOTICE OF RESEARCH PROJECT ~IEI~C~ ~FO~M~TION EXCHANG~ AMA Education and Resea.-ch Foundation • |TL[ OF lll~ NO. ' /~/.C O.'T'/t/',~_ agents. "Effect:..of nicotine on llver function and the interaction of ~e with known hepatotoxlc Givenme~ depo"me,ts, o~d officio! titl.s of PRINCIPAL IHVESTIGA~ORS ond ALL OTHER PROFESS!~AL PERSONHEL enio~ed ~ *he p,oi.ch ~,:Gabrlel L. Plaa, Ph.D., Professo~ and Chairman V~'~tmen~ ~. of~ Pha~acology .~ ~.' . ~ac~Ity: of, ~edlclne Unlve~slty of Montreal Montreal, Que., Canada MAW[ AN{) AODR[S$ OF' IN$~TU~ION: Montreal; Que., Canada Department of Phammacology, Faculty of Medicine, University of Montreal, P.O. Box 6128, ~AJMMARY OF PROPOSED WORK - (200 w~s o, I~ss.)r In ~* Sc;~c. I.~oti~ Exoh~* ,~.mo,les of v~,k in p,og,ess o,. ¢x~9~ ~th ~mm~t ~d p~vole ~mcies supping ,eseo~n, ~a ore for,~,ded ~ investigates who #e~est su~ inl~oti~. Your su~a~ is ~ ~ us~ ~ The appll~an% ha~ b~n ~n%ezes£ed in th~ ~ffec%s of various ~hemi~al subs%anc~s on liver fu~ctlon. The majo~ pa~t of h~s research efforts has dealt ~th th~ acute hepato- toxic ~ffects of the halogenated hydrocarbons, partlcula~Xy carbon tetrachloride (CC14). Another part of hls studies has been to Investlgate the experimental prSduction of Int~a- he~tlc cholestas~s in rodents by means of alpha-naphthyllsothlocyanate (ANIT). The applicant now proposes to study the effect of nicotlne on 11ver function and the interac~ion of nlcotine ~th kno~ hepatotox!c agents. For ehe latter, attention ~11 focus on the acute flyer injury p~oduced by CC14, on the alteratl6ns in hepatic hemodynam[cs induced bY¢14~ on the acute development o£ intrahepatl~ cholestasis induced by ARIT, and on the chzonlc develo~ent of billary cirrhosis induced by ANIT. The applicant wilI use ethods which have already been developed in his laboratory for carrying out the bulk of these studies. The proposal will be divided into three parts:" i) effect o£ nicotine on 11vez function, 2) effect of n~cot[ne on ~14-induced liver injury, and 3) ~ffect of nicotine on ANIT-induced 1!vet injury. Initially, several of the~e aspects w~11 be developed slmultaneously. However, when fruitful experimental leads wit! be developed, those aspects will be studied more intensively, until ~easonable conclusions can be dravm rega~dlng the effect of nicotine on these systems. ~GNA~URE OF PRINCIPAL INVESTIGATOR. PROFESSIONAL SCHOOL (medical, g,oduote, etc,) Gabriel L. Plaa, Ph.D. ~edical Gabriel L. Plaa, Ph.D. was awarded a grant for a period of three years beginning ~ovember I, 1968 with a total budget of $48,620.00. The approved budget for the first year is $18,920.00. "

(CIGARE1$) SYDN}'.Y--DR, CO]1ER HARVEY~ PRES]DEN] OP 1HE AU$IMALIAN COUNCIL ON S~KING AND HEALIH, SAID IODAY A R~POR1 ON SMOKING BY A COMMI11EE OP WAS PARILY ~INANCED ~Y IH~ tOBACCO INDUSIRY, K~ ADD~,D ~AI ~IS ~AD B~EN ~LL KNOWN IN POR CANCER. LUNG DIS~:AS~ AND HEAR~-AXL~N]S ON CHICAGO--,'~H~ AI~RICAN I~DXCAL A$$OCIA]IeN SAI) '~OI)AY 11 HAS NO~ CXGARE~E SMOKING AN~ 1K£ INCXB~NC[ e~ LUNG CANCER** P~X~£N] OP ]~ AUSTAALIAH...COUNCXL.¢N SMOK~HG AN~ 1~ tOBACCO IN~USIRY, " CIGAREttE SMOKING AN~ ~HE INCI~ENCE @F LUNG CANCER 1~ $1U~Y O~ CIGA~1E SMOKING AN~ HEALIH, "NEI]HER OUR SCIEN]I$1~ NOR ANY O]HER~ HAVE B~EN AB~ ~0 ~ARN..E COMPLEX BlO*CHERICAL REASONS,* 7/IO**GEI I~IA "GC (Note: No newspaper references to this have been seen.)

¥ITH A~IHAL T|$$U£$o IN TH~ PA~T IrL'V Y~AI~$. :~'~/~J~AL RESE;ARCII~E$-HAVE;- BE;£N INV£STICATING- T~IE; EFI~E;CTS OF VARIOUS CHE;HICAL$ ~OUN. ~ Zl~ TH]; CA~E;OUS. PAINT OF CIGA~E'T SHOl~ - THEY NAV~ COIgC:ENTI~ATE:I~ PRIHAJtlI,¥ ON THE CII~HICAL$ INHIBITING TH~ ACTION .OF THE CILIA THE TINY HA, IRLII~ ORGANS T~T LI~ ~E BR£AT~I~ ,~ ~ACT -'T~ CILIA~ P~SE IS TO S~P OUT ~ G~N FOUN~ ~I~NC~ THAT ~ ~GAS~S W~ FEOH ~LOV T~ A~~ZCOTI~ CIGarS ~I~E;$SE;~'TI~ LUNG CELLS ABILITY TO IrlGHT CTEEIA o IN TACT OF THE CIGarS T~STE~~ ~S T~ ~ST OFF£N~R NA~E NO ¢¢~i~RAL CONCLUSIOn/ ABOUT TI~ ~OZ~S SClE~IFIC PAPAS O~ SHOKI~, THE AHA~ A~AL B~ TEE ~Y~-~S SAI~,~ P~SONALLY VAS CO~INC£~ ~T -TOBACCO SHOKING IS A SERIOUS HAZAR~ ~LTH- AN~ THAT ~OH£ ~£~IAL ACTIOn. ~$T B£ TA~N- ~ CUkB THE S~EA~ OF THE HABIT ~R C~~ E SCHUST~ O~ T~ UNIVERSITY HICEIGAN TOL~ THE CO~[~ION THAT S~£ ~UG$ ¥I~ELY I~£$CRIB£~BY PHYSICIANS TO HELP SHOXF~S QUIT HAVE ~ZTH~t -4~ £FIr£CT HAT ACTUALLY aq'. |0 44 AM [~T (zO) (zg) o. M. (~o) c. w. (ze) Bld, -26th. Flooz -- |

Etiology I.~c~rcase' or 1968 estiw.~te 1969 estimate I~ecre.'.se Total ...................... 208 $30,632s000 Office of the Scientific Director............... Solid Tu~or-Virus ..... ... C~rcino~enesis ........... Demography Contracts..... Special Virus Leukemia... Contracts.............. 268 $30,675.000 --- *$43,000 2b ~06.000 26 807.000 --- *I,000 69 1,590.000 89 i,609.000 -'- .19.000 103 I.S83.000 103 I,S98,000 --- ~IS,000 --- 6,195,000 --- 6,196,000 --- --- 1,850,000 --- l',SSl,000 --- *I.000 ~0 727,000 $0 ?32.000 --- --- 14,497,000 --- 14,497,000 ...... Introduction The Etiology area is char~ed with responsibility for the major share of the lnstitute's programmed research on cancer causation and preventions includin~ the major portion of the Special Virus Leukemia program. Its investigations extend fred the studies of cancer induction in defined human and animal populations to studies under laboratory conditions of the ftmdamental aspects of the mechanisms by which viral and chemical agents produce cancers by alterln~ the ~etabolism in living systems. Scientists are responsible not only for their individual research, but also for provision of stron~ central leadership in the concep- tualization, design, and implementation of an im~Inatlve and integrated attack upon these problems, in collaboration with other investigators in this countr~ and ebroad. Central to the Etiology area's approach is the concept of an interaction of multiple causative factors contributed by man as a host and by his environ- mant. The Demography prorrams (further described under "Biometry, epidemiology and field studies") in addition to providin~ a continuous monltorinX of cancer incidence, prevalence, end mortality rates end trends, are desil~ned to analyze defined populations having tmusual risks to specific cancers or known exposure to hi£h risk envlronnents, to reveal statistically silmificant cause-and-effect associations and dissociations leading to the discovery of etiologic factors and agents. The experimentally oriented xmits of the Etiolopy area select end combine, under carefully controlled conditions, those host and environ- mental factors which appear to be si~mificant in cancer etiology. From this point, the)' proceed to verify or deny such si~nlficance by success or failure in producing cancer in animals. It may then be seen that the synthetic approach on one hand and the analytic approachon the other ~re purposely united in the ~tiology area to complement one another.

" ~Mr. Hvt~. It has been charg_ed, Doctor, fl~at the Federal Oovern- meat has placed too much emphasis on research and not enough on medical service. Some s~y that the NI~ lo?se management of ~unds encourages people of mediocre scientific talent to pursue_careers as x~-~ea~l~ers instead of going into the care of the sick. If this is true, ~'II~ policy contributes to the shortage of health personnel. Are ~-e ~ ndi~ too much for research and not enou~'h for medical serv~ces~. . • Dr. S~wA~r. We are not spending too much for research. We are n^t s,~,~din~ enou_~h in the ed£xcation side The NIH progzams which developed over the 19~0's. and ~1960"s were a~med at develop.rag the xe~earc-h effort in the country. Since the research worl~er or t~he man ~'ho is head of a department in a medical school or something else also teaches, it has provided an overshoot of building the educational programs a~ far as it could g~_. Since the purpo~ of the pr_ogr_ am w.as ~nerer education, there was a lag of the educational effort b~hind the research development in the medica.l, schools. say that the increase of rese.~rch and the research effort caused this. " ~ anything, it kept it from happening earlier than ifwould have • States. challenge the statement on happened i~ the United ~I woul~i the loose handling of grants at 1~rIH. I think we have had su~cient ~eview by various groups who feel that our review mechanism is very Idgh caliber and assures ns that we are supporting good research. ~r~ H~ ~St year ~ve provided around tlm area of health p_ro.blems caused b~. air po_llution. ~asthere been any .improvement in this very_ serio.us mtuation ~. S~'zwA~.. There has been zmprovement because we have .h.ad the 1968 automobiles with ai_r_poll_ution devices on and they are putting out less air poll_uriah. It will ta_ke time, because the devices are re-. quired only on the 1968 c_ars and thereafter. Secondly, we have had abatement actlons--nine abatement actions---which have led td chan~es in pract_ices o~_ fuels or the use of fuels in majorcities, which is going to cut down the amount of sulfur oxides in the a~r. We have i~ad a Clean Air Act.. ' • - .~la: HvLu.Such as steel mills~ ....... Dr. ST~w,~R~. Yes. Mostly powerplants, though, in this instance,. that use fuel ~il, and coal. There are problems in the country and there are area~ in the coun.try where low sulfur fuels are not readily available. We have recognized that the teclmology of removing sulfur ~wm fuels s.o they can be used is way behind. There was a directive in the Cle.~n A~r Act of 1967 to increase our r,e~_earch particularly along the line of removal of sulfur from fuels. T~ • had a supp|emental on this, and we do have an increase in the bud.~et in here. So there is ma~or movement in attempts to do somethin~about air pollution. Mr. H~.~L. ~rh~t diseases., specifically, do you attribute or have tea-. son to believe may be attributable to air p~llution~ " Dr. STZWAnT. ~re think that air pollution is.a contributin_~ ~.actor in tl~e chronic respiratory disease are~. This is axr pollution in'the gen- eral environment, Mr. H~]|..~ am not talking about air pollution in factory where you may be using beryllium or something like this. it is " i~-~s~--~~t. ~ " " "

a contributi~tg factor. I use the word eonh'ibuting factor" because we recognize in these chronic diseases that thet'e are ~ultiple cause, and ~t a~ ~llution may not be the sole cau~ of the~. We al~ have ~a w~ch has been demonstrated iu Japat,, in ~ew Orleans, in ~adon, but this a]~ is characterized within the respiratory diseases. ~. H~.. Could you estimate what percentage of the total aunua] n~r of hcidents of each such diseases is cau~d by air pollution Dr. S~w.~ar. ~'o: you c~m~ot. ,kll you can say is that tI~e chronic ~iratorv di~a~ i~cidence and deaths are incr~sin~ very rapidly ~ the ~u~trv. ~'e do know ~'e have thesc acttte epic's w~erc there ~ an increa~d mortality over what )'otl wouldexpect. There is clini- ~I ~d epidemiologlca1 e~dence, and some laborato~ evidence on ~ ~ch leads to ~is ~ntributing factor. One can l~k at this evl- d~ce and lea~ to this contributi~g factor. I cannot quantitate it at the p~ent time. I thi~ ~z'om the public health standpoint one has to take W~t action isneces~rr, since ~'e reco~ize the~ pollutants are in- ~s~g. This action o~x-iouslv has to be-shaded with what is techni- ~lly feasible and what ~'on't destroy the eco~tomy. So one has to -~lance the actions that are taken against this, pursuing our kmowledge ~ ~pi~y as we can. ... ~~AL DIS~IO~" OF CANCER AN~ DE~AL ~RCH ~: H~. Do~tor, ~e h~re noted in the ~ast that there is a ~r ~te~ geo~hi~,~l distribution of c~ncer institutes of centers. Mo~ of t1~e~ ~nshtutes or cente~ are ]~ated in the northern part of To make the ~ttack on ~n~er ~ truly nation~I endeavor ~hat centers ~ve ~en ~tab]]shed o~-er the last year and where are they ]~ted ~Dr. S~WA~T. b~r. Hull, tlmt c~me u~ in the henrin~ ]as~ ~ear, and .. ~ere h~s ~en some action taken. It is in the justificati0n uniter C~n' ~r ~stitute and you will ~ hearing about it from Dr. Endicott or I ~ ~t the ~ustifi~tion out. • ~ There are two new institutes that are coming into being and they m ~k~g into account the geogral)hic distribution as was recognized by t~ con~mittee last.year. • . . ' - ~i H~L. Following along the same line, fou~" new denthl reseax~h ~nte~ were i~ the p~a~min~ sta~e durin~ ~hese hearings last year . Dr. S~wARr. )'es. " ~ ~ - . . - - " ~. H~ They were to be geographically dispe~ed in all parts o~flmcountrv. • ~ -~. . Dr. S~'~T. That is de~ribed in the ~ustification for the National ~itutes o~ Dental Research and you will be hearing a~ut that when they come up before your committee, as to where the locations ~r~ ]DP-N'TIFICATION 01" CO.~STITU~N~S IN CIGARETTE S.~[OKE ~'HICH CAUSE DISEASE :bit. H~t,L. I will now get into another field, Dr. Stewart. I am sure you share my concern and the concern of the members of this subcom- mittee with respect to the increasing pressures on the Federal Treasu~T. "You ~vou]d agree, ~I feel certain, theft we have a joint, obligation to de- 50207 7238

mand that we get a dollar's value for each dollar spent by'Federal agencies. Following along with this thought, last year I asked you if-any constituent had been identified in cigarette smbke since the Sur- geon General's report of 1964, that had been fo..und to be responsible ~or any human d~sease and you said you didn't know. Mv question is: Now that yea have spent another $7 million in the fi~Id of bio- medical research, can you illuminate us as to any constituent wltich can be identified as being responsible for a.n)" human disease~ _ Dr. ST~w.urr. Mr. Hull, at the present t~me, ~vhat we are doin~ is trying to identify all the con~itnents in,cigaret:te smoke and in'~he g~_seous phase which are ~rcinogenic. ~ e have a long list. of rhode ivhich are potential catches of carcinoma in hmnan beings_, and which sxs cvtotoxic ~d produce changes incells and in animals which are ¢ompah~ ~'ble with being carcinogenic. We have not identified the item in ¢~g,,trette smoke or in the gaseous phase. Iwould like also to poin: out that we are be~nning to thi~k that there may be some potentiation of .items in the cizarette smoke and items in the environment which lead to it rather than being a single ~tem. It may be a multiplicity of ~. I,~h~ink we will spend a lot more money before we have identified specific elements of ci~!rette smoke or fl~e gaseous l~U~. of the smoke as the etiological substance whid~ causes lung .ca,nc.er in , vemgs ...... - Mr. Hvx~. That leads me on to this question. Last year I inquired if there were any spec;.fic agents in cigarette smoke which could be pointed .to as the cause of lung cancer and you ~tid there ~'as not. Pre3mnablyyou have spent, a ~'eat deal of money over the pagt year in pursuit o,f,,~his elusive--if existent~agent and I ask you, Can you report that ~ ou ha~,:e finally: loc~a texl such an agent ? . -. Dr. SZ~W,tRT. ~No~ butI t.lfink that the question is not quite what the answer was. I think we have many agents in cigarette smoke which are hi_~hly~, _ p_.robable as._ heine,. ~,.the. etiological_ agent~_ of hm~_ cancer. . But ~ cannc;t ~y this specific ~tem Is ~t. " • , " Mr. Hw~. The 1964 Surgeon General's report on smoking stated, at page 3~, that nicotine was not an important health hazard a~d, at page 75, stated that nicotine probably does nol~ represent a significant health m'oblem. Last year when you were asked about this to deter- mine w~ether there hhd been an~ change in scientific thought about nicotine, you indicated that there was a re,dew beh~g conducted by the PHS of the current resehrch and that the review would be issue~l when it was completed, l~Ias the review been completed and can you now tell us if you can give us some concrete information along ~his Dr. Svzw,urr. Yes. The review is the report that was sent to the CongTess as required by law last year, which_brings up to date tl.e scientific evidence that has developed since the 1964 review. There is one interesting study reported in there which lends one to hare creases the oxygen demand of heart muscle. This is a very interesting

findings it this is so, because it could possibly link nicotine to cardio- vascular diseases. Again, I say this is just an addition. We also know that some of the _properties that cause physiolo~cal dependence on cigarettes are in the nicotine area. There has also been some research done on the enzymes which handle the nicotine in the body~ and the ability to characterize smokers and nonsmokers as havin~ different enzymes. There has been some prooress made on mcot~ne s~nce the 1964 report• I think the conclusion of the 1964 report was correct with the evidence that was available. But I think we need to pursue it a lot further in the scientific realm before we could draw any other conclusion than what was in the 1964 report. - .... ~Ix. Huz,~,. In other words, we will spend probably sereml million in an effort to establish nicotine as a he~lth ]~azard notwiths~u~ding the 1964 report? . ' :. • - . Dr. STmW, ZT. I think what we are doing is we are spending ~veral mglions to find what it is that makes cigarettes hazardous to health. In exploring, this we will be looking at the hydrocarbons, the _ea~es, the tars, and the mcotme. We am looking at a]l avenues. It seems to me with the..55,000 lung cancer deaths and a rising rate of lung cancer ., Mr. Hv~_~.. :Do you attribute that ~o smoking ? " ~ " Dr. ST~W~T. I think we attribute very much of it to smoking cigarettes. - : .... : ....'..~: ....... ~Ir. Hvz~. How much ~ .. . • ,. Dr. STew,tin'. One cannot say, but it looks, as if, from the data we haw it is the major contributing factor to the cause of lung cancer. The conclusion Of the 1964 report was that it was a cause-and-effect relationship between cigarette smoking and lung cancer. • • :.,.:. . . :...- .... ., : ~. ..:-.--0: .. . • Mr.Dr. Ste rt: last oar had infooatio t:o t.h that the l~'ational Clearlnghou~ had awarded contracts t~ot.aling o.ver half ~ million dollars ~ending people around to tryto determine what, people think about smoking_. Similar surveys have been conducted since last year's hearings. Assuming that such questions can be a productive or useful field of inqulry~ ~'h~ch I do not, can you now tell us if the PI-I~ has dlscoveredhow people feel about smokino ~ . . :Dr. Sw.wA~vr. Yes~ we have had some additional information about bow people feel about smoking,~hat was the reason for the rise in filter cigarettes. A.Iso+ much more important, and we have concentrated much more on this as to why peo~>]e smoke cigarettes. We have found that there are a variety of _types of smokers: some who are addicted~ ..me ho.a.re. psych.o.]o61cally d.ependent, some who are in a social en- v~ronmen~ where th~s is a soclal part of the picture, some who are physiologically dependent. We didnot know this before. We thought all cigarette smokers were more or less alike. The later information has broad implication.s on trying to develop programs to help cigarette smokers become nonsmokers. - -- • . ~Ir, I-Iv~. :Dr, Stewart, you have been spending all thls money try- in~ to find out what people think about smoking and what makes" thegn sn~o.ke or not smoke and. you have been. s~>~.endin¢,~, a great deal of money trying to get the American people to see things your way.

71 - Dr. S~w.~a-r. Yes; we would identify th.is a.s a hazard. If you are talking about how you protect your healtlh this is c_ertaialy one of the thinH _on wlfich we would provide information if the school sys- tem wanted to incorporate it into their curriculum. Mr. Huz,~,. If they wanted to. • .. Dr. SrzwA~. Yes. They decide on the curriculum. We do not decide on that. ~ao~r~.o. ox S~ZOKrXO " ]k[r. HULL. Don't you really believe, Doctor, that there is ~ substan- tial number of people in the American Cancer Society and conceiv- ably in your own Public Health Service who would love to see a Vol- stead Ac.t for tobacco or, failing to achieve that, at least a social climate or emotional climate created which would approve cigarette prohibi. tion~ Is that what you are getting to ~ .... Dr. Szzw~z. I cannot speak for the Cancer. SOciety, but as far as I am awara of, nobody in the PHS is talking that way. ' "" L~ICO OANOER TASK FORCE Mr. Hb'z~. Isn't it true that when you formed your lung cancer task force the people who favored prohibition strongly recommended that educational methods aimed at preparing the mental climate in this ~ountry_ for cigarette prohibition be supported in advance~ Dr. Srzw,~z. The hn_~ cancer te, sk force has come up with a pro- gram of three avenues to%'ard the problem of lung cancer. One is to motmt a research program on etiology of cancer, lung cancer. Thi_s would be a level where it would cover occupational exposures and other exposure~ to lung cancer. The second avenue is to improve the diagnosis and treatment and the.third is to pursue a less hazardous cigarette. We have now formed work groups around the three avenues and the work group on the less hazardous cigarette is meeting on March 11. Mr. HVL~. In connection with the emotional climate you and your associates are trying lo produce in this co~mtry_, I woul~l lik_'e to turn to the subject of several pamphlets which the Public Health Service has sponsored recently. " • ~ . R~P0ar O~" "OIO.kl~l"g S)gOKD,'O A-~,'I) ~re,~,I,TH CHARAC'rr, R, ISTICS~ First, let me ask you about a report called "Cigarette Smoking and Health Characteristics." You are, of course, familiar with it~ Dr. Szzw.~wr. Yes; I am. • Mr. Hv~. Is this the publication you referred to in a March 196~,, speech as a report "soon to be pfiblished" which would show the relationship of cigarette smoking to morbidity, disability, and bed- Dr. Srzw.~Rr. That is right. . . .Mr. Hr~. When was tKis report, actually published ~ . Dr. Sa-zwaRr. I have to ,,-et that for you. Mr. HVL~. ,~[av 19~7. ~'n this speech, which I believe xvas deliverdd on your behalf b)" Dr. Guthrie, you referred to such fi~res as 19 nail-

lion more chronic conditions, 300,000 extra coronary attacks, more than 1 million extra cases of peptic ulcers, et cetera; isn't that right~ Dr. ST~w~T. That is right.. _ _ _ ]Kr. Hv~.~. Isn't. it correct that you said in that speech that while you_ could not sp_y with certainty how many of the conditions represented a cause-and-effect relationship subject to reduction by reducing cig- arette smoking, the probabilfty is that the reductions would I~e tre- mendous. Dr. S~w~T. That is l~g_ht. • -M.r. Hu~. ~Vas the information collected in connection with the study then in completed form, Dr. Stewart~ .. Dr. S~wA~rr. I would have to find out. I don't kmow. ]~.r. HULL. ~ill you put that in the record ~ .-~ ! ~ ~... Dr. S~w~T. Yes ..... (The information follows :) ' . •: ~o tabular analysis was completed at the time of the speech, but because of manpower and other problems it was another ~ear before the report was ~r~s~ic~L ~ssocn~o.~ ~rr~T.~.,r c~o~r~cre s~or~so ~.-,'v v~uovs ~r~.~ Mr. Hv~., Am I correct in stating that whenthe report actually did appear it contained the following statement: The most these data can do is to demonstrate the lack of or the existence of a • elatlonshlp between cigarette smoking and ,various health characteristics; it cannot establish any existing relationshlpas a causal one~ ]~fr._HULL. I take_it what that statement means, Doctor, is that sta- tistical associations do not amount to proof of cause and effect--is that~ ~Dr. ST~W.~T. l~ot without supporting data. ~Ir. HVL~. The Public Health Service later published a pamphlet entitled "Smoking and Illness" supposed to he based on ~th~is study~ did it not~ Dr. S~w~.~r. I th_ink so; yes. ]~r. Hu~. Did the statement ~vhich I have just read appear any- where in that pamphlet ~ Dr. S~w~r. I don't lmow. ]~Ir. Hu~.~ It does not. Wouldn't you say, Dr. Stewart, that both your speech a~d the pare- pldet, which ~-as put out by the ~ational Clearinghouse for Smoking and Health, are designed to lead a person hearing t~ne speech or readin~ the pamphlet to heheve that the statistical associatlon does amount to proof of cause and effect ~ " Dr. Sr~.w~r. No !~ I do not think it was trying to do that at all. It was saying that if ~ou are a cigarette smoker t]~ese are your health characterlst~cs. If you are not a cigarette smoker these are your h~ealth characteristics. In fact, the pamphlet states: "The Pt~blic Health ~er~- ice's new study is not concerned with the medical and ~.ther reason~ why cigarette smokers are ill more often than nonsmokers, it simply esta~- |is~hes the fact." . • 0

73 Mr H~L. Now. Dr. Stewart, with resp~_ ot .to the study conducted by th~ National C~nter for Health Statistics--and which states very p~_ainly the statistical associations do not establish a causal relation- ship-t-_I'd like to ask you the following questions: 1. Is it not a fact t'hat 60 percent o] t'he information .a.bout men who had ever smoked was obtained from other people~ Isn't that a quaint way of obtaining infor..mation ~ Dr. Srew,~T. I dont see the relationship, 60 percent of the infor- mation about men. Mr. HVL~,. Pardon~ Dr. ST~.w,urr. Is the question, Where did we get the information about meu nerer smoking'.~ - Mr. Hu~,~,. Yes. Dr. Svew.~ev. There has been a multiplicity of studies. Mr. HUL~. Going to other people rather than going to the people • that smoke. Dr. Sr~w,~r. You mean going to nonsmokers ~ Mr. Hu~,~. Yes. - Dr. S,~wA~. How would we go to nonsmokers to find out l ]~Ir. Hw~,. I don't "know but you wo~ld find a way. Dr. ST~w,~az. I just don't understand your question. Mr. HvL~. Isn't it also a fact that the person being interviewed was not only charged with interpreting smoI~ing patterns but also forced "to mak_e a diagnosis with respect to such illnesses a_s sinusitis, emphy- sema, heart trouble, liver trouble, hypertension without heart involve- . ment, et cetera ? Dr. ST~WA~rr. Now you are back to the National Health Survey. Mr. Hull, I would be gla~ to provide you a series of scientific docu- ments on the sampling tecl'-'dque, the error in sampling. These have been reviewed by all tl~e sample survey designers in the United States since 1955. . Mr. HUL~. If you will. (The information follows :) ~ " " Full details of the statistical design of the Health Household-Intervlew Survey and a full discussion of methodology used in the Cigarette Smoking and Health ~haracterlstics study are found in PHS Publication 584--A2 and 1000-Series 10, No. 84. " Dr. ST~W^~T. It is true we _asked people questions_. What the National Health Survey gives you is those people that people ca.n tell you about. We know the accuracy of whether they can ~ell you this or not.. This is all published in the back of every report. We have .added to this in order to get the health characteristics of smokers. ~e used the normal health survey and added questions which found out whether people were cigarette smokers or not. The rest was all a national health survey. Mr. Hv-~. The next question I was going to ask, Have you checked to see how accurate such methods are ? If so, what did you find ~ Dr. SteWArT. There is a ~..h_ole series of publications on the meth- odologT that is used in the .N ational Health Survey which I will be ~la~l ~ supply to you. I am not competent to jt~dge on sampling Mr. HuL~. Is it correct that former smokers had higher rates than present smokers for most of the conditions reported on ~. -

Dr. S~w,urr. I would have to get the data out. I think that is cor- rect, but I am not sur~. ~Ir. HXn~L. If ~, ~'ouldn't that show statistically fltat it is not safe ~weup~mokin~ ~ . " ~r. S~w~r. ~ o; I do not thh~k it shows that at all. 3~. H~. Di~'t the report sho~r that people smoking up to one ~ck a day, and I undet~tand that ~pr~ents ~ell over half of the ~oking ~pu]ation, had no more "',dl throttle couditions" than per- . ~ns who ne~'er ~oked ~ " ~ " Dr. S~w~w. This is correct, 31r. IIull. This confirms other evi- d~ce we have that the amount you smoke is rdated to the conse- quences. ~t is why we f~l if people would mode~te their smok~g R would have a major effect on the health problem. . _ ~. H~ Did you repo~ in your pamphlet or in your speech that ~e-paok-a-day smoke~ ~ere found to s~nd fewer days ill ~n people who had never smoked ~ . .~. .. " Dr. S~w~T. I doubt it. I don't know. . " ~. H~. Doe~'t the report, by singling Out smoking, ignore the ~ct that people ~ffer in many ~'ays without ~cg~xrd for whether they ~oke or not • Dr. S~w~. ~ich re~rt; are you on the pamphlet ~ ~r. H~ Y~. D~sn't the repo~, by singling out ~oking, i~ore ~e fact that people differ ~ many ways w~thout regard to whether ~ev~okeornot~ • . . • .. . -. ~r. S~wA~. ~re ~ow that people differ in many ~-ays rega~clless o~ ~hether thgy ~oke or not. ~en you cha~cterize people on ~ltether they do mnoke or do not smoke yo~ have one set of ~ealth ~racte~sti~ among the smoke~ and one set of health characterlstics ~ong the nonsmoke~ That is what it says. " " . ~. H~. D~sn't the ~port also say that the p~mnt smol~ers who ~oke up to a pack a day had a rate of heart condition about the same ~ tho~- ~ho never smoked ~ Dr. S~w~z. That is what it said. This is our whole idea of h~w the m~leration might hare an effect on the health consequences c~arette ~oking. ~. ~lr. H~. ~ow, D~tor, ~ note in your Clea~nghouse pamphlet ~oking and illne~, ba~ed on the report which ~ have %een asI~ing you about, you refer to 7, million excess lost ~orkdays associated cigarette smokinff each year. Does that figure appear in the report~ ~m~re appears omy m the pamphlet. " - • ~[r. H~L. How was that figttre arrived at ? . Dr. S~w,x~T. ~n the NatiOnal Health Sm'vev routinely, as X said, ~l~en we ask people if lhev have a chronic condition or an acute condi- tion, ~ea~so want to kno~ the disabling consyqt~ences of it. The only measures that we can u~ which were responszve enough is .how many ~vs did you lose from work, how many days did you .have to ~vend ~d. ~% call this days of disability. ~n our characterization o~cig- arette smoke~ and n~nclgarette smokers, ~'c found this difference ~ days of disability among cigarette smol~ers and noncigarette smok-

ers. When these rates are applied to the total population i~ the work :force, age specifically, total estimates can be derived. . air. Hu~ You really mean that the fi,.aure is an estimate vrevared by the Clearing,house based on this report ~ • Dr. S~w,~T. The figure is based on the report and the report itself ¢~ates the standard deviation around the estimate which was done by the national health survey itself. . " . air. H~LL. Doctor, !sn:t it true that the same type of statistlcs iudg- meat has been emplo~ ed in preparing the justification for the Clear- inghouse request ? . " Dr. Svr-w,t~r. I do not understand the question. . " ]~[r. Hvt~. By what fi~re did you h~ve to multiply each smoker _represented in the study included in the 60 percent that were never interviewed to arrive at the figure ~ " " - . Dr. Sr~w,~. I would have to know what survey you are talking about, ]~Ir. Hull. I have o. hunch you are referring to survey method-. elegy and sampling survey tech_niques, o_n which I assure you there is a great body of literature as to how it is done. - .. • ]~fr. HV~L. Smoking a.nd illness. . .. Dr. Sv~w,~'. Is that the national health Survey~ ~ . " .. " ~Ir. Ho~-,~. In health characteristics. • Dr. S~w,te'r._This would be the sampling of the popule~tlon ~f the l:/nited S_tat..e_s, the inter_viewing techniques.under the national l',ealfl~ .,t~ey.,I.,wil.l ~et.you the metaodology wh|ch has been published on tnac ann ~ne ~ecnmques. . .... air.Hr--,. I would like it. - ..... - .. .. ~ See information p~rovided on p. 73.) " " note in the justification of the Clearinghouse that whoever wrote it could not resist the temptation to follow the Clearinghouse's tra- ditional method of exaggerating in an apparent atte.m~t to mislead the reader. For example, you talk about this report ~sued b:~ the National Center for Health Statistics which is said to show h~gher rates of disabili.ty among cigarette smokers. The justification then ~hey account for 10 percent of the ~'~ million bed days spent each year by those aged 1~' and over; 13 percent of the 2.379,000 days of restricted activity, and 19 percent of the 399 million workdays lost per year. Now, Doctor, I got the report and looked at it. I could not find a single one of those figures in it.. . Dr. Sraw,teT. Yes. That is the difference between the figures of total" bed disabilities and those of noncigarette smokers and cig~rette emokers. Mr. HvL~. MY point is_ this: I_don't think the Clearinghouse has played fair in these justifications by trying to make it avvear that its position is supported by the National Center for Health ~ati~ics, an~i by using figures that are ba~ed on a study, which admittedly doe~'t prove any cause and effect relationship bet~ sen cigarette smokin~ and disability. I would like for you to take a look at the justificatioi~ and tell me whether or not you believe it is misleading. " - Dr. ST~w,tr, r. I dont think ~t ]s m~s_leadln~,_at all~ l~.fr. Hull. The statement in the second para~'aph of the justification .is a statement of fact, that there is an associated large amount of d~sabilitv from cigarette smol~ing among the citizen.~ of the United States ak~¢l they

.76 give the figures which give the amount. One has to remember this justl- ]~cation is-based on some i,000 reports, not nece~snrily on tlds pRrtlcu- far one. An~ one staHst[cal assocmtion does not leRd to c~u~ and effect by itself, as we h~ve {alked sbout. But wheu ~ou ~ve runny, all showing the same association, then you ~g~n to wonder as ~o whether there m~ght not bo a cause, and, e~ect a~t~on. I th~nk s~ ~ ~erms o~ protecting the public's health, I do not th~nk we wa~t ~t~ we hnve every mov~ ~ hays ~ }ong h~sto~ o~ movement against c~olerR~ of move- ment ~a~n~ malarla, ~al~ pox~ R movement aga~n~eve~ other d~se~Before we h~d all the fa~ts in, w~th r~uRs. ~r. H~. That is a diffe~nt situation than tMs ~tu~tion. ~r~ I have been ~nfused about the Public Health Set,rice's ver- non oI exactly or ~ven approximately how runny smoke~ there are ~n " ~is ~t~, a fi~ which would ~em ~ have some ~ng on ~hc ~ensio~s of your task, the appropriate size of your agency, and the ~o~t of appropriations foryour antitobacco crusade. ~st y~r, when asked ~y R~r. Na.t~her if there were a~t~t 70 million ~okem~ you said : "That is close ~o~h." - " ~ the 1967 HEW ~port ~ the Con~ the fi~re of 49 million ~as u~. • " ~ a pr~ ~nference on Au~st 17, 1~7, Dr. Endi~tt ~timated that a~ut 75 million Americans ~oke c~gamtt~. . If you ~ot ~me ~fltin 25 million of how many Ame~ms do ~ok% how ~n you ~ll how martyr if any, die b~use of smoking as you have ~n doing ~ sp~h~ and li~mture this past year~ Or how ~ it a fact that this is pure ~e~timate ? .... ~. S~wA~._N%~t is not. The report on deaths is a well-developed m~ha~sm in the Unit~ Stat~ wl~ich ~me into 1~'~ I do not fl~ink there is much error in re~rting hmg cancer d~ths. We do have studi~ which show ~he amount of-error rate . ~po~ng deaths. ~ far as ~timating the number of cigarette smokem, there are multiple ~ur~s of how many cigarette smo~e~there are. The Depa~- merit of Agriculture puts out a report on t.hi~. ~e toba~o indu~ pu~ out fi~ms. We get fi~res from flint type of ~rvey. There is vana~on dependm~ on how fl~e surveys are carried out. The 70 mflhon fi~e was used in the 1964 Surgeon Gener~d's repo~ ~d ~cludes ~fl~ adults and teenagem, and cigar and pipe ~okem ~s well as cig~%- ~tte ~oke~ Mr. H~.. Doctor, I am sure you are familiar with the pamphlet entitled "The Facts About Smokin_a and Health" publishdd by the :National Clearinghouse for Smokin~ and I~Iealth. Dr. Svzw,~T. Yes. :~fr.:I-I~. lqow much did this publication cost~ I)r. Svzw.~T. I will have to get that for you, 0

• ¢HILDREH'S 8UR[AU PUSLIC~.TIO~i$ .o. .: ... ; F-tsca,~l~outar 1.~j~: " " " .' " *' ~" " Can Quit Smokln;°'. .......... .: .................... ~hy Ni~ ~e Ci~aret(~ is U~ht on ~e $ubj~t o~ Smokinl". ..................... ytar 1967: , " ~o~inl Health and You". ............................. kit o~ S pub~at~ns: • . • ~O SmokinK". .................................... ' Ho~# a~ut the ki~ ................................. I,~, ~ni People Who Smoke". ............................ ~t y~arlS6S: ,, kit ol 5 publications: "No Smoklni ......... ......... " T~I .................................................................... • - ~13ZE ]:ILEAL'I~ C0~'SEQU'E~C£$ OF 63[OKI~'0" " ' 3It. ~L. ~is is supposed to be e summ~ of the information ~other PHS publicat~%n, "The Health ~nse'quenc~ of Smoking." Do yod f~ this pamphlet is aa accu~te summa~ of that larger ~ublication; - - " "~.'.. - ".- . .: Dr. S~w~. I thi~ ~, y~. " ' " .... " ....... ~. H~. Do you t~nk the larger publication is en a~umte apprai- ~l of ~e cur~nt s~te of ku'owle~ge on smokiug and health ~ Dr. S~W~T. I do not think there]s any question a~ut it. - • ~. H~. ~o actually did the ~view of re~amh pr~ei;ted ~e H~lth ~n~quen~ of Smoking," Dr. Stewart ~ " .- Dr. S~w~. T~ w~ done by our staff. " • -.- . F~t let me ~ve the histo~ behind this. ~en the La~.lin~ Act w~ ~ for ~iga~tt~ them w~s a ~qui~ment,that.the Sec~eta~T of ~W ~po~ ~ Gonads_on the scientific ~udies that ~ave been done ~n~ the 19~ report, and the health ~n~uenc~ was this t~port. The ~icl~ ~em put ~ summa~ fo~ and reviewed by the staff ~d then ~viewed by a m~ber of experts, including some ofthdmem- ~ of the 196~ ex~ ~mmittec t~at pmdu~d the 19~ report. All ~e mem~m of the 19~ committee rev;ew~ the draft of the report ~at went to ~n~e~, and all agreed that it w~ a continuation in a • ~ of the 19~ repo~, bring~g ~t up to date. ~ 3It. H~. How active were fl;e mem~ of the 19~ Surgeon Ge~- eml's Ad~sory ~m~tte~ on Smoking and Health f Did they actually pa~icip~te in the ~view of the papem you cite in this publi~atioa Dr. S~W~T. That I ~nnot ~ay. I d~n't know. I know they all re- newed the repo~. ~fr. H~L. Would you put it in the record? " Dr. S~eW~T. ~ainly.. ... _ : ..-.. : • (The infom~ation follows .) .. Some of ~e members of the 1~ expert commltt~ particlpat~ In parts cf the 1~7 review, one pa~lclpated In the entire review, and all review~ the draft of the re~ before It went to Congress. 3It. H~. Would you say the final res, onsibility w~ for the tional Clearinghou~ ~or Smoking and Health ~ Did they actually pa~icipate]n the re~.iew of the papem you cite ~ this publication ~

Dr. $~w.~. That I did not say. I don't know. I know they reviewecl the report itself. Mr. H~L. Would you put it in the record ~ Dr. S~zw-~T. Certainly ..... -: ' " - (The information follows :) • : " -- " - : Members of the staff of the Clearinghouse participated In the rerlew." ~blr. Hb'L~,. Would you say the final responsibility was for the National Clearinghouse for Smoking and Health ? Dr. S~'zw.~. That is where it was charged; yes. ]~Ir. Hv~. Doctor, I would like to ask you some que~ions about this ~-called factual pamphlet. ~Vould you agree, first of all, that the pamphlet i_~nores a number of studies which do not support the ofllcia] PHS pos~tion on smoking and disease ~. Dr. S~w.~T. ~'o; it does not i~mre studies. - Mr. H~LL. IS it not also a fact, Do_trot, that_you have selected por- tions of cert,~in studies to_ report on the pamphlet and collected other conclusions not in accord w~th-your theories contained in the same studles~ Dr. S~'~w.~,,z. ~Ve have selected~ but not on the bas~s that you are statin_~. " • ~[r.'~I-IvL~ I refer specifically to the Swedish studies of smoking a.n~ nonsmoki,n~ twins ~vhich conclude that constitutional factors r~ther than mnok~ng practices account for coronary heart disease patterns in the twins. - .. Dr. S~r-w~T. ~[r. Hull, we have never said there was definitive proof of a cause-and-effect relationship between coronary heart disease and cigarette stooling. ~Ve said there ~s statistica| association and other evi- dence that warrant Public H_ealth ~ction on cigarettes. I will be glad to have a scientific review of that Swedish study and our reaction to (The informatio.n follows :) As stated in "The Health Consequences of Smoking": "One study of a small pOl~.uhtion of twins in Sweden, as reported by Ltmdman, suggests that smoking monozygotic twIa~ tend to have lower cholesterol levels than their nonsmoking control twins, although the difl'erence~ are not statistically significant." ~'- ~[r. HuL~. I ~vould continue, is it not a fact that you made no refer~ ence in your pamphlet to t_he coronary heart disease findings although .the studies are mentioned in connection ~vith respii'atory diseases~ Dr. Sr~w~r,T. We did not make reference in the pamphlet but it was referred to m detail m the full document, "The Health Consequences of Smoking," which reflects our scientific judg~uent on that article. ~[r. HUL'~. Is it not also a fact that even on relying on material pre- viously published by the PHS you have careen|Iv om~tted any ing material--as you ~id in references to the illhess.and disability port issued in May 196~ ~ " - .. . " • :Dr. S~w-~r. No; we haven't.. • , " --- ~IO~:Ik~°G ~,~'D E31:PIIYSEMA Mr. Hu~.u. Let me glve you another example of omitting language ~-hich is not in accord witt~ theories you are pushing. In th~'~ you :'ef~r to ~aol-~ing and emphysema. Let me ask you ~vhether or not you would 92-6S~----6S--pt. ~------6

.8O say it has been scientifically proved that cigarette smoking is the cau~ of pulmonary emphysema~ • Dr. Sxr-wAwr. Did you say scientifically proved, to be the bause of emphysema ~ . Mr. HVL~.. That is what you are t~ing to prove w~th th~ others. Dr. S~w~z. I am ~y~g the ~ientists reviewed all the scientific Hteraturo in 19~ and came up with a cause-and-effect relationshi~ ~tween ci~a~tte smoking and lung cancer. They had ~es, e~physem~ ~clu-ded~ peptic ulcer, urina~ cancer, and other thin~ in ~I~ch they said there was a strong a~ociation or relation- ship wMch they co~d not identi~ as cause-and-effect relatio~hip. Their total ~nclusion was that i~ you add all this together includ- ~g the cause and effect, that this is a public health problem of suffi- cient ma~tude~ and that prompt remedial action fs required. Mr. H~. Is ~t not ~ fact in the study referr~ to in fins pamphlet on ~e health con~uences o~ smoking, £he fl~t statement is made that until some mechamsm sho~ng ~hat smoking Caus~ emphysem~ is di~overed, it ~ot be said t~at smokin~ is the ~u~ ~. S~w~T. Yes, I just finished s~g ~t. " ~Ir. H~. I wantedyou to s~y it a~ain .... Dr. S~w~T. I ~idwe have not~een able to ~t~blish an ~bsolute ~u~ ~nd eff~t. -, • Mr. H~. You use it, though; don't you ? . . ~. S~w~. I fl~ought I was ~ying just what you said.: ~sz ~ ~ ~z~oxsme ~sz~zzx cm,~s~ s~o~xo . ~ DISUSE " Mr. H~. You my.in the pamphlet that them a~ no longer any qu~tions berg asked a~ut ~hether cigaret~ smo~g ca~s ~i~ase; ~thatcorr~t~ • - : " - ~. Szsw~. I thi~ flint is trite. " " .': •. " " Mr. H~. Do~ this mean there is no research going on ~ tMs ~vernment ~ de~e the ca~ or ~us~ of di~.~at yon have linked with cigarette ~ok~g ? Dr. S~w~T. It ~oes not. I am saying that the debate over whether cigarettes are hazardous to 'health or not h~ ~en ~ttled. How much era hazard and what is ca~g it requir~ ~ ~eat d~l of re,arch. Mr. H~. D~tor, im~ it tree that them am ~ientifio ~ople ask- ing que~ions and that they are asking if ci~ar~tes cause Dr. S~wA~. There are some p~ple wh% raise that qu~tion, yes. ~. H~. ~e statement ~ this leaflet is ~u~ not true, v~. Dr. STzw~. I do not ~ow what you are gay~g about the ~atement. Mr. H~. About the scientific people asking questions. " ~. S~w~. There are always ~me people who raise qu~tions. Mr. H~. You seem to my there are stil[questions with respect to the ma~er in which cigarettes cause or speed the cause of disea~. ~ that m~n that you~ave concluded that cigarette smoking ~u~s di~ but you do not ~ow how ? . . Dr. S~wA~. I am saving that t]~ere is a cause-and-effect relationship betw~n cigarette smoking and hmg cancer. If one decreases the amount of cigarette ~oklng ~ a population ~oup, the amount of

.81 lung cancer decreases. I am saying .that we can take action through just stopping smoking cigarettes and decrease the amount of lung can- car. I am not saying that we know what it is within the constituent smoke .... . • - Mr. Hrr,~L. How do you Imow it will stop lung cancer, if you were to quit smelting ~ Dr. ST~W.~RT. I would be very happy to provide the study of British physicians. In fact~ this was one of the mc~-t interesting new findings in the 1967 report. , • • • Mr. HU~L.'In other words, you say that • question remains as to the amount of death .and disability .which could be prevented if people had . zmt smoked or if they gave it up Dr. Sz-zwA~rr. That ~s correct. " Mr. HULL. Does that mean that you have concluded that smoking does cause death and disability but thatyou don't know how much? Dr. STzwa~rr. I do not think there ~s any question that cigarette " smoking causes lun~ ~ncer-which is 95 percent ~ata!. major portion of it-but not all of it. We]mow that some nonsmokers get lung cancer and we know many hcavy smokers never get lung ~ancer. • Mx. Hu~. You are looking at one. Aren't we l~ft with this, you don't know how the disease is caused Dr, STI~WART. ~To, sir. " ~. :': ' " ' " Mr. HV~L. You do not know ho~" much d~sease is being caused but yo.u _still say that th~ q,u~tion being asked today no longer includes ~hether or not cigarettes ~ause dlsease? " . " Dr. SZ~WA~T. l~do not think there is any question that cigarette smok- in~ is causin_~ adverse health reactions ~n people, and is causing lung cancer. I thi~k the other questions which-ar~ researchable questions are unrelated to whether one takes action to protect the publicfs health. Mr. Hv~. At the bottom of page I you say the cigarette smokers tend to die at earlier ages and experience more days of disability than ' comparable nonsmolcers? : • Dr. S~.w,~T. That is correct. " Mr. Hv~L. How can you be sure that a cigarette smoker is compar- ~ble to a nonsmoker in all respects except hi~ cigarette smoking? Dr. Sz~w.~wr. That was not the purpose of tl~is report. This report . says that in people who are characterized by whether they do or do not smoke cigarettes---- - • Mr. l=Iw~z,. You are comparing them ;.aren't you ~ " " .- Dr. ST~ws~,T. No, sir. We are reporting what we found in these two population groups. Mr. Hvz,L. By the very nature you are comparing them. Dr. Sz~w^~r. The ohlv question around the facts is the range of ~rror around the fact itself. - We have said that in cigarette smokers here are the health charac- teristics and in noncigarette smokers here are the health character- istlcs. These are the facts. Mr. Hv~. Are you not familiar with the following statement which .appears in the study on cigarette smoking and heal-th characteristics m discussing possible explanations for a statistical relationship~ ~Some third factor, possibly psychol.ogic or biologic~ is causing both the condition and the smok~ t~, habit ~ "

Dr. S~zwA~rr. Pardon, some third factor is causlng~ ]~Ir. Hv~,. Possible psychologic or biolo~c condition other than the ~okqng habit. Doesn't that say in fact that ~okem may not ~ compa~le to nonsmokers in all r~pects ~ • Dr. S~wAsT. Except those things which ~pa~te ci~tte smoke~ ~om non~oke~ may be separating more su~eptible ~ople to le~ ~ptible people. ~re know so~e d~tt~ smokers do no~ get lun~ ~n~r. This is not peculiar to disease in this pa~i~lar age~t,. Th~s ~ ~e ~ all disease. • - Mr. H~. On page 2 of the pamphlet there is this ~atemont~ it w~ro not for eiga~tte smoking a ~r~ion of the e~rlier de~xths of mentm~nD~or,~r~~t'g~n would not have ~eurt~d." What d~s that state- Dr. S~w~T. We are saying that tho~ who a~ ci~rette smoke~ have a l~rge .inc~l risk ~ cardiovascular di~a~. I~ xhev were non-cigarette-smoke~ they would have 1~ risk to ~rdior~scuIar di~. We ~nnot quanti~, how much the~ would ~. '" " "~O~ $}[0KI~'O A~'D CA~IOVA$C~AR DISE;~E ~. Hv~. D~ this mean that ciga~tte smoking ~s orin some w~y ~ ~ntial to the derelopment ol~rdiora~ular di~ase? Dr. S~wa~. No, sir. Among cigarette sm~e~ the ~sk o~ death ~m ~ova~ular dis~se is g~ater than if ~ ou a~ a non-ci~rette- ~. H~. On page 10 there is ~hls ~atement: --In 1~ ad~flonal e~dence ~lnted even more strongly ~var~ clgareRe ~o~ng as s ~use o[ death Item corona~ heart disease. ~y~D~tor, is this so phras~d ~ :" :" ' " Dr. S~wA~. The studi~ that h~tve ~en ~viewed from the I964 ~ the 1967 ~port stren~hen, I think, the feeling that there i~ ~ rela- tionship, but ~t ~ill does not pro~'ide us with cause and effect., Rs w~ ~ying. I~ you have one epidemiological study and you have as a~ociat~on, you cannot make any cause-and-effect relationships on ~at one study. But if you ~n ~petitively have ~udi~, if the~ is not an ~eiation one woul~ th~nR tht~ug~t random distribution you wo~d eventually get a distribution in the other dilation and you do not get it. ~is is a phenomenon in epldemiolo~ called convergence. Mr. H~ ~y say evidence point~ more strongly to cig~xrette ~o~ng as a ~use~ ~y not say "Evidence prow that smoking ~us~rifthat isyour position ~ - " - • - Dr. S~wa~. The added data, ~cause el studies that had been go- ng on a~ong veterans, the stu~ in Canada, the studies ~ England, some el the dat~ on nicotine and the heart oxygen demand, and a law other studies, all-fit into a pattern el it ~g a cau~ and effect~ but not enough yet. ~ " • Mr. ~ Isn't it a fact that il ~e evidence justified a statement o~ direct causality, you would, have made an.unequiv~al statement

• ! ~[r. Hw.~. Isn't it a fact that the evidence is too inconclusive at this l~oint that you cannot say "causerie" and are forced to use uncertain ~hrases ~ Dr. SZ~W.~RT. Mr. Hull, we have never said cause and effect to the initiation of cardiovascular disease, never once since 1955 when the ~ports started. ~ e have said that the evidence keeps accumulatin~ that makes the association stronger and stronger. Someday we get the key evidence. All the evidence points toward it, but I do not ~hink one can make the statement that (he scientific evidence supports it. We never have. .. • . • Mr. Ht-L~. ~'hat ~ the ~fference ~tween thee t~o phrase: (1) ~Cigarette smoking is a major cause~f * * *"; (2) "Cig~ret~ sm~: ~g * * * greatly ~creases the r~k of dy~g from * * *"~ • Dr. S~w~. Cigarette smoking, a cause-and-effect relationship, says ~at this pr~e~ of cigarette smo~g ~ causally related to a d~a~. lung cancer. Now to move to another picture, ~f~ou divide people int~ ¢~re~e smo~e~ ~ne r]s~s ~rom having cardiovascular disease is n~r thnes higher than among no~mokers. They are two different ~atement~ Mr. Hr~ Doctor, what does tl~s mean: "Cigarette-smok~g-relat~ ~sease" ~ Dr. S~w~. That is the assoc]ation. Mr. H~. D~s this me~ that ~sease ~ caused by cigarette - ~. ~W~T. NO; ~e are saying the risk of t~s disease is higher among cigarette smokers than nonsmokers. . .. ~[r. H~L~. How about ".~ ass~iation exists ~tween cigarette ~ok~ and..." ~ D~s this mean "caused" ~ . . Dr. S~T. No, it d~ not mean cause and effect. It means ~igh]y associated and the risk of having this disease if you are a c]ga- ~tte smoker is much higher than if you are a nonsmoker. • Mr. H~. How about "diseases'strongly li~ing ~ith cigarette ~okin~," d~s they mean caused ~ Dr. ~W~T. No; this means that the risk is much higher than thee that ere c~garette smokers and ~e ]mre more and more evidence which is moving toward po~]ble cause. • Mr. H~. "The relationship between cigarette stooling and"--does this mean caused ~ Dr. S~w~r. No; this means that the r]s]~ from t.he~ diseases higher among cigarette smokers than noncigarette smokers. If you are a cigarette smoker, you car~ this Hsk. . Mr. H~L. So in fa~t, Dr. Stewart, ~e shoul~ ~ssume you mean Ucaused" only ~hen you actually say "caused," isn't that co~ect ~ . Dr. S~W~T. That is correct. ~Ir HVL~ Dr Stewart. on na~e ~ of this pamphlet you describe a ~e~t ]ncrea~ in the per capita consumption of cigarettes since 1900 Dr. S~w,~w. That is correct.

" : "-- + • ..~ +~, :. - ~ESPI,RA"/ORY DISEASES ". ..-o! ]~h'. H~u,. ~ou ~hen refe~ to a substantial ~crease ~ cer{aln rem- ]~to~,ise~se~ ~ " p • • .... ~..~ Dr. w~r. That is ~rr~t. /'. ... : ..- ~r. H~. Is it no~ a fact tha~ respirato~ di~ases as a whole have d~l~ed sub~antially since lfl00 ~ , ... :. Dr. S~wa~. Ce~ainly. . ' " ~ " . ~fr. H~. %'ould you put some figure in the r~ord on the total att- ar of deat~ from res~ratory disea~s in 19~ per 100,000 as com- pared with the most recent year for ~hich Can you do fltat~ • : • . ~ " Dr. S~w~. I will pro~de you with the death rates for 1900 and 1965. (The ~formation follows:) "" ";'~ Tuberculosls ~! the res;)iretory Wstem ..................... ; ......... . " = 174.5 " tg Di~ases ol ~e res~ir~to~ ~s~em. i~ludin= Influtnza and exclu~in~ " ~ma and di~ases of ~ thyroid ................................ ~E.S .-JL~ s Federal Securffy .A.~e ncy. U.S. Public He:~Ith Servi,:e. Nalional O,~¢e of Vital Statistics. Vital stat;stics rates in the Un~'ta¢l St~,tes 1900-40, Wa~m~iton~ Government Pcinfin80ASce, 1947. . " - a U.S. Public Haalb5 Serwce. Vi~al staUstics of the United States 1965, v. II, Washington, Governmtnt Printing O~'ice, °Because ol chan2es in de~n~ons and co~n| procedures it b i~p~ssible to quanU~y t~e exact deiree Of comparab~ity ~ these c~,togories. . • . ..... . . . . .. .... - . . ,- ; -. r.-~,.. ~Ir. Hw~,. You refer to an increase in hmg cancer. I wotfld appre- ciate your furnishh~g usinformatlon showing ~lle relationship) be- twee~ the nmnber of hmg cancers in men in 1930 as compared to • women~ and also information with regard to smoking p~ctices be- twee~t men and ~-omen in 1930. " " " ~ ". ...,: " ~here are no data available that give the detailed statlsUes the smoking habits of men and women lu 1930. ~[r. Hv-~. I understand that the ratio of lung ~mcer in males to females ~v~;s 1.5 to 1 in 19~0 and .t~hat it has been reported as steadily increasing to about 6 to 1 today~is that your understanding~ Dr. Sww~. Yes. I ,~-ould'like to point out~ though, that the rate of lung cancer among women has-gone.up 50.porcent.

Mr. Hu~-~..Also I have the impression that the ratio of male to :[emale smokers has been goin_~ the other way; that is~ a greater pro- ~ion of women have ~oke~ h ~ch d~ado ~nco 1930 than mnoked at tl mt t hte. Dr. ~w~. That ~ ~r~t. ~[r. H~. You ~ght include a sho~ expl~at[on~ ~ you care ~ ~vo it now, con~m~g the apparent ~co~istenoy ~ the ~oking ~d lung ~ncer tl~o~" ~. ~. S~w.~. ~ o ~toat think there is any inconsistency. Relatively few women in the ago ~oup wMch di~ of lun~ cancer have beea ~oking cigarettes hearty enough or long enou~ to ~ affected in • e large num~m that men are. - - - • " ~. H~. Woul~'t you ag~e that a,g~d deal of the increase ~ ~nyer ~ due ~ ~proved di~aos~s and a~g ~pulation and mcm~ m poptd~ioa ? • . Dr. S~w,~. ~ o, sir. I tM~ we ha~e ~own how .to diocese lung ~nc~r since 1950 and yet we have ha~ two and a half tim~ increase ~ l~g~n~r. I do not t~k a~ng of the pop,orion has anyth~g to do wit~ it. The ~pulation ~om ~curred in 19~6, which m~ ~ave is 92 yearn of age. Yet we have had a ~nsistent inc~ of hmg ~ncer s~ce 1950. I tM~ I can ~t you ~e age sp~c m~ wldch would neutralize the a~e ~ulation ~om the ~mb~ed re~lts of the s~es ~ewed by i~ mem~rs, the Ad- ~ ~itt~ ~nclud~ that to~ ~e is causally related to ~e follow- ~g four ~s: ~cer of the lung, ~n~r of the larynx, ~ncer of ~e Hp, and ~ronic b~onchitis. The epldemiologIc meth~ ~upl~ with clini~l and labora- to~ ~servations provld~ the basts for ~ese fo~ ~ncluslons. Cigarette smoking Is causally related to l~g cancer In men ~ the ma~itude of ~e effect of cigarette smoking far outweighs all other factors. The da~ for women, though le~ extenslve, ~Int In ~e ~e ~re~lomz •otaI mortaIi~y tr~d.~The death ~te for ~n~r of the l~g (international ~st n~m 162 ~d 1~) almost doubl~ ~tw~n 1950 (12.2 deat~ ~r 1~.0~ ~pulation) and 19~ (24) deaths ~r 1~,~). Not much of this rise could be a~b~ted to the ~angi~g age ~m~sition of the ~pulatlon. ~e ~r~nding ageadJusted rate likewise almost doubled (11.1 deaths per 1~,~ for 1950 and ~.7 deaths for 1~. table 2). The annual humor of deaths from lung cancer ~ from 18.313 deaths in 19~ to 45,~ In 1~. In this l~year ~od deaths ~ lung ~ncer to~l~ approximately a half minion (467,~2 death). • Public Health Service : "Smoking and Health," report of the Advisory Committee to the Surgeon General of the Public Health Service. PHSPub. ,~o. 1103, Washington, Government Printing O~ce, 196~, p.

an~ 1~ mor~Hty trom lung cance~ omong w~te women more than doubl~ ~e age groups ~ to ~ years on~ 43 to ~4 years (~b~e 2). ~be g~otest ~rcentoge ~cr~se orer ~ls l~yea~ ~od (116 ~cen~) ~os fo~ ~e oge ~oup ~ to ~ea~ For su~diu~ age ~o~ps ~e relative in~rease lessen~--amo~t~n; to o~y 13 ~rcent at ages T5 to ~ years. The ~mmlttee suggested that these ~x d~erentia~ may ~ attributable to ~fferences In length ot exposure to one or more factors related to lung cancer. Uu~ke the ~ttern f~r me~t. the death rate for cancer o~ the lung among women ~ years ~d orer ro~ steadily with advance ~ age for each year of the perlod 1~ (~ble 2). The female cohort ex~rlence shows ~at the death rates ~or ~n~r ot ~e lm~g increased for ~e cohort to the end of ~e ~fe ~an (fig. 3). ~e st~puess o~ the mortality curves shows that morality f~om l~g cancer a~ ro~ more rapidly In more recently born female cohorts. ~he cohort approach ~hows ~rger rises in mortality from lung cancer ~tween successire female co- ho~s born after World War I (cohorts B, C, and A) than the corres~nding rises ~n coho~ ~rn earlier. Mr. H~ Y~.:~er ~ pag~ ~-ancl~3 of the pan~pl~t to substa~- tial ~c~ ~ deaths from chronic bronchitis and emphysema. Woul~'t you a~'~ that a g~d deal of this ~c~ represe~ts p~ved diagnosis and changes in fl~e reporting of the ~ o~ death ~. S~w~T. I thi~.there is ~roba~ly ~me increase he~'e bemuse of the change in diamonds. Emphysema is a little more all,cult • ug~ that~ lu~g cancer and t.l~ere ~uld be ~e~ and the~e has been ~e, ~provement. . " For exuml)le, the rise in devths from 4,0~ to 23,000 from emphy~ma ~ a fe~ yea~ refle~s more titan just a change ~ dia~tic pattc~s. ~. H~. ~is cow, tree in its re~ort l~t y~r noted that 3 years ago additional funds ~e~ made available by Con~'~ for research ~physema ~ that the ~n~itute ~as a~]e ~ Iaunch a number of ~ant-supported projects. It ~as hoped that these ~search projects wo~d sh~ light on the cause of tl~ disease emp~y~ma and its mys- ~rious incense ~ recent years. ~ut informat~o~ do you -have to repo~ tl~s ~ar on the progr~ that is ~ing m~d~ to di~over~tl~e ~u~ or ~uses of emphy~ma~ .. . Dr. S~w~T. I ~o~]d]~ave to get that for you. " Mr. H~. If you ~o~d for the r~rd. (The information follows:) . " . .~he PHS f~l ~lut for research on emphysema ~esldes with the National Institutes of Health. A detailed report on research progress sup~rted by the National Institute of AHergy and Infamous Diseases has been forwarded this ~mndttee. Further details may be discussed ~lth ~e Institute Dlr~tor, when he testifies. We stilt do not know pr~lsely the cause or ~uses of emphysen~a but there Is a major epidemiological evidence from several sources of an ass~la- finn ~tween emphysema and cigarette smoking. ~his evidence continues to sup- ~rt the ~ncluslon of ~e 19~ re~ to the Surgeon General that "the doutinant a~latiou In the United States Is between ciga~ette smoklug and chronic respira- ~ry diseases." ~s ~cludes emphysema. As stated In the ~967 ~port on "The Health Consequences of Cigarette Smoking": "The observation that other prob- able ~uses of p~monary emphysema may exist should not detract from the strong tela~o~p that has been shown to exist between cigare~e ~oklng and emphysema."

93 3It. H~. On page 3 of the pamphlet there is a ~ctioa titled "~al Experiments." Dr. ~r~w.~nT. That is correct.. 3It. 1Ic~. Iu that. you ~fer to animals having been expo~d to to, coo smoke and chemical compounds contained ~ smoke. Are you ~tually spealfing there of i~mlat.ion studi~ or are th~ the mouse- p~tm_ experiments ~ Dr. ~w.~v. These are sevend different kinds of studi~ including ~alation studies and skin-painting studies. " ~. H~. ~en ~ou refer to com~ounds being cancer produclng~ a~n't ~ou ~llv sa*'m~ that ~ah ~m~o~ds painted on the bac~s of ~ h~ve ~used cancer ~. S~W~T. They cause ~n~r.~ snlm~ls. " " . . It ~uld ~ throuff~ ~ainting, it could be t~ough ing~tmn, ~t ~uld ~ ~ugh ~ new ~o~:ement ~Ir. H~. You am familiar with the French study by Lazar and othe~ ~dicathg that one of fl~e ~mpounds to wldch I am sure you ~fer~ Benzpyrene, is not p~ent h s~¢ient amouuts to. account for ~ot~orsinanimals? " ~ . Dr. S~w~v. I would have to get the judgment on that. I just don't ~ow. • ~. H~. ~rould you a~e that mo~ investigators put ~ther ~mited reliance on the Skin-painting experiments? ~. S~w~v. I will have to get ~th the ~rcinogeni¢ people. ~. ~I~. Isn't it tn~e that in the report~ "The Health Consequeuces of Smoking," the report, refem to the failure to pr~uce human-type lung cancer in animals by inhalation ? . Dr. S~w.~T. That is ~ight. " " " ~Ir. H~. ~y don't you say anything about t~is in the pamplflet Dr. S~w.~e~. A pamphlet ~or people. 3~at do they .know about tliat ~ ~Ir. H~. ~at do the~- know about an~hing in connection with th~ studie~nlv what you tellfl~em.- • • • Dr. S~w~nv. ~his is producing lung ~ncer in animals. This is a veD. difficult scientific problem. Mr. H~. I am satisfied it is. Dr. S~w~v. If you would like us ~o add an addendum to the ~mphlet on all the problems involved in this~ I ~ill ~ glad to do it. Th~ mak~the ~amplflet 400 pages long. " Mr. H~. ~ ith res~ct to the section on "Clinical and Autopsy Studies," are you relying for the most part on the work of Dr. Oscar Auerbad~ ? " . • Dr. S~w~r. I haven't any idea. Mr. H~,. ~y have you not included any r~ference to the work of thee pe~ons whose studi~ are in disagr~ment ? Dr. S~w~r. I can give you the biblio~aphy that was used. ~Ir. H~L. If you will, please. (The ~fo~t ion follows :)

Auerbacb, O., Hammond, ~. C., 0arflnkel, L. Smoking in relation to atherosclerosls of the coronary arteries. ,New England Journal of Medicine (Boston) 273(15) : 775-779, October 7, 196.2. "~trong, J. P., )[cGill, H. C., Jr., Rlch~rds, )L L., Eggen, D. A. Relationship between cigarette smoking habits and coronary atherosclerosis in autopsied males. Circulation; Journal o! the American Heart Association (,New York) 33-34 (Supplement 3) : 31 October 19C,6. Anderson, A. E., Jr., Hernandez. ;L A.. Eckert, P., Foraker. A. 0. Emphy.~ema In lung macrosectlons correlated with smoking habits. Science (Washington) 144(36-°1) : 10"25--102.6. )Iay 22, 1064. Anderson, A. E., ;It., Heruandez. ;I. A., Holmes, ~V. I~. Foraker, A. 0. Pulmo,ary emphysema. Prevalence, severity, and nnatomlc~d patterns in macrosoctions, with re.~ect to smoking habits. Archives o! Environmental Health (Chicago) 12(~) : ~kq--~77, May l~O. Auerbach, O., Hammoud, E. C., Klrman, D., Oarflnkel, L. Emphysema produced in dogs by cigarette smoking. Journal of the American bledical Assoclatiou (Chica- go) 199(4) : 241-246, 3an. 23, 1967. Auerbach, O., Hammond, E. C., Kirman, D., Oarflnkel, I,., Stout, A. P. Histologicai chaziges in bronchial tubes of cigarette smoking dogs. East Orange, N. J., U.S. Veterans Administration Hospital, )Iarch 1967. (UnpubLished.) 8 pp. .Auerbach, O., Stout, A. P., Hammond, E. C., Oarflnkel,' L. Changes in bronchial epithelium in relation to sex, age, residence, smoking and pneumonia. New ]~gland Journal of Medicine (Boston) 267(8): 111-119, July 19, 19~,2. Auerbach, O., Stout, A. P., Hammond, E. O., Oarflnkel, I~. Smoking habits and age in relation to pulmonary changes. Rupture o! alveolar septums, fibrosis and thickening of walls of small arteries and arterioles. New England Journal Medicine (Boston) 269(20) : 1045-1054, Nov. 14,1963. _Auerbach, O., Stout, A. P., Hammond, E. O., (}arflnkel, L. Interrelntlonshlps among various histologlc changes in bronchial tu~Jes and in lung parenchyma. Amerlcan Revlew of Respiratory Diseases {Baltlmore) 90(6) : 861'-876, Decem. her, 1964. ."Hernandez, ;L A. Anderson, A. ]~., Foraker, A. O. Interrelationships between bronchial alterations, emphysema in lung macrosectlons, and smokl,g. Pre- eented at the 62rid Annual Meeting of the American Association of Pathologists and Bacteriologists, Philadelphia, Pa., March 5-7, 10coS. (UnpubLished.) 2 pp. Hernandez, ~. A., Anderson, A. E., .Tr., Holmes, 'W. L., Foral~er, A. O. Pulmonary parenchymal detects in dogs following prolonged cigarette .~moke exposure. American Review o~ Respiratory Diseases (Baltimore, Maryland) 93(1): T8-83. January 19~6. "Mouzakls0 S. T. Personal commmdcatlon. Athens, University o~ Greece, )lay 1967. "Petty, T. L., Ryan, S. F., Mitchell,R. S. Cigarette smokI~ig nnd the lungs. Relation to postmortem evidence o! emphysema, chronic bronchitis, and black lung pig. mentatlon. Archives of Envlronmental Health (Chicago) 14(1): 172-1~7, January 1967. "Robbins, W. ~P. Bronchial epithelium in smoking and nonsmoking college students. Journal of the American College. Health Association (Ithaca) 14 (4) : 26.5-26~, April 1966. "Rockey, E. E., Spoer, F. D. The Ill effects ot cigarette smoking In dogs. Intern.~- tional Surgery (Chicago) -16(6) : 520--530. December 1966. .Auerbach, O., Stout, A. P., Hammond, E. C., Oarflnkel, L. Multlple prlmary bron- chial carcinomas. Cancer {Philadelphia) 20(5) :699-705, )lay 19G7. .Auerbach, O., Stout, A. P., Hammond, E. C., Oarflnkel, L. Hi~ologlc changes in esophagus in relation to smoking habits. Archives of ]~nvironmental Health {Chicago) 11(1) : 3uly 1965. .Anerbach, O., Stout, A. P., Hammond. E. 0., Oar~nkel, L. ~ne role o~ smoking in the development of lung cancer. Proceedings o~ the National Cancer Conference (`New York) 6:49T-501, 19~4. ~[r. HULL. "YOU are familiar ~v|th the testimony of I)rs. Carn~.~ and Moran d,t'ing the 10~5 cigarette labeling hearin~.f Dr. Sr~w..~T. I recall tl~eir testimony, yes. - :~-

100 Mr. HULL. ~ith regard to c~rdio~as~u]ar dis~a~ discu~e~ on pages 9 and I0 of the, pamphlet, ~ou ~e selected potions o~ ~e Surgeon Generals report and then said, "By 1907~ additional evidence ~ted even more strongly toward cig~tte smoking as a ~use of ~eath from coronary heart di~a~." Isnt it a fact that in 196~, the Ad~ Committee did not ~d ~hat cigarette smoking was the ~e of coronary hea~ disease~ Isnt it also a fact that there is con- ~deraMe ~sa~eement in .thi~ ~rea ~ Dr. S~wA~. That is right. We have never said it was a cau~. I do not thi~ there is any ~a~eement. ~. H~L. Doctor, let me read y?u the o~ning thr~ paragraphs ~om a Harvard Univemity Pre~ relea~ in an article wh~c]i appeared ~y: A ~len~st In ~e dew,meat of nutrltion of the Harvard Sch~l of Pubic Health challenges .the ~atements of the U.S. Public Heal~ Se~ce, ~e American Heart Assoc~on and others who claim cigarette smoking Is causally linked ~o ~creas~ deaths from corona~ heart disease. Dr. Carl C. Seltzer, research a~iatton e~cle in ~e current i~ue of the Jou~al of the American Me~l As~Iation, ~veal~ that he based his dlsagr~ments on a ~vlew of the "epldemlolo~cal e~dence" in ~e ~nt m~ical literature concerned with relationships be~'~n ~na~ hea~ disease and cigareRe smoking. • It ~ * * * ~cult to ~e from the new epldemiologlcal dat~ how valid causal ~eren~s can ~ drawn that cigare~e smoking is linked to excess corona~ b~rt ~ dea~s or ~at ex~ ~rona~" heart di~ase deaths are "caused by" cigarette smoking. We do not ~ow whether 0r not there ~ a cau~l connec- tion ~tw~n cigarette smoking and increased deaths from coronary heart climax. Wa~'t Dr. Seltzer • contributor ~ the 196i Smoking and H~lth Re~ to the Surgeon General ~ . . . Dr. S~w~RT. Yy~ he was. I would like to ~int out, however, that he was inaccurate m his sta~ment iRthe JAMA a~icle. We have ~ever ~id there was ~ causal relationship. Mr. H~. Hasn't he ~l~ writteu that there are significan~ differ- ences ~tween smokers and nonsmokers such as body build, that are not the r~ult of smoking ~ Dr. S~w~RT. Ce~ain~y. . Mr. H~. Have-,'~ou read the a~icle Dr. S~WART. Yes. Mr. Hv~, Do you agree or ~isag~e with Dr. S~WART. On the fact that we cannot ~tablish ~u~ and effect ~twecn cigarette smoking and corona~ ~ I~TNDXI~'O I~OR ALI# S:SIOKINO A~'D ~-~EALTH I~ROJ'ECTS Mr. Hw.L. Now, Dr. Stewart, I wduld like ~or you to ~urnish this subcdmmittee for th~ record complete information on all smoking and health projects being supporte~l in ally way b~' this Government~ inoluding a description of the project and the period of time covered and the cost and the division or institute having control.

-I01 Is it correct that at this time funds for project grants formerly .under clearinghouse control are handled by the Office of .the Surgeon General? If so, please describe these and you can give that to us. Are any smoking and health projects funded as cancer control project grants or project grants in any other areas, such as heart dis- ease control or respiratory control ? I~so, please include them. (The information follows :)

ACTIVE I~EAI~H GI~AI~TS CONCERNED WITH SHOKING AND IfF.ALll~, I~ISC, AL YEAR I |l|~l|ltlII Ulll|ln| | |0¢ this 50207. 7260

NATIONAL CL(AI~NGHOUSE FOR SMOKING AND HF.AI.TH t nsrftotkm Onscd~ion ~ d~ns Ameer harlot. 1~4eerch Irrendation of the State Unlv~ of New Yo~k ........... To.i~nto.~m |rndns 7 thro~.. 12 in peblic, l~iVato. end.par0chlal scho~ eboM July |, |9C6 to Jvae 30, 196~ ............... 96 8S6 [ne health dan~ers ol cllarette smoKm0, and to lavelee them in smokln8 ' I:ontroI pro~ranis. . Idaho Oepa~mont of Hearth .................................... To desil~u..orcanlze, .dev~. Io~. end ¢o~_ dinMe o Sininwide health ndvceliee .lilly |. |~ to Jure 30, 1968 ............... 36. . proEra.m oy the Id.aho In|era/In ,n~cy I;Ommittee on Smokin0 I~d Health. Mississippi State rfon~cl of Health ................................ /oprovirm support to the Miss,ss, ppi fnterallency Council on Smokinl end July !. 1966 to Sept. 30, !g~8 .............. 27, 915 • Health to develop and coordinate effective smokin~ and health programs in the State ol M~ssissiPpi. . • District of Celnmbin I~parlme~! of Health ........................ .Con~e~n.at'.~n el !nt~razency plarmlnl f~f smokln0 control activities .......... Nov. !o 1965 to OcL 31, 19~8 .............. 82,667 ^meeican Publi~ Hearth Association .............................. ~upport o! pohh¢.at,on "Mooical rfmletm on Teba~"co.°'. .................... Jan. |, 19C~4 to Dec. 31o t9~8 .............. 2|5, 805 Institute for Social a~l Personal Relations ........................ To, cl.evelop .e.ffe~l. ~ve techniques ~lor he|pin0 individuals to stOp smokln|; to July 1,1964 to AI~'. 30° 1968 ................ 240° 068 :noentif.y me .oynamics undedytnl the smokin| habit and thus try to dia|reea , T tyl~S oe s~mo~, e~e a~ .l~eSctibe aPl~Oi~iate trcalmenL . Unive~sily Of Celifm'nia, Santo Bighorn ........................... ~_o st.ndy.eedy s~.e~ls Of !!vmE pa.l.l~o, ly in s~..kinl collele students ............ July !, |966 Io Jure 30, 1968 ............. |o Los Anlelos branch, American Concec Satiety ..................... Io oevezop arm coo~omate enectwe smo~mz and health IXOltams in Ihe Nov. ~° 19~6 to OIL 31, 19~8 .............. 43,C~X) metlopolilrm area of Los Angeles. Maine I)epartnm~t Of Health Warfare ............................. T_o plan for a statew?de ap.p~ech to smokin~ ¢ontl~l pcolfams .............. July I, 1965 to Jane 30° lg~ .............. 6, Florida Committee on Smokin| and Health ........................ /o PrOvide suppoit ~o snmKin,p and health p, olrams, with padicalar emphasis July I, 19f~ to June 30° I~G8 ............... 34,468 on youllh ls'rmps. Tuberculosis Assail|ion of Oreatec New Orleans .................. Support of efforts of volunta~' and of~ctM aloncies in education epinst Mar. I, lg~7 to Feb. 28, 19~8 .............. 12° threats el smokin| and health. MM'.~hiP.n.X.e.alth_cou.n~l. :.-...:: .................................. To~ev~.l.opandooo~Oi~teeltectivesmokinpnd hoalth ixolramsinMk:ldpn.. Jure !, tgr~to Jure 300 1968 ............. emon st t ospilaS, memnapons, led ............................ TO help inpatientS in e Zeeeral hospital to stop smokin., by elto~inl u smeki,~ |toy. l, 1964 1o Oct. $1o 1967 ....... ". ...... 69,263 withdrawal Ctini¢. New Yo,k Stato I)epartmrmt of lteaHrf ........................... To develop cao~dinste(f~ effective smekin~ and health ptwlrams thl.relhout th4 ..... do ................................. 37,83~ State. Uniwrsity Of On~,on Medical .~ ............................. To test and demrmsltato .Iho hypotheses that (t) n smokin~ I~ ~ July I, |9~6 to Jure 30,1960 .............. 46, ~am can .be d .evelopnd m echonls without major sllifts in basin cm'rk:ulvm; (2) questmnna,ru methods can obtain inlos'matkm on tim vadebins of at.ti~.e, knewZe~., a~ ~r~ r.~a.r~d~ .~K~.. i~l; (3) e v~tl.doeein~ ~ucat,on IX~lram m schOOls wnl oner trm v~in and innd to a rndu@. tree in smokin...Ind (4) krmvdndle and attitude ebo~t smokinl urn rive el smokin,~ oehavlo~. ~in I)~,rtmen~ of Itoel~ ............................ _To ,~avel~ e~...ooe~..di. _nate.ofW~li~ smebt.nI end health Im~rams in Oldo ......... do ................................. ~S~ ~ American ~.anc~'su¢ioty ............................ "..'~." .~ipouso~'gslp i~ wo~o l.:ontere,lca on Smokinl and Health held in New Yo~k ,Inn. 1,196'/to I)1~. 31,1~8 .............. City, Sept. 1t-13, t9~7. Pe~ssyfvania Ce, m~dttoe e,s Smebll~l red Hreflll of yilk .......... To develop and ¢on~dinate effectiea smebin¢ ond honllh p~t~rams. ~ ........ July !, 1966 to Aul. $|, 1961 .............. oo 50207 7261

Utah S~le I~lwtme~t e4 He~ltl~ .................................... do .................................................................... cl~ ................................. ~t;7

141.656 IS~. I~ 317. 283 185.335 15~343 22. I~

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109 Mr. HVLt,. I note that Finland has about five times more lung cancer deaths per 100,000 men than Norway. Do you claim cigarette smoking accounts for that? " . . Dr. S~wa~rr. I would have to find out. (The information follows:) ... In response to Mr. Hulrs question with respect to the explanation for the ~vefold greater risk to lung cancer attributed to Finnish males in relation to Norwegian males, it can only be stated that at this time the Public Health ~ervlce does not have a definitive explanation. It Is true that the mortality rates reported for lung cancer in males, by Finland and Norway, are 64.5 per • 1000000 and 14.2 per 100,000, respectively. Wae National Cancer Institute has been very much concerned about the prob- lems a~soclated with differing practices in the collection of mortality and inci- dence data, both internationally and with.in nations, for the past 15 years or so. The different practices may account for the difference in the mortality rates r~ported by Finland and .N'orway, but it is improbable that the disparity can be • dismissed entlrely on that basis. Any attempt to invoke an explanation based upon genetic differences would have to account for a known remarkable similarity o5 lung cancer mortality rates between the Finnish and the Norwegian women. ~aere is me very great probability that the differences can be explained, at least "in lmrt, on differences lq environmental conditions, including personal habits end smoking practices. Mr. HwL. Would .you agree in discussing ~this question of there being a difference in populations, that people who smoke may consti- tute a very different kind of population or group than people who do not smolce~ .. " " ]Dr. S~zwa~'r. I am not sure of thati, whether that is so or not~ whether the cigarette smoking habit itself differentiates people into different groups or whether they are different themselves and tlmt is why they take up cigarette smoking and others do not. ButI do not think that has anything to do wit!~ it. " . . ~ . Mr. Ht~Lt,. Are you making an:~ studies? ..... " " " Dr. Srrw,~Rr. Yes. What we are interested in is the host factor. As I mentioned earlier there are heavy smokers who do not get lung cancer~ and there are people who are not smokers who do get lung cancer. We are interested m whether there is some factor w~thin the person himself which is prevdntive or selective. • ]~r. HULL. ]Slx't it true that many doctors think it comes front a coll.~ Dr. S~wa~r. ~No; I think most doctors think ~t comes from cigarette mnokinlz. . " . Mr. Hv~.~. Where do the youngsters, and we have thousands Of young~ters that die every year with cancer or leukemia Dr. Sz~wa~r. Not lung cancer. . ' Mr. Hv~.L. Leukemia or some other. . Dr. Sz~wA~rr. Cancer is a generic name for many diseases which may have a multiplicity of etilogies. Virus is one ~ve. are exploring very rapidly now. " . . • Mr. HVL~ In some material submitted to this committee last ye,-tr, de~ling with a so-called s.-tfer cigarette program, t_he statement is made that a prospective clinical trial to determine whether smokers dif- fered from non-smokers in important Ways other than their smoking habits should be inau~trnted. No other form of study eliminates what the author, I assume someone in the Public Health Serdce, calls the constitutional hypothesis and avoids the selfselection of smokers and nonsmokers.

110 ~Yhat does that mean l :l)r. S,tv.w,~T. It is the same thing we were just talking about. Mr. H~. That is why I am confu~ about some of the~e. ~. S~w~n~. This is ~'di$cul~ one becau~ you are ~cttin~ ~to the ~net~c p~tten~s and possible ~nborn resistance or su~ephbd~ty wh~c may be fa~o~ which select p~ple out. " ~. H~. Is anyt~ng of this so~ being done in the Public Health ~ce~ It is ~po~nt~ isn't ~. S~VART. Yes; it is. Actually ~his was one of the svenues o~ pursuit of resenrch thst the lung ~ncer task ~orce has come up with, ~e host ~actor. Are there con~itutional ~acto~ thst separate people~ The les~s on z~earch are not tremendous but ~r. ~nd~cott seems ~o ~ thee are ways of doing R. This would ~ host factor in re]atlon ~l~g cancer itself. .. • ~.~L. This is in Public Health. .... ~. S~w~z. That is correct. The researc~ pr~ects may ~ carried out ~ ~ve~itles or within the Public Health Serdce supported by ~ants or contracts. . .. Mr. ~. Isn't it important if smoking cigarettes rosy only refl~t ~ns mo~ likely ~o get a disease ~hat ~u~ which might demon- ~a~e th~s be suppor[ed ~ ~ ~ " ~. S~w~. ~ [hink that is right, but I would like t~ ~int out ~t ~ thi~ this avenue has ~o be pursued qui~eth~rough]y. But I do ~ot want it to imply that there .is so~e selection ~ac[or ~re]n~ed c~ret~m the lung cancer. I ~hink ~he study t~at Doll and Hill ~ Grit Bri~aln ~dica~e that the remova] of ~he cigaret[e caused a drop ~ lung cancer ra~es. " ~. ~L. Of course, ~en]ize ~here would be ~ lot of red ~a~es over at the P~S i~ this is the case. On ~l~e other hand, perhaps ~he an~ety w~ch manypeop]e ~ee] a~ut ~he~r smoking would ~ eRsed and ch~l- ~n expo~o some of ~he anticigare~e propaganda would stop ~o~g a~ut every ~ime ~nd lit • ci~ret[e. Isn't there some re- ~rch which hns ~n recommended ~hnt you in(en~ionally avoid ~l~ng about so-called snfer c~gnret[es ~ . ~r. S~WART. ~O, sir; we are not neglecting any arena except ~or the limitation o~ funds and knowledge ~o do i~. Mr.~ Mr. Michel .... -. . R~RGA~'IZATION Mr. ~[XC~ZL. Dr. S~wa~, do you favor the reorganization of ~E~ ~r. S~wA~. Ye~ I am fully support.lre of ~he propo~l put ~or- ~ard ~v Secretary Gardner. . Mr. Mxc~z~, Dr. Stew~rt, I have a clipping from ~he ~all Street Journnl 9~ January 11, 1965~ with your commen~s on flze rcorganiza- ~on of ~E~V. You nre quo[ed as saying, "~st of ~he ~organiza~ion ~n be put in~ effect wifl~out ~hc lawmnke~ approval, but Secretary Gardner hnsnt yet deck]ed how much ~o ignore congressional ~n- ~. Some chnnges migh~ be mnde quietly ~hile Congress is ou~ of ~wn. 0r, {he legisls~ors could be given a chance ~o hol~l public bent-

118 Mr. ]~[~c~r~. The Public Health Service Act at section 301(i) •tates that the Surgeon General may "adopt * * * such additional means as he deems necessary or appropriate to carry out the purposes of this section." You are, I am sure, aware of the recommendation of the Fountain report, because of the abuse of this section in the making of sn un- precedented grant of $~1 million over a 5-year period to Sioan-Ketter- mg Institute, that this provision be amended to clarity and limit the authority it contains. Do you believe any clarification is necessary Dr. StewARt. Again I would refer to the Department's response to' the conmfittee's report. It is our feeling that flus particular authority was not abused in making the award to Sloan:Kettering Institute and that the type of ima~natlvc, responsive, and, therefore, produc- tive program essential to the effective use of Federal funds would be greately hampered by limiting this authority. You will note that we intended to fbrmalize to a greater extent the circumstances in which this authority is actually employed. . • . OOVF.,ILN'MENT ROLE IN ADVISING CONSUMERS Mr. M~CH~ A~n area of intensive concern for me personally and, I am sure for many other members of this committee and of the Con- gres~ is the effort which is currently being made under the guise of ~.ublic health efforts to place the Government in the role of an ad- visor on consumer products. " " A current example is the ever-increaslng involvement of the Gov. ernment in the cigarette industry. While I am not a smokeri I do realize that the cigarette industry is important to many nlillions of Americans in an economic manner and to many Americans froht the apparent pleasure derived from the use of cigarettes. I understand that not only has the Government involved itself in the identification and seeming promotion of certain brands or tyves of cigarettes having low tar or nicotine, but suggestions have'also been made by certain Government officials that lengths of the cigarettes manufactured in this country be controlled. It seems to me, as an observer, that agencies of the Government may properly be concerned with what they feel is an important national health problem and may properly advise the public of scientifically established facts. When, however, the Government~on ~-hat I am advised is less than scientific evidence--proceeds to publicize product comparisons--particularly comparisons wlfich may be misleadin_o~ I have serious reservations about where such a precedent may lead-us. Dr. S~w^Rz. The Congressmen are probabIy re~erring to the ac- tion of the Federal Trade Commission in testing cigarettes for the tar and nicotine levels of their smoke and in publicizing these results. The Public Health Service supports the Commission in its concern about the tar and nicotine levels of cigarett~ smoke and feels, in the words o~ a report ot 2 years ago, that ~rthe preponderance of scientific evidence strongly suggests that the lower the 'tar' an.d nicotine content of cigarette smoke~ the less harmful are the effects." The Service be-

llO lieves that the consumer is entitled to "know what levels of tar and nicotine are in his cigarette• Mr. ]~cHr.~. That is all~ Mr. Chairman. • ~,Ir. F~ooD. Thank you~ Dr, Stewart• SPzc~L We will place the special statements we requested on certain diseases ~-here s~gmficant activities are bem~ carried on by two or more di- visions in the Public Health Service. (The statements referred to follow :) 0 p~

Other ~eas - 3ureau oF Disease li'even~ion izid ~aiylro,~en~ll. Control in the National Center t'or Urban and Industrial lieelth~ the Occ~llational Health Pro~r~ budget covers about ~ll2~Tt000 yearly ~rect o~nt~ons ~ a~ou~ ~ In re~earch ~r~t~ to ~tu~y the ~re~ence ~ etiolo~ o~ c~on1¢ 1~ disease asi~lated vith )ation~ factors. " " ~e Neti~ ~enter ~or Air ~llution Control su~rts lntr~.ural ~ extr~r~ ~esearch o~ the re~at~sht~ o~ ~l~t~ts to ~esplratory dlso~ers. It 11 haltered that e~lty ~d lndustr1~ air ~ll~t~on are sl~itlc~t factors In the causatio, ~d, certei~ the ~ravation et c~on~c respiratory disease. ~tl~ I~titute ot ~er~ ~ ~ectio~s Diseases ~ ~ ~a~h for ~tter ~eaL~ent ~ p~de ho~ ~d r~liet to those disabl~ by ~hyse~, research has been c~duete4 In the early dctectio, ~ tre~t~nt o~ the disease. ~a~ ~ct~ tests have been develo~d. ~s ~d ln~ation thera)y tec~tques have been tested. ~lot rehab~lttet~ centers have been esta~lished to train p~sici~s~ nurses~ ~d technicians ~lng In t~e trea~ent o~ ~yse~a ~atlents. lnvestlR~tor~ are pro~lng ~he re~tionshtp between i~o~n~ an~ air ~ution an~ e~se~. ~ieyo~d Treatment to P'x'even~t~on ~he csuse or causes o~ emphysema are not now knovn. At one time, it yes considered I diieise entit~ if~ec~n~ only ~he alveolij iluy lit 8icl clustered around the ends of she bronchial tubes deep In the funi tissue. ~vever. s~e scientists no~ Juspec~ that emphysema Is actually conditions possibly preclplta~ed by a series of "insults" to one or ~re ~rclons of the resplratory trac~. These insults nay be acute viral and bac~erlal infections. 811erslc reactions such as 8st~a and~h~y fever, or the Inhal~ion o~ noxious a~en~s such as cigarette s~ke or the soo~ and g~s of urban envlron~nte. Other Investi$srors belleve that livi~& condlclons and Kenecic factors may contribute to c~on~c obstructive respiratory disease conditions. ~sths ~der-reporre~ • ~D &rantees at the University of Colorado~dlcal Center have ua~ntalned an ~physema Registry for ~he pas.t ten,ears ~n an ef~or~ to obtain d~ta for testin~ the hypo~hesls that • nu~er of di~feren~ ~Isease conditions are involved In emphysema. In monltori~ ~helr the scientists have discovered ~ha~ cany deacE, actually attributable to f~ 0

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lh';'Geor~e K:lel= sz~8, asso¢la~es~-~r~ollnska Ins~ltu~e: 8tcck,1~1.s~ ~ e~de~ce t~ t~y m s~c~A: ~ the t~r. ~n b~o~sy s~c~as ~tt ce~s ~ tested ~al~ ~ra ~rA~d t~: ~r~tt ~ ce~s ~re'~sed. It Is ~t ~t ~'~ It t~ t~or-mlsted ~u~es ~ve s~ t~t ~s~ 1~1~ the ~s sleplex ~n o~c v~ses, c~ ~ter ~he c~fie ~tttem o~ cel~ ~d ~~ ~r~tt ce~ls~ ~ l~utlca~ ~r ~e vas ~d ~s. It Is ~t ~o~ ~f ~he C ~r~p c~s~ a~om~lty ludlcates or present vl~s l~e~lon~ or ~ t~ ~r~r ~~ Is ~sp~t~a P~I~Ip~t~ ~ t~s ~. - .- " ~ "-" ~lates fo~d c~=~1 a~o~ltles ~scterlstlc o~ ~r~tt the ~tt ~s. ~y ~so f~d e~nce for t~ tr~ ssion ~es ~e~l~ty c~ ~sea~ l~u~lon ~e~s ~ ~ ~en ~nt~ ~ls~ ~It~s at Blo~tlcs ~eses~ ~rstories~ ~loa ~th t~ ~ ~11 ~s ~ cont~n ~.. ~th o~ t~ ~es ~m ~avll~ t~ected ~th ~ lodlcatl~ ~ssib~# t~ t~s- ~ssio~ o~ ~ ~ for t~ flr~ tl~ ~ ~ ~ ~clplen~# ~ ~t step in p~ducl~ ~r~er ~o~ts o~ ~s m~1red for ~der~ ~sslble ~c1~ develo~nt. Osl~ e~r~ts o~ ~ cells ~ to ~aln ~# ~. 8a~ Steve# ~d ~r e~rlier obse~atlon t~ ~sters ~ve~op a ~cep~tlc s~ ~ to death fo~o~ lntracere~r~ ~ ce~s or ceZ1 e~racts ~ to contain ~s-~s. lnve~l- ~ators at ~s~ Park ~k~al Iu~ltutex ~o~ Nev ~ork ~ ~ed ~lar e~rlence ~th ~'~ ~ttens. ~n~ ~ed e~n~ coherently t~t ~k*s ~sesse# ~ s~te

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"£ nay approach to studies ot vlral-lnduce~ t~ors lnvolvl~ ~lelc ~lds~ ~A (deo~l~clelc a~ld) ~ ~;A (~clelc acid) m ~d by ~. ~lce G~e~ ~d ~e~s~ 8~. ~s Uni~rs~ty. ~s ~ Is ba~d on t~ ~vle~e t~t ~ cont~ls t~ ceO's bl~:~c~ p~ces~s ~ Is ~s~d on f~ ~eneratlon to ~d t~ A~o~atlo~ In ~A As tr~scrl~d to ~A v~ch, An t~ ~. Green m~ed t~t ~sse~er ~ c~ed by ~ of ~ ~e~s As p~sent In t~r cel~s o~ ~sters lanced ~nt. ~ v~ s~:~lc ~sse~er ~ acts as s biologlc~ " ~ gi~s m~s~le l~o~t~on as to v~ of ~ver~ ~ses vas ~s~asl~ for l~ctlon o~ t~ t~r .... ~. O~en ~ ~s ~soclates ~ ~v ~r~ ~der c~tract ~th t~ ~d ~r VA~s ~ to e~e~ t~lr fln~s ~ studies t~rs. Us~ ~l~es dewlo~d p~l~ In t~ir ~ratory~ t~y ~ e~ l~e ~rs of ~p~ntative t~s o~ ~ t~r4 for t~ ~ll-tsle presence of n~clelc ~ld ~te~als ~c1~1c for ce~n e~r~t~ ~ ladled ~ ~4 ln~tl~ It ~th s ~1£1ed ~. A ~sitlve m~lon--t~ £o~ation of a ~A-~A ~c~e t~ ~m~ace of ~r~-~c~le ~A ~d ~11 p~ e~ace ~t t~ ~ ~e~s ~ ~en ln~lved In t~ ~ ~e~le ~lds Of ~s t~ ~se ~r ~ ~s ~ ~1~ ~ed to ~te~ne t~lr pro~le~ ~d t~lr ~e o~ ~lon. Xn o~ stu~, ~. 8~I W. ~rs~ NCI, ~ ~ntr~rs ~ ~ ~A. ~led ~ Is uee~d to ~de a ~pid tl~ assay for t~ p~nce ot t~t~, es~cl~ for ~es ~ fate of the ~r~ ~ In t~ .~11 It ~. ~v C. ~aco¢k~ ~st~ Broth, NCI: ~d ~s associates . ~ ~ t~ ~ lnvestlaa~rs e~d In develo~l~ ~t~s for ~atlon ~d ~scterlzatl~ of ~A. Usl~ s tec~ st ~s~ ~ ~tfe~t Unds of ~A ~ rat ~r~ U~ey~ ~ ~r~u ~c~s~ t~ ability O~ sclentl~s to ~s~erlze ~d elucl~te t~ ~lec~ar ~ls of S v~lety of blol~ie~ ~ ~nc~ ~ne sis • t"" 0

• " ~wo new task f0rces--the Lung Caucer Task Fol~e established at the dlrection of th.e President, an~i the Breast Cancer Task Force es- • t~bl~hed by ~he ~Rt~on~l Cancer ~nstltute~w~ll ~ all,areal ~unds to develop their progntms. " . ' L~g cancer ~s responsible ~or more deaths than any o~her ~orm o~ ~n~r. The cdre x~te is st~ll only about ~ percent. Smoking is recog- n~zed~ o~ cou~e~ as the principal cause o~ hang cancer. Research into the development o~ a le~ 'hazardous c~garette has there~o~ ~en given M~h prio~ty by the Lung Cancer Tas~ Forcd. , _ . ~upational and atm~pheric exposures are also being inv~t~gatyd ~us~ of lung cancer. This ~qui~s maaty ~l)histicatedresources, ~n- clung f~ly ~efined analytic testing and :screening systems and s~Heffp~pIe to establish and operate them. As another approach~ it ~a~.~ p~ible to modify the biologic makeup of the h~dividual in a ~on that would ~duce hi~ susceptibility to hmg cancer. Thi~ is a h~ghly speculative po~ibility but o~e that sl~ould not be overl~ked. If all this work should be started t~ay and sho[dd ~ucceed, ma~$ ~ple ~ould still fall victim to lung cancer befo~ the mtuation could ~ ~ery mudt improved ~cau~ of tlxe exl~ure which.they Itaveal- ~dy ~d. To cope with the lung cancer situation in whibh .we ~ H~g,-we need much ~ttermethods of detecting and dlagn~ing the d~ and much more effective meth~s of t~eat~ng it; as we ~0w, u few c~ a~ cu~ by surgery. I think ~rhaps the~t-kno~ ca~ is that of Arthur ~odf~y who is ~, 6~ T yearn past surge~ for lung ¢~tltcer, .. - • " • Improved outlook for the patient under ~re~tment has ~lways been a m.aj~or goal of the NationaICancer Institute. . .-Mr. F~. You ~y surgery for cancer produc~ a ve~" minimal ~ving of life. - ~, . - Dr. E~x~w. In the case of cancer of the lun~ and ca~cer of the ~omach, the cure ~te is awfully low. It is on the order of 5 pe~ent. ~ ~ncer of the b~ast--~ well as many othe~the batting ~vera~ ~ ~e~ much ~tter. " " . -Mr. F~o. Is this the'~moval of th~ enth'e breast ~ " " Dr. E~x~. Yes, s~r; ra4~cal removal of the ~re~t. " " " " ~. F~v. If u cancer t~es place in the right_breast ~n~ then is ~oved~ could there be a r~ur~nce in the left bre~ of the same ~ncer~ .... • • • • ~. E~'v~c~. Could be, becau~ there a.r~ vascular co~ect~ons which cro~ m[dline and th[s sometimes happens. P~sumably that woman has ~me kind o~ su~ept~b]lity or she ~'ould not hu~e go,ten the fi~t one~ and the risk of her getting a new cancer in the other brat ]s sub, ant]ally greater than Yn the normal woman. ~ Mr. F~v. Is cancer of the breast more common than we th~nk~ Dr. E~zc~. No, sir. I think that this is one ~orm of the di~ase wMch ~ ~Idom m]ssed, the diagnosis may be made ~me~vhat late~ but I doubt that there are very many ca~s of cancer of the breast that are ~~zed.. " to~esun~

Dr. E~v~co~r. Well, s~r, there h~s b~n relatively little research work but a lot of work has been done in plana~ng what we sh_oald do when we.do start, and this has beea very thne consuming and we are ~ot a.uy where near the end of this stage We are g~ring first attention to the csgarette problem and to examidmg the possibi1~ties of produ .c~.g a less-hazardous cigarette. A work group is ~ctively discu_ssing thi~. Thgy will be me~ting fairly. _freq. uent-ly id .t.h.e .co .ruing months... One of the problems is deciding on what kind of cnteri.a you will use to determ~_e whether you am malting progress or not m modifTing the_ fil~r~ the tobacco~ or whatever it i~ you are attempting to do to make the oigarett~ less hazardous. ~rlSSION OF I*~NO ~ANCER TASK Mr. NATC~ Dr'. Endicott'| let me ask you, is t_he lung cancer task force which was named on August 17~ 1967~ direct.e.d to pursue research into the causes of lung can~r~ or was it pr|marily set up to p_revent ©|garotte s_moking and to loo_~ into a less liazardous elgarette~ Which would be the road ~ou intend to travel~ . ' • : ,. ". ; Dr. E~'Dzcorr. V/ell, the task wh|oh I have assign _ed to the task re_roe m to _examine the whole problem of lung cancer and to recomr~_end to me what avenues of research they think would b~ the most productlve in brinz|nz lunff cancer under control. Part of the efforts i~ certainly go|ng t'~ b~ dire-cted towartl some improved method for -early dete~- rich. Efforts must be made to improve the effectiveness of treatment. & G.percent cure rate is simply f/ig_htful._So a s.ub.stantial part of the. efforts will have to go into the questi.on of the climcal managemen~ _of the disease when it occurs. The rest ~s aimed at trying to prevent the ~sease. We have alread~ identified some areas Where we feel real progress can be made from a research standpoint. ! will try to enumer- ate them. - - " First, of course~is the cigarette. . • " " . °- : • Second is a series of exposures which occur which we have already identified in industry. There ar~ probably others we do not Imow about but we have identified certa|n types o~exposure in industry wh|ch are clearly associated with an increase in lung cancer. The problem of the role of atmospheric pollution has to be examined intenslv-ely. There is really no doubt in my mind that this is making some contribu- tien to the pr-oblem. . Another possibility whi_ch cannot be exclud.ed is_that viruses .may p_l_ay a role and may set the stage~ so to speak~ and that these o~n_er thi/~_g?~-industrial exposure~ atmospheric pollutlon~may trigger the reaction from the stage being set b~ viruses~ but this must be actively explorec~. ' • Then, finally~ of the workers in .the ~actories ex _l~osed to the dust m~_d fumes only a relatively few of them get cancer of the lung~just as ~ela.tively few c~aretta smokers get can-c~r of the lung~ andthere ob~'musly sometlung here which determines whet.her you do or you don't.. If ~'e could reall~- find what this is we might be able to attack the probl.e.m at that point by doing something to modify individual sUS~e~ ptibility. • • So:my charge to the task for .co was to look at the.whole problem, ~ll me xvh~t am the possibilities, what they regard ss the most likely to be

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duc~ little intbrmation tlmt bears on what a filter should do, how would you evaluate an~" new development in cigarette filtration .~ Dr. ~..~-vt¢or~. 'I"his ~s at the,heart of the problem I have put to the group on which the representatives from industry, I hope, Will work1 • and tha~ is, what set of criteria| biologicM measurements, can we accept as indicating the degree_ of hazard. That is, if you are going to change filters, or if you are going to add a filter to a cigt~.rette in the first place, ff you ~m g~ing to be aSle to determine that ~his has improved some. thug, first you have to have some criteria as to ~vhat constitutes im- provement.. There is qtdto a variety of biological tests that can.be made and them is at this point in time f~tr front • consensus as to what they mean and whiclt ones we should do and which ones we should rely on and what weight we should give them. A whole long st.ring of tests could be done and the problem_they am wrestling with-is wltich ones shoulcl be used and wliat weight br value sl~oul~ be assigned to the ~'esults. - .... • • - Mr. lq'a'rcsz~. Just assuming for the p .urpose of a.rgtu-p~ ent that the task force decides it has foun~l ~ ,fil,,ter which would make cigarettes .m. fer~ what would you do about it? .~ ould the Government seel~legisla- tionto make such a filter mandateD" ? Would tha Government manu- facture the ~Iter~ "What would you recommend assuming the task force would come up with a conclusion such as I have ~ust-indicated? Dr. E~'v~corr. Ig the; task force came to me tomorrow and s~id, "We have concluded you should put such-and-such a filter on cigarettes," I would send them home because I ~vould -know that as of now they have not arrived at any criteria with which they_ could convince me. So the question is an i_fly one but if I unde~ta~id the intent of your question, my feeling is that the prop~er role in thise~ort, the~proper role ~or the lung cancer task force and the National Cancer Institute, is primarily a role of biolo~cal evaluation, and that if anytldng is to be accompl.ished it will prbbably have to be accomplished by working with indwidual companies ~'ho tlxemselves are attempting to their own products, and our role will principally be one, as best we ~n~ of providing t_he biolo~cal tests ag~inst wldch they can m~sure the effectiveness of .th.e.ir manip_ulations of the product. • I had not thought ~t likely that the lung cancer task force would itself become involved in the manufacture o~ filters or of cigai'ettes or the modificatio~t of tobaccos~ tobacco culture and curing. That is not our area of competence or our cup of tea. 'We thought the contribution we could make ~vas a biological yardstick. . Mr. N~,'~'cHz~. Dr. End~'-'cott~ if you are sure that cigarette smoking ~uses lung cancer, can you tell the committee just l~ow or.by wha~ mechanism cigaret.te smoking causes this disease ? • . Dr. ]~'DX~OTr. ~N o, sir~ I cannot. . - . _Mr._NzTc~iz~. Now, Dr. Endlcgtt~you refer ~ th~ ~ustifications to Mentification and m~ification of industria~-~tmospheric-~cupatlon- al hazards. Have they b~n identical ~. ~xc~. ~e h~ve identified ~me o~ tlxem. One ~ asbes~s. ~other ~ ~ryHi~. The~ a~ ~th du~s..~o~he~ ~re the oxid~ of chromium. ~ot.her are certs~ nickel dusts. ~other are fumes .~-

age of lung cancer deaths could be expected. Only when the shape of the lung cancer mortality curve by age is markedly displaced or other~vlse changed (as may prore to be the ca~for .uranium miners) could a pro- nounced shift In average age at death result. . Because the average age at death has been an insensitive and inadequate indicator of the magnitude oF changes In lung cancer risks, the studies conducted by the National Cancer Institute have emphasized more direct comparisons based an age-specific evidence.and mo.rtallty rates. .. Mr. Hm~ Is it not true that in the ~ of workers who h~.ve • _~pcs~_d to radloac_tive_ materials or chemicals which cause lung cance_r, that t_he age at which t_hey develop lung cancers does apl~ar to_be ~_lated to_ the amoun_t of exposure they l~ave had to these materials; that is~ the greater the exposur~ the earlier, lung cancer occurs~ Dr..Em)~co~. I. could gt~ve you an impression, bht I would rather ~e~kit and putit m the record. " . ..., " - . . It ~ true that workers exposed to radioactive materials develop lung cancers at an earlier age, related quantltatlvely to the amount of exposure they have had to the radioactive materials. ~-ais Is probably else true In the case of workers ~ to a chemical/Industrial atmo~phere, but the difficulty in quantltatlng men's exposure to chemicals makes this a quallaed answer. Of course, in chemical earelnogenesis in animals, as exposure Increase~, the animals develop more tomom earlier. -... Mr. Hv~. If this is the case, is it com~ct to say that aigrette smoke does not seem to have the same characteristics as these industrial and oceup~_tional agents ~'hich have been identified as causes of lung cancer~ You can'also put thatin the record. . C~,tRAC'rZ~STXCS O~ C~GAR~rT~ SMOKS VZaSUS IN~USTa~A~ £~n OCCUPATIO.~'A~ ~- AOE.~TS PI~T~NO TO LU.~O Cigarette smoke, per se, being a t~mplex mlxturs of substance.~ is not truly comparable to any single industrial/occupational agent, although it may be comparable to a given industrial/occupational environment or condition In ~vhich a variety of agents are pre~ent. In comp~risens bf cigarette smoke with indus- t~lal/occupatioaal environments, striking similarities and differences are found. Carcinogens found in selected lndustrial/occupatlonal conditions include poly- cyclic aromatic hydrocarbons (industries using or producing mineral oil, coal tar, waxes, asphalt, carbon black, or rubber), arsenic, chromium, nickel, beryllium

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zette, would make a cigarct te "s~t re" ~ • Dr. E,xoxco,rr. The~ are a number of substances which are capable . :.:. of causln~: serious biological damage. They are, however, present in very small amounts usually, and fallen alone not any one of them, hal[eve, is pre3ent in sui~ciently high concentration to assign it the responslblhty for th~ observedeffects of smoking. Either we have missed ~. very powerful one and have ~ailed to identi_fy it or we are de~ling here with a combined effect of a very complex mixture to wl~ch, perhaps a dozen Or two dozen different chemical substances are . contr.d~uting. ' -" . It m almost certainly in this latter thing. I do not think we ~re going to sudde~dy find the thing. "We are Up against a very, very tough and di~cult prob~lem of a complex mixture. . Mr. Hv~. Dr. Endicott, assuming cigarettes to b~ unsafe, which I do not accept~ can the removal of some ingredients make them even less s~fe ~ " • " • Dr. E~xmco-rr. It is quite p~)ssible to make them worse; yes, sir. " Mr.Hvz,L.What is an anticarclnoge.n.~ " " '." " " Dr. Esvxco'rr. The scientists use t.hm term to refer to a substancA wMch will counteract the effect of a chemical which causes cancer. In other words, they have a system of using a known chemical care[hOgan and add one more chemical to the mfx and neutralize the cancer-causing effect. '. Mr. HvL~.. Are there any anticarcinogens in cigarette smoke~ Dr. Es'~xcoz'r. Yes, sir ;I think there are. Mr. HULL. Would you give us a summary on that for the record Dr. E~,'vzcoa-r. Yes, sir. ' (The information follows :) . . : .. ... A..WYIO4~C~OGI;NS L~" (~tOAR~-~T~; ~MO~r~ A~ticerclnogens are those compounds which have in common an ability to ~hlbit the induction or cancer by other materials or eompaunds. The aubJec~ of antlcarcinogenesis has received sporadic interest since Berenblum reported the experimental inhibition o! tumor induction by mustard gas and other compounds in 19-~, 19~31, and 193..~ (see re~erenees 1, 2, and 3). Other investigators (refer- ences 4 through 10) have since demonstrated inhibition of a potent carcinogen by a ~-eak carcinogen..~iore recently, n broad spectrum o~ chemical agents have been shown to retard the rate o! tumor induction. Kottn etal. (re~erence 11) have demonstrated anticarc[nogenic proporties in compounds related to car- eino~ens.. • One or the more widely accepted explanatlon~ for antlcarcLno~enlc action compounds related to a carclnogen has been based on competition between the t~-o compounds for a limited number o~ sties for action on the v~Inerable cell. ~nls phenomenon Ls comparable to that observed between vitamins and some of thelr closely rela'ted derlvatives, termed antlvitamlns. •hese obsexwatlons "are particularly pertinent In attempting to assess the quart- tRatlve role of carcinogens present In polluted urban air and cigarette smoke in the pathogenesls o! lung cancer" (re~erence 12). ~e available evidence polnts to presence o! anticarclnogens in cigarette smoke although the anticarclnogens have not been identified tully or charaeterlzed w'Ith O

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! , ; . "! .: .. would not change .the ~N'ational Cancer Institute .as an organizational " .... . ~t~ty nor the Division of :Environmental Health Sc|ences, which .. :. ao;v in the NIH as an organizational entity itself. . - :~ " " :Mr. ttb"t~. Dr. :Endicott, do ~'ou not feel th0~t massive .talent hunts • ". by HEW divert doctors who nught oth.erwise be available ,to .take care ..... .. Dr. ]~,~,mo'rr. Y~, sir ;.they do. " " - " : _Dr. S~A~-xo~. Mr. Hull~ I cannot let that statemea_t go by. i " . ," In Che first place, on the average, somewhat more .than .~0 percent : " o~our scientific stab are non-M.D.~ and in any expansion of the activity ~his ~ould.also obtain. _ In the second place, I would say ~e donor ha_vea massive talent hunt under.way ~cause ~ve do not propose any substantial change in " .-.. " theslzeoft~heoperati.o.n ........ . .. . :.. I ~think {hat curtailment of support for .the scientists at work will "probably result in their working less eifectively~ bt~t not in less of .then, • .work'in~ inresearch or in science. • ' . • • ... : • So I ~hink curtailment of .the budget will limi.t the capability of ~|entlsts while, at the .same t!me, not providing additional physici~/ns for~hedeliveryofhealth services. . . . " - ' . • ' . ::Mr. tIv~.x,. Dr. :Endicott, as the Federal C:rovernm~nt be. comes more end more ~h~ source of .research money~ do not sclen,tists become more ._ :Mr. l:Im.z~. :Do you not suppose:tlils mokes them more cautious.in - disagreeing with any olii_cial__and HEW policies~ _ ~" - ~ I)~. :E~'D~co~r. :It might affect some. ofthem.~ sirLbut they are the most independent lot I ever had anything to do ~dt.h. . • Mr. Hvc~,.:Dr. :Endicott, do you object to the marketing of 100-milli- - -- meter cigarettes and, if so, ~v_hy.l _ • Dr. ]~-~zcorr. Sometimes I buy them. " " ~-: Dr. E.x~xcarr. Sometimes I buy them. " Mr: Ft,oo~. What does that me~xn ~. Does it mean you smoke. ~hem -- .:Dr. :Ex~xcow. "Yes, sometimes. • • , - Mr. l~Iv~,~. Dr. :Endicott, are you interested in developing shorter .¢_igarettes ? " - - :- Dr. :E~,wxcorr. If I thought that was the w~y to solve the problem - would be, but frankly, I ~o not think, that is the way to solve the problem because people seem to like to buy the 1.ong ones. Mr. Hwz,. Or are you interested in low-tar-and-nicotine cigarettes~ " • Dr. E~c~morr. Sir, ht our present state of knowledge, it is my ~udg- ment that moving in the direction of low tar and n[cothm is moving

• " "" " ;....". ,'~'z.~."'-,~.#'~-.,~'-..,'--',.',._.~';;~-.~..'..'_'.L.~.'-.'.'~'~'.~.C,..,.~;~-~.JJ._~.~o~,~_L~'~_ " _~_..~_~_'~:'_~.~':,~'j.._ ~.,'.,,._." . . }.. • in the right direction, but the problem is mor~ complex than tsar. I i. do not tl~ink it would be solved by that alone. - • -. ~ If I may. expand on that a little bit, we have a complex mixture : - i here and selective removal of certain things will p~robabl~, tu_rn out to ! be more effective than just the nonselective reduction of tar and nicotine.. :.- Mr. HVLL. IS it not just a g~_ ess that t_here may be some advantage : "to a cigare.tte with less tar and nicotine~ . : Dr. Exwcorr. Yes, sir; I think that would be consistent with the " ".- total _body of evidence, that less tar and nicotine is probably less ' hazardous. - " ~ Mr. HULt.. Dr. Endicott, would you say evidence, if there is any, favoring low-tar-and-alcotine .c!garettes i~ very strong~ • ~ You could put it in the record ~fyou care to. ' . " : . ; " . Dr. E - xcovr.. Aft right. ... ( .. ..: " (See page 439. ) : Mr..H_~.L. D_r. Endicott_, would_you ~y it has .been demonstrated -. beyond doubt that increased tar and nicotine means ~ncrvased hazards# ~ Dr. E~-vxcoz.r. Yes, I think there is evidence in that direction. • ": Dr. S~.~ .,,'~-o.x. ~r. Hull, I think t.h~tt series of que~io.ns m~y warrant '~ ~ some clarification. There is emphams on tars because flus is the fraction of the smoke that contains the mixture of material that can be sl~own to have certain biological properties thatare presumed to'be r~lated - : either to the p.roduct~on of lung c~ncer or to tim triggering of cancerous condition. • .Mr. Hvz.L. 'I~he reason I asked this question was to determine the present state of lmowledge about so-called safer cigarettes. ])r. E~'DICOTT. If yOU cal~ reduce the ones that carr~ the hazardous substances, the inference is you likely h~we improved the cigarettes, ~ hut there is no direct, proof this is the case. That is my opinion, that is an experimental inference rather than rigid proof that a specific thing has ~en accomplished. " " ~ Mr. Hv-~.. I believe that is hll, 3Ir. Chairman. Thank you very much, Dr. Endicott, and you, Dr. Shannon. Mr. F~oov. Thank you, gentlemen. : . - " ~0 O

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In emphysematous lungs, the walls of the avcoll are irreversibly destroyed and broken down, resulting in large, lnei~clent ~lr spaces devoid of small blood ve~els. 5~e flow ot air is resisted, gas exchange impaired, and breathing becomes tremely strenuous. Meanwhile, the heart must pump harder to circulate oxygen- poor blood to body tissues. I! the p~tlent is untreated or treated too late, he may. suffocate or die ot an overworked heart. -" To provide hope and relle! to those disabled by emphysema, research has been conducted .and supported by the Public Health 8ervlce-.-lneluding the .N'ational /nstitutes of Health~ln the early detection and treatment of the disease. Pul- monary functloa tests have been developed. Dcugs end Inhalation therapy tech- ~flques have been tested. Pilot •rehabilitation centers hare been established ,to train physicians, nurses, and techaielans specializing in the treatment o[ em- physema patients. Investigator~ ~re.probiug the possible relationship be~veea m~oking and air pollution and emphysema.. . • •. • ~rOHD "~EF~'~MENT "~0 PgEYEN~ION The medical professlon .realizes that ~n all-out effort is necessary to e~xse the suffering of those no~" a$1cted with emphysema. However, it is also .recognized • .. that ~o reduce,the rate of death ~nd dis~blli.ty, Inten~ifled efforts must be focused • ... on.research Into the cause azd prevention of the disease. . T~e cause or causes of emphysema ~re ~not now known. At one time; it was" considered a disease entity affecting only the aveoll, tiny air sacs clustered ~tround the ends or the bronchial ~ubes deep In the lung ti~ue. However, some scientists ~ow suspect 4:hat emphysema is ~ctu~lly .a cluster of Conditions possibly pre- elplta,ted by n aeries of "Insults" to one or more portion of the respiratory tract. These Insults may be acute viva| and bacterial infections, allergic .reactions such as ~bma and hay fever, or. the Inhalation of noxious agents such ms cigarette smoke or the soot and fumes o1~ urban environments. Other lnvestlga~;or~ believe that substandard living conditions ~xud genetic factors may contribute .to chronic obstructive re~plratory disease conditions. ~ sr~a~c~ ~os causes The 89th Congress, recognizing the need for a program of basic .rese-~rch with a long-term goal o~ prevention, appropriated an additional $1 million to the l~.a~ior~al Institute of Allergy -and Infectious Diseases, for Investlgations into the ~tuses of emphysema. In this effort, ~e strategy of the Institute has been to utilize the interrelated disciplines of .allergy, immunology, virology, pathology, mlcroblology, and cellular biology. NIAID grantees at the University of Colorado 5Iedical Center have maintained an emphysema registry for the past 10 years In an effort to obtain data for testing the hypothesis that a number of different acquired disease conditions are involved In emphysema. In monitoring thelr registry, the sclentlsts have discovered that many deaths actually attributable to emphysema and chronic bronchitis find their way into "vital statistics records as deaths due to such L~soclated conditions as pneumonia, heart failure, and ~ometimes stroke. In their recording of the nature and extent of gross and minute changes in the lungs, the Colorado investigators are now beginning to relate atrophy and thlnning of airway walls to a physical flabbiness of the walls, which results in • ready collapse of the bronchial tubes on expiration. ~'beir studies also include the location, nature, and degree of airway obstruction and the effect on total lung capacity. At Harvard University and Boston City Hospital, scientists are describing the mechanism by which cigarette smoking may Impair the protective processes of the lung and thus increase its su~ceptibilityto microbial infection. They are also evaluating the effect of socioeconomic conditions on the progres- sion of chronic progressive respiratory disease. Current Indications are that the disease is more severe in lower social and economic groups. o

• """' ':'" .. [. " " :.... ~ . . . -. ::...." ."" . . ....- .- ~.-..~ .. ; "...~-" . - ..-. ~...~ ~- .. • " . "~..'-_ ~l~ at the ~llular and subcellular levels. ~ey are attempting to characterize ' " 7." . ~ :'~ ~ ~e res~ase of respiratory tract cells wbea challe~god by ~te~tlally i~Jurious " '" " _-~ agents such as ~r~rne ~ntamlnaats acting in co~so~ with microbial ageat~. -." ~ ~ho shed light on ~e pr~ess by which iuhalated particles are clea~od tram . -" -": .~ ~e lower ~lons o~ the human lung, the scientists a~e studying the clearance - . " ~.~ me~aulsm o~ frog lungs. A~d they are~nductiug other lnvestlgatlous~prlmarily -.'':'. ~~ ~ ~tten~ with emphysema and chro~ic bro~chRis~orrel~ting measurements " ~. "- .-.~ of pressur~ and flow In the inug with airway structures In au effort to explain ~-.. - ..-: ~ whyairmovement~omesdl~cult~diseasedlungs. . ~ ' - " - .~ : ~ The cllla~tiny hairlike cell proJ~tlous attac~ed to ~e lining of the resplra- ~ . ~: tory tract--are being examlned meticulously.for their role in chronic respiratory d~eases. In their healthy state, cilia ~'lbrate and, by their constant motion propel mucous and foreign matter"(such as dust and pollen) toward the mouth where it can be removed by "clearing the throat." The Duke University studies indicate that clearance of this forel~n matter Is enhanced by water deposition, increased temperature, and breathing movement, and Is reduced by, drying. Another team of scientists--working at Hektoen Institute for Medical Research in Chicago--are also studying lung clearance and the effects of microbial agent~ on the activity of the cilia. Disappearance of particles labeled with radioactive ~old is being observed in normal subjects and In patients with chronic bronchitis and emphysema. Results are being correlated with bacteriological, vlrological~.. and lmmuunlogtcal analyses of bronchial secretions and biopsy specimens. "~t Yale University Schcot of Medicine, scientists are" assessing the role of Tlruses, mycoplasmas, and other microbial agents In the causation of emphysema. At a nearby VA hospital patients wRh emphysema are contributing to a study of blood specimens, waste products and, when possible, bronchial secretions. " Because of the anatomica! similarity of the horse's lung to that of man~ and because pulmonary emphysema of the horse (commonly known as .the heaves) closely simulates emphysema in man---a preliminary investigation of this equine disease has been undertaken. In examining the lungs of horses exposed to urban environment and those living In rural areas. It was found that nearly all of the older horses examined had ~severe emphysema while the younger animals ~howed little if any evidence of the disease. Further studies are underway to try to determine ~'hether viruse~ and other infective agents play any role in the causation of equine emphysema and bronchitis. At the University of Utah College of ~/edlcine, I~ patients with chronic bronchitis or emphysema are being studied to determlne the relaltonshlp at age, ~ex. race, resldence, and occupatloa to the diseases. ~he Utah grantees have developed a complete pulmonary function laboratory where patlents in early stages of the disease are tested and followed over many year~. O~ particular interest is the role of latectlon in the natural history of the disease. Complete studies of lung functions are made.perlodlcally to correlate Imcterlologic findings with the disease's progress. & technique called trans- tracheal aspiration makes po~Ible withdrawal of secretions from d~ep in the lung to ~ore thoroughly explore the events occurrlng in this vltal.~egment of the organ. ~gIMASY AND SECOND~RI~" Northwestern University l~ve~tSgators are using the same technique in an attempt to pin-point the principal and secondary factors in the progression o! chronic obstructive lung disease. Studies are being conducted with 2.3 patients and We control subjects who have pneumonia0 using transtracheal aspiration to

,-.:,... , . , ;. . 7.20 ., .'+.. .,. ~., ~... ,. ;:., . ~. : obtain secretions for bacterial, fungal, mycoplasmal, and viral cultures• A search o o t~ ~Iso .being made tar possible aut.oimmune hypersensitivity factors In the de. velopment o! chronic lung disorders, .+ Simlla~r microbial organisms found in the nose and throat are being investigated "by scleu~is~ at the University of Vermont, Particular emphasis is being placed on an assessment of the protective role of Immunoglobulln and antibody In respiratory secretions and serum..S.nd the el~ects at antibiotic therapy and viral vaccine~ on the course of bronchitis are being evaluated. Sclentist~ o~ the School of Public" Health at the University o! ~Ilchlgan for some years have been conducting health and disease investigations In ~ tb'ptcaI ~x~erlcan community at Tecum.seh. :},Ilch..In early sL-udles (supported by the s~ational Hear~ Institute). it ~'as discovered that more than 10 percent of the population over age 15 (or ~,~0 individuals) had chroule cough and sputum pro- ductlon, both common symptoms of chronic bronchitis. ~ow under• support, persons with es~hlished or an, fly chronic pulmonary dlseo,ses are fat- lowed intensively end their symptoms recorded ~-eckly, If a change develops in an individual's ~sunl state of health, specimens are collected to determine whether rlruses or other microbial ors~nlsms are present..VVorktng .on the hFpothesfs that healthy relatives of emphysema victims are more likely to develop the condition than the general population, members of the ~amlly of p~tleats chronic pulmonary disease are also being kep~ under continual medical ~,. ..4,t ~he U'nlversity of Southern Catltorntu Schoot of ~Iedieine, ~lentlsts are evaluating the relationships bet+s-ecn the individual components of smog in the Los Angeles area and the production of chronic bronchitis, emphysema, end ~ertaln virus infections. 8~udi&s of mice exposed for several weeks to air Containing different e~n~rations of nltrugen dioxide (.~0~) shoxved mar~:ed Inflammatory changes in lungs and alteration in lung ~truc~ure. When the animals warn removed from the ~'o~ a~mospbere, the inflammation subsided but the lung architecture did not return to normal, The alveoll were enlarged and in some cases had rul~ured wails. simllar to the changes seen in emphysema o! man. The USC grantees ats~ found that animals with lungs damaged by .~0~ inhalation were more s~sceptible to airborne bacterial infections. Studies are continuing to determine what alteru. ttpns In the lung~ mn~ be brought about b~" .N'O~ and such virus l~fectlous as I~tuenza. • 8clenl~Ists at l~ylor ~niversLty College of ~31edlclne in Itoustou are seeking additional knowledge regarding the basic fmmunologlc characterlstlcs of the cells which line the respiratory tree, Their ez+perlmeuts led to the discovery of autlge~ss (antJbo~y-producln~ substance) which are unique to the respiratory tract. These antigens also bane been found in the sputum of patients with various resplr,+. tory diseases. Current Investigations Involve the purification of these antigens m~d further study of antigens In the sputum of patients, Investigators at the University o~ Oklahoma bledical School are attempting to determine whether emphysema prevalence differs in three racial Iroups: Caucasian, +~e~o0 and American Indian. This study is horsed in part on earlier reports that a deficiency of nntitrypsin (a substance u'hich inhibits the action of the pancreatic enzyme trypsin) is a genetic characteristic and is related to chronic obstructive lung disease, o+,lso, the Oklahoma scientists are evaluating the presence of various organisms in the sputum in the development of ohstruc- Uve lun~ disease.

,N2AID grantees at Washington University School of Medtctne In St. Louis have undertaken a systematic evaluatlou of the effects of acute virus and c¥co- lilasnia resplrator¥ infections ou the pulmonar~ function o~ adult~. Thelr hl- ~esls Is that such In~ectlons ~use remarry aboormalltle~ In ~ctlon which ~rslst belond the acute illness and ~rbaps lead to chronlc disease. ~, what otherwise would k minor Infections real prove serious Ill ~ses o~ chronic pulmoua~ disease because o~ the added burden of diminished ~Imonary ~uuctlon. These studies are being conduct~ wlth ~ medical and uu~Ing students and with ~ ~tlents wlth chronic pulmonar)" lusu~clency, using appropriate techniques for Isolatlug viruses, my~plasmae, and bacteria ~om ~roat swabs and st~l s~cimens at re.far ~te~als and durlug at a~te respl~tory infections. • At ~e Res~rch Foundation of State Unlvenlty of New York in Albany, two ~udles are currently unde~vay on lysoz~me (a protein found In saliva, tears and many animal fluids) which acts as a bacterial enzyme. ~ one investigation, the scientists are ~ll~tlnl tears from patients wlth ~onlc bronchop~mona~ disease, for quantitative analysis o~ immunoglobulln ~n~nt of lysozyme activity. Such lulo~ation may lead to earlier dla~osls ~e .~nd study--a new approach to the subject of air .~llutlon and tissue ~ma~involves the fmmunologlc reactlvlty of ~rtaln nltr~oleflns, ~ought ~ ~ ~rtant constltuents of automobile exhaust fumes. ~e primary goal ~s project ~ to observe the effect o~ iubalatlon of notro~leflns in sensitizing ~ea plgs and in producln~ lun~ ~s~se. :. - :. ~ addl~on to the emphysema resehrch actl~:Itles desc~bed a~ve, the Instl- ~ al~ sOp~s the followlnl ~llel investigations which may provlde.valu- able leads to the ~owl~ge o~ emphysema and other chronic ~structlve A itu~y at ~e University of ~llnols ou the relatlo~hlp o£re~ated Inlec- finns and the pro~e~lon of chronic bronchitis. ~ appraisal by ~lentlsts at ~ulslann State Unlverslty on the lm~qct ~mb~ed vlral and bacte~al In~ectlons on respiratory function. - ~ evaluatlou by University of Pennsylvania scientists of the ~latlon. ~Ips betw~n broncblolltis (a disease In which the small bronchloles are d~troy~) nnd allergic ns~ma. One of the ma~or problems con~rontlng scientists seeking ibe ~use of emphy- ~ma ~ the need for a la~ratory animal m~el. Such an animal, H~ng In a con- ~oll~ envlronment, ~uld ~ sub~ect~ to the same facto~ sus~cted of precipi- tating the disease in humans and the e~cacy of varlous re~mens ior treatment and preventlon co~d ~ evaluated. Ste~ toward thls goal were taken in 1~ when the first Interd~cIldlnary sym~slum on the sub~ect was Jointly s~nsored by ~e Instltu~e and the Division o~ Research Grants. Seventy scientists and pbyslclans shared tbelr knowledge and views as to natural and ex~rlmeutal animal m~e~ for the study o~ emphysema. Animals considered to warrant more Intensive Investl~tlons were the germ.free rat, the ho~, and the plg. ~clentlsts at the Institute's Maryland and Montana laboratorles continue to make contributions to the search for knowledge about the role of viruses and other mlcro-organlsms In chronlc degenerative diseases. Recent reports front the NIAID laboratories revealed that when viruses attack the halr-llke clIla project- • fag from the lining oF the respiratory tract, the cllla lose thelr normal ability to propel foreign matter out of the tract. Tbts inability, it has been suggested, may be one of the early steps leadlng to chronic obstructlve respiratory dlsease.

. :- . _ ~. 8en~ there are no clear-cut leads as to the cause or causes of emphysema, no • l quick solution to the problem can be anticipated. Many complex questions remain .. :~ ~ ~ answered. ~ Institute beUeves that these answers will emerge from the ~ ~ " .:~ multidlsclpllued ~pproach being pursued. Prevention o~ emphysema will ~...~ . -..~ ~e effo~s and sup~rt of ~lentlsts, medical educators, public ~ealth o~clals, .. ~ ~.- ~vernment leaders, andthe Amerlcan~ople. , ,. ...':~.~ .: Mr. F~ Regarding the Gorg~s ~[emorial Laboratory, they re- -. ;~ ~ive $500,000 in grants a year. Are we getting our moneys worth out • ~ Dr. DA~s. I think we are getting our. money s worth. They are . .... ? dang very excellent re~rch o~nfectious di~ase~ in an area o~ .".- ~. ~--~ . ~ntral Amerlc~ which ts of ma~or conceptive Umted Stat~. They -~: .... :~ have a strong staff which is increasing in capability. They feel there . . .,:~. a~e many problems which a~ not de,It with here completely in the " ";:. :~- " One of their studies, for instance, concerns malaria in South Amerl- " '~- can mo~eys which might be t~nsmitted to man or which can be us~ ~-. " ~-~ tar ~valuatlon o~ d~. They a~ interested in the insect-~rne viru~s 0~ that p~ o~ the world which could in~ade the ~nited States. They • .... e~ have a ~o~ study in diarrheal diseases o~ child~n. ' Mr. F~v. DO you get re~lar re~rts from th~ ~ople~ .~ . - Mr. F~v. Do your people audit this institute ~ . ....". ~.~ ,, ~.~ '-~ Dr.DA~s.We receive re~dar reports. ~. " ' " - ~ Mr. F~v. Do you audi~ this institution ? " ' ....' ' ~,. '~ -. ~ Dr. D~s. The ~500~0~ is audited~ ;~ Mr. ~[AOR~E~. I do not think we do, sir. This is handled, I ~lieve, :~ ]~ by a ~ard of directors, of which there is a treasurer. I cannot ~mem- ~r his name. ~[r. Simpsou is the secretary of the ~ard o~ dlrecto~. ~ Mr. F~D. You mean they audit fl~em~lves~ . .[ Mr. ~I,XOR~ER. NO; they have an audit but I do not think it is a ~ ..... ~ " 'I r~nslbility of our agency. We iust handle the transfer of the ~mds. ' ~ " Mr. F~. Should it be ~ . ~ ~ Dr. SHA~-XO~'. ~[r. Chairman, this is a respouslbility of ~h~Depa~ " ~ meut ~hlch has the general audit ~nction for all of these programs. ..~ Thisis the fiscal audit ..... " . ' . . ..~ ~ : Dr. SHA~'Xox. The ~ienti~c audit, il you will, takes plac~ via dsRs .~[ andby their annual report. . -. : ~ '-. :~ {The ~ollo~-ing ~as subsequently submitted :) : ~he Oeneral Accounting O~ce ~rto~ms annual examinations o~ t~e flnanclal .~ ~atements of the Gorgas Memorial Institute. By an arrangement betw~n the ~mptroller General and the President of the Oorgas Memorial Institute, the ~ ~ ~rt of the annual audit o~ ~e records at the Institute is included In the annual ~ ~t of the work and o~rations of the Gorgas Memorlal ~boratory for the :~ ~me fiscal year. ~his ze~rt is transmRted annually to the Confess.by the ~ Pzesldent at the Gorgas Memorlal Institute. .. '~ Dr. D,~s. I have here a copy o~ the 39th aflnual report. " ~ MrJDAv~. This is dated Janua~ ~3~ 1968.

:- concern himself with the possible risks as ~'ell as the potential benefits • of technological change. ' ... In recpgmtion of tl~e problems of environmental health, the Public ~ ,-Health S~rvice has dereloped major control and research programs. :~ the c~ss of control prog~ms, the primaw aim is the ~pplication of ~ ~t~ay's k~owledge to the solution of t~ay~s problems usm~ the most ~ .~Sd~-anced technology. ~r. Prindle and oilier members of the But~Ru of " -D~ PRrention ~nd Environmental Control Imve discussed these . - p~ams with you previously. " .: .~ the ca~ of research pro~'ams f~used in the Divisio~t of En- .~ental Health Sciences, the priamD' go~l is to advance funda- mental ~owledge and to develop a scie~ti~c base that will serve to p~de a~wem to p~blems that man's interaction with his enrl~n- meat bare c~ated an~ will inevitably generate in the coming decades. . It ~ these p~grams thatl -will discuss t~ay. ~ .. In brief~ the minion of the Division is to unl~k the unknown in endmnmental hazards to man. Tim major responsibility for the appli- :ration of this knowledge ~ v~ted in other organizations with ~om "" ~e National Endronmental ~ealth Sciences C~nter, tlm int~murai ~h p~m of the Division, has initiated rematch that pemdts Ihe slmul~an~us applications of divers ~ie~ti~c di~iplines ~tegorica~ app~a~hes_to meet exi~ing needs that are incapable most likely to identify and appra~e p~blems ~ they ~erelop in the inc~sing tem~ of our t~olo~l ~dvanc~.. The ~ven cla~ of envi~nment~l agents oit which we a~ now " ~itiatln~ ~a~h programs a~ natural products, metal compo~ds, hyd~arbn nactios p~uct~ tobacco smoke ~onstituentt l~l)mer du~ pestlcideb and pesticide~yBergists. . . " • . . R~arch on the~ ~gents and their inter~ctlon with man's well-being Will ~ ~nce~ned w~th the chronic, the less obvious, and the unexpected eff~t~ but aI~ with the acute and more obvious. Chronic effects arc ~ difficult to a~ciate with ~ s~cific causative a~ent; they are ~ily m~i~ed by ~ondary inte~tctions with oiher agents. Hope- - ~lly,by studying these ~condary i~te~tctions, we may be able to idcn- ti~ an~ to cavitalize upon ~tentially beneficial modifications. . Multidi~iplinary, ~unctional resea~h is underway in cell biology. - ~al~lcal and synthetic chemistry, pharmacolog.~, and toxlcolo~', and the animal ~ience and tec~olo~" branches at the National Enrich. mental Health ~iences Center. " ~: In addition ¢o extension of ongoing prepares in 1969, we are e~plor- ~ng the ~slbilit£ of ~ broadly ba~d epidemiolo~" program. The identification of the bases ~or variations in res~]~e to environmental i~ults among indidduals must ~ correlated with experiment al la~ra- ~ data to provide the important principles and generalizations for ~e development of ~idelines for t~e u~e of feudatory agencies.

again. We are almost compulsively concerne~ wlth relevance of all dol- " l~rs in the Division ~udget to its mission. In order to translate tltat concern into action~ adequate staffing is mandatory. . • Mr. A o,Ea. Dr. otin, last year you told the commltte that you planned to sp_end $480,000 in thi~ area of tobacco and health. Will you t_ell me now how much you e~timate you will have spent in this area by the end of the fiscal year1965'l . " .:, " . Mr. ~x'rc~. Tgh~.t projects are presently underway in your laboratory, Dr. Kot in, ha~ng to do yith tobacco and health ~- .. - Dr. Ko~=~. There are three, m~t]or actit, ities going on. We are the recipient of all the cig-.~.ret.tes that the Federal Trade_Commission does not use in their quantification of tar and nicotine. ]~ecSusc they have to buy a ]a.rge number for ntndom samples, and by n_=eans of the very elegant technique of emission spectroscopy we are doing trace metal analyses on ~ very large sample of ci~;~rettes as a baseline for other o_.z~goi _ng studies; we are concerned w~th_t~e toxicological effects~of disturbances in trace-metal balance in. the intact host and in cell " Anot.her activity ~.vith which .we are concerned_ is the hazard that may exist incldentai to funga| contamination of toT~accos and par- ticularly clg~rette tobacco which, by ~.~rtue of storage for a long period of time, provides a fine cult are medza. " . " We are asking three questions: Are these contaminant~ delivered into the smoke1 .... .- . . " " . Mr. lq'ATCH~. Right at that point, Dr, Kotln, how much of your money are you e.||ocstln.g to this particular fun~ts study ? C~n you ~ive the committee some zdea ? Just approximately_. • " Dr. KOT~..'~. By .the end of the year it wou|d be about ~'~tT~O~N°AL '~'OBACCO SF~EAItCH LABOP, ATORY o~.T V.N'IN'~RSITY OF XENTUCKY Mr. Na~CHr.R. DO you know of the wot'k now being conducted in the Nstional Tot>acco Research Laboratory at the University of Kentucky Mr. N~TCHr-~. Do you know the type of research that they are csrryin~g on out there, Doctor ? ~[r. ~.,tTCH~. Isn't this a complete duplication t ~ Dr. Ko'ri.,,'. ~°ot at all in the sense tltat we are aware of their ap- proach. ~re are much more concerned wit.h the. basic mechanisms of ~ungsl persistence. They are concerned pr=marfly with the--you can correct me on this, perhaps--their activity is not concerned with profiling t,o~acco. They do not have the large samples of tobacco that we have. V~e, in essence, are using the samples of tobacco we get through the Agricultural Experimental Station "We are under r)rocess of negot=atmg a contract wh=ch wdl be concer=~ed with determining if there is any wtty that you can preclude the development of mold or create an en~-ironment that would be unfavorable to the de- velopment of this mold in tobacco. Our approach therc is essentially "to work out the mechanism to determine the presence of the hazar~ 0

with a vlew to identifyin~z techniques for buffering ~agalnst, or protect° ing against the hazard. This is not being done, a~ I recall, in the Uni- versity of Kentucky. " .. Mr. N,~TCttP.e. Now, Dr. Kotin, what other program's do you have tmderway in the l~eld we are t~lk'ing about? Dr. Kdaxx. VTe are not doing anytlting yet except evolving the tech. niques for the other side of t-he boin.. Pesticide residues in tobacco; we are concerned with the tobacco being a crop, as ~vith all other crops, edible or otherwise. Is there tt httz~trd in the residues of pesticides wMch remain at the time the consumer gets th~ product~. Mr. NA~etzR. Right at that point, Doctor,.do~_ou -know whether or not this type of rese~xroh is under way at the University of Ken- tuc_ky as far as pesticides are concerned ~, . . .: • . Have you ever checked, Doctor, to ~ind out just what the,v are doing down there? • : . " . Dr. Koa'xx. Yes, sir...I g~_t their quarterly and semiannual raper.as through the Deldartmen~ of Agr_iculture, I am aware of the $I.~ mil- lion • p_propriat[on they received and have been receiving for seve~l y~rs. The-Surgeon General was requested by the Secreta_ry of Agrt~ culture to designate a responsible person to represent the Department of Health, Education, and Welfare, and the Surgeon General. Terry, at.t.h.at time, designated me..I have been to Lexington. I would say within the last year no less than four scientists from the llniversit'y_ of Kentucky program have visited the National F.nvironmental Health Sciences Center. Dr. Burdick and Dr. Stedman, and Dr. Wood. ward and Dr. Senci from the Department of AgT_iculture, have been to the Ne, tional Center all within the la~ S montl~. In addition, several • discus*i0ns have been held ~vith Dr. Hoover of the Department of Agriculture. ' - " Mr. NXZ~HF.~. YOU were down there, Doctor. What did you find out. about research in regard to pesticides used in tobacco Dr. Kozr~'. _A_t tlie _University .o.f Kentucky, at t_hat.time there was tad mention of it in the presentation that was made that I attended. Mr. N^~roz~ze. The fact that it wasn't mentioned in the presenta- tion made during your presence doesn't mean it is not underway, does it ~ Dr. Korrr~. In the agronomy sch_ool there is a large amount of activity going on in the field of pesticides. • ~ $1ONXFICANC~ OF TOBACCO rN'D~S*I~° ~'OR Mr. NATOHZa. YOU know, Doctor, I serve on the Subcommittee on Agriculture Appropriations and I have for li years. The tobacco in- dustry is a $10 Dill[on industry. In .o9 States 700,000 families are in- velvet] in raising tob~xcco. ,~Iy home State of Kentuc.k~z'produces.mo.re tobacco than" ,any other three States in the United ~tates, with the exception of ~North Carolina. Beginning in 1958, Dr. Kot.in~on the Sub(~ommitte(~ on A~'icultural Appropriations, I informed the Depart- ment of AgTiculture that we needed more research in regard to tobacco. if tobacco is harmful to the health of the l~. ople in this cotmtry, we want to know about it. ". Finally I got the Departme~it of A~riculture and the House of Representatives to go along on an increase of about $'2.50,000. We

~ised that amount up to $1,5(~0,000~ which.as you know, is simply "drop in the bucket. When you consider all this money that you have ~ants, ~ the Department o~ Health~ Education, and ~ions o~ dollar~$1~5~,~0 is ~ust a drop in thv bucket. Do you agree to that, D~tor ~ - " ' " " . • " ~. K~-. It is certai~y R comparati~:~ly small amount• /bit. NA~cH~ When ~. Terry appeared before the Committee 0nAgricuIture after rel~sing the report o~ s~oking and h~alth, he ~as asked the question: Is there need at th~s t~me for additzonal re- .arch ~ tobacco~ You can go back and check the hearing. He said "Ab~lutely/' ' ~ .. "" " -'." - " ~e needmore research now." " ~ • " ". ~- " " That was within a m~tter o~ ~ weeks alter the ~port was re~ea~ed. ; Now~ Dr. Kotin~ in the State oI my colleague, )it. Hull here ~s~uri, and in my home State ol Kentuckw~all we are askip~ you and your a~iat~ to do is not to destroy a $10 billion industr~ until we have a chance to do ~meth~g about it.... . This is an im~rtant matter to a lot of people. We ~arted long you did, D~tor, and we started• ~n a small way~ and we are mnce~, and we ar~ honest"in our effo~s..We don~t intend lot yo~ 0r any~dy el~ to destroy the tobacco program. That is the reason that I am as~. ing you thee questions. " " " " .' .~ We have made a sincere effo~ and we ~ goin~o continue our ~ff0r~. My people, t~ay, Doctor, in 'the State o~entuckv believe that i~ tobacco is harmful to the health o~ our people, we must~lo s0me- • ~g a~ut it. But we want to stop all this~tesslng, Doctor. That is ~all we ask. ~t's ~ust stop the guessihg. " " . , That is the ~ason I am propounding these q~estions to you, ~d I am going to propound them to you as long as I serve on th~s committee. I ~y that to you frankly, . . " . • ~. Now, all we are trying to do is to make a g~d, hone~ e~ort to out what the trouble is and, i~ it is caused b~" tobac~, we Want to do .~mething a~ut it. That applies to you, D~tor, and ~t a~plies to all -o~your associates. ~hat is our feeling about this matter~ Doctor. .. Dr. K~x. I dont think we are ~ar apa~. ~en th~ Scientific Ad- ~ry Board to ~he ~bacco industry was establislted~ I was invRed ~ a charter mem~r and ~rred ~or 10 years on the c~mitt~. I obvi- ously ~elt that it was a situation that merited scientific attention and I a~umed I was invited ~cause of inter~t in the problem. However, had I lelt the situation was all locked.up and all the ~acts were kmown~ I never would have accepted mem~rship on the c~mmittee. I serve on the American Medical A~ociation Committee on Smoking and Health, on their advisory con~it~ee as further evidence of my conviction that. additional information ~s nece~ary. I ~ow the concept of a le~ hazardous cigarette is something t~at I have contrlbutedto, in part, ~ its evolution, and in term~ ofconviction ~cau~,.agaln, life is ~ho~ to spin wheals on things whidt there is little ~easibility achieving• • I don't tl~ink we a~e nearly as far ~part as would appear. Mr. Natcher. . • - that w% understan~ each other a little ~tter.. .. • . . .~. " :.. : ."

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; ~[r, N,~'ccm:R. The ~ational Cancer Institute has requested an propriation of $~.~ r~illion toward the support of a lung cancer task ~or_ce~ o~ ~hich you are a member. " . .' • • (}ire the committee some idea as to the use of this money and just what is being done. . " ... ~.~ - Dr. Ko~x. The lung cancer task force is concerned with initiating and supp0~rting studies concerned with identifying environmental fac- tors associated with increased risk to lung cancer, identifying the .compo.nent.s of the environment responsible for this!ncreased risk, and determining the mode of action of these agents for the purpose_ providing a firm scientific base on ~rhich to suggest methods for reduc- _~ or elfminating the hazards from the environment or protecting the ho~t ag~tinst their effects. Environmental experiences associated with an increased risk to lung cancer include urbttu residence, cigarette smoking, and certain occup.~tional exposures such as to chromates, nlcke], coking operations, asbestos, and alpha-ray emissions as .occur in uranium ~ines. The lung .cancer task ~orce proposes to initiate ~dies concerned with all of the environmental experiences associated with an increase_d risk to lung cancer and factors "concerned .with ~uscept~ility and resistance. In addition; resea_rch aimed at.~acilitating early diagnosis and i_mproved treatment is to b~ supported. " • In implementing _these. activitives it has already established a sub- ~ommittee concerned with the development o~ a less haz~trdous cigar. ette. This sub~mmittee is made up o~Fe_deral and hen-Federal sc~en- ~ the latter including representatives from the research laboratories of the tobacco industry. One meeting has already been held, and a O--day meeting is scheduled for May I and 2. At this time a rdview of the cur- rent_status of the problem will be completed and a series of recom- mendations for future efforts will be formulated. A plan of action to serve as a guideline has been evolved, utilizing a systems approach,. the_reby assuring the most effective utili_zation of fu'nds with pro~-m~m review procedures and decision points identified. The Division of E~- v~ronmeutal Health Sciences is collaborating w.ith the National Can- cor Institute and the National Heart Institute m this effort. • • Mr. NA'r~Hr~. I understand the lung cancer task force has proppsed t.hs investment of some $32 million, in the next 5 years in its total as- mgnment. Presumably a signific_ant percentage of that sum would be .d.dvoted to the smoking aspect of its assignment. In additiou, the Na- tional Cancer Institute, the National Heart Institute, the Chronic Dis- ease Control Center, and the Surgeon General's O~ce are requesting £~nds for research relatlng to tobacco and. health. I believe that correct, Dr. Kotin. V;'hat ~s your relation to these programs~ How does your Center fit into this ? ..... Dr. Ko~x. Our effo~'ts in this area are devoted exclusively to re- .re. arch for the purposes described in my answer to your earlier ques- tion on this subject and have no programmatic relation to the efforts- of the National Center for Chromc Disease Control The latter is con- earned with public educatlon and social aspects of b!~arette smoking as a patten~ of behador. The Directors of the three ~ IH components. concerned (Environmental Health, Cancer, and Heart) have met, and a~,zeed that with the approval of Dr. Shannon, the Division of En- vironmental Health Sc|ences would assume managerial responsibility for the collaborative efforts independent of the specific funds that

may be ava~able from ead~ of the .NTI-I nnits that have research in- terests and responsibiliti~ in this area. This will in~re a broadly ba~d, c~rdinated effo~ free of unnecessary duplication and, fur- thermore, will permit immediate im~hmentation o[ the results of re- .arch. Scientists ~om the three ~'IH components will meet at re~tlar laterals for the purpose of reri~w and measurement of p~ress. The l~g_caueer task force will ~ included as o~e activity wRhin this e~rdinated approach. " .... . ~ . ,.... • ' ~r. ~A~c~. Dr. Kotin, do ~ou ~lleve ns~stos may ~ e~using ~me cases of lung eaneer~ Is it true there is ~ g~d dea~ of ~sbestos ~ our general environment and in the ~tmosphe~ ~ Isn't it a fact, Kotln, that the inhalation of even one asbesto~ ~ber can cause n seri- ous r~plr~to~ problem, perhaps even lung c~neerJ " ~ ~. K~-. Occupational. exp~ure to ~sbestos t~ a~ociated with ~n ~cr~asad r]~ ~unff_eaneer. a~d_ withi~th~¢~~~" ~owledge, asb6stGs ~v ..~ 6aid t~ cause s~cases of .]u~ ca~c~-~r. The~ have ~en severa~ rece~ichYth~u~,~med e~*ther at autopsy o~ "surge(y--fr~ human . ex~d to asbestos ~'~ ~as the a~pearanc~ of ~sbe~. In addition, bod~es having m~c~optc characteristics ~f asbestos~ieg have also been ob~.ed. " "" A~stos fiM~ h~ve Men demonstrated in the lun~ of urban dwelle~ in Cane Town.~outh Africa: Montreal, Canada; Pittsburgh, Pa.; Miami, Fla.; and Bew York, ~.Y. The occurrence of fl~eSe bodi~ wried from ~0 to 30 percent s~ci~ens i~ some studies to as high as ~ vercent in othe~. • - : ~t~ at pr~ent are inadequate to state with ~alnty that the halation of one asbest~ fiber can cause ~rious r~piratory p~oblems or even lung cancer. Quantitative studi~ are now m prog~ m some in, rarefies to determine these matters. - Mr. ~A~VHZe. Have you any plans t0 have your Division mak~ ~V~tigatio~ to determine whether asbestos may ~ hazardous to mum " " " • " ~. K~x~-. We are certainly concerned with the auestlon as to the extent to which asbestos may be a health hazard. The Division, through its epidemido~- p~gram, is partidpatin~ in the ~cupational studies now in-p~re~s in the Public Health Service. The comphtion of the phase H construction of the X~HSC will make pogqibh the utilization of total-body ex~su~ cham~. Inhalation studies using ¢x~rlmental animals ex~ed to fibrous materials includin~ as~st~ are p~anned at present; though, of coupe, the knowhdge gained during" the next ~ yea~ may cause us to alter our s~ciSc resea~h plans. Individual scientists, including ~vself. are consulting with scientists at unlve~ities now e~gaged in inhalation studies on nsbest~. Mr. ~A~n. Dr. Kotin, thank you very much.. • " " Mr. H~. Dr. Kotin, I would like to concur in Mr. ~atcher's statement ~neerning your ability and hope for mutual unt]e~tand- ing, if I may. ~ .... .~xo~t~"0 .~xv. ~.~t,~,,~ -. e 1967 Publio H~alth Service ~vlew entitled VThe Health Con- en~s of Smoking' stat~ on page ~5 that the typical cha~cterlstics mn ~uamous-cell lung ~ncer have not heen experimentally pro- ? ~..

duced by to~cco smoke in animals and goes ~on to s~.v that this may never !~ achieved not only ~u~ it m~y not ~ ~ible to duplicate ~'s smo~g a~ion in ~nimals, but ~ ~cau~ of "diffe~uces ~ul~r ~pon~" ~tw~n m~n ~d amm~Is. ~ you ague with that ~-atlon ~ • . - . .... - Dr. K~H. The qu~tion is, Is there any re~zt why ci~tte smoke ah~d no~ ~ c~p~ble of inducing lung cazzcer in experimental ani- ~s ; is that the question ~ . • . • ..--.. ~., . ~ -. Mr.H~.Yes. " " ." .... ..~- -. " ~. K~'. I ~]ieve under the app~pr[ate conditions that• if, indeed, ~tte ~o~ng is the initiating and promoting cau~ of lung cancer, ~ ~rimenta] mede] can ~ developed. . : • Mr. H~ Would you al~ agree that the ~llular z~pozzse of the ~u~ of the s~n of mice is pro~bly diffe~nt from that of the human ~. K~'. At the ~e]lu]ar le~'el; y~ szr. _ . ~ ~. H~ In other w0r~, is it corot to ~y that the fact that Con- de~t~ of tobacco smoke can preducetumors on the skin of mice is n~ s ~entific~lly v~lid demo~tion that ci~tte smoke ca~x du~lung~n~rinmanl . • ' "~ .. • , " Dr. K~a'. ~o, I think that is going t~ far, sir. ~ think ~or other ~nts which we know can pr~uce tumor on the skin of mice, that h~ve un~uiv~1 e~dence ~f pr~ucing tumo~ of the lung in animals, ~e~ ~ examples ~'he~ thzs zs a fine izzdicator. ~at is corot. ~ Mr. H~. ~en the statement is made that ~ncer, producin~ chem- z~ a~ pr~ent in ci~rette smoke, it means only that these chemicals ~I p~uce cancer fn some animals and under experimental condi- fio~; is that co~t1 • . .. . : " ; " .. Dr. K~z~'. That is ~rrect.. " • ~ " • . " " Mr. H~. In view of the ~act that the~ are differences in cellular ~n~ ~tween animal ti~ues and human titus, isn't, it a fact that any effects produced inanimals with tobacco smoke or some con~itu- eat of smok% may not occur in man ~ . . . . Dr. K~z~'. I would say zt would ~ hkely to ~cur m man. ,.. " ~r~tTZO~" WXT*Z ZOS.(CCO " Mr; HVL~. ~'ow, Dr. K?~in, do youha~'e an oplniozz wi~.h regard to ~~ion ~'~n HEX~' and the tobacco industry ~ Dr. K~z~-. ~ ~ a ve~ strong one. I think it is almost itxdispensable to the ~lution of the problem. "Mr. HvL~ It has ~curred to me during the~ hearings that some of the statements ~ing made by the ~'ational Clearinghou~ axxd othe~ ~ ~yond the ~ientific ~act~ Don't you think that this makes it mox~ d~cult to ~t. c~nxtion ~ . " . " Dr. K~[~'. I thiztk for the ,~cord, fit~t, as ~ component of ~IH, ozzz. activities, except for ~ing undez' the axn~e Public Health Sez.s'ice b~lla, a~ unz~lated to the actix-lties of the clea~'it~ghot~se. . F~m the point of view of the effect of clearinghou~ stateme~ts on the c~perattve index, the e~ciencv of in~ormatlolt transfer" betxx'ee~t ~ience a~d indust~ and ~ience a~d governme~t, I ha~'e ~ot found it to ~ low or p~r. I have welcomed scientists h~m industry i~t out' Di~:ision, and ~-hen I visit ~ientists in indust~ labs, ~he w~Icome is m~t ~rdial. " . ." " ~ " .

Mr. HULt,. Doctor, would you have any sugge,stions.to make as to how HEW could get away from saying on the one hand that some.thing has been established and then ~.~king for substantial funds to do re- search.on the same subject~. . " " • Dr. Ko'r~.~'. I think this Is more or less the history of the evolution o5 control of disease. The establishment of the existence of a disease does nc~ carry with it the inevitable corollary that you can do n.othing about it. In fac~, however, when you want to commit the resources to .doing something 0.bout something--independeut of what tlxe p~obhm m~_ you should have a_ .bpdy of inf_o .rnmtion to_ warrant this effort._ I would submit at thi_s stage of_the an_me the information--at least to me--would be such that an efgort to do something ~bout it is not • only warrauted,, but highly desirable. , .. " OT~R RESEARO~ Oh" .~0~[1¢0 AND ~"rEALTR ..~. r. I:I~LL. ~ow.many dit~erent kinds of tess_arch progri~ms de_alin.~g w~ tobacco and healtl/, Gover~ment supported or not, are you famil- iar with, Doctor ~ - • • .- ' ....:..,~. " -. .... Dr. Ko'rz,-¢. I guess most would be it. • . Mr. H~.~.. Y~/u can l?ut it in the record. Such as Ab[A, Agriculture, NCI, your own, Council for Tobacco l~esearch, et cetera. • .-. Dr. Ko'rzt¢. I will be glad to answer that for the record.... ..... (The information.requested follows:) - " " .. - ~ I described in my testimony earlier, I am aware of the research program being supported by the b'atlonal Institutes of Health. In answer to the broader aspects of the question, through mY membership o~ the American Medical AS-. aoclation Committee for Research on T~bacco and Health, I am quite specifically aware of.its activltle.& This committee Is most particularly supporting rt~search In the areas of chronic obstructive respiratory dlsoas'e and degenerative resp[ra- tow changes and the cardiovascular eeeects of tobacco.. Studies are being sup- ported in private research Institutions as well as university and medical school laboratories. The Department ot Agriculture is concerned with providing bio- logical scientists with tobacco grown under controlled conditions so that the effects of genetic modification of tobacco plants as well as manipulation during growing, curing, and manufacturing can be studied. Further. studies related to the use of pesticides, suckering agents, and mlcroblolo~cal contaminants de- pond on Dermrtment of Agriculture cooperation. The Council for Tobacco Re- search (U.S.A.} is concerned with a broad program Involving the direct effects resulting from tobacco exposure as well as studies of many'human factors associated with relatively longer life and with relatively earlier death in human populations. They are trying to find out bow habits other than smoking tend to cluster with smoking or with uonsmoking or how these may serve singly or In groups as mathematical predictors of longevity. They also are supporting work to develop new mathematical methods of handing .large n~ultffactor studies in the Seld of epidemlology. • Mr. HUr~L. What is being done by each of these programs, to the ex- tent you haven't already told us~. " Dr. Koz~s-. Again, I think I could supply this for the ~cord ¢ausg_ each of the individual programs has a segment of the probhnt peculiar to the people w~o are responsib..h for it. " . Mr. Hu-~. Would b ou say then that-these are all pretty sound programs? . " ' I~r. Ko,rzx. I would say that all programg in tobacco and health are probably no different than programs ii~ other areas of biology. There m brilliant work, pedestrian work, and probably some that doesn't quite measure up.

879 ~ ]~[r. HIw.,L. Would you tell us how these programs are coordinated Dr. Ko'n,x. These pro~q-ams are coordlnated'by formal exchanges of information including reprint exchange ~nd conferences, by informal joint meetinff~_ and contacts, personal associations and acce~ to cane tral repositories of seientLfic information. The A.~fA Committee for Research on Tobacco and Health and the Council for Tobacco and Rese~rch exchange listlng~ of research projects by title and investl- gator. Research supported by the PHS as well as by other recognized granting agencms mcludmo various foundahons anc| other components of Government are listed in the Scientific Information Exchange. The title of the investigation, the name of t..he investigator, and brie~ ab- stracts o~ the proposed .research are avadable ~rom S.I.E. In addition, ~o~nt membe~-hip by scienti~s on several com..mittees proride~ impor- tant communication. For example, one scientist is'a member o~ the A~,[A committee, a member of the Scientific Advisory Board of .the Council for Tobacco Rescarch (U.S.A.), aud in addition serves on one o~ the advisory groups to the U'.S. Public I-[ealth Serv'ice. • In the past, X have served on tim Scientific Advisor)- Board of the Tobacco Research Council; I am at present on the A.~[A Committee on Smoking and Health and share responsibility for the NIH pr_ogram in tobacco and health. In addition, my associates and I are advisers to the D.epartment of Agriculture in relation to research support at the University of KentuckY. The lung cancer task force mem-t/ershlp in- ©ludes _representatives ~rom the Department of Agriculture, private research organizations, and the tobacco industry. Thus, coordination of these act~vlties is carried out through formal'administrative struc- tures as well as through the exchange of information resulting from publication of research findings in the scientific liter~ture. Mr. Hca.~.. Don't you believe more could be done by the Governme~it to coor~erate with ~he tobacco industry in the area of smoking and health? Dr. l~o'n~'. This is almost a l~_licy_ matter, and I am perhaps the wrong one to ask because from the days of my tobacco ihdustry re- search committee membership my relationships with the industry-have been so cordial that it has to be brought to my attention that there • eally isn't this cordiality up and down the line. • Mr. Ht'LL. ~[~" fiual c~uestJon is, what do you su~rgest to improve on thepresent situation. ... Dr. Ko'r[.,,'. In relation to industry? Mr I-Iv-~,t.. Yes, and you can rut that in the record i~ you like Dr. Ko'ns. One, I thm'~ industry representatives are, ~rom a techno- logical point of view~policywise--indispensable to the development of the scientific program within the Fe..d, eral Government, and I think Dr. Endicott has emvhasized his successful efforts to get industry represent.atives to deliberate and participate in programs. The Divi- sion certainly does this in terms of the body of in format".on the industry has. It is, first, not only deeper than a~-ailable ~rom other sources. but it can provide an effective base from ~-hlch w~ can build so there will be as little duplication as one can achieve. • ]~r. I'IVLL. Thank you, Doctor. . ' " '. "

THE AMERICAN MEDICAL 535 North Dearborn Street, Chicago, Illinois 60610 • • Area Code 312 527-1500 ASSOCIATION For A.M. Release Friday, May I0, 1968 CHICAGO--One of medical science's most intensive investigations gained additional scope today with pledges by six tobacco companies of an additional $8 million for the American Medical Association Education and Research Foundation's inquiry of smoking and health. 1973. into the relationship The new pledges assure support of the research program through All of the funds will be allocated by the Foundation to independent scientists conducting research in their own laboratories. Costs of administering the grants are paid by the American Medical Association and not from contributions. The program began in June, 1964, shortly after the ~rgeon G~n~al's Report on Smoking and Health was issued and the then- Surgeon General, Luther Terry, M.D., called for further research into the problem. Financial support c~me from the nation's physi- cians and an initial $I0 million grant from the same tobacco companies. Since then, 104 investigators or teams of investigators have been at work on the problem in 50 institutions in the United States and five foreign countries. 0

- 2- Association has repeatedly warned hazard; and this opinion has been scientific organizations. The companies aiding in support of the program are American Tobacco Co., Brown & Nilllamson Tobacco Corp., Liggett &Myers, Inc., Lorillard Corp., Philip Morris, Inc., and R. J. Reynolds Tobacco Co. Both the original grants from the firms and the new pledges were made without restrictions, said Gerald D. Dorman, M.D., vice- president of the Foundation. The only condition is that the money be used for research on tobacco and health, he said. Contributed funds go directly to the Foundation, and grants are awarded by a six-member co~,~ittee of scientiots. The committee includes two scientists who served on the original advisory com- mittee to the surgeon general. "For many years," said Dr. Dorman, "the American Medical that smoking may be a health supported by numerous other "But major questions about the problem remain unanswered by anyone--what is the exact chain of events inside the body when tobacco smoke is inhaled; which specific ills might be directly attributed to smoking; what are the elements in smoke which might create health hazards, and can these elements be minimized or eliminated?

-3- "~hese are ~mong the questions the Foundation is seeking to answer through basic research. "This matter of the relatlonshlp of smoking and health has become an emotion-laden issue, and the Foundation feels it is very important and that all avenues of exploratlon be kept open. Unless you have the scientific facts and explanations, you can't make absolute judgments." On June 19, a score of the independent scientist grantees from this r~atlon and abroad will report their findings to date to the nation's scientific co~unity during the AF~'s Annual Convention in San Francisco. At the same time, more than 90 additional reports will be published. Early drafts of those reports suggest several important find- ings. These include: * The most compelling evidence to date that dependence on smoking as a habit is psychological in origin, not physical. * Clinical trials which indicate that frequency of smoking can be reduced by intravenous injections of nicotine; but that two drugs widely used to help smokers quit either have no effect or may actually increase smoking frequency. * Further evidence supporting the long-held belief that patients with heart disease increase their risk of complications by smoking.

-4- * Extensive studies of pairs of twins, some of them smokers and some non-smokers, which indicate that genetic and environmental factors other than smoking also may play an important part in the development of angina pectorls and bronchitis. Subjects of other reports during the symposium will range from a clinical study of the effects of cigarette smoking in women to highly sophisticated physiological and biochemical studies of the effects of smoking on tissue. '~Ii of these investigations, some clinical and many quite basic in nature, add significantly to the body of scientific know- ledge about the effects of smoking on health," Dr. Dorman said. "But answers to the major questlons--what are the exact, scientifically documented effects of smoking on the human and his tissues; what, if anything, can be done to make smoking more safe-- are still inconclusive. "This reseach must be continued in the years ahead if answers are to be found." The tobacco companies, in pledging the additional $8 million grant, endorsed this goal. Five of the firms, Brown& Williamson Tobacco Corp., Liggett & Myers, Inc., Lorillard Corp., Philip Morris, Inc., and R. J. Reynolds Tobacco Co., pledged their support over the five years from 1969 to 1973. The sixth firm, the American Tobacco Co., currently pledged its support for the year 1969.

o 5- Members of the Foundation's scientific advisory committee for research on tobacco and health are: Maurice H. Secrets, M.D., Ph.D., chairman of the co~.~.mittee and chairman, Department of Pharmacology, University of Michigan Medical School; Richard J. Bing, M.D., chairman, Department of Medicine, Wayne State University; Robert J. Hasterlick, M.D., professor of medicine, University of Chicago School of Medicine; John B. Hickam, M.D., chairman, Department of Internal Medicine, Indiana University Medical Center; Paul S. Larson, Ph.D., chairman, Department of Pharmacology, Medical College of Virginia; and Paul Kotln, M.D., director, Division of Environ- mental Health Sciences, National Environmental Health Science Center. - 0-

IdeeClng of the C _c~m__ i~Cee for Research on Tobacco "~.u.d Heal~h !;~i:"": Januar7 30, 1968 (Afternoon Sess(0n) ~""- " i Part£cipants~ Committee for Research on Tobacco;and Health Tobacco Industry C. F. HeCsko American Tobacco Cor~ ldr. Philip R. Gran~ Vice President and General Counsel p. Lorlllard Compau~ 14~. Milton E. Harringccn Presiden~ • Mr. F. P. Haas Vice President and General Counsel Li88ett & Myers Tobacco Company Mr. George We£ssman Mr. Paul Smith Vice President .and General c~eel ~, .- David Hardy . philip Morris, Inc. Mr, A. H. Galloway President Mr. H. H. Ramm Vice President and General Counsel R. J. Reynolds Tobacco Company O 0

~obacco & Health Council for Tobacco Research American~edical Association w. N. T. Hoyt -. Executive Director Dr. Robert Hockett • - Scienti£tc Director Milford O. Rouse, M.D. F. ~J, L. Blas~u~ame, M.D. Executive-Vice President Ernest B. Howard, M..D. Assistant Executive Vice President Charles L. Hudson, M.D. Inmediete .Past President .and " :Dlrector~ DlVo. o£ Health Service ~- Director, Viv. of $ctentl£tc A~tlvities Ira Singer, Ph.D. Secretery, Conmittee got Research on Tobacco and Health INTRODUCTORY REIa~KS I Dr. Rouse called the meeting to order atl:30 p.m. end expressed the AHA's appreciation ~at the represenCative~ o~ the tobacco industry had come to meet with the Com=l~tee to evaluate the goals and progre~ o£ the Project for Research on Tobacco and Health. Hedi~ommented that'" in his travels as President of the Association he had~nd genuine interest ln, and approval of, the search for evidence which the industry is supporting through the Foundation. Dr. ~lasingame indicated that the Board o£Trustees had instructed him to initiate a discussion o£ the cooperative eg£orts between the .~ tobacco industry and the Foundation during the las~ four years and the future of this relationship. This meeting was arranged to give the industry representatives an opportunity to meet the advisory committee and to discuss its activttiesooespecially the "progress report" ~o the public, industry, and pro£esston which will be included in the program of the Council on Scientific Assembly at the AHA Annual meeting in San Francisco in Juneo-and, £rom an:~admfnistrative standpoint, to ascertain whether this program will be continued, modif~ed, expended, or phased out.

Tobacco & Health " - Dr. Seevers reported that the Committee had viewed C~e problem of tobacco and health as a whole Co determine .~ha_mosc aff~cCiva~use of the induscry's contribution. ~W£chin of Federal ~nds available aC ~hac ~Ci~ ~for aii~C~e~bf~-~se~ch and the level of support for work in carcinos~es~s~"~e~~E~e• ~ec£ded co concentrate its efforts on f~d~n~al cardio~v~.q~ui~k, ~rebpirs~o~, and psycho-pha~acoiosical re search.~ I C ~s 6ush~ ~,t~f'~ul~Y"~ onsolns p~oJecCs by cllulcal ~nvesCfsaCors ~ch?~d~#~t~~e~d ~apabilicles In chess li~ced areas. The C~ccee general c~cepts, with the addition of a fell~~~r~ ~ncended co increase ~nCerest in ~his field.- {~.~ probl~ had pried unsaCisfacto~, ..-.~ Dr. B1aslng-- added t~ his Co him suggested ChaC the reasons fo~-~ch~-"JO£~::~ ~derscood and chaC the-~ posiCl~ had been~:sC~e~Ch~ed, has conducted an appropriate health eduction people buc ~inca~ns Chat no causal ~elaei~shlp;:~e~een:.cobac~ health has been de--aerated and ~cher ~esear~h: is~necessa~ co elucidate any ~htch m~hc exist.- ~adielonally~ .such debate sh~ld be carried on through the ~'s scientific publications and noC through the ~ss co~unicactons medta DISCUSSION OF PROG~ ._S.a.n Fr, an¢tsco Meeting Dr. Seevers reported that the Comm~tCee had :received:cwo abstracts from each of its grantees and would select eighteen r~o ~Cwenryl papars representln& the basic and clinical aC the day-long ~en ~eClng. -Durlng.:Che people ~I~1 s~rlze these obse~ac£~s ~e brief abstracts ~111 be published In the g~erai~.~o~sm and the more deca£1ed reports on the status and progress~of~e:-~d£~duai" pro~ects will be published In a separate book.

Tobacco & Health Publlca~ion of Research: In response to Hr. Smith's question about-~he Committee's in~ent of publlshin8 neaatlve as well as :-:-~: positive results, Dr. Seevers pointed out that the Comaittee no mechanism for this and that only the editors of the Journals to which grantees choose to submit their manuscript.s~e~i~" in a position ~o make this decision. Dr. Hickam added that a"~kn~tee would feel some compulsion to publish unexpected answers in order~o conv£nce the Committee that his accomplishments merlted~contin~}i~ In ~nswerlng a subsequent question from Dr. Sockett, indicated ~he Commiteee had discussed the possibillty of publie~,~ an annual report but concluded that its program had not been operaelon long enough to prepare a ~eaningful evaluation.- the reports fr~n ,the San Francisco meeting should constitute~St~ Dr. Singer described the procedures followed after tha recon~nends appx'oval of an application, emphasizing that the @m subject to annual renewal and this is based on the inveseigaeor~s~ report of his progress--positive or negative--and that thismat~Y~al is available upon~equest. S~atus.of P~oJect ~ ~~ Dr. -Seeve~reported that almost $7 million of th~origi~al con~ribution had been committed. In response to Hr. Ye~len, ~ indicated thac the Committee had been able to approve grants considered worthwhile; it rejects about half of the _some t~enty applications submitted to it each quarter. Dr. Singer has en- deavored to interest deans o£ medical schools and particularly well qualified scientists in this p~ogram.although the Committee doesnot automatica~ly approve solicited applications. Recent awards have averaged $~0,000 - $100,000 over a t~o- to three-year period. Areas of Research Hr. Hetsko asked the Con~nittee., on the basis of their previous experience with this p~ogram and their knowledge of recent developments in the areas they had been supporting, if it intended to continue to direct its ~unds into these fields or if some would be emphasized more than others.

Tobacco & Health Dr. Kocln agreed thac ch~sCabllsl~aenc of sc~e prlorlC~es was inevitable in approv£ng~so~ applications buc no~ others, however~ the Committee is ltmi~@d by the requests sub~i~ed ~o ic. In Judging these applica~£bns, the Committee also considers ~he ~ric o~ ~he work~ ~he~c~e~ence of ~he investigator, and,~he relevance co ~he goals o~ ~h~oJec~.'~- Cancer: Dr. Seevers explained ~ha~ ~he C~it~ee had e~hasizsd ~ ~ - areas o~her than cancer research because of £~s inability ~o c~e~e w£~h ~isC£ng larse scale .e~fO~Csand ~he .difficul~y of discrl~na~£n8 between proble~ rela~ed s~.~c~f£cally ~o ~obacco and ~hose c~cerned ~h carcinogenesis of ne~ak~' Nevertheless, Dr. /~o,~i~.~Ced .Chat ~he Cousn£Ccee had pupporCed some excellent research ~r~laCb~Co' this problem althoush che£r.~ relevance is noc apparenC~!~i-Cheir.cttleS because che~ are.con- cerned with the cellular ~e~onse tocancer. One £nvestiSaCbr has been ensaged in an accempC/~o,decermine if enz~nnactc de£e~ses can be enhanced suf£1cienClyCo~proCecC an£mals exposed to carc£no~enic chemicals. Anocher sCud~ has traced Chebiolosical path £ol~owed after an agent attacks Che~receptor stte wiChin the cell in order to elucidate the mechanism o£ clearance. .Cardio-vascular: Wlch'regard Co card,o-vascular research, Dr. Bfngmeution~d' tha~ a s~udy supported by ~he Couxnit~eehad produced ~he signf~lcanC~.~iscovery chat circulation in the normal system is not ir0pa~red by smoking, whereas it is in a ~.seased~ o~e. Respiratory: Dr. Hickam cited a recent discovery~-~uthis field ~hich associates the lack of a specific immmoproCein with the early development of emphysema regardless of whether the ~ndtvid~al smokes. The ConzntCtee has Just ~ade a ~ranc for a survey o£ iu~amopro~eins ~u t~e blood co learn if there ar~ ocher ~elated abnormalities and to determine if there is a segment of the p.~pulaCion which ~s~ore suscep~ible co emphysema. psychopharmacolo~ical: Dr. Seevers described so~e ofthe psychological approa~he~~poin~lng ouc chacsmoking isa partly psychological and partly pharmacological drive. That nicotine does not produce physical dependence,~has been reasonably well established in ~ower animals buC the~data are difficult to extrapolate. ~oreover, iC has been necessary to establish more

Tobacco & Health -~. sensitive methodology to determine the amount of nicotine in clrculating blood and its fate in the body. A current study has shown that an intravenous injection of 4mg ofni~otlneper hour is necessary co af£ecc the smoking patterns of humanvolunteers. Increases in heart rate and blood pressure su~es~.~£hat one :of the drives to smoke may be a blood pressure too lowtb.~ibe comfortable. Evaluatlon Id~. Ramm asked the Conznittee to con,~ent on th~ criticisms of individual projects raised by members of his scientific staff. For example, he questtcned the advisability of' 8rants.i;O study the influence of nicotine on HC1 secretion by the stomach, and-the~!eggeccS of nicotine on hi~tamlne levels. Dr. Larson objected that the abstractsi...andi~.~e'sdlstrlbuted to the industry ~ere an Inadequate basis for such Jud~nts, po~nting out that the HCI study ~as an attempt to understandt~-mechanis~ involved In this phenomenon. Dr. Kotln affirmed that the ~ile~nce of the actual experimen~l protocol is the critical basis for evaluation. Because of the wide spectrum of response to insult found In any population, it is Imposslble to identify the Indlvldual who is at risk unless ~he ~undamental mechanism is understood. In reply toHz. Hetsko*s inqulr~abou~he ~ults from the $~0,000 gra~c on smoking and cough presently be~ terminated, ~r. Hasterllk report~Cha~ in reevaluatlng this work, which was ~es~gued to analyze ~atterns of sound and describe .the different phases of cough related to differences in abnormal pulmonary function such as chronic bronchitis, the Committee felt it had produced some important information but the potential yield.was not as profitable as other possibilities and cons~queuc~ ~!~ ~L.was.c~ b~ck, Liaison with Council r Staff of both groups concurred that .in spiteof somedupllcatlon of support at the time the project was Initlated, they ihave effectively discouraged investigators from applying to both organizations. In add~t~.on to the staff communication, chert is an over~ap..i~i membership

~obecco & Health ..... ~ on the advisory ccms~Lttees and better methods of screening ~ppli~ions have been developed. However, Hr. Hoyt stressed the. need o~ possible c~1~cac~ons as the reduced avattab~li~y of Fede~~ds ~ncreases the n~er of app1~ca~ons sub=~ed ~o ~he ~o groups. ~ On behal~ of the Committee, Dr. Seevers expressed thel that ~t ~ould be posslble to continue the present pursue the exploration of ehe n~ny remaining unsolved this area. It is £elt that such support £rcnn the will be increasingly ImporCanC~ both because che reduced its spending and because ch~s approach enables Co plan his research more than one year in advance. l~c. Ra~ thanked the CouzciCCee £or the opportunity them and indic~Ced that the decisions o£ the individual with regard to authorizing ~urCher support would be communlCl rheA HA as promptly as possible. -:--..:~:i..... "

TH~ /k~ICAN ToB,~cco COF~PANY OFI~C~ Ol~ 'I'HE PHESIDENT AND ~HA|RJ4A~ Ol~ ~'HI~ ]~OAHD February 29, 1968 Doctor F. J. L. Blasingame Executive Vice President American Medical Association 535 North Dearborn Street Chicago, Illinois 60610 Dear Doctor Blasingame: I am writing you to give you my thoughts regarding my Company's continued participation in the work of the American Medical Association Education and Research Foundation to which tobacco companies have been contributing under a five-year grant that ex- .pires with 1968. In this connection, I have had the benefit of a report by Mr. C. F. Hetsko, our Vice President and General Counsel, of the discussions at the recent meeting in Chicago at which I understand there was a consensus that smoking and health ques- tions have not been resolved and that additional research is indicated. I also understand your own feeling to be that research will be far from completed by the end of the present grant period. With these considerations in mind, we are pleased to advise that for 1969 we will continue to contribute on the same basis as heretofore, namely, $500,000. We will then again consider the progress being made and what our further contribution to the research program may be. This arrangement, X hope, will be satisfactory to you. In closing, let me say that we here very much appre- ciatethe constructive attitude with which we under-

Doctor F. J. L. Blasingame -2- February 29, 1968 stand the AMA Education and Research Foundation has been and ks approaching the subject of smoking and health. R~,I~erely' rt B. Walker President and .Chairman of the Board

173~ K ,~TF~E~-T~ NORTHWEST WASHINGTON, D. C. 20006 February 24, 1968 Mr. Robert B. Walker President and chairman of the Board The American Tobacco Company 245 Park Avenue New York, New York 10017 296-8434 Dear Barney: I have given considerable attention to your letter of January 2, 1968, concerning continued support of the American Medical Association Education and Research Foundation Project of Tobacco and Health--which letter, as you may know, was delivered to me only upon my return to the office after gaining doctor's approval. Pursuant to your suggestion, I have taken this matter up with the other five companies. I am glad to report that the industry appears to be nearing a consensus. More precisely it appears that four of the other five companies favor another five-year commitment. The other company presently prefers a commitment for three years. I gather from your letter that you are thinking in terms of five years also. As to the amount of annual dollar contribution, the other five companies incline to the same total amount per year as heretofore; whereas your letter indicates a preference for a reduced total annual contribution. Speaking as one of your representatives, I believe that. the willingness of the A.M.A. to endorse another five-year program of the same total amount is a clear indication to the public that, in their judgment, a real controversy exists, the answers are not in, and they will not be in for many years. While I would not say that a shorter period or a

Mr. Robert, S. Walker - 2 - February 24, 1968 reduced dollar volume of support would completely destroy those benefits, it does seem to me that it puts the industry in the position of saying that the problem is not as complex or as difficult to solve as the A.M.A. is prepared to admit. Obviously it disadvantages us to minimize the complexity of the problem. I shall be glad to discuss this matter with you by tele- phone, or when the doctor permits me to travel, if you wish, I will come.to New York. On the other hand, it occurs to me that you may wish to invite the other chief executives to meet with you for a discussion of the matter. Kindest personal regards. Sincerely, '~ .. 5-.. .... ~.~RLE C. CZE~mNTS ECC/pmp

March 26, 1968. American Medical Association Education and Research Foundation, 535 North Dearborn Street, Chicago, Illinois. 60610. Gentlemen: The undersigned companies and TheAmerican Tobacco Company in their joint letter to you dated January 31, 1964, severally expressed their willingness to contribute to the Foundation during the period 1964 through 1968 the total.of ten million dollars to be used together with other funds made available for the purpose in financing the research project proposed by the Foundation to determine which significant human ailments may be caused or aggravated by smoking, how they may be caused, the particular element or elements in smoke that may be the causal or aggravating agents and methods for the elimination of such agents. Acceptance of the offer of the various companies was expressed in your letters dated February 12, 1964 to each of them. In our recent discussions in Chicago, the Foundation indicated the inconclusiveness of research to date and the necessity for continuation of research in the years ahead if answers are to be found. To enable the Foundation to plan for and continue sponsorship of needed research the companies involved were requested to continue beyond 1968 their financial support of the research project. The undersigned companies are willing, upon the same terms as set forth in the letters dated January 31, 1964 and February 12, 1964, to continue their financial support of the research project during the period 1969 through 1973 by contributing a total of $7,500,000, the contribution of each of the undersigned companies not to exceed the amount set underneath its name. The contribution of each would be paid in approximately equal annual amounts. It is our understanding that you have received a commitment from The American Tobacco Company to support this research by an additional contribution of $500,000 to be made in 1969. Hopefully that Company will renew such contribution

American Medical Association Education and Research Foundation. March 26, 1968. Page 2. in the subsequent years included within the commitment of this letter. Please indicate to each of the undersigned whether you are agreeable to receiving their proposed contributions in accordance with the terms indicated. Very truly yours, BROWN & WILLIAMSON TOBACCO CORPORATION ~ ~" _ " President Amount: $1,380,000. 1600 West Hill Street, Louisville, Kentucky. LIGGETT & MYE$S TOBACCO COMPANY ...~:", ~ - , / Pres'ide~t Amount: $ 780,000. 630 Fifth Avenue, New York, New York 10020. ~/~esident Amount: $ 982,500. 200 East 42nd Street, New York, New York 10017.

American Medical Association Education and Research Foundation March 26, 1968. Page 3. PHIL]IP MOR~JS INCORPORATED C ~a~rman o'f the B~ard. Amoun ~: ..$1,222,500. i00 Park Avenue, New York, New York 10017. R. Jo REYNDLDS TOBACCO COMPANY Amount: $3,135,000. Winston-Salem, North Carolina 27102.

Meeting of the Committee for Research on Tobacco and Health January 30, 1968 (Afternoon Session) ' " Participants: Committee for Research 'on Tobacco and Health Tobacco Industry SUMMARY MINUTES Maurice H. Seevers, M.D., Ph,D., Chairman Richard J. Bing, M.D. Robert J. Hasterllk, M.D. John B. Hickam, M.D. Paul Kotin, M.D. Paul S. Larson, Ph.D. Mr. C. F.Hetsko Vice President and General Counsel American Tobacco Corporation Mr. Addison Yeaman Vice President and General Counsel Brown & Williamson Tobacco Corporation • .. Chai~nv~-~ LLu ~u~d Mr. Philip R. Grant Vice President ~and General Counsel P. Lorlllard Company Mr. Milton E. Harrington President Mr. F. P. Haas Vice President and General Counsel Liggett &Myers Tobacco Company Mr. George Welssman President Mr. Paul Smith Vice President and General Counsel Mr. David Hardy Philip Morris, Inc. Mr. A. H. Galloway President Mr. H. H. Ramm Vice President and General Counsel R. J. Reynolds Tobacco Company

Tobacco & Health "2- Council for Tobacco Research American Medical Association Mr. N. T. Hoyt Executive Director Dr. Robert Hockett Scientific Director Milford O. Rouse, M.D. President F. J. L. Blaslngame, M.D. Executive Vice President Ernest B. Howard, M.D. Assistant Executive Vice President Charles L. Hudson, M.D. Immediate Past President and Director, Div.. of Health Service Hugh H. Hussey, M.D. Director, Div. of Scientific Activities Ira Singer, Ph.D. Secretary, Committee for Research on Tobacco and Health INTRODUCTORY REMARKS Dr. Rouse called the meeting to order at 1:30 p.m. and expressed the AMA's appreciation that the representatives of the tobacco industry had come to meet with the Committee to evaluate the goals and progress of the Project for Research on Tobacco and Health. He commented that in his travels as President of the Association he had found genuine interest in, and approval of, the search for evidence which the industry is supporting through the Foundation. Dr. Blasingame indicated that the Board of Trustees had instructed him to initiate a discussion of the cooperative efforts between the tobacco industry and the Foundation during the last four years and the future of this relationship. This meeting was arranged to give the industry representatives an opportunity to meet the advisory committee and to discuss its activities--especially the "progress report" to the public, industry, and profession whichwill be included in the program of the Council on Scientific Assembly at the AMAAnnual meeting in San Francisco in June--and, from an administrative standpoint, to ascertain whether this program will be continued, modified, expanded, or phased out.

Tobacco & Health -3- Dr. Seevers reported that theCommittee had viewed the problem of tobacco and health as a whole to determine the most effective use of the industry's contribution. Within the context of the large amount of Federal funds available at that time for all types of research and the level of support for work in carcinogenesis, the Committee decided to concentrate its efforts on fundamental cardio-vascular, respiratory, and psycho-pharmacological research. It sought particularly to support ongoing projects by clinical investigators with demonstrated capabilities in these limited areas. The Committee would continue to follow these general concepts, with the addition of a fellowship program intended to increase interest in this field. Dr. Hudson stated his belief that the objectives of this program were worthy of further pursuit inasmuch as other approaches to the problem had proved unsatisfactory. Dr. Blasingame added that his correspondence and comments made to him suggested that the reasons for the joint endeavor were better understood and that the AMAposltlon had been strengthened. The AMA has conducted an.approprlate health education program directed at young people but maintains that no causal relationship between tobacc4) and health has been demonstrated and further research is necessary to elucidate any which might exist. Traditionally, such debate should be carried on through the AMA's scientific publications and not through the mass communications media. DISCUSSION OF PROGRAM San Francisco Meeting Dr. Seevers reported that the Committee had received two abstracts from each of its grantees and would select eighteen to twenty papers representing the basic and clinical aspects of the problem to be presented at the day-long open meeting. During the final hour, a panel of four people will summarize these observations and suggest future objectives. The brief abstracts will be published in the general program and the more detailed reports on the status and progress of the individual projects will be published in a separate book.

Tobacco & Health -4- Publication of Research: In response to Mr. Smith's question about the Con~nittee's intent of publishing negative as well as positive results~ Dr. Seevers pointed out that the Co~nlttee has no mechanism for this and that only the editors of the scientific journals to which grantees choose to submit their manuscripts are in a position to make this decision. Dr. Hickam added that a grantee would feel some compulslon to publish unexpected answers in order to convince the Committee that his accomplishments merited continued support. In answering a subsequent question from Dr. Hockett, Dr. Seevers indicated the Committee had discussed the possibility of publishing an annual report but concluded that its program had not been in operation long enough to prepare a meanlngful evaluation. However, the reports from the San Francisco meeting should constitute such a summary. Dr. Singer described the procedures followed after the Committee recon~ends approval of an application, emphasizing that the grants are subject to annual renewal and this is based on the investigator's report of his progress--positive or negatlve--and that this material is available upon ~equest. Status of Project Dr. Seevers reported that almost $7 million of the origlnal contribution had been committed. In response to Mr. Yellen, he indicated that the Committee had been able to approve grants considered worthwhile; it rejects about half of the some twenty applications submitted to it each quarter. Dr. Singer has en- deavored to interest deans of medical schools and particularly well qualified scientists in this program although the Committee does not automatically approve solicited applications. Recent awards have averaged $50,000 - $i00,000 over a two- to three- year period. Areas of Research Mr. Hetsko asked the Committee, on the basis of their previous experience with this program and their knowledge of recent developments in the areas they had been supporting, if it intended to continue to direct its funds into these fields or if some would be emphasized more than others.

Tobacco & Health -5- Dr. Kotin agreed that the establishment of some priorities was inevitable in approving some applications but not others; however, the Committee is limited by the requests submitted to it. In judging these applications, the Committee also considers the merit of the work, the competence of the investigator, and the relevance to the goals of the Project. Cancer: Dr. Seevers explained that the Committee had emphasized areas other than cancer research because of its inability to compete with existing large-scale efforts and the difficulty of discriminating between problems related specifically to tobacco and those concerned with carcinogenesis of neoplasms. Nevertheless, Dr. Kotin stated that the Committee had supported some excellent research related to this problem although their relevance is not apparent, from their titles because they are con- cerned with the cellular response to cancer. One investigator has been engaged in an attempt to determine if enzymatic defenses can be enhanced sufficiently to protect animals exposed to carcinogenic chemicals. Another study has traced the biological path followed after an agent attacks the receptor site within the cell in order to elucidate the mechanism of clearance. Cardio-vascular: With regard to cardlo-vascular research, Dr. Bing mentioned that a study supported by the Committee had produced the significant discovery that circulation in the normal system is not impaired by smoking, whereas it is in a diseased one. Respiratory: Dr. Hickamcited a recent discovery in this field which associates the lack of a specific i~,nunoprotein with the early development of emphysema regardless of whether the individual smokes. The Committee has just made a grant for a survey of immunoprotelns in the blood to learn if there are other related abnormalities and to determine if there is a segment of the population which is more susceptible to emphysema. Psyc~opharmacological: Dr. Seevers described some of the psychological approaches, pointing out that smoking is a partly psychological and partly pharmacological drive. That nicotine does not produce physical dependence has been reasonably well established in lower animals but the data are difficult to extrapolate. Moreover, it has been necessary to establish more

Tobacco & Health -6- sensitive methodology to determine the amount of nicotine in circulating blood and its fate in the body. A current study has shown that an intravenous injection of 4 mg of nicotine per hour is necessary to affect the smoking patterns of human volunteers. Increases in heart rate and blood pressure suggest that one of the drives to smoke may be a blood pressure too low to be comfortable. Evaluation Mr. Rammasked the Commlttee to comment on the criticisms of individual projects raised by members of his scientific staff. For example, he questioned .the advisability of grants to study the influence of nicotine on HC1 secretion by the stomach, and the effects of nicotine on histamine levels. Dr. Larson objected that the abstracts and titles distributed to the industry were an inadequate basis for such judgments, pointing out that the HCI study was an attempt to understand the mechanlsm involved in this phenomenon. Dr. Kotln affirmed that the elegance of the actual experimental protocol is the crltlcal basis for evaluation. Because of the wide spectrum of response to Insult found in any population, it is imposslble to identify the individual who is at rlskunless the fundamental mechanism is understood. In reply to Mr. Hetsko's inquiry about the results from the $400,000 grant on smoking and cough presently being terminated, Dr. Hasterlik reported that in reevaluating this work, which was designed to analyze patterns of sound and describe the different phases of cough related to differences in abnormal pulmonary function such as chronic bronchitis, the Committee felt it had produced some important information but the potential yield was not as profitable as other possibilities and consequently this grant was cut back. Liaison withCouncll Staff of both.groups concurred that in spite of some duplication of support at the time the project was initiated, they have effectively discouraged investigators from applying to both organizations. In addition to the staff communication, there is an overlap in membership

Tobacco & Health --7-- on the advisory committees and better methods of screening applications have been developed. However~ Mr. Hoyt stressed the need for awareness of possible complications as the reduced availability of Federal ~unds increases the number of applications submitted to the two tobacco groups. SUMMARY On behalf of the Committee, Dr. Seevers expressed the hope that it would be possible to continue the present program and to pursue the exploration of the many remaining unsolved problems in this area. It is felt that"such support from the private sector will be increasingly important, both because the government has reduced its spending and because this approach enables the investigator to plan his research more than one year in advance. Mr. Ramm thanked the Committee for the opportunity to meet with them and indicated that the decisions of the individual companies with regard to authorizing further support would be communicated to the AMA as promptly as possible.

The Broadmoor Colorado Springs, Colorado • Novembe~ 1-3, 1966

Your badge is your ticket of admission to all events. PROGRAM CONFERENCE AND WORKSHOPS FOR RESEARCH ON TOBACCO AND HEALTH Stanhope Bayne-Jones, General Chairman Sponsored by American Medical Association Education and Research Foundation Committee for Research on Tobacco and Health Maurice H. Seevers, Chairman Richard J. Bing Robert J. Hasterlik John B. Hickam Paul Kotin Paul S. Larson The Broadmoor Colorado Springs, Colorado November 2-3, 1966 The contents of this program and the abstracts are not for publication.

12:00 - 5:00 p.m. Mc, zzanine Tuesday, November 1~ 1966 Regi strat ion 9:00 - 9:45 a.m. Oval Room 9:00 9:05 9:15 9:20 10:00 - 12:00 El I'on~ar Room Wednesday~ November 2 General Session 1966 Welcome on behalf of the American Medical Association F. J. 1.. Blasingame, Executive Vice President 1'he Education and Research Foundation and its relationship to the project for research on tobacco and health Hilford O. Rouse, President Elect, American Hedical Association Introduction of guests and Con~nittee ]'he goals of the project for research on tobacco and health, how such goals are being satisfied by means of current awards, and the various lines of research supported blaurice tl. Seevers, Chairman, Conunittee for Research on Tobacco and Health Session on Pulmonary Function and the Effects of Smoking (Section 1, abstract book) Hoderator: John B. Hickam Department of Medicine Indiana University Rapporteur: Alfred l'. Fishman Department of Medicine College of Physicians and Surgeons, Columbia University

10:00- 12:00 E1 t'omar Room 10:00 - ]2:00 Ova I Room Session on the Effects of Smoking on Cardiac Metabolism (Section 3, abstract book) Moderator: Richard 3. Bing Department of Hedicine Wayne State' University Rapporteur: Ray Pryor Department of Medicine University of Colorado Session on the, Psychopharmacological Action of Nicotine and Smoking (Section 6, abstract book) Moderator: Paul S. 1,arson I)epartment of Pharmacology Medical College of Virginia Rapporteur'. E.F. Domino Department of Pharmacology University of Michigan 12:15 - 1:15 p.m. Copper Room 1:30 - 4:30 p.m. E1 Pomar Room 1:30 - ,"~:30 p. E1 po>~ar Roo> ] :30 - 4:30 p.m. Oval Roon, I,uncheon Session on the Effects of Smoking on the Respiratory Tract (Section 2, abstract book) Moderator: John B. Hickam Department of Medicine Indiana University Rapporteur: Alfred P. Fishman Department of Medicine College pf Physicians and Surgeons: Columbia University Session on the Effects of Smoking on Cardiovascular Function (Section ~, abstract book) Moderator: Richard J. Bing Department of Medicine Wayne State University Rapporteur: Ray Pryor Department of Medicine University of Colorado Workshop on the Relationship of Carcinogenesis and Infection to Tobacco Use (Section 5, abstract book) Moderator: Robert 3. }tasterlik Department of Medicine University of Chicago Rapporteur: Matthew H. Block Department of Medicine University of Colorado

1:30 - 4:30 p.m. Sun Room 6:30 - 7:30 p.m. Ballroom 7:30 p.m. Ballroom Session on the Biochemical Pharmacological Properties of Nicotine and Smoking (Section 7, abstract book) Moderator: Paul S. Larson Department of Pharmacology Medical College of Virginia Rapporteur: E.F. Domino Department of Pharmacology University of Michigan Reception Dinner 9:00 - 12:00 Oval Room 9:00 9:20 9:30 9:50 I0:00 10:20 10:30 10:50 II:00 Thursday, November 3~ 1966 General Session Report of Workshop on the Relationship of Pulmonary Disease to Tobacco Use Alfred P. Fishman, rapporteur Discussion Report of Workshop on the Relationship of Cardiovascular and Coronary Disease to Tobacco Use Ray Pryor, rapporteur Discussion Report of Workshop on the Relationship of Carcinogenesis and Infection to Tobacco Use Matthew H. Block, rapporteur Discussion Report of Workshop on the Pharmacological and Psycho- pharmacological Action of Tobacco and Tobacco Components E. F. Domino, rapporteur Discussion General Summary Stanhope Bayne-Jones, general chairman

EVALUATION OF PHYSICAL DEPENDENCE. PSYCHOGENIC DEPENDENCE AND TOLERANCE TO NICOTINE IN THE MONKEY~ O. A, Deneau,~ Retzo In.okts. and Daniel E. BrLtton Department of Pharmacolog),o The Untverstt~ of MtchL~n Medical School Ann ~rbor. Michigan These h~vesttgattons were designed to determine which of the more common elements of drug abuse, ff any, are attributable to nicotine. In the study of phys..lcal dependence, 4 groups of § monkeys each were used. Ono group received 118 mg/kg nicotine sc every 6 hours for 90 days (calculated to be roughly equivalent to the nicotine absorbed by a ~.-pa~,keoa-day smoker). The second group received 9./$ mg~kg sc every 6 hours for 90 days. The third group received 9./3.mg]kg sc every 0 hours inttislly, but the dose was raised as rapidly as possible consonant with good health of the monkeys. This " group was treated for 7 months, the ultimate dose being 17 mgIkg every (} hours. The fourth group was not treated -- it served as a growth-rate control group. Water solutions of the'a~kaloid were used throughout in concentrations such that the dose per kilogram was always contained tn 0. 9.5 co. A 48-hour test withdrawal w~s conducted after one month of treatment, The group on the ascending ~tose was withdrawn for 6 days at the end of three months before treatment was resumed. No outward signs indicative of an abstinence syndrome were observed in any group at any withdrawal period. It must be concluded that physical dependence to nicotine did not develop under the conditions of this experiment, Tolerance developed to several of the effecis of nicotLne such as increased heart rate, respiratory rate, emesis, and convulsions.. The tolerance, 5020"/ ?320,

l~ge B t~chyphylaxis would be a better term. was demonstrable in normal monkeys within $0 minutes and persisted for only 90 minutes with resider to change in heart rate and respiratory rate. After a period of chronic dosing and then withdrawal, the monkeys lost their tolerance and, in fact, became supersensitive to nicotine in 24 hours. The supersensitivity' persisted for 7o10 days. Although the LDs of nicotine was not determined, reports in the literature, coupled with experience from ace|dental overdosing, indicate that the LD~o is below |7 mg/kg, which was salt|safely attained in the chronic studies. From this, it is assumed that tolerance also develops to the lethal effect of nicotine. " P'sychogenlc dependence may be sa|d to have been demonstrated ff a monkey voluntarily initiates and maintains self-administration of a drug. In one o ¢ experiment, nine monkeys, housed lnd|vldually, .had a choice of drinking tap water or solutions of nicotine water. The consumption of both was recorded. In concentraUons up to 100,, gm/ml of nicotine, the monkeys appeared to be unable to discriminate between nicotine solution and tap water. monkeys developed an aversion for the nicotine solution. At 400. gm/ml, the There was no clear evidence of psychogenic dependence to nicotine in this experiment. In another experiment, 7 monkeys were prepared with intravenous catheters and by pressing a lever they could activate an injector to deliver an intravenous dose of nicotine. If the monkeys did not spontaneously initiate self- &dmb~istrat|on, injections were automatically delivered at hourly intervals by • timer mechanism. In this mode of operation, the monkeys could take supple- ss~entary hlJectiorm by pressing the lever. At a dose of I0 p grn/kg, none of the

Page $ monkeys initiated self-administratlon, even after a B-month period of hourly- ~_!~ed injections. When the dose w~s raised to 25 p gm/k~ 2 of the monkeys initiated self-lnjectlon; and with periods of priming, ranging from 2 to |0 days. t~e other 5 n~'~nkey~ began to self-ad~....i;~i.~ter ntcotL~e. At Intervals of approx- lxnately one month, the individual dose~ were raised successively to 50. 100, 200, 500, 10~) and 2000/~ gmlkg. With r.ach increment in the single dose. the monkeys took fewer doses per day. but the average dally dose increased. One monkey died of accidental cause at a dose level of 25/~ g'm/kg. One refused to self-administer 50 ~, ffmlkg; 2 stopped at 100 ~ gm/kg, and I each, at 200, ~00, and 1000/~ gmlkg. In spite of severe and distressing toxic signs, 1 monkey contInue~i to self-administer nicotine at the 2.0 mg/kg dosQ level. In summary, all '/mop, keys developed psychogenic dependence to some degree. aSupported by a grant from the AMA Education and Research Foundation and USPHS Grant ~..Y5320. SPresentaddress~ S~,uthern Research Institute, Btrmlngham. Alabama, sl~resent addressl Osaka Untverslty. Osaka, Japan. 0 0

~020"~ 733~q

PULMONARY FUNCTION BEFORE AND D~ING THE COURSE OF PROLONGED ABSTINENCE FROM SMOKING IN A GROUP OF CHRONIC SMOKERS Richard A. Krumholtz and Joseph C. Ross (grantee) Department of Medicine Indiana University School of Medicine Indianapolis, Indiana Certain aspects of pulmonary function in chronic cigarette smokers have been sho~J~ to be different from those found in a similar group of non-smokers, the smokers' functions tending to be less normal than the non-smokers'. In a previous study we found that short term abstinence from smoking minimized these differences. The present study was undertaken to evaluate pulmonary function during long term abstinence from smoking in young cigarette smokers who have smoked at least 5 years and compare the results with parallel studies in non-smokers and smokers who continue to smoke, and who are in the same age group. Three groups of subjects, then, are being utilized: I) non-smokers, control, 2) chronic cigarette smokers who stop smoking, 3) chronic cigarette smokers who continue smoking, control. We plan to incorporate 20 to 25 subjects in each group. Measurements are being made at 0, 1½, 3, 6, 12, 24, and 36 months in the smokers who quit and 0, 6, 12, 24, and 36 months in both groups of control subjects. Lung volumes, spirometry, mechanics of breathing, dis- tribution index, response to exercise, and pulmonary diffusing capacity (DLco) are being determined. At this time 3 smokers have completed 6 months of abstention from smoking. With this small number, only general statements as to trends of functional change can be made, but all three subjects have had increases in total lung capacity, functional residual capacity, and residual volume after 6 months. Maximal voluntary ventilation and FEV200_I200 were also elevated in 2 subjects at 6 months. Airway resistance was reduced in all 3 subjects at 3 months and in 2 subjects at 6 months. DLco at rest and with exercise was increased in 3 subjects at 6 months. These preliminary studies in the 3 subjects who have completed 6 months of abstinence from smoking demonstrate that certain functional changes take place in the lung of the chronic smoker during a period of 6 months abstinence from smoking.

RADIOISOTOPIC STUDIES OF THE EFFECTS OF CIGARETTE SMOKING UPON DISTRIBUTION OF PULMONARY VENTILATION AND BLOOD FLOW Kenneth M. Moser (grantee)and August Miale, Jr. Department of Medicine Georgetown~ University Hospital Washington, D. C. This project will combine radioisotopic and pulmonary functional technics to determine: (a) the effects of acute and chronic cigarette smoking upon ventilation and blood flow in the lung; (b) the correlation between such effects and alterations in spirometric performance and arterial blood gas values; (c) pharmacologic and other methods which may prevent or reverse the effects observed. Initial studies will involve perfusion and inhalation .radioscans, utilizing the scintillation camera (SC), in normal subjects and patients with chronic obstructive pulmonary disease. Such subjects also will be studied by standard spirometric technics and (resting) values for arterial Po2, Pco2 and pH. During this control phase, developmental efforts will include: preparation of Tc99m albumin macroaggregates; study of the influence of various technical factors on inhalation scans; evaluation of special methods for improvement in the quality of data provided by both perfusion and inhalation Further phases of the investigation will be concerned with sequential studies (spirometric, blood gas, inhalation and perfusion scans) in subjects with and without pulmonary disease before, during and after cigarette smoking.

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EFFECTS OF CIGARETTE SMOKING ON LUNG CLEARANCE O17 PARTICLES IN ttUMANS AND THE EFFECTS OF INHALED IRRITANT GASES ON LUNG CLEARANCE OF PARTICLES IN DONKEYS Roy E. Albert (grantee), Morton Lippmann, Jack Spiegelman and At~thony Liuzzi Department of Environmental Medicine Nexv York University Medical Center New York, New York This study concerns the characterization of bronchial clearance by measurements of the gamma radiation emitted from the lung by inhaled monodisperse radioactive iron oxide particles in humans and donkeys and the modifications of bronchial clearance produced by cigarette smoke and related pollutants. Methods for generating the aerosol will be described as well as the techniques for assessing the lung burdens of radioactive particles. Bronchial clearance curves in humans wil] be described for 17 smokers and non-smokers, as well as those obtained in 21 inhalation experiments on donkeys.

ACUTE EFFECT OF CIGARETTE SMOKE ON LUNGS OF RABBITS (A NEW HISTOLOGICAL TECHNIQUE) William H. Anderson Department of Medicine University of Louisville Louisville, Kentucky A technique of fixing cubic centimeter specimens of lung in the inflated state has been developed. This is accomplished by exposing the extirpated piece of lung to 100% CO2 at atmospheric pressure. The lung specimen expands spontaneously arid is then fixed in the expanded state by flooding the specimen with 10% formalin saturated with 100% carbon dioxide. This histological technique was used to examine the lungs of rabbits which had been exposed to cigarette smoke. The rabbits were anesthetized, respiration paralyzed, and a burning cigarette placed in the inspiratory side of the circuit of an intermittent positive pressure respirator. Control animals were treated in a similar manner with the respirator, but were not exposed to cigarette smoke. The following changes were observed as a result of acute exposure to cigarette smoke:. 1) Disruption and distortion of the general architecture of the mucosa and submucosa of the bronchi; disruption of the bronchial epithelium, vacuolization and swelling of cells with actual breakage of cell membranes. 2) Infiltration of monunuclear cells in the submucosal, peribronchial and interstitial spaces. 3} Parenchymal atelectasis with alveolar exudation and hemorrhage. 4) Desquamation of large, swollen, granular filled cells (granular pneumonocytes) into the alveoli. 5} Macrophages and round cells were also found to enter the alveolar spaces in large number. 6} Fraying. and spreading apart of the collagen bundles in the alveolar walls and the submucosa of the bronchioles was demonstrated by the trichrome stain. 7) Even though these extensive changes in the lungs were found, there were not profound changes in arterial pO2 or pCO2. However, the animals developed a marked metabolic acidosis and a significant decrease in cardiac output preceding death.

SMOKING AND COUGH R.G. Loudon Department of Medicine University of Texas, Southwestern Medical School Dallas, Texas The relationship between smoking and cough is being studied, using several avenues of approach. Specific items under study include: (1) The frequency with which smokers and non-smokers cough. (2) The relative strength of various factors affecting cough frequency in healthy smokers and healthy non-smokers. (3) The acoustic and physiologic characteristics of cough in smokers and non-smokers without overt respiratory disease. (4) The frequency and other quantitative characteristics of cough in.patients with various respiratory diseases, in relation to smoking history. Interim analysis of the first two items has revealed several points of interest. While cough frequencies vary considerably from one situation to another, those who smoke during the period of observation cough about twice as often as those who do not smoke. The ratio of cough. frequencies in smokers and in non-smokers is remarkably uniform for the varied situations observed. Factors other than smoking which influence cough frequency include sex, time of day, season of the year, and observational situation. The study of acoustic and physiologic characteristics of cough in smokers and non-smokers with and without respiratory disease is progressing favorably. Methods have been evolved to measure flow rates, esophageal pressure, volume expelled, air flow resistance, and work on the lungs during coughs and during maximal expiratory efforts. Methods and results will be described. Cough frequency has been measured in patients with a variety of respiratory diseases. The three main disease categories studied are pneumonia, chronic obstructive respiratory disease, and pulmonary tuberculosis. Mean cough frequencies per hour for smokers and non-smokers respect- ively in these disease groups are: pneumonia, 17.0 and 11.6, chronic obstructive respiratory disease, 26.8 and 43.5 (only two cases in non- smokers), pulmonary tuberculosis 7.5 and 4.5. Results will be presented by sex and by severity of disease. Implications of results will be discussed, and plans for future studies presented. 0

CILIOSTATIC EFFECT OF PHENOL AND RESOHCINOL Tore Dalhamn Institute of Hygiene, Karolinska Instituter Stockholm, Sweden Several substances have been reported as taking an active part in the ciliostatic effect of tobacco smoke. One of those attracting particular interest is phenol. Experiments with this substance have been conducted mainly on frogs or on lower animals such as mussels. The present authors have aimed at producing a method for screening tests on the tracheal mucosa in vitro from mammals. The effects of phenol and resorcinol (in various concentrations) have been compared, which is interesting in that it is only a hydroxyl group which distinguishes these two compounds. The results suggest that phenol is more ciliostatic than resorcinol.

EFFECT OF TOBACCO SMOKE ON RESISTANCE TO RESPIRATORY INFECTION Arnold Spurgash and Richard Ehrlich (grantee) Life Sciences Division IIT Research Institute Chicago, Illinois A study was undertaken to determine whether tobacco smoke can change innate resistance to respiratory infections. Two experimental protocols are utilized. In one, Swiss albino male mice are challenged intranasally with Diplococcus pheumoniae type II, III, or VII and then exposed to cigarette tobacco smoke 1 or 24 hours later. In the other, mice are exposed to cigarette smoke and then challenged intranasally with D__:_. pneumoniae 1 or 24 hours later. Control mice exposed to cigarette smoke only or challenged with D. pneumoniae only are included in each experiment. A specially designed smoking apparatus generates the cigarette smoke into a Lucite animal chamber, which houses the mice during exposure. The duration of smoke exposure is 1 hour, and the quantity of smoke is equivalent to 20 cigarettes. There was no statistically significant difference in the mortality or the survival time of mice challenged with D._~=_pneumoniae only and those challenged and then exposed to cigarette smoke. Likewise, there was no statistically significant differences between the mice challenged with D._:.. pneumoniae only and those exposed to cigarette smoke and then challenged with D..~neumoniae. No deaths occurred in mice exposed to cigarette smoke only.

SURFACTANT EFFECTS OF CIGARETTE SMOKE Watts R. Webb Department of Surgery The University of Texas Southwestern Medical School Dallas, Texas The surfactant effects of cigarette smoke on minced rat lung extract and dog and human bronchial washings have been evaluated utilizing a modified Wilhelmi balance. Cigarette smoke reduced the surface tension of rat lung surfactant from an average 55 dynes/cm at full area and 9 at 20% area to 38 and 17 respectively. Human bronchial washings were comparably altered in surface tension by exposure to cigarette smoke. Bubbling the smoke through water did not change its effect at all, presumably because large bubbles do not allow removal of the smoke particles. Use of a Sentering bubbler partially removed the smoke effect and filtration of the smoke through millipore filters (0.45 or 1.25 microns) removed all the effects of the smoke so that the filtered smoke produced no alteration of surfactant. This effect possibly could be due to either a chemical or a nonspecific dust effect since the effective chemical (if present) could be carried by the smoke particles. Interestingly, dust from the laboratory floor was found to alter the surfactant curves in much the same manner as cigarette smoke. Likewise, cigarette smoke bubbled through saline caused a marked reduction of its surface tension with a surprising degree of hysteresis. This reduction of surface tension, if similarly noted in the alveoli, would reduce their expulsive force in exhalation and tend toward emphysema, which is freq,~ently associated with chronic cigarette smoking. Washings from chronic cigarette smokers taken during a routine smoking day likewise had a significantly reduced surface tension and stability index. Also washings taken immediately after a cigarette showed a more abnormal curve than those taken after a period of abstinence.

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EFFECTS OF CHRONIC NICOTINE ADMINISTRATION ON MULTIPLE MOLECULAR FORMS OF MYOCARDIAL ENZYMES Duane G. Wenzel Department of Pharmacology University of Kansas, School of Pharmacy Lawrence, Kansas Unpublished studies from our laboratories have demonstrated that the chronic administration of nicotine to rats produces a significant reduction in myocardial aspartate aminotransferase (AAT). An initial elevation is produced by a dose of 2.28 mg/kg/day (2 pack equivalent). This effect is blocked by either puromycin or ethlonine and the block of the latter reversed with methionlne. The stock colony of Sprague-Dawley rats was lost following the initial results and rats of this strain from other colonies have not demonstrated the.observed sensitivity to nicotine. Studies are currently underway to explore theuse of other strains of rats and to sensitize Sprague-Dawley animals through mild stress. Animals are to be chronically treated with two doses of nico- tine, 0.14 and 2.28 mg/kg/day, in their drinking water. These doses approximate the effect of nicotine obtained f~om one-elghth and two packs of cigarettes. Groups ofanlmals will be sacrificed at intervals of one to one-hundred and eighty days. Both AAT and lactic dehydrogenase and their Isozymeactlvltles will be deter- mined with entire hearts. A preliminary study with ~cute doses of catecholamlnes has shown a shiftln myocardial isozymes toward the skeletal muscle form. • Further objectives of the study are to evaluate the mechan- ism of possible nicotine-induced effects through the use of block- ing agents~ and with adrenalectomlzed and hypophysectomlzed rats. Catecholamine concentrations of the heart are to be determined in relation to isozyme patterns. Other multiple molecular forms of enzymes are to be similarly evaluated. 0

THE EFFECT OF NICOTINE ON MYOCARDIAL METABOLISM Norman Brachfeld Department of Medicine Cornell University Medical College New York, New York Mechanisms responsible for the apparent cardiac toxicity of nicotine are unknown. In brain, nicotine toxicity may be expressed as interference with cellular respiratory metabolism. Experiments to determine the effect of this agent on myocardial lysosomal, mi~o- chondrlal and supernatant enzyme systemswere performed in the isolated flow demand perfused rat heart. Control perfusions were compared to hearts perfused with Krebs Ringer buffer containing 5.5 mMglucose + 2~0 ~g. nicotine base for 30 minutes. Nicotine caused a highly significant release of acid phosphatase and ~-glucuronidase into the perfusate (96%, 53% > controls, p < .001). Perfusate concentration of lactic dehydrogenase increased 263%. Cytochrome oxidase concentration was unchanged. ~here was a 100% increase in lactic acid production with an associated 52% increase in glucose consumption and increase in QO2. Heart rate increased 24%. pH, perfuslon rate and other performance characteristics were unchanged. Response was fixed through nicotine concentrations of 2.0 to 20 ug/ml. Our data indicate that nicotine stimulates myo- cardial anaerobic metabolic rate and inhibits HLac oxidation. Evidence suggests the mechanism to include inhibition of DPN depen- dent dehydrogenations without inhibition of electron transport or mltochondrial integrity. Mechanisms responslble.for increased lysosomal fragility and increased permeability of the cell wall to LDH will be discussed.

EFFECT OF NICOTINE ON INCORPORATION OF CI4-AMINO ACIDS INTO PROTEIN Slgmundur Gudbjarnason Department of Medicine Wayne State University Schoolof Medicine Detroit, Michigan The effect of nicotine on in vitro incorporation of cl4-amlno acids into cytoplasmic and nuclear protein of heart muscle has been studied. In an aerobic system, .there was no effect of nicotine (1.5 x 10"4M) on incorporation of labeled aminoaclds into heart muscle protein. In an anaerobic system (KCN) the addition of nlco- tlne significantly increased the rate of incorporation both into cytoplasmic as well as nuclear protein. The effect of nicotine was also studied in presence of added G-6-PDH, since nicotine has been reported to activate G-6-PDH. The addltlonof G-6-PDH signifi- cantly reduced the rate of incorporatlbn, but nicotine again stimu- lated the incorporation to the same extent as before. The effect. of nicotine on the reaction rate of G-6-PDH .(from hearts brain, and liver) was studied, but no effect was observed with the direct spectrophotometrlc method. Addition of TPNH (NAPDH) (10"3M) inhibi- ted significantly the incorporation of cl4~amlno acids into nuclear. protein, both in absence and presence of KCN, whereas the incorpora- tion into protein of the cell-free supernatant was only inhibited in presence of KCN. Nicotine again effected an increase in incorpora- tion in a system containing both TPNH and KCN, particularly in the cell-free supernatant. It is tentatively concluded that TPNH may regulate certain reactions of protein synthesis as indicated by the inhibition of cl4-amino acid incorporation upon addition of TPNH or TPNH-generating system and KCN. Nicotine seems to be able to stimulate the oxidation of TPNH to TPN+ and thus indirectly • stimulate incorporation of cl4-amlno acids into protein. If this hypothesis is correct, nicotine might influence metabolism of ster- oids and llpids via TPNH. An investigation of the effect of nicotine in vlvd on protein and nucleic acid synthesis in heart muscle and on.enzyme patterns of heart, brain, and liver, is in progress. In these experiments the nicotine is administered to several groups of dogs, the first group receiving 50 ~g/kg 5 times a day for 3 months. The dose has been increased and presently animals are being studied that have received 400 ~g/kg 5 times a day for 3 months. These studies are still in an early stage and therefore inconclusive.

CATECI~OLAMINE METABOLISM FOLLOWING CIGARETTE SMOKING AND NICOTINE ADMINISTRATION Thomas C. Westfall Department of Pharmacology University of Virginia Schoolof Medicine Charlottesville, Virginia It has previously been observed that cigarette smoke inhala- tion and nicotine administration results in an increase in the epine- phrine (E) and to a much lesser extent noreplnephrlne (NE) content in the blood and urine of man and experlmental.anlmals. Although the amounts of free E and NE excreted in the urine are very constant they represent only 3-6% of the total excreted amine. The majority of amine is recovered as the o-methylated metabolltes metanephrine (M) and normetanephrine (NM) or .3-methoxy-4-hydroxy mandellc-acld- (VMA) as well as minor amounts of other acld and conjugated metabo- flies. The present expeflments were carried out to study the effect of nicotine and cigarette smoking on the major catecholamlne (CA) metabolites as well as the important precursor dopamine in order to further supplement our knowledge of the action of nlcotlne.on the sympatho-adrenal system. Rats were placed in individual metabolism cages and allowed 507 days for accllmitization to their enQironment. Twenty-four hour urine samples were then collected before and after the adminis- tration of various doses of nicotine. Each rat thus served.as his own control. One aliquot of the urine was taken and used for.the extraction and determination of VMA acc0rding..to'the method of Pisano et al. (Clin. Chim. Acta, 7:285, 1962). Another aliquot was pl~ced on a strong cation exchange resin (Amberllte CG-120). for separation of NE, E, NM, M and dopamine. Subsequent procedures and analysis of the amines were carried out by the methods descrl- bed by Haggendal (Scand. J. Clin. Lab. Invest., 14: 537, 1962). Although these present experiments are not completed, results obtained to date indicate an increase in the urinary excretion of E, M~ and VMA as a result of nicotine administration whereas no increases in the excretion of NE, NM or. dopamlne were observed. ' Similar experiments are being carried out on healthy human subjects substituting cigarette smoke inhalation for"nlcotine administration. Urine samples are being collected during three 30 min periods in which the subjects are smoking 3 cigarettes per 30 min period. Sufficient data to merit mentlon~has not yet been obtained. 0

EFFECT OF CIGAR AND PIPE SMOKING ON LIPID METABOLISM Samuel Bellet Division of Cardiology Philadelphia General Hospital Philadelphia, Pennsylvania In studies of the effect of smoking on lipidmetabolism, sub- jects showed greater free fatty acid (FFA) mobilization with ciga- rettes than cigars, which was reversed when cigars were inhaled and cigarettes not inhaled. In dogs, with the inhalation factor constant, there was no difference in FFA or triglyceride response to cigarette, cigar or pipe smoke; lipid effects of nicotine were similar to tobacco smoke. Catecholamine excretion during 4-hour periods of smoking was greater with cigarettes than cigars. In" dogs there was no difference in catecholamine output with cigarette, cigar or pipe smoke when.similarly administered by tracheal inhala- tion. The nicotine content of urine collected during 4-hour periods of smoking was greater with cigarettes than cigars or pipes. This was reversed when cigars and pipes were inhaled and cigarettes not inhaled. In dogs, with inhalation constant, there was no difference in nicotine excretion. Blood specific activity measurements after smoking radioactive tobacco showed greater absorption of pyrolysis products with cigarettes. The findings demonstrate that the greater lipid and catecholamine response to cigarette smoking is due to the tendency to inhale cigarettes with resultant greater nicotine absorption. This is substantiated by the higher level of nicotine excretion with cigarette smoking which is equalized by cigars and pipes when they are inhaled. In progress are studies of the effect of nicotinic acid on the lipid and catecholamine response to the different smoking forms and its effect in nicotine absorption (urinary excretion) during smoking. Also being studied is the effect of smoking and nicotine in the synthesis and metabolism of triglycerides and other lipid fractions in man and dog. In vitro tissue studies and in vivo perfusion experiments in dogs are being initiated in which the relationship of the lipid effect of smoking to cyclic AMP will be investigated.

NICOTINE AND NEUROGENIC VASCULAR TONE Ove A. Nedergaard, John A. Bevan (grantee) and Sandra Corbett Departments of Pharmacology and Pathology UCLA School of Medicine Los Angeles, Callfornla The action of nicotine on the response of vascular smooth muscle to sympathetic nerve stlmulatlon and on the restlngmuscle tone has been studied using the isolated recurrent cardiac nerve-pulmonary artery preparation of the rabbit. This i_~nvltro preparation was maintained in a buffered physiological salt solutlon(pH, 7.4) at 38° and aerated with a mixture of 95%02 and 5ZCO2. Electrical stlmulatlon of the recurrent cardiac nerve containing the post- gangllonlc sympathetic nerve supply, of the.pulmonary artery caused a very rapid contraction of the vessel followed by a return within -3 mlns to the original level of tone. Using stimuli of supra- maxlmal voltage, frequency 5/set, the effect of different concen- tratlons of nicotine on the contractile response to trains of 25, I00, and 200 stimuli res~ctlvel~ was determined. .After 30 mlns incubation, nicotine (10 V-3xl0"OM) reduced significantly (10-20Z) the ma~nltu~e of all contractions. Higher concentrations (3x10"v-10''M) however, potentiated the responses to nerve stlmu- lation by up to 60Z and occasionally.also caused a small increase in resting tone. The percentage potentiation caused by nicotine became larger as the train of stimuli was made longer. Inter- mediate concentrations had no effect on the magnitude of the responses. Since nicotine at pH 7.4 exists in both an ionized and unionized form, it is of interest to determhLe which of t~ese is mainly responslble for the pharmacologlcal action of nicotine. The effect of this alkalold was therefore compared with the quaternary compound, DMPP (dlmethylphenylplperazlnlum), which is fully ionized and possesses pharmacologically specific nicotinic properties. In contrast to nicotine, DMPP at concentrations of 10-7M and higher caused only a decrease.ln the contractions elicited by nerve stimulation. ~fter 30 mlns incubation the response was completely blocked by 10"~M of DMPP. This concentration also caused a smallIncrease in the resting tone of the artery. From these prellmlnary results it is speculated that the potentiating effect seen with nicotine is mainly due to the unionized part of the molecule, while the inhibitory effect observed with DMPP is related to its complete ionization. Experiments to further elucidate the site and mode of action of nicotine and related drugs on vascular smooth muscle is in progress and the results of these will be pre- sented and discussed.

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EVALUATION OF THE EFFECTS OF CIGARETTE SMOKE IN THE INTACT GUINEA PIG S. Carson, R. Goldhamer and E. Clemente (Bernard L. Oser, grantee) Food and Drug Research Laboratories, Inc. Maspeth, New York A comparison of a number of cardiopulmonary parameters ~as been employed to evaluate the pathophysiologic consequences of acute and chronic inhalation of tobacco smoke by the intact guinea pig. The responses of the respiratory system, as the site of initial impingement, has been assessed in terms of the series of events which follow. Full body plethysmography using the technique of Mead and Amdur for acute exposures and that of Murphy for chronic or repeated exposures permit continuous evaluation of pulmonary function. Simultaneous recordings of right intraventricular pressure are obtained by permanent catheterization of the ventricle as described by~Popovic, with intraventricular and limb lead recordings. These are supplemented by the ~ecent addition of a gas-liquid chromatograph, for analysis of respiratorY gas concentrations in inspired and expired air and as a means of providing evidence of active compounds in trace concentrations of blood. Groups of guinea pigs were exposed to cigarette smoke for 5 days. a week in chambers using maximal tolerated doses, which would be leth~l if the exposure period were continued beyond this period. Simultaneous changes were observed in intraventricular pressure and in pulmonary compliance. The decrease in lung elasticity, seen after prolonged exposure to cigarette smoke, was accompanied by a marked increase in ventricular blood pressure. Findings in acute and chronic exposure regimens will be compared. Of particular interest are the differences in responsiveness observed between albino and non-albino guinea pigs.

THE EFFECTS OF SMOKING ON THE ~ART AND PERIPHERAL CIRCULATION IN MAN: MEASURED BY BLOOD PRESSURE, PULSE RATE, SKIN TE~[PERATURES AND ELECTRICAL IMPEDANCE PULSE VOLUME DETERMINATIONS Robert D. Allison Department of Physiology Lovelace Foundation Albuquerque, New Mexico Grace M. Roth Vascular Laboratory Lovelace Clinic Albuquerque, New Mexico Standard smoking tests were carried out on°60 male cigarette smokers ranging in age from 20 to 60 years. A non-occlusive four electrode impedance system was used to measure changes in pulse volume and blood flow to peripheral segments and the thorax. Simultaneous skin temperature, blood pressure and pulse rate were measured concomitantly. Such information has provided insight into the simultaneous effects of smoking on various portions of the body. The skin temperatures of the fingers and toes decreased more than the skin temperatures of the arms and legs. Likewise, the impedance pulse volume of the fingers and toes decreased more than the impedance pulse volume of the arm and leg segments. Smoking produced an increase in systolic and diastolic blood pressure and an increase in pulse rate. Blood flow in this study has been expressed as the product of pulse volume and heart rate, and despite an increase in heart rate, vasoconstriction dominated and resulted in decreased blood flow in peripheral segments. The thoracic pulses (thoracic impedance pulse changes synchronous with the cardiac cycle) as an index of pulmonary pulse volume changes indicated a reduction in pulmonary pulse volume during cigarette smoking. Heavy smokers demonstrated increased levels of carbon monoxide as established from infra-red analysis of alveolar gas.

MOTOR RESPONSES OF THE MICROCIRCUI..~i'ION FOLLOWING INHALATION EXPOSURE TO CIGARETTE SMOKE Paul A. Nicoll Department of Physiology Indiana University Medical Center Indianapolis, Indiana The motor response of both arterioles and venules when the animal is exposed to tobacco smoke have been investigated in the subcutaneous vascular bed of the wing membrane in unanesthetized bats. Commercial brand cigarettes obtained in the local market were smoked in an apparatus that gave one 35mi puff of two second duration once a minute. Each cigarette gave 7 to 9 puffs depending on the butt length. Animals were subjected to either a continuous environment of stQred diluted smoke or brief 5-15 seconds per minute exposures with each puff. The composition of the smoke varied depending on the procedure. Storage sharply reduces the particulate and so nicotine content of smoke. Continuous exposure to stored diluted smoke where the smoke concen- tration is 10% or less does not produce any significant response in the motor activity of the minute vessels. With higher smoke concentration some initial increase in motor activity is evident but this is soon reversed as inhibitory actions develop. Brief intermittent exposures to fresh cigarette smoke produce definite increase in motor action. Both arterioles, precapi]lary sphincters and venules showed increased strength of contraction and reduced resting length of the muscular elements. Inhibitory action does develop with repeated cigarette smoking at short intervals. Both the quantitative analysis of muscular response and the time aspects of the reaction have been followed with a new technical procedure. Using a closed circuit television set up the movements of the vessel walls due to muscular contraction may be detected by the use of photo-cells attached to the T.V. monitor screen. Magnitude of tonic action (reduced resting length) and the brief cyclic contractions are followed by this technique. The photocell readouts are recorded by a conventional polygraph and allow detailed analysis of duration and activity response.

OXYGEN DEBT ACCUMULATION IN S~K)KERS AND NON-SMOKERS Robert B. Chevalier Krannert Heart Research Institute Marion County General Hospital Indianapolis, Indiana Our data have shown that the oxygen debt accumulation of smokers is greater than that of non-smokers for a given exercise load. Additional work was done to account for this observation. Non- smokers were exercised and oxygen debts were calculated as the ratio of oxygen debt to total increased 02 uptake. The subjects then inhaled carbon monoxide until their carboxyhemoglobin levels were comparable to those of smokers. The subjects were then re-exercised and the 02 debt ration was found to increase under the effect of CO. The assumption was made that the CO in someway made the non-smokers have an exercise response more similar to a smoker. In view of these findings we have been undertaking some further observations as to the basic mechanisms involved. We have observed that there is a difference in the initial rise of the 02 uptake curve between smokers and.non-smokers This may be best demonstrated by the following lllustratlonl B represents the total increased ~0p uptake during work. C represents 02 debt. A represents The lag or "oxygen deficit". A large number of non-smokers in the past had a relation of A/C of approximately 0.75 to 0.80. In other words, most of the 02 debt went to repay the "oxygen deficit". On the other hand, smokers had an A/C ratio of approximately 0.50 -- a significant difference. In l0 non-smokers, the calculated A/C ratio was 0.85.

Oxygen Debt Accumulation In Smokers And Non-Smokers Page 2 This figure corresponded to the one obtained in a large group of non-smokers. After the inhalation of CO the A/C ratio in the same subjects fell to 0.50. In conjunction with this there was no significant change in area B. The 02 debt or area C did increase. The reason for this change has not been fully analyzed at this point. One speculation might be that the CO causes a need in increased 02 uptake that cannot be met aerobically. Therefore, the subject never reaches the steady state for the exercise and load that he does when no significant COHb is present. proposed Direction of Work for the Second Grant Year The methods of study of the subjects will be essentially as outlined in the grant proposal. No significant change in this technique is proposed. The aims of the second grant year will again be those outlined in the original proposal. In addition, we are anticipating studiesinvolving the 02 debt accumulation at higher work loads. In the past, thework loads selected have been sub-maximal. It is anticipated that studies will be undertaken that will involve maximal exercise in smokers and non-smokers with analysis of 02 debt. Such studies may add information as to the mechanisms of increased 02 debt accumulation in smokers.

THE STUDY OF THE EFFECTS OF NICOTINE ON THE HUMAN HEART BY ISOTOPE SCANNING AND BY REGIONAL MEASUREMENT OF CORONARY BLOOD FLOW Richard J. Bing (grantee) and Karel Rakusen Wayne State University School of Medicine Detroit, Michigan During the period sponsored by this grant, from July, 1964 until the present moment, we have been concerned with the effect of nicotine on the heart. Much of the time has been devoted to the technique, consisting in a study of the measurement of coronary blood flow using coincidence and isotope.scanning, and in the measurement of the capillary blood content of the heart. In the first method, we could establish the reproducibility of the technique, and show that variations in the counts on arterial blood have no influence on the results. We have furthermore demonstrated that we are measuring nutrient blood flow rather than total coronary blood flow, and that in the isolated perfused heart, the calculated flows check closely with those 6btalned by the direct Flick. Finally, we have now demonstrated that large changes in flow d~ocause alterations in the percentage myocardial extraction ratio. However, the quantltatlon for the measurement of coronary blood flow does not depend on measurements of percentage extraction ratio. We have found that smoking of cigarettes or the injection of nicotine has resulted in an increase in coronary blood flow in the normal, or a decline or no change.ln patients wlCh coronary artery disease. The behavior of nicotine is, therefore, similar to that of other coronary vasodilators. The second portion of our program dealt with a search for the effect of nicotine on alterations in coronary blood flow.. It was first our intent to measure this with scanning techniques. This course is being pursued, but the technical difficulties of producing 1-124 coupledto oleic acid and to albumin are considerable, and the process is. very expensive. Therefore, Dr. Rakusen in this laboratory has centered his attention to the effect of nicotine on regional capillary blood content in various portions of the heart under the influence of nicotine. His data have not demonstrated any significant changes in regional capillary blood content in the heart muscle following nicotine. However, nicotine resulted in an increase in capillary blood content of skeletal muscle.

THE EFFECT OF NICOTINE ON THE CANINE CARDIAC ACTION POTENTIAL Kalman Greenspan and Suzanne B. Knoebel Department of Medicine Indiana University School of Medicine Indianapolis, Indiana The effects of nicotine on canine myocardlum were studied, utilizing small strips of ventrlcular tissue and Purklnje fibers (false tendons)~ Continuously perfused with oxygenated Tyrode's solution containing nicotine base at a concentration varying from 2 - 20 micrograms per c.c., individual ventrlcular or Purklnje cells were impaled with glass mlcroelectrodes filled with 3 M. potassium chloride. Action potentials were elicited with bipolar stimulating electrodes, at rates varying from 60-120/minute and visualized on oscilloscopes which permitted simultaneous photographic recording. Characteristic changes in transmembrane action potential configuration were noted in both ventricular and Purklnje fibers, at intervals varying from I to hours after continuous exposure to the al~alold. These changes consisted, of attenuation or obliteration of the phase two plateau, phases two and three becoming confluent and resembling an exponential curve. This was observed with no alteration in the basic driving. rate, and was unattended by any significant change in the transmembrane resting potential. Such action potential alterations occurred more promptly with the higher concentrations of nicotine. Less commonly observed changes, following exposure to nicotine, included: reduced rate of rise of phase zero depolarization, with development of a 'step'; 2) loss of 'overshoot'; and.3) a decrease-of trans- membrane resting potential. The loss of overshoot was not necessarily related to the reduction in the resting potential. The development of spontaneous depolarization of PurkinJe fibers was also occasionally observed after nicotine administration. This was followed by a progressively more rapid rate of spontaneous depolarization (ca. 120/minute), and associated with the development of a marked 'step' or notch in the phase zero upstroke. The complex, thus altered, closely resembled that customarily recorded from A-V nodal cells. The physiologic basis for these action potential changes (i.e., acceleration of repolarization without a reduction in resting membrane potential) remain open to conjecture. It may be suggested,

The Effect of Nicotine on the Canine Cardiac Action Potential Page 2 however, that the aforementioned changes in repolarization may be" attributable to an enhancement of membrane permeability to potassium. The latter, in turn, may be ascribed to a direct effect of nicotine; or mediated via the release of endogenous acetylcholine, a character- istic effect of nicotine administration. The development of auto- maticity, on the other hand, cannot be explained in terms of enhanced membrane permeability to potassium. However, the occurrence of spontaneous depolarization may have resulted from endogenous eate- cholamine release, also a classically described effect of nicotine administration. ~ 0

SYMPATHOHIHETIC ACTION OF NICOTINE J. P. Long Department of Pharmacology State University of Iowa College of Medicine lowa City, Iowa There are a number of possible mechanisms by which nicotine may activate the sympathetic nerve terminals and release noreplnephrine. The major proposed mechanisms are: (1) stimulateganglia, (2) stlmulate "ramifying" ganglia, (3) stimulate the nerve terminals directly or, (4) in those organs with dual autonomic Innervatlons, activation of the parasympathetic nerves may indirectly release noreplnephrine. The. underlying mechanism of action for the sympathomlmetlc action of nlcot~ne has been the object of a major. part of our research. There is a wide species variation asfar as atrial responses to nicotine are concerned. The action of nicotine was evaluated for negative and positive chonotropic and-inotroplc action. ~These parameters of action were evaluated in atria from the rat~ guinea pig, cat, turtle, chicken,dog, frog, and rabbit. The decrease in force of atrial contraction was significant in all species except the frog. There was significant speeding in all species except the rat~ turtle~ and frog. There was significant increased force of atrial contraction in the rat, gulnea plg, cat, and rabbit. Therefore since the cat shows significant slowlng and speeding, as well as significant decrease and increase.in force of contraction to nicotine a considerable amount of work was done using these species. Inhibition of the parasympathetic nervous system with hemicholinium (HC-3) abolished both the positive and negative responses to nicotine. Both of these responses could again be observed after repeated washing over a 1-3 hour period. HC-3 did not inhibit the response to sympathetic nerve stimulation nor did it block the response to nicotine administered when the vagi were not stimulated. Similar mechanisms of action were found when evaluating the ability of nicotine to increase the vascular resistance of the mesenteric arteries of the cat. The innervation of the cat's iris definitely does not appear to be any interaction of the sympathetic and para- sympathetic nervous system. We are completing a study of the action using the cephalic vein of the" dog..In this preparation nicotine is very feeble in activity. Our work indicates that the sy~pathomimetic action of nicotine varies widely from species to species and there does not appear to be a singular or simple mechanism of action that initiates the sympathomimetic action.

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STUDY OF THE EFFECT OF POLYCYCLIC HYDROCARBONS ON CHROMOSOMES E. Douglas Rees Department of Medicine University of Kentucky Lexington, Kentucky Some polycyclic hydrocarbons are powerful carcinogens, e.g. 3-methyl- cholanthrene, 7, 12-dimethylbenz(a)anthracene, and benzo(a)pyrene (one of the carcinogenic components found in tobacco tar). Oral administration of these compounds to rats induces cancer almost exclusively at a distant site - mammary gland. Since induction is markedly influenced by • carcinogen dose, age, sex and strain, this experimental cancer is an excellent tool for the study of carcinogenesis. Chromosome abnormalities are frequently noted in neoplasms, and it may be that changes in chromosomes are among the primary factors involved in the genesis of cancer. Accordingly, the effect of polycyclic hydrocarbons on the chromosomes of rat cells in being studied. Karyotypes of femur marrow cells from rats of strains with different susceptibility to induction of this cancer have been analysed. The very susceptible Holtzman rat has a karyotype similar to that of the relatively resistant Long-Evans rat, except the latter has a polymorphic pair of chrornoson~es (the $3 pair). ' Variations in karyotypes of cells from untreated rats of these strains have been defined and (for the Holtzman.rat) compared with changes occurring after carcinogen administration. Following carcinogen administration, a normal proportion of marrow cells remained .diploid but the range of number of chromosomes per cell was increased and aberrations in karyotypes were demonstrated. • Studies on rats of other strains have not been completed. Studies have also been started to demonstrate the presence or absence of the polycyclic .hydrocarbon carcinogens and their noncarcinogenic congeners on chromosomes.

INDUCTION OF INCREASED BENZPYRENE HYDROXYLASE ACTIVITY IN THE LUNG IN VIVO AND IN VITRO Lee W. Wattenberg (grantee) and J. Lionel Leong Department of Pathology University of Minnesota Medical School Minneapolis, Minnesota As part of a study aimed at determining methods of protecting the lung against the carcinogenic effects of polycyclic hydrocarbon carcinogens, the capacity of a number of heterocyclic compounds to induce an increase in benzpyrene (BP) hydroxylase activity of pulmonary tissue has been determined. A large series of compounds has been tested and of these the following, when given by oral administration, have been found to induce an increase in BPhydroxylase activity of the lung of the Sprague Dawley rat: several 5-memberedheterocyclic compounds with diaryl substitutions such as 2, 5 bis-(4-pyridyl)-l, 3, 4 thiadiazole, a number of phenothiazine derivatives, several flavones, 2.-phenyl benzothiazole, dibenzothiophene, and 5, 6-dimethy]- 2-(3-pyridyl) benzimidazole. Data pertaining to the effects-of various structural alterations of inducer molecules on their inducing capacity have been obtained. Induction can be carried out by the intratracheal route but results in no greater activity than with oral administration. A]HeJ and C3H/HeJ strain mice show increased BP hydroxylase activity in their lungs in response to oral administration of inducers effective in the rat. The untreated Syrian hamster has a lower pulmonary BP hydroxylase activity than the rat or mouse and is relatively unresponsive to most inducers. However, a " high activity can be induced in this species by beta,naph~hoflavone. In addition to in vivo induction, it has been possible to induce an increased BP hydroxylase activity in small pieces of rat lung cultured in vitro.

TIlE ROLE OF AI.PHA-EMITTING ISOTOPES IN TIlE EFFECTS OF CIGARETTE SMOKING Robert L. Bogner Nuclear Science & Engineering Corporation Pittsburgh, Pennsylvania This study is designed to investigate the significance of polonium-210 and related radionuc]ides as health hazards associated with smoking. Urinary excretion rates of Po-210 by smokers and non-smokers as well as abstaining smokers are being evaluated. Results have confirmed that smokers excrete substantially more Po-210 in the urine than non-smokers. The average urinary daily excretion of 0.14 la~ac Po-210 by a heavy smoker was approximately five times greater than the corresponding urinary excretion of 0. 027 ~ c per day by a non-smoker on an identical diet. The urinary excretion of Po-210 by the heavy smoker did not show a significant decrease following abstinence from smoking for over 40 days; apparently an appreciably bod.y burden of Po-210 developed in the heavy smoker over his twenty year smoking history. Selected dietary constituents such as beer and cola drinks have been identified which markedly influence the Po-210 excretion in the urine and strongly affect the values obtained on spot urine samples. The content of polonium-210 and its precursors, radium-226 and lead-210 will be determined in autopsy and surgical specimens of human tissues, particularly lung parenchym.a, bronchial tree, teeth, bone and various soft tissues, of smokers and non-smokers, of individuals in different geographical areas within the United States and different parts of the world, and of urban and rural inhabitants. Methodology has been refined for the analysis of the very low levels of 1'o-210 in lung tissues. It is now evident that natural 1'o-210 can be detected in dog lung specimens as well as in other soft tissues of the body. Human lung tissue obtained at autopsy is being analyzed to determine the influence that sampling techniques and sample handling procedures (freezing, fixatives, etc.) may be expected to have on the analytical results. After it has been demonstrated that specific portions of human lung should be procured and treated according to a standard technique, collection of autopsy and surgical samples will be instituted on a much more compre- hensive world-wide scale and appropriate smoking, occupational, and residence histories will be accumulated. Results of human tissue analyses will be related insofar as possible to the naturally-occurring levels of the radionuclidcs in tobacco and smoke, atmosphere, water, and diet. Arrangements have been made to obtai.n 50207 7389

TIlE ROLE OI," AIJPItA-EMITTING ISOTOPES IN THE EFI,'ECTS OI," CIGARETTE SMOKING page 2 samples of the airborne particulate matter from the National Air Sampling Network of the U.S. Public Health Service, as well as from the local Allegheny County tIealth Department. Similar samples have been collected by NSEC at various sites in the greater metropolitan Pittsburgh area. Analyses of over eighty samples from near Pittsburgh reveal that Po-210 concentration range from 1 x 10-5 to 2 x 10-4 ~tac per ft3 with some suggestion at present that collections near power stations that burn fossil fuel show Po-210 levels near the upper limits. Analysis of samples from the national network so far indicate that reasonably similar Po-210 levels may exist elsewhere. World-wide samples of cigarette tobacco have been analyzed for Po-210 and except for a few apparent exceptions (e. g. India and Luxembourg), the Po-210 content closely resembles the content of American cigarette tobaccos. Attempts will be made to trace the cause for low Po-210 levels in the exceptions. All samples analyzed for Po-210 have been set aside after plating. After sufficient grow-in time, they can then be plated for Pb-210. Following the Pb-210 determination, the samples can then be run for Ra-226. This sequence provides a minimum of analytical problems. 50207 7390

[~o III

EFFECTS OF PHARMACOLOGICAL AND PSYCHOLOGICAL VARIABLES ON SMOKING BEHAVIOR IN NAN WITH SPECIAL EMPHASIS ON THE ROLE OF NICOTINE Benedict R. Lucchesl, Charles R. Schuster (grantees), and GraceS. Emley Department of Pharmacology University of Michigan Medical School Ann Arbor, Michigan Nicotine has been considered by some to be the decisive factor in the effects of tobacco in those "addicted" to smoking where the pharmacological actions of nicotine play a greater role than its local effects. Previous studies by Johnston (1942) and EJrup (1963) have attempted to assess the role of nicotine in the smoking habits of man. Their results suggest that parenteral administration of nico- tine will alter an individual's smoking frequency. The present investigation s~udled this relationship ~n human volunteers who were unaware of the true nature of the study or the drug being administered. During the past year I0 male and 2 female volunteers between 21 and 26 years of age participated in this.study.. The subjects were confined to ~ soundproof booth for a duration of 6 hourson each of 15 consecutive experimental sessions. Sessions for nico- tine or normal saline administration were randomly selected. Solutions were given by the intravenous route and controlled by a peristaltic roller-pump with variable speed so as to adjust the drug dosage. Throughout each session the.subjects were assigned a definite schedule of behavioral testing and were permitted to smoke ad libltum. Blood pressure, heart rate and respiration were continuously monitored. Smoking behavior was not altered slgniflcantlywhen nicotine was administered in a dose of I mg for 30 minutes every hou~ or 2 mg per hour continuously for 6 hours..In five subjects, receiving 4 mg/hr, there was a significant decrease in the total number of cigarettes consumed. The systolic blood pressure and heart rate recordings indicate that the physiological alterations in these~ parameters produced by smoking can be reproduced by parenteral nicotine. Specificity of the effect of nicotine on smoking behavior is suggested by the failure of this drug to produce any changes in the behavioral ~arameters neasure'd.

EVALUATION OF PHYSICAL DEPENDENCE, PSYCHOGENIC DEPENDENCE AND TOLERANCE TO NICOTINE IN THE MONKEY Gerald A. Deneau Southern Research Institute Birn~ngham, Alabama NO ABSTRACT SUBMITTED NOT IN ATTENDANCE

"THE EFFECTS OF NICOTINE ON TIMING BEHAVIORIN THE RAT; I. EFFECTS ON ACQUISITION OF THE BEHAVIOR; II. PERFORMANCE OF THE BEHAVIOR FOLLOWING WITHDRAWAL OF THE NICOTINE" Irving Geller Department of Pharmacology and Toxicology Southwest Foundation for Research and Education San Antonlo, Texas Hungry rats will be trained to time precisely by rewarding with food. Lever responses will be spaced 20 to 22 seconds apart, During the training period, one-half of the rats will be given chronic administrations of physiological salt solution. After the temporal discrimination is established in all animals, the nicotine and saline injections will be discontinued and the animals will be subjected to the same behavioral procedure. The purpose of the study is to determine: (a.) whether chronic administrations of .. nicotine will influence the rate of acquisition of the temporal discrimina- tion; and (b.) the effect of abrupt wlthdrawal of nicotine on the performance of the discrimination. Another project has yielded preliminary results on the effects of nicotine discrimination in rats. In this experiment tone stimuli are randomly presented to hungry ratsin Skinner Boxes. If a light is on above the lever during, the tone stimulus, a lever response. produces a food reward. If the light is off above the lever.durlng the tone stimulus, a response produces a 30-second blackout period. For a second group of rats, light stimuli above the lever are ran- domly presented to hungry rats. If the tone is present during the light stimulus, a lever response is rewarded with food. If the tone is absent during the light stimulus period, a lever response is punished with a 30-second blackout period. Records are kept of correct and incorrect responses during the experlmental-sesslon. Preliminary results show that most doses of nicotine increase both correct and incorrect responses. However, .some doses of nicotine appear to decrease incorrect responses. Thlsmlght con- ceivably be interpreted as a tranquilizing effect of nicotine. 50207 7399

BEHAVIORAL EFFECTS OF NICOTINE IN SQUIRREL MONKEYS T. R. A. Davis, H. J. Bronsteln, C. J. Kensler (grantee) Arthur D. Little, Inc. Cambridge, Massachusetts The effect of nicotine intraperltoneally was studied in three behavioral schedules: a multiple fixed Interval/flxed ratio schedule, a Sidman avoidance schedule and a vertical acti- vity schedule. The vertical activity schedule involves physical work by requiring the animal to operate two levers, one at the. bottom and one at the top of a two meter pole which must be tra- versed to operate the levers for positive reinforcement. Know- ledge of the dlstancetraversed between levers, animalwelght and time of traverse allows computation of work done. Of five doses examined in the multiple fixed Interval/flxed ratio sched- ule, nicotine produced an increasedrespondlng rate at 0.15mg/kg during fixed interval periods but had no effect on fixed ratio. In the avoidance schedule, nicotine produced an increased res- ponding rate at doses of 0.05, 0.15 and 0.45 mg/kg. In the verti- cal activity schedule nicotine produced no.changes except a decrement of performance at 0.45 mg/kg both for work done and for the rate at which work was performed. It is concluded that nicotine at effective doses produces an increased responding rate in those schedules in which physical work is not a primary component. A learning schedule, a steadiness schedule and a nega- tive reinforcement physical work schedule are at various stages of completion and is proposed that future objectives include comparison with other compounds whlch have similar effects. In anticipation of this program change comparison of nicotine with d-Amphetamine is presently underway and preliminary results indicate that nicotine effects are similar to those of d-Amphetamlne.

PROGRESS .REPORT OF THE ACTION OF NICOTINE AND NICOTINE DERIVATIVES ON LEARNING AND RETENTION. Danlel Borer Department of Pharmacology University of Sassarl Sassari, Sardinia An earller report (1963-1965) indicated that nicotine induced a central stimulation and has a facilitating effect on the acqui- sition of a conditioned avoidance response in rats. Using various recently developed automatic devices, the effect of drugs on different types of conditioning, vlsual discrimination and maze learnlng was compared.ln rats and mice. The action of nicotine on maze learnlng was similar to that exerted on avoidance learnlng. Furthermore, avoidance conditioning of inbred strains of mice was used to analyze the effects exerted by genetic factors. This indicated that the action of nicotine is strain dependent and that the degree of facilltatlon is generallyhlgherIn the strain characterized by a low performance .level. ~ .- Comparison was made between the effect bf nicotine, nicotine derivatives, scopolamlne, mecamylamlne and other chollnerglc drugs. Nicotine and scopolamlne were found to exert two different patterns of facilitatlng effect on avoidance conditioning of.nalve animals. Mecamylamine impaired acquisition Of avoidance condltlonand and antagonized the action of atropine. Striking dlffer~nces were observed when a drug was administered to naive and previously treated animals. In a study concerned with the effect of nicotine on the-rat in the running wheel, opposite effects were observed in relation to the nyctemeral rhythm. The same dose of nicotine had a stimu- lating effect when injected during the daily rest. period and a sedative effect during the night period, usually characterized, by maximal spontaneous activity. The results are discussed in relation to thevarlous functions exerted at different levels by cholinergic mediators on.the central nervous system and to the existence of a dual mechanls~ of learning and retention. • 5020";

RESEARCH ON BEHAVIORAL ASPECTS OF SMOKING Dorothy F. Dunn University of Illinois • Department of. Health Science Urbana, Illlnols This preliminary report, concerns-the smoking habits of fresh- man students on the University of 111inols Urbana campus. Data for 102 variables were obtained through a self-admlnlstered precoded questionnaire from enrolled students and from a transfer of infor- matlon from the Student Data System magnetic tape. Of 3,567 students 2 in 5 smoked regularly and 98.0Z were resl- dents of Illlnols. Seven in I0 were men, and there were over 2 in 5 of the men and I in 3 of the women who smoked. A total of 95.2Z began to smoke before age eighteen. Of the I in 5 from farms and rural nonfarmareas i in 4 smokedand-for Chicago thls-was almost 1 in 2. Showing a relatlonshlp with mobillty of residence were the education of the father, occupation of head of household, and the education and smoking habits of .the mother. There. were I in 5 of the valedictorians and l.in 3 o~.thesalutatorlans of high.schools who smoked. For students in the James Scholars honors program approximately 1 in 3 smoked; and for those receiving full financial support entirely from scholarships this was approximately 1 in 5. For students with spending money of less than $5,~3 in 10 smoked and students with over $10, approximately I in 2 smoked. Of stu- dents who participated over 5 hours a week in organized campusactl- vltles, 1 in 3 smoked, and of students who had not held membership in any organization during the last 12 months almost 1 in 2 Smoked. If a student who smoked had a roommate who also smoked, he was more llkely to have increased the number of.clgarettes he was smoking during the past 12 months than the student with a roommate who did not smoke. Only sllght differences of opinion in student nonsmokers and in those who smoked regularly regarding parental attitudes were evident: I in 5 strongly disapproved, 2 in 5 disapproved, and less than 1 in 20 reported that their parents approved of smoking. The more cigarettes a student smoked a day the more times he had attempted to stop smoking. Of 4 in 5 who smoked cigarettes with filters, I in 4 smoked more than one pack a day, and i in 6 consumed all the tobacco portion of a cigarette with a filter. Almost 9 in I0 believed that a cigarette smoker has a greater chance of developing lung cancer than the nonsmoher and the same number disagreed with the statement that cigarette sales should be banned on campus. There were ~ in 5 who believed that freshmen students in college are adequately informed regarding potential dangers of smoking cigarettes. NOT IN ATTENDANCE 50207

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PHYSIOLOGICAL DISPOSITION AND BIOTRANSFORMATION OF LABELLED NICOTINE C. G. SchmlterlSw (grantee), E. Hansson, G. Anderson, L. E. Appelgren and P. C. Hoffmann Department of Pharmacology Royal Veterinary College Stockholm, Sweden The distribution of cl4-1abelled nicotine in mice and cats has been studied using Ullberg~s autoradlographlc method. Whole-body autoradiography, autoradlography of. the brain and the adrenal, and mlcroautoradiography of the superlor, cervlcal ganglion have been employed. These methods visualize the distribution of the radioactive isotope.present in nicotine and/or its metabolltes. Nicotine and its metabolltes very rapidly accumulate in the brain but obviously leave the brain fairly soon. The accumulation of nicotine and/or its metabolltes in other target organs than the brain, such as adrenal medulla, suPerior cervical ganglion, gastric mucosa, and blood vessel walls is described. Microautoradlography of the superior cervical ganglion reveals that only part of the ganglion cells take up radioactivity following administration of cl4-nlcotine. Paper chromatography of chloroform extract from. the brain, liver, kidney and stomach after intravenous injection of nicotine-methyl-Cl4 indicated that nicotine ~as rapidly metabolized to continue. The latter compound was isolated and identified by physical and chemical methods. No other radioactive compound in addition to C1402 was observed by-the methods used in this study. The metabolism of nicotine has also been investigated in tissue slices of various organs of the mouse using cl4-1abelled nicotine and thin-layer chromatography. Of those tissues studied, the liver, the kidney, and the lung were found to metabolize nicotine, while the brain, diaphragm, spleen, stomach, small intestine, and adrenal glands did not. The metabolic products identified were continine, y-(3-pyridyl)-y-oxo-N-methyl- butyramide, hydroxycotinine, and C1402. Two unidentified products have been separated chromatographically. Further work concerning the distribution of C14- and H3-1abelled nicotine in the brain at the cellular and subcellular level is in progress.

STUDIES ON 14C LABELED NICOTINE METABOLITES Herbert McKennis, Jr. Department of Pharmacology Medical. College of Virginia Richmond, Virginia During the mammalian metabolism of (-)-nicotine, the alkalold undergoes a number of changes, including an oxidative deterioration of the pyrrolidine ring. Studies with both isotopic and non-lsotoplc nicotine have proceeded to the point where general schemes of the metabolic pathways have been clearly delineated. In extending these studies quantitatively to the cellular and organ level,need for ~)-nicotine and its metabolites wlth.a high specific activity of ~C has developed. .. The objectives of this study have been met in principle by a series of synthetic steps starting with nicotlnlc_acld. For the radioactive steps, the highest specific activity 14C commerclally available was employed. This provided a labelingin which approxl- mately 80 per cent of the carbon atoms adjacent to the pyrldlne ring are in the form of 14C. . Nicotinic acid was esterlfled, and the resultant ethyl nlcotlnate was condensed with ethyl succinate to obtain ethyl nicotinylsuccinate, which was hydrolyzed and decarboxylated.to obtain 7-(3-pyridyl)-v- oxobutyric acid (I). A reductive methylamination o£ I provided (+,-)-y-(3-pyrldyl)-y-methylaminobutyric acid (II). II was converted to a (+,-) benzoyl derivative [(+,-)-III] and resolved with L-(-)- ephedrine. (-)-III was hydrolyzed and lactamlzed to obtain (-)- 25 contlnine, characterized as a monoplcrate, [a]3461 +27,5°. The synthetic routes under investigation in this study haveprovided totally synthetic (~)-nlcotine with the required label. In addition, these and related synthetic routes provide (+)=nicotine and a. number of nicotine metabolltes: y-(3-pyridyl)-y-methylamlnobutyric acid, ¥-(3-pyrldyl)-¥-hydroxybutyric acid, ¥-(3-pyrldyl)-¥-oxobutyrlc acid, cotlnlne, demethylcotinlne, and y-(3-pyrldyl)-¥-oxo-N- methylbutyramide. The possibilities of detailed study of many facets of the metabolism of nicotine can be increased through use of these and related synthetic routes, which make possible the utilization of small, so-called physiological, quantities of nicotine and its metabolltes in tracer studies. Preliminary biological studies done in collaboration with the Department of Pharmacology, Royal Veterinary College, indicate a high level of excretion of .,-(3-pyridyl)-..,-oxobutyric acid-~1-14C after intravenous administration to the mouse. 5020?

SOME STRUCTURAL ASPECTS OF NICOTINE PHARMACOLOGY Charles H. Jarboe Department of Pharmacology University of Loulsville School of Medicine Loulsville, Kentucky A program to synthesize several types of nicotine derivatives has begun. Parallel studies on selected aspects of their biological activity are in progress. Inltial emphasis is on the production of compounds selectlvely quaternlzed at the pyrrolldlne nitrogen with alkyl halides. Nicotine has been reacted with methyl iodide and benzyl chloride to yield complex mixtures of products. The desired compounds were i~olated by the use of Column chromatography and plcrate formation. Structural assignments were made on the basis of elemental analysis, infrared, ultravlolet and nuclear magnetic resonance spectroscopy..These are the first of a group of compounds selected to demonstrate the effects of structural change on nervous system activity of the nicotine structure. Pharmacologic assay of these nicotine derivatives was performed using Ran.__~a piplens rectus abdomlnus muscle and a gulneaplg ileum preparation. The former measures activity at voluntary muscle end synapses and the latter activity at ganglla. All of these measurements are relative to nicotine as a standard agonlst. The bioassay work on both compounds is still in progress. The data presently available indicate quaternlzatlon with both halldes to effect receptor affinity and intrinsic activity. This effect appears to be greater for the benzyl derivative, indicating the possible existence of both electrlcal and sterlc factors in the reaction between biological receptor sites and these substances. This is being pursued further with the synthesis andevaluation. of other model compounds. No evidence has been obtained which would indicate either of the two compounds now under study to have blocking properties. $0~0~

QUANTITATIVE METHODS FOR THE DETERMINATION OF THE DISTRIBUTION OF NICOTINE AND ITS CONGENERS IN BIOLOGICAL SYSTEMS Herbert McKennls, Jr. Department of Pharmacology Medical College of Virginia Richmond, Virginia With increased interest in the quantitative determination of nicotine, its metabolites, and congeners in biological fluids and. cellular extracts, needs havedeveloped for methods that are accurate and rapid when small and limited amounts of biological material are at hand. Although much has been reported on gas-llquld chromatographic methods for the determination of nlcotlne, most methods appear not to provide the sensitivity desirable for many types ofmammallan studies. One approach to a solution to this problem under study hasbeen to provide, by chemical-alteration, nicotine-and-lts congeners ...... with groups known to have strong electron affinities and thus extend gas-liquid chromatographic methods to the ultimate capabilities of electron-capture detectors, which have usable- sensitivities under proper conditions several-thousand times as great as flame-ionlzatlon detectors. The two methods chosen for initial study provide for the introduction of a double bond in conjugation with the pyrldlne ring (I), and the introduction of a maximum usable number of fluorine atoms (2) The procedures which, in principle, have already shown success are now being refined for possible biological application. 3-Acetylpyridine (Aldrich Chemical Co.), a reported bacterial metabollte of nicotine and a product from fermentation of nicotine in cigar tobacco, has been subjected to gas-llquld chromatography on a column (Oronite polybutene 128, 2% on AnakromABS, 3'x 118") at 110°. The signal (retention time of 60 seconds referred to benzene as one) obtained under these conditions with an electron- capture detector gives usable information with known solutions containing as little as 2 x 10-12 grams of material. The electron- capture detector appears also to be suitable for determining esters of y-(3-pyridyl)-y-oxobutyric acid, a mammalian metabollte of nicotine, and nicotine that has been chemically converted to a ~-perfluoro- acylmetanicotine. Conditions for the application of these and related procedures to biological material are under study. 50207

ELECTROENCEPHALOGKAPHIC CHANCES IN MAN FOLLOWING SHOKING AND NICOTINE Henry B. Murphree and Carl C. Pfelffer Bureau of Research in Neurology and Psychiatry New Jersey Neuropsychlatrlc Institute Princeton, New Jersey Quantitative electroencephalography provides reliable and sensitive methods for assay of drug effects upon the central nervous system. These methods have beenapplied to study many different kinds of drugs, including ehtanol and other substances with "antlanxiety" effect (Arch. Gen. Psychiat. I~0:446, 1964) and In~ludlng stimulants or "antidepressant" compounds (Ann. N.Y. Acad. Scl. I0__~7:1045, 1963). This provides a set of r.eference standards by which many factors .affectlng. the central nervous system can be. gauged. The-studies reported here were conducted to determine the effects of smoking and nicotine according to these standards. The subjects .were smokers and non-smokers of both sexes, ages 21-43. Plain and mentholated cigarettes with and ~ithout filters were studied; as were pipes and cigars. Trials included pufflng,~ unllghted;in-- haling, unlighted; puffing, lighted; and inhaling, lighted. All trials were with subjects shplne, eyes closed, in a partially darkened, sound attenuated room. EEGs ~rom left or both left and right occipital areas were analyzed by the Drohockl method (Int. Rev. Neuroblol. ~:265, 1965) and recorded on magnetic tape for time series and frequency analysis by means of a digital computer (Int. J. Neuropharmacol.. ~:97, 1964). Results so far suggest that the most prominent effects.of smoking, those after inhaling, occur very rapidly, in less than a chest-to-head circulation time, so that reflex mechanisms are probably involved.

THE EFFECTS-OF SMOKING AND NICOTINE UPON CEREBROVASCUI~R ACTIVITY Sheldon H. Steiner Department of Medicine Northwestern University School of Medicine Chicago, Illinois ~he purpose of this research was to determine the effehts of nicotine and smoking upon cerebrovascular reactivity. The method proposed to measure changes in cerebra] blood flow as that of determining the cerebral uptake fraction of 4 lodo]31antipyrine after a slug intravenous injection. The cerebra] uptake of indicator in the absence of redistribution was caIculated by extrapolation to initial delivery. The first goal of this investigation was to determine the validity and reproducability of these extrapolations under controlled conditions in a precisely calibrated model. An eight-compartment recirculating flow model was connected in series to a ]50 m]. compartment which served"as a cardiac mixing chan~er. All other compartments were in parallel. Total volume of the system was 14 I, and compartment volumes ~anged from 0.5 to 3 L. Compartment flow rates were varied from I20 to 2140 ml/min. Total system flow was maintained at 5.]2 L/min by a calibrated f]owmeter. ~nf]ow to each chan6er was measured without disturbing the system. Each compartment was observed in turn by a collimated scintillation probe which led to a linear ratemeter with a l-second time constant. Rates of change of indicator (Cs137) input and washout were recorded. IRe difference between these mDno-exponential functions was extrapolated to TO semilogarithmica]ly. Counts per minute at T0 were converted to a~raction of the injected tracer by counting a known amount of injectate using identical volume and geometry. Systemic fIow was ca]cu]ated by the Stewart-HamiIton indicator dilution method. Three methods were used to calculate compartment flow: (]) Extrapolation to T0 of indicator input and net rate of redistribution; (2) Extrapolation to T0 of change in organ indicator content in the absence of recirculation; and (3) Using the "t½" of change in organ indicator content in the absence of recircu]ation. ]'he T0 of the injected fraction (Methods ] and 2) was multiplied by calculated systemic flow to determine compartment flow. Comparing actual and calculated flows gave the following mean percent errors and standard deviations: B~thod I (-0.]5 i 6.86); Method 2 (-0.65 i 11.]I); Method 3 (-2.07 i ]1.69). ]'he correlation coefficient for each method was NOT IN ATTENDANCE

THE ROLE OF NICOTINE AND RELATED SUBSTANCES IN THE GENESIS OF PROLONGED GANGLIONIC FACILITATION Gerard L. Gebber Department of Pharmacology M~chlgan State University East Lansing, Michigan High frequency pregangllonlc stlmulatlon-and repeatedexposure to nlcotlnlc-llke agents, produce a state of prolonged synaptlc facilltatlon in autonomic ganglla. The facilltatlon is char- acterized by enhanced gangllonlc discharges to injected acetylchollne as well as to other exogenously admlnlstered chollnerglc agents. Since the effect of repetitive pregangllonlc stlmulatlon and injected nicotine may be r~tmlcked by chronic smoklng~ It-seems reasonable to investigate the factors re~ sponslble for the genesis of prolonged gangllonlc facilltatlon. It is evident from the works of several groups that post-activation facilitation (post-tetanic potentiation), in autonomic ganglia, cannot be explained solely be each or a combination of the following: (1) changes in the presynaptic terminals which, in ..:tgrn,_.m~ght influence transmitter release;-.(2) sustained~ curare- sensitive depolarlzatlon of the gangllon cell; (3) sustained atroplne-sensltive depolarization of ~he gang!.ion cell. _A proposal has been f0~lated which suggests .that the genesis of post-activatlon facilltation may be associated with changes in the afterpotentlals whichcharacteristica1Iyfdlldwdischarge of the ganglion cell. Such changes presumably would beInduced by a ~itherto unsuspectedsction of-thesynaptic med#ator"and of exogenously administered nicotlnic-like substances.

RESPIRATORY~ CARDIAC, GASTROINTESTINAL AND EEG~EFFECTS OF CHRONIC NICOTINE ADMINISTRATION Roy V. Hudson (grantee) and Gerald M. Department of Pharmacology University of Michigan School of Medicine Ann Arbor, Michigan Carlson This investigation is primarily concerned with the pathophyslologlcal effects of~chronic intravenous administration of doses of nicotine comparable to those obtained during smoking. A modlflcatlon of the strain gage force transducer developed by Jacoby et al. (J. Appl. Physlol. 18:658, 1963) was sutured on the left ventrlcle, the perltoneal surface of the diaphragm and the pylorlc antrum of the Rhesus monkey. Independent monitoring Of !ongltudlnal and clrcular muscle activity of the antrum can be achieved by this method. A silastlc catheter was placed in the ~Ight aurlcle via the external Jugular vein for drug administration. EKG and blpolar EEG electrodes were also" Implanted. These anlmals .are presently for programmed drug administration. In preliminary studies partially restrained unanesthetlzed dogs (prepared as described .above) received doses of nicotine (25-200~g/kg) on an accumulative basis, at 15 minute intervals. Minimal cardiac slowing was observed following 25 ~g/kg. The accumulatlve dose 50-100 ~g/kgproduced an increase. in myocardial contractile force and a bradycardla which gradually returned toward control levels. No significant EZGalteratlons were noted. Resplratoryrate and depth were increased. An Inltlal bradycardla followed by a tachycardla was produced by the 200 ~g/kg dose. Myocardlal contractile force wasenhanced. Contractions Of t~e antrum were inltlallydepressed. This depression was closely followed by restlessness, retching and licklng.but never emesls. The retching was associated wlthlarge~contractlons, of the antrum and diaphragm. This phase of antral hyperactivity was followed by a second period of depresslon and gradual recovery. When 200 ~g/kg was given as the inltlal dose muscle tremors, salivation, defecation and urination were produced. This was never observed when the 200 ~g/kg dose was administered on an accumulative basis. receiving nicotine on a chronic baslsutillzlng ame~h0d ....... 50207 ?q12

EFFECTS OF NICOTINE ON ISOLATED ~SCLE George B. Weiss Department of Pharmacology Medical College of Virginia Richmond, Virginia A number of approaches have been utilized to obtain informatlon~ concerning the mechanism of action of nicotine in isolated muscle systems. In frog sartorlus muscle, an increased Ca45. uptake is induced by. nicotine at doses much lower than those which elicit contracture. Both the contracture and lucreasedCa45 uptake are inhibited by In- creased K iOn concentrat.lon or decreased pH. Lowering the pHfrom 8.4 to 7.4 inhibits the contracture, the increased Ca45 uptake and the uptake of C14-nicotlne. Lowered pH apparently decreases the access of nicotine to a cellular site by diminishing the proportion of unionized nicotine available. Increased K ion does not inhibit C14-nicotlne uptake or Ca45 efflux induced by nicotine, and may therefore block nicotine contracture by dlrectly inhibiting the increased uptake of calclum ion normally associated with the action of nicotine. The nicotine contracture occurs even .in zero Ca.Ringer's solutlon containing 4mMEDTA. However,..the increased Ca~5 efflux obtained under these conditions Indicates.that nicotine can release bound calcium from cellular sites. Experiments using calcium-free solutlons indicate that part of the calclum speclflcally released by nicotine is the self-exchangeable calclum, The uptake of C14-nlcotlne is quite rapid andequillbrlum is attained in approximately ten minutes. This uptake is inhibited by lowered pH (decreasing entry rate) or lowered temperature. The monoamlne oxidase inhibitor Nialamlde also appears to decrease uptake of C14-nlcotine. In longitudinal smooth muscle from gulneaplg ileum, nicotine causes a transient contracture, an increase in Ca45 uptake and a decrease in total calclum content. Various approaches indicate that nicotine may also act to release membrane-bound calclum in this tissue. The extracellular space has been measured and the uptake of C14- labeled histamine and serotonln has been dellneated in order to compare the movements of these agents with those of nicotine. 50207 7~113

A STUDY ON THE MECH~ISI4S OF ACTIO~ OF/,NICOTINE O~ P~ ~E FA~ .ACIDS Ins tituto dt Ricerche Fa~olo~iche~-~r~o ~lan, The purpose of this investigation ~!8 ~to, obtai~.~ore.'information about the ~echanis~ by which nicotine Increases. ~he/-i~ve.!~!Of plasma .free fatty acids (FFA) in expertmentaI:.ani~al|, ~F~,pe~.i~ts ~alll be designed in order to answer a number of basi©~questi.oUS~:~i~i • a) to establish whether the o~ an increased lipolysie- c) d) e) a possible direct action on adipose tissue £) drugs ~hich may prevent the effect of nicotine NOT IN ATTENDANCE

EFFECTS OF SHOKING UPON UTERINE CONTKACTILITY AND PLACENTA IN HUMAN PREGNANCY Charles R. Echt and Richard W. Stander Department of Obstetrics and Gynecology Indiana University School of Medicine Indianapolis, Indiana It is a well known fact that pregnant patients who smoke seem to have infants of smaller size than non-smoking patients. The purpose of our investigation, which began in July of 1965, is to determine, if possible, the etiology, of low weight infants in smoking mothers. In order to do this in v~tro and in vivo studies of uterine contractility are being done in smoking and non-smoking patients and these results are being correlated with placental function in pregnancy. The in vitro studies are being done upon the uterine musculature in pregnant patients who come to cesarean section. Myometrial strips preliminarily have shown increased activity when bathed in nicotine. In vivo studies are being done by external toco- graphic measures. The placental function study, which is presently being used in an effort to predict fetal outcome, is that of urinary Estriol determination. These determinations are being done on 24-hour urines in the first, second, and third trimesters of pregnancy in smoking and non-smoking patients. The uterine contractility in vivo studies are being done simultaneously with the urinary Estriol determinations. At the writing of this abstract, the results were very preliminary, as the study had just been begun. 50207 7~17

I I I I i I I I I I I I I I I I I I I EFFECTS OF SMOKING ON THE FETUS IN UTEROAND AFTER BIRTH Thomas H. Kirschbaum Department of Obstetrics and Gynecology UCLA School of Medicine Los Angeles, California The proposed studies are aimed at investigating the effects of smoking by the mother on utero-placental and fetal circulations and metabolism in animal and human subjects. The animals to be used are pregnant sheep, monkeys and cats. Maternal and fetal arterial pressures, uterine and umbilical blood flows, maternal and fetal P02, pH, pCO2 and carboxy- hemoglobin will be measured in control, smoking and recovery periods. In a series of chronic experiments on pregnant sheep, maternal and fetal circulatory and respiratory parameters will be measured in the conscious state in control, smoking and recovery periods. In the smoking period, the sheep will be placed in a specially constructed chamber with the atmosphere saturated with cigarette smoke. The human investigation will be carried out on pregnant women in various periods of gestation. The effects of smoking on maternal hem~dynamics will be recorded. The time for initiation of breathing by the newborn will be recorded in the smoking group and compared to that of nonsmokers. Fetal blood composi- tion will be analysed in infants born to a group of smokers and compared to that of nonsmokers. NOT IN ATTENDANCE 50207

NICOTINE ABSORPTION IN RATS DURING PREGNANCY: A BRIEF PROGRESS REPORT R. F. Becker (grantee) and J. E. King Laboratory of Perlnatal Studies Duke University Medical Center Durham, North Carolina Pregnant rats injected twice daily with 0.5 to 1.0 mg nicotine per kg exhibited no changes except for the very mild convulsive episodes following each injection. They did not develop a tolerance for nicotine over this 21 day period. The doses were in range of those purported to be absorbed by the heavy smoker. Gestation times, birth weights, survival and developmental status of the young differed no whit from similar parameters in untreated, or saline-injected controls~. With slightly higher doses twice daily (3-5 mg/kg), pregnant rats consumed less food, wasted more by spillage, and gained far less weight than control mothers. They delivered young 2-4 days beyond term; the young were underweight and fetal in appearance. Stillbirth and infant mortality rates were higher than in controls, but not as great as in young delivered 2-4 days post-term from mothers receiving Antuitrin-S to purposely delay delivery. There were no abortions and no premature deliveries. Surviving young had no difficulty establishing air breathing. They were pink and healthy, though immature in appearance. Along with decreased birth weight went a shorter transverse skull diameter; shorter vibrissae; less ossification in radius and ulnar, than in term control neonates. They often lacked nails. The placentae, while small, were firmly attached and, apparently, functional, despite the delayed delivery. In contrast, post-term infants of the Antuitrin-S group were heavier than term controls; had wider transverse skull diameters; longer vibrissae and nails; and a greater degree of ossification in the long bones. Placentae were infarcted and very tenuously attached. Neonates were cyanotic and in respiratory distress. Few survived. Many were hump-backed and club-footed, whereas no teratology appeared among the nicotinized group. If nicotine were fed in the drinking water even at high dose levels, maternal convulsive episodes were prevented. A more uniform drug titer could be protracted over 24 hours. Imbibition at intervals more nearly resembled a smoking situation.

Nicotine Absorption In Rats During Pregnancy: A Brief Progress Report Page 2 With daily intake of as little as 2 mg/kg/day, food consumption was reduced 5% and water consumption 34%. There was no maternal weight loss during pregnancy; young were born at term With birth weights equal to those of control neonates. With intakes of i0 mg/kg/day, food consumption dropped to 45% and water consumption to 60%; mothers lost weight during pregnancy; delivery was again delayed; young were underweight and immature in appearance. The only, difference had been the method of drug administration and the elimination of convulsive seizures in the mother. Are the effects observed due to nicotine intake per se or to the starvation and dehydration effects in the face of nicotine? When pregnant rats were deprived of as much food and water as the heavily nicotinized group, mothers lost weight and the neonates • were undem~eight at term. But, delivery occurred at normal times and the neonates, though lighter, had all the characteristics of term animals. It would appear that decrements in birth weight represent starvation and dehydration effects. Changes in the gestational period and signs of immature development appear to be nicotine effects. When exactly in utero, the developmental time schedule is slowed, and how nicotine acts to do this are still matters for further investigation. In the rat, at least, prematurity does not seem to be a salient feature, rather postmaturity with retardation in development. • 5020~ ~20

Yeb~u~t'y 27, 1967, .J and Hea~th, American 14edlcal Assoc£atlon. 535 Hor~h Dearborn Street, Chlcs~o, X111nols. 60610. Dear Dr. 81rigor: Enclosed is a copy of have received fro~ Dr. N. S. copy o£ my reply to h/~. As I indicated to you on the telephone it that any exper~nent endeavorLnS; to aecer,~taLn the o~£oots o£ smoking cil;arettes should ~o1.1ow a ~,sok.f~l; proOoduro as similar to that £olIowod by human rockers as you my know sacking msclttnos ~hSVe b..~,n dovelopod ~or thls,i • purpose and certain a~ceptod 0~oktnS. pe~to.~tns have boon _~ollow~.d. Research that does not ~o11~q. acceptable standards O~ Saol~t~ ,. would be highly questionable and t~ho ..results Subject to chal~ense. As I Indicated to you we havo~.mado it a pract~S not to ~urnlsh cis~rettes directly to £nV0StLsato~e. ~n order to". avoid all questions we £ool £t~prof~o~itblo .£or £nveet£~to~s to pu~se c~rettes on ~e ~t In ~.~Sm .~er t~t ~~rs Vice l~'esident and Oenoral Counsel.-

Dr. N. S. Assali, Department of Obstetrics and Oynecology, School of ~diclne, The Centdr for the~Bealth Los Angeles, California. On receipt of your letter of February 15. 1967 advised ~ t~t on ~ assyrian t~t t~ intent of y~r proJ~t ~ng of cigarette and ~uld differ in o~lltlon f~ t~ ~lnst~ ~ko of ctsa~t~s. ~y r~rt ~t th~ mid not .~~nd ~he bu~ing of ~ba¢co tn ~lk fern. With respect to supplyLn~ a terse mmbor of eisarettes for y~ ~ ob~tn ~e ~oo~ ci~rottes In ~e ~t p~e. souse and kind o~ cl~t~l used In ~t ~r~nt. Xt ~uld so~ ~t ~ east of cl~rottos J~ld ~ eonside~ a pert of t~ cost of t~ o~all p~J~t for ~t~h ~ds s~ being ~pplied. I am send~ng • copy of your coummicetlon and of this letter to Dr. Ire Singer for hie information. li. H. Kams. Vi~e President and ~enerel Counsel. 50207 7~25

February 23~ 1967 Mr. H. H. Ra~m Re: Drs. Assall and Kirschbaum AHA - Education and Research Foundation The letter from Dr. Assali~ dated February 15~ has been discussed with Dr. Nielson. It is assumed that the intent of the experiment is to study the effect of cigarette smoke. Accordingly~ smoking of cigarettes in the customary manner is recommended. Smoke generated by burning of tobacco in bulk form would differ in composition from cigarette smoke. Therefore~ use of tobacco in bulk form for these studies is not reconsnended. HS:has 50207 7tl26

NIVERSITY OF CALIFORNIA, LOS ANGELES BEREELEY * DAVIS * IRVINg ' LOS ANGELES * BIVERSIDI~- • S&N DIEGO • SAN FRANCISCO DEPARTMENT OF OBSTETRICS A~D (~YNECOLO~Y SCHOOL OF ~EDICINE THE CENTER FOB THE HEALTH SCIENCES LOS ANGELES, CALIFO/~FIA 90024 SANTA BA~BAP~. • SANTA CRUZ February 15, 1967 H. H. Ramm, Vice President R. J. Reynolds Tobacco Company Winston-Salem, North Carolina Dear Mr. Ramm: Dr. Ira Singer of the American Medical Association advised me to write to you with the hope that you might direct my letter to the responsible person. Dr. Thomas H. Kirschbaum and I have a grant from the Committee for Research on Tobacco and Health of the American Medical Association-Education and Research Foundation to study the effects of smoking on the fetus in utero and after birth. The project is divided into several parts. The first part consists of studying the effects o~utero-placental circulation, and fetal circulation and oxygen consumption in pregnant sheep. We would like to have tobacco in bulk form so we can burn it and channel the smoke via proper instrumentation to the lungs of the ewe. It seems to me that this way is preferable to burning cigarettes which would cost more in both time and money. If you believe it is not feasible to use tobacco in bulk form for these studies, could you send us a large number of cigarettes. Any help you might be able to give will be very much appreciated. Sincer ly yours, ~ ~ Professor of Obstetrics and Gynecology, and Physlology NSA~jmw 50207 7~ 28

Pages 413, 454, 455, 457 and 458 from the TODAY'S HEALTH GUIDE published by the AmerlcanMedical Association edited by W.~ W. Bauer~ M. D. Director Emeritus Department of Health Education American Medical Association.

CA~CER field has tended to lend weight to this theory. Although no human cancer viruses have yet been isolated, ~'iruses that cause different can- cers in mice, hamsters, clfickens, and rabbits have been found. Dr. Charlotte Friend of the Sloan-Kettering Institute in New York City has discovered a virus that causes leukemia in mice. Using this virus, mice have been immunized against leu- kemia, or cancer of the blood, with some de- gree of success. This limited success in the field of animal experimentation holds real hope for human beings. The electron microscope has shown Dr. Leon Dmochowski and Dr. John A. Sykes of the University of Texas Medical School virus-like particles in leukemic cells of mice, chickens, and menmparticles that ap- pear to be strikingly similar. Thus, if a mouse can be inoculated with a virus against leuke- mia, it may be possible to do the same for man ~providing that the human leukemia virus can be found and a vaccine created. To this end, much experimentation on leukemia viruses is being carried on. Other scientists have been experimenting with limited success with vac- cines made from cancer patient's own tumors. The common occurrence of cancers in the same family has led to much thought about the part heredity might play as a Cause. Biologists 413 have been able, though with difficulty, to breed a cancer-susceptible strain of mice. However, most authorities at the present time agree that there is no real evidence to call heredity a cause of cancer. The fact that several cases occur in a family is regarded as a coincidence due to the increasing frequency of the disease in an aging population. Common Sites of Cancers Breast Crower: The leading cause of death from cancer among women in the United States is breast cancer. An estimated 64,000 new cases occur each year, of which about 25,000 are fatal. One out of every 17 women will have the disease in her lifetime. The common type of breast cancer affects a gland. It is most curable when found while still sn~all in size and con- fined to the breast. Hence, detecting it early is extremely important. This can be done by monthly self- examination which any woman can easily learn. The American Cancer Society has a film available for free showing on this subject. Also, regular visits to the family doctor--particu- larly if any suspicious lump is felt--are vital. Ninety-five per cent of women with breast lumps wait too long to see their doctors. In a Scotland study of several thousand women on whom breast cancer surgery was performed, the average size of the tumor was a little over an inch, three times the size of the smallest lump that can be felt. Lung Crower: The leading cause of cancer deaths in American men is lung cancer. About 40,000 deaths are recorded in the United States each year from this disease. Yet, a large portion of these deaths could be prevented if there were no cigarette smoking. The more cig- arettes smoked and the longer they are smoked, the greater the risk to the smoker. On the other hand, studies sho~v that in those who stop smok- ing, the risk of lung cancer decreases directly with the length of time they have stopped smok- ing. Pipe and cigar smokers who do not inhale run little risk of lung cancer, but they are more prone to cancers of the lip, tongue, and mouth than are non-smokers. Lung cancer is cured in only al:~out 5 per cent of cases even though the potential cure rate is as high as 50 per cent if operated upon in time. Unfortunately, it often gives no clue to its presence until it is too advanced for cure. Prevention by not smoking is the best protec- tion. (See Part XII, Chapter Three.) 5020? 7~130

CHA~'EK THREE SMOKING: FACTS YOU SHOULD KNOW AMERICANS SMOKE about 500,000,000,000 cigarettes, the equivalent of about 2,777 cig- arettes a year for every man, woman, and child in the country or over seven cigarettes per day. The smoking habit usually begins in the early teens. By the 12th grade from 40 to 55 per cent of all children are found to be smok- ers, according to one stud),. Another survey in American secondary schools indicates that about one of every four boys smokes cigarettes, and one of every, eight girls. The boys also are heavier smokers. This ratio follows through in adult life. Figures fluctuate, but it has been esti- mated that 60 per cent of American men smoke compared to 30 per cent of American women. Since 1939, numerous scientific studies have been conducted to determine whether smoking is a health hazard. The trend of the evidence has been consistent and has permitted sound evaluation of the health risk. Based on evidence derived from human'population studies, clini- cal and autopsy studies, and animal experi- mentation, the smoking of cigarettes does con- stitute a definite risk to health. Skilled research personnel have conducted studies that prove tobacco smoking, particularly cigarette smok- ing, is associated with a shortened life expect- ancy. Cigarette smoking is regarded as an important factor in the development of cancer of the lungs, and cancer of the larynx, and is believed to be related to cancer of the bladder, esophagus, and oral cavity. Male cigarette smokers have a higher death rate from coro- nary heart disease than nonsmoking males. .Cigarette smoking is regarded as the most im- portant of the causes of chronic bronchitis in the United States, and is also a significant fac- tor in laryngeal cancer. A relationship does exist between pulmonary emphysema and cig- arette smoking, but it is not established that this relationship is causal. The majority of physicians and researchers believe these ob- servations to be corr,' .ey~d say, "Don't smoke! If you don't smoke, don't start." Some competent physicians and research perso, anal age less sure of the effect of cigarette smoking on health, although their number is d~s~dling. They believe the increase in these diseases may be explained by other factors in our complex environment, although evidence to support this view has not been forthcoming. Nevertheless the)- advise: "Be moderate if you must smoke." An individual may try to reach a solution about his own smoking by studying the evi- dence, ma "ldng a rational decision, and acting on it. Accordingly, let us review some of the evidence that has accumulated from the re- search of many investigators during the last decades. Ph~'slologlcal Effects What is smoke.'? Smoke, a product of com- bustion, is a mixture of gases, various Vapor- ized chemicals, and millions of minute particles of ash and other solids. These are drawn into the nose and throat during smoking and into the lungs by inhalation. The smoke includes some vaporized nicotine, a toxic substance found in tobacco, although much of it is changed by heat. It contains tars and other products from the partial burning and distilla- tion of the tobacco. A smoker gets more nicotine and tar if he smokes a cigarette to the end. A significant amount of carbon monoxide is also produced which is quickiy picked up by the oxygen- 454

SMOKING: FACI'S YOU SItOULD KNOW 455 carrying hemoglobin of the I~lood and reduces Among other effects of smoking are those of its oxygen-carrying ability, an apparent tobacco allergy in some sensitive persons and aggravation of peptic gastric ul- Effect on the Respiratory System cers. Patients with these conditions are gener- ally advised not to smoke. As smoke is drawn into the breathing pas- While all tobacco smoking affects health and sages and the air sacs of the lungs, the gases life expectancy, cigarette smoking appears to and particles in the smoke settle onto the sur- have a much greater effect than cigar or pipe rounding membranes. One point of great con- smoking. Among the possible explanations are centration is where a large tube (bronchus) that cigar and pipe smokers often do not inhale divides into two smaller ones. Interestingly, and the temperature at which the tobacco this point is where most lung cancer begins, burns is different. Pathologists~physicians skilled in the Filters and denicotinization of tobacco or microscopic anatomy of disease---consistently cigarettes are alleged to ,reduce the hazards. find that the lining membranes of the air pas- However, denicotinization~has no effect on the sages of smokers are thickened and abnormal, kind or amount of tar in the smoke, and filters The hairlike ciliaon these membranes become can only reduce, not eliminate the hazards. damaged and are less effective in removing the ( ,oxic and irritating chemicals introduced by Psychological and Social Aspects ./~e inhalation of smoke. Pathologists also have found that smoking That smoking is related to psychological • not only thickens the lining membranes of the and social situations is well known not only in air passages and obstructs them with secre- ~e reasons people give for smoking, but also tions, but also stimulates a contraction of the in other obvious reasons which they do not give. muscles in the air passage walls which narrows Young people often start smoking in imitation them and further reduces air flow. There is con- of older people who smoke or as an expression siderable evidence that a single cigarette will of a subconscious wish to be like them. Older markedly reduce the air flow of even an ex- children and youth want to be accepted by their perienced smoker. Potentially harmful patti- friends and associates. Often friends dress des are deposited into the air sacs, the point alike, talk alike, and have other behavior in where emphysema develops. Recent patho- common. Smoking may be part of this attempt logical studies in humans suggest an associa- to conform. Not smoking could also bc part of tion of these changes found in smokers and a group pattern. development of this disabling lungdisease. As a means Of relaxation, the mechanical Smoke also affects the membranes lining the aspects of smoking are recognized. Under ten- larynx or voice box. A pathologist identifies a sion or during an awkward lull in activity, ( ~moker's larynx by the thicker, often swollen smokers probably do relax by taking out a ,'ocal cords. The changes in the voice box are package of cigarettes, choosing one, getting .- similar to those that occur in the air passages matches, lighting the cigarette, and handling it. and in the lungs. These irritations cause swel- Some authorities suggest that a cigarette rep- ling and increased secretion and result in resents a reward that a smoker can offer him- "smoker's cough." self whenever he wishes, or that the act of ;: smoking represents a means of self-expression. Effect on the Circulatory System In young people, it may represent freedom to • do as one pleases, or be a reaction against adult Smoking affects the heart and blood vessels, authority. Others believe that people smoke Nicotine,. if injected or taken in tobacco because of the need for oral activity to fulfill an ; smoke, stimulates that part of the nervous sys- unsatisfied sucking reflex. tern that controls the heart, blood vessels, and Recent studies have shown that youngsters • other internal organs that function almost whose parents smoke will also tend to smoke. automatically. For years, smoking has been If older brothers and sisters smoke, the younger known to be related to Buerger°s disease, a ones are more likely to become smokers. constriction of the small arteries in the hands Much research remains to be done before an and feet that can lead to gangrene and neces- understanding is reached regarding the factors sitate amputation. Smokers also die more often in smoking that produce satisfaction and often from coronary heart disease, lead to h.abituation. ! - • ~:~" ': ..... ~ .... ~--~.,",-~,r-~,~:.-:-~.~ • " .......................................................... .5020

You SHOUIcD ]~.WOW 457 Physicians, other scientists, and many health agencies have studied the relationship of smok- ing to health and most are in general accord. The most extensive examination of smoking was published in January, 1964, by the Ad- ~Jsor.v Committee to the Surgeon General of the U. S. Public Health Service. The committee reported that "cigarette smoking is causally re- lated to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. The data for women, though less extensive, point in the same direction." The dangers in smoking, especially heavy smoking of cigarettes, are recognized all over the world. Statements on the subject have been issued not only by the United States Public ~-- Llealth Sen'ice, but also by the Royal College ." Physicians in Great Britain and a special committee of the World Health Organization. The American Medical Association stated officially at its Annual Convention in 1964: "The American Medical Association is on record, and does recognize a significant re- lationship between cigarette smoking and the incidence of lung cancer and certain other dis- eases, and that cigarette smoking is a serious health hazard." The House of Delegates of the American Medical Association has officially endorsed the actions of the Joint Committee on Health Problems in Education of the National Educa- tion Association and the American Medical Association. This Committee, recognizing that "the specific components of tobacco exerting "arnfful effects on the human organism have ..or yet been defined and the exact pathological and physiological actions of these components have not been determined, nor the psychology of smoking fully understood, recommended authoritative research...in smoking such as that being conducted by the AMA and others." The Joint Committee also resolved "that -schools, physiciang, health departments, and other community agencies cooperate in an ag- gressive program designed to discourage chil- dren from starting the smoking habit and to influence youth who are smoking to discon- tinue the habit." The American Medical Association has not confined itself to mere endorsement. It has never allowed tobacco advertising in its health magazine, Today's Health, since publication began in 1923, and it banned tobacco advertis-. ing from its Journal for physicians and its exhibits at scientific meetings in 1954, long before the hazards of smoking became scien- tifically apparent. It is sponsoring clinical and scientific research, as well as an educational program on a continuing basis to call to the attention of the public, particularly young peo- ple, the known evidence against smoking. Manufacturers are trying to reduce the haz- ards of smoking by modifying tobacco, reduc- ing nicotine content, and filtering tars. The long- range effects of these efforts are not known. Research has been initiated to find and iso- late or refine harmful substances so that those who smoke may continue to smoke safely. Thus far, the results have~been discouraging. As part of its concern with" this problem, the Amer'ican Medical Association is sponsoring a large-scale study to determine mechanisms by which human ailments may be caused or ag- gravated by smoking, in or.der to define more accurately the role of tobacco in diseas.e. While to smoke or not to smoke is a matter of individual choice, most authorities now agree that never to smoke is preferable[ Fur- ther, they would agree that significant evidence is accumulating which indicates the desir- ability for the heavy smoker to stop smoking or cut down to the point of moderation. The longer one smokes, and the more one smokes, the greater the risk of developing lung cancer. In those who quit smoking, the risk is diminished. Pipe smokers run more of a risk than nonsmokers, but far less risk than cigarette smokers. Medications are being sold which are tended to keep the smoker from smoking. Un- fortunately, these have not been successful. Antismoking clinics are being continually veloped and may help.many smokers. Persons who contend that smoking helps them control their weight by decreasing their appetites can find more healthful controls. Whether to smoke or not to smoke is a major decision for anyone to make. A person who has not started the habit should carefully consider all the facts before doing so. For those who really wish to discontinue smoking, the following suggestions are offered, out of the experience of a physician who suc- cessfully stopped smoking cigarettes, and has not resumed after 13 years. It takes doing, but it can be done. How to Quit Smoking To quit smoking is not easy. It makes no difference whether the daily consumption is three cigarettes or three packs, or any number " 502~)7 7q33

458 of cigars o; pi~s. to quit smoking is a dilficul: t~sk, Success d~pends on wanting to quit, wil)- power, and ~e use of v~ous gimmicks to break the h~bi~ O~ w~ b not sold on quitdng may stop for e ~cw days or even • few weeks, but always reinstates his habil. Wanling In quit involves ~ a rational reach (ba~d on fae~s which ere now well d~umcnled) and a ~at leads to ~slt;ve action, ~e actu~ ~t of ~pping. ~erc ~r~ ~'o ~b~ o~ thou~t on ~e press Of stopping. One ~dv~ales ~adual ~dr~wal, ~e eulfing o~ s~g in h~ e~ch day fill ellmlnafion of ~e l~t smoke m~ke~ ~e ~n a~tslner. ~e ~r teen--ends ~e ~d~en cutoff, How you ~oke~now you ~n t. For m~t ~ople ~radu~ wi~drsw~ ~re fikely ~o ~ail, sin~ ~e pre~ ot ~ and ~ knowledge ~t It can ~ smoked d~ul~ ~e ~lve ~o quh. Sudden ~Io~ may ~co~ uncomfo~ab~, ~ ph)'s;c~ly ¢modona~y, but has s cen~n .fin~ly ~I~. ~s ~ an "elt~r~r" situ~fion where one ~ows whet~r o~ ~ s~Hng or ~t stooling. ~erc h no c~slon a~t b~ much h ~ked, or whe~et o~ ~ ~ quota for ~c d~y. ~e habit patt¢~ of smoking have a pa~ of ~ ~ial and business ~e of the smoker. Most smokers ~ave e cigarette after etch meal. Knot'ing ~is, s~clal cKo~ must ~ made to do somcthing ~ter me~s, not ~o~ly ~it~d wi~ stooling. Students who ~ot smoke ~ class do ~ during ~elr ~ng ~twecn clasps, in a s~ilar way off~ce wo:kers smoke dering ~it coffee breaks. In s~h ca~s, the desire to ass~iat¢ smoking ~'hh • e~ ~ic op~rtunitlet must ~ rec- ~d and one's ~ha~or at ~es¢ times chased as much ~ ~ssible. It is easier to quit smoH~g w~en ~c whole ~g pattern to which on¢ is accustomed can ~ chased. ~e most common of the~e h vacation. With ~e timing of events diKerent from the routine of o~ or shop, the signal for another smoke i .... artless oflf~. H~pital~alion for t~ea~ment of an illness or fo~ surgery is another such op~nunhy. ~ough not pleasant in many cases, it d~s pr~ v~¢ a change of pace end habit and scver~ days of forced abstinence on which t0 build. Smo~ng is a grcgarlous habit. Usu~ly when o,e ~on lights up. o~her smoke~s wiB. The person who has quit h tempted. He must state h~s Pofldon. It is therefore a wi~e precaution, trier being su~ that t,> qult smokin~ is ~he de. sired end, to tnnou~e that you have quit smoking, It may cause ~me g~ natured ~k- ~g, but it will reduce the offers of smo~ng ma- ~als. It will ~so eslab)ish a s~ial patle~ w~ch ~e ~on quitting d~sn't dare smoke, and ~is has I yen" healthy influence. ~en ~he typical smoker qui~s hc can t ~rtain pattern of ex~rlencet, ~e first day Is not bad, his cn~usiasm is at high pitch. ~c next few de,up Io a week or mor~ar¢. uncountable. Pe~ of ~e discomfort is ~ pain of bret~ a ha~t, pa~ Is ~e elimination ot ~ chemlceh ab~r~d from tobacco smo~e. By ~e ¢~ of ~vo weeks ~e cravleg it gone, ~ough it returns on ~cw~g ~he~s smo~g ~ on t~i~g smoke. By now ~ ~ of ~te and smell have improved ~4th them.ap~ti~e. F~ tastes so much bette~ ~at ~eat care must ~ taken not to overeat. But e%~n ~ou~ ~e tmo~g ~bit is we~. ¢ned, It h ~: broken. One ¢lg3rette or o~ cigar can return the backsUde~ to the t~s of ~d smoke~. At ~is stage, unfortuw truly, t~ ones who return m~y ~moke ~s much or ~r¢ ~an ~ey ~d ~fore ~-~g to quit. S~ccess comes ~ three to six months, when a former smoker can go through his daily rou- fine and as~iate wi~ smokers w~le having no desire to smoke himself. ~e ecme reached when at ~e end of a )~ar of a~stinence • e former smoker ove~eacts. ~od an effort ~ade to avoid places where ~ople and there may even ~ a tendency to ~ crit;c~ of ~e ~ople them~lves. %%~¢~e d~s one's physician fi~ into this pic- ~r¢? Where are ut'o circumstances in which should ~ consuhed. Medical supe~'ision dur- ~g the ~st few wee~ of ~bst~ence could support one during this change ~at Uou:>lc-. ~me reactions would ~ less likely. ~c oth:r circumstance is the case "~e spirit is t~lliag but the ~esh is • c resolve is made but the will.wet to carry ~rough is lacing. Here your d~tor can scH~ drt~gs that may help som~, altboufh is not always indlca~ed. For some ~op]e such d~gs can make the n~tvous ten~ions ated wi~h breaking ~e habit less a~noylng. "Secret" drugs which can ~ put in:o smoker's fo~ or ddnk without his have no 5020

#157 Title: "Pathogenesls of Nicotine Induction of Calclfic Athero-arteriosclerosls with Thromboarterltls in Rabbits" Rating: 'fC" The work is being done to determine whether nicotine induces the release of free fatty acids (presumably high mglecular weight acids, i.e., stearlc acid), calcium, certain ~terols, 6tc. ioto the blood. It is believed by some workers that~ presence of these material~, in the blood stream aggravates cardiovascular problems. It is likely that the levels of some of these materials will be raised by presence of nicotine. However, the significance of t~.£~ findings would be a matter of speculation.

NOT FOR PU~tICATIC;N OR PU 81_ICA TION RE F EF~E,14 C F" NOTICE OF" RE, SEARCH PROJECT SCIENCE INFORMATION EXCHANGE SMITHSONIAN INSTITUTION AMA Education and Research Foundation T,TL~OF ~,OJE¢~: P~tho6enesis of Nicotine Induction of Calcific Athero-arteriosclerosis with Thromboartoritis in Rabbits. 'Givenames, depor,ments, ~dofficialtiIlesoIPRINCIPALiNVESTIGATORSondALL OTHERPROFESSIONAL PERSONNEL engogedonlheproiect. George M. Hass, M.D., Prof. of Pathology, Univ. of Ill. Coll. of Med.; John P. Ayer, M.D., Prof. of Pathology, Univ. of Ill. Coll. of Med.; Reuben Eisenstein, M.D., Assoc. Prof. of Pathology, Univ. of Ill. Coll. of Med~,; Donald R. Henson, M.D., Asst. Prof. of Pathology, Univ. of Ill. Coll. of Med. , NAZI ANO AOOR[S$ OF INSTITUTION: Presbyterian-St. Luke's Hospital, 1753 W. Congress Parkway, Chicago, Illinois 6061~ • SUt,~ARY OF PROPOSED WORK - (200 ~rds or less.) - in the Science Information Exchange s~maries at ~rk in progress ore exchonge~ with 9ovcrnm~ and pdvo/e ag~cie~ supporting research, and ore |orworded to investigators who request su~ in|ormotion. Your summary is to be used f" "~5~e ~u;poses. Rabbits will be subjected to various combinations of dietary cholesterol, intramuscular vitamin D and subcutaneous nicotine dissolved in mineral oil. The effect of a variable amount of each component on the development of athero-arteriosclerosis complicated by thromboarteritis will be assessed by necropsy studies involving extensive microscopic examination of all arterial systems. In an analysis of the pathogenesis of nicotine enhancement of vitamin D action and thromboarteritis attention will be ~irected principally to the adrenergic action of nicotine. This will involve quantitative studies of serum free fatty acids, calci~., phosphate and certain sterols related to steroid hormones cr vitamin D. Some aspects of nico$ine action will be eliminated by adrena!ectomy and the use of adrenergic blocking reagents. Attempts to dup.licate nicotine action ~#il! be made by -use of other neuroh~&moral v~soactive agents. SIGNATURE OF PRINCIPAL IN VE.STIGATOR PROFESSIONAL SCHOOL-, (medico|, g,oduote e,¢.) ~JJ[l~V. Of " George M. Hass, ~[.D. was awarded a grant for a period of three years beginning~ February ~, 1968 with a total budget of $6~ , ,3S0.000 The approved budget for the first year is $21,600.00. 50207 7t138

#163 Title: "The Control of Ciliary Morphogenesls" Rating: "E" ~" Comments are the same as for #158.

NOTICE: OF RInSE:ARCH PROJECT |~ No ~ ~cation ~d Rese~ch Foundation " TITLE PROJECT: "Tb, e Control of Clllaw ~ho~nesls" Gi~ n~mes, 4~F~mmtt, md offiCiol fitl.~ of PRINCIPAL INVESTIGATORS ~d ALL OTHER PROFESSI~AL PERSONNEL ~ged ~ ~e p,o~ect. -~ ':.~ ,~;..~':, ~,.~, ~; ~ ,. =.:~ P.~.~, ~tir~ ~soclate Professor of ~a~.. ~~en~ of ~ysiolow-~at~ • , :..~;;;- : - ~ :~.~.. ,, "> ~.: B. H. ~tir~ ~se~rch ~sociate SIGNATURE OF PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL (medicol, 9.o~uote0 etc.) Peter ~azir University of California, Berkeley, Ca!iforn±~ 9-~20 Peter Satir, Ph.D. was awarded a grant for a period of three years Neginning February I, 1968 with a tQtal budget of $65,009.00° i~.~-~.Th~ app=oved budge~ for the first yenr is $25,009.00. 50207

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NOT FOR PUBI.ICATION stIP~ORTIN G AG[NCY: " • SMITNSONi&N INSTITUTION • ~ Education a~d Resea_~ch Four, dation .Action of ~cot~e, nor~co~ne ~d bio~c atones ~ isolated or~ns from ~=eated and from chro~cally nicotine treated ani~Is. ~D~.-~*e~,~es;~. ~:D;:;: M.Ph,, Professor of q~ B. Thoa, B.S., M.S.., Ph.D.,: Instructor of Plmrmacology - Co-principal Investigator lesearch Assistnnt or Technician to be appointed Iradeate Student, Assistant. to be appointed .,.~,.o,oo..'ss o~ i.STiTUTIO": . Georgetown University,. 3~.th&..0.stree[s, N. W.. Washington. D.C. 20007 ~ ~ernmcn! and pfivote ogencie$ suppcmin9 ~e|~'ch, on4 o~e ~,~rwor,,ea ~ mves~ga;ors WhO ~eque$~ su~n m~om~.~- ............ . The ~esponses to nicotine, nox~dcott~ a~d a number of btogcnic amines as. agonists of some isolated o~gans of male guinea pigs, e.g. aortic strip,, vas deferens, heart, intestine, diaphragm~ will be .studied. The organs will be taken from untreated animals and their reactivity compared w'~th organs taken from guinea pigs chronically treated with nicotine. Two doses of nicoUne will be selected, one within the range absorbed by heavy smokers and the other ten-~old higher. Any difference in smooth muscle reactivity among the control and the nicotine-trea~ed animals wi!l be studied to learn the mec|mnism of such c.h~ng~, and to increase the understanding of nicotine effects in smok~:s. Gertrude D. Maeeg~&'n-Davies, Ph.D., H.Fb. was awarded a grant for a period o~ ~¢o'years bogi~£ng F~brua~y ~, 1968 ~£~h a to~a~ budget o~ $~2,618.00. The approve2 budget £or the ~ir~t ve~z is g20 98~,00 50207

Title: #172 "StUdy of the Effects of Nicotine and Related Substances on Neuroendocrlne Function" Rating: "B" Various effects of nicotine will be studied, including suppression of appetite. It is believed that effects may be discovered which may throw a favorable light on human smoking.

NOT FOR PbBI_ICAT;O~-I PUaL.:CA TION SUPPORTING AGENCY: NOTICE OF RESEARCH PROJECT SCIENCE [NFO[~MATION EXCHANGE SMITHSONIAN INSTITUTION AMA Education and Resea_-ch Foundation TITLE OF PROJECT: "'Study of the effects of nicotine and ~elated substances on neurDefldocrine function" Give names, depa,lmenls0 o.d official liLies of PRINCIPAL INVESTIGATORS a.d ALL OTHER PROFESSIO~IAL PERSONNEL ,.gaged on lhe p,oiecl. Robert George, Professor - Department of Pharmacology, School of Medicine, UCLA Norio Kokka, Asst. Research Pharmacologist III, Department of Pharmacology, School of Medicine, UCLA NAME ANOAOO"ESSOF mST, TUT'O": University of California at Los Angeles, School of Medicine, Dept. of Pharmacology, Los Angeles, California 90024 SUt~ARY OF PROPOSED WORK - (200 ~,o,ds or less.) - In the Science Info,matio. Exchange summa,ies of v~ork in progress ore exche.ged w;th ~avc, rnment on~ private agencies supporting research, and are |orwar4ed to investigators who eeques! such iniormat;on. Your summary is to be used nese purposes. .The purpose of the p~esent study is to determine the effects of nicotine and • other cholinom~metic agents on neur~endocrine functions. ~.ne r~le of the hypothalamus in ~egulating anterior pituitary functions is well established but the mechanisms whereby impulses from other areas of the brain modify the activity of hypothalam/c sec~eto~y neurDns a~e not kno,~n. The~e is experimental evidence to i~dicate that a cholinergic mechanism may play a part in the cont~ol of hypothalamo-hypep_hysea! activity, and the ~epor~ed p~esence of acetylcholine in the hypothalamus and its ,known r~ie in synaptic tmans,~ission is consistent with the concept of chemical trans- mitters influencing hypothalamic activity. A systematic study combining the techniques of.systemic and focal cent, Pal injection of drugs, electrical stimulation and electrolytic destl~action of discrete sites in the brain, and direct measurements of plasma ho~r.onai levels will aid in determining the followin~: (a) Localization of cholinergic sites and pathways within the central nervous system which modify neuroendocrine activity; and (b) Dete.~nination of the acute and chronic effects of systemic administration of nicotine on endocrine activity. Cats and rats have been chosen for experimental study because ste~eotaxic techniques for placing cannula guides, electqxxJes and lesions in specific brain areas are well established for these species. SIC, NATURE OF . PRINCIPAL INVESTIGATOR . hober.t George PROFESSIONAL SCHOOL Robert George, Ph.D. was awa~ dc_d a grant for. a period of three years beginnih~ February : 1968 with a total bud~e~ of $56, -~ 763 00 The approved budget for the first year is $18,921.00. 50207

#173 Title: "Effects of Nicotine on Learning Behavior and Brain 5-Hydroxy- trypta~ine Metabolism in Rats of Different Temperaments" Rating: "A" Effect of nicotine on balance mechanisms will~11kbe studled.actlonTheSeln experiments may show that nicotine exerts a tranqu~Izer--i-e some excitable animals.

NOT FOR PUBLICATION OR PUBLICATION REFERENCE SUPPORTING AGENCY~ • NOTICE OF RESEARCH PROJECT |=,~NO. SCIENCE INFORMATION EXCItANCE 1 SMITHSONIAN INSTITUTION AMA Education and Research FouNdation TITLe OF P.O~CT: Effects of Nicotine on Learning Behavior and Brain 5-Hydroxytryptamine Metabolism in Rats of Different Temperments Give names, departments, and olficiol titles of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the proiect. Dr. John Adams Rosecrans~ Assistant Professor of Pharmacology NAMe" AND AOORE$S OF' INSTITUTION: Medical College of Virginia Department of Pharmacology .-~vernm~t and private ag~cies supporting research, and ore forwarded 1o investigators who re~esl such information. Your sugary i$ to be used • ese purposes. ~1s in~es~a~on ~Lll L~volve a s~udy o£ ~be e~£ec~s o~ n¢co~ne on tndolam~ne sysCe~ o~ male ~lb~no ~a~s. ~n a~ce~ ~o co~ela~e ~hese e~£ec~s behavioral eve~Ls vLll also be ~a~e. ~o~ ~o beh~¢o~al and chemical ~ousal" level o£ each an~l w~l~ be delegated by s~b~ec~Ln~ each ~a~ ~o emo~Lo~l¢~y CesLrng ~n the open ~eld and ~o cl~ssLc~ cond~o~g using a s~a~cle ~esponse. ~¢~1s o~ sLm~la~ a~ousal levels ~£11 ~hen be g~ouped ~nd scudded using ~a~Lous ~oses o~ ~icoCLne. ~eha~Lo~l s~u~es ~1~ ~n~olve bach s~le c~Lon avoL~ance and e~ecCs o~ n~co~ne~ bo~h 5-hyd~ox~amine and ~s ~o~ ~e~abolLCe~ 5-hy~oxy-3-tndolacec~c aci~ v~l be used as rn~ces o~ ~eu~onal SIGNATURE OF ~,,.. - ~...,~-..~..,...: :..~ ~ ° PRINCIPAL INVESTIGATOR ~. , ,-"'~', ~ ~" ,,J PROFESSIONAL SCI400L (medical, graduate, etc.) John A~-kosecrans, !~-'[~D. was awarded a grant for a period of three -,,ears. beginning February !, 1968 with a total budget of $58,832.00. The approved budget for the first year is $35,750.00. 50207 7qqq

#174 Title: "The Influence of Nicotine on the Secretion of HCI by the Stomach" Rating: '.'F" It has been known for many years that nicotine initiates the secretion of HCI in the stomach, as do many other agents, including most foods.

NOT FOR PUBLICATION OR PUBLICATION REFERENCE SUPPORTING AGENCY: NOTICE OF RE~SP'ARCH PROJECT SCIENCE INFORMATION EXCHANGE SMITHSONIAN INSTITUTION AMA Education and Research Foundation NO. n TIT~.Ir OF PROJECT: The Influence of Nice,Zinc on the Secretion of HCI by the 3tomach Give names, depo,tments, end official titles of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the p,oiect. John G. Forte, Assistant Professor, Dept. of .Physiology NAME AND ADDRESS OF INSTITUTION: .. T~o-~-olov California 94720 Deoartment of Physiology, U. of California, ......... j, , " 'MARY OF PROPOSED WORK - (200 wo,ds or less.) - in the Science Information Exchange summaries of work in progress are exchange4 with t' :rament and private agencies supporting research, and ore forwarded to investigators who request such infom~tion. Your summary is to be used |or these pu~oses. "~" ~ The purpose of this proposed research is to systema~ically -invesL'igate :-he action of nicotine on the secre.~ion of HCI by the stomach using a mul:-ilevel physiological approach. The study ~.,ril! include several types of gastric preparations cur- rently being used in '-~ ~,_~ laboratory: ].) isolated gastric mucosa (rat, frog), consis~.-ing of secretory cells and connective tissue, !~_i~ ._~ ..... om.n_u~_al ~lem_n~.,. ~) i~olated wno!e stomachs, 2) acute in o__~t__u_ per:<used stomach '~.;~_th blood vessels and vagus innervation undis_-urbed, and I4~. chronic ~astric pouches of the cla~sica~ ~oe. Tn~ actions of nicotine wl!l of primary concern, ouu there experimentally ~aa~._ble these effects will be corapared ~.~th tho~e resulting from inhalation of tobacco smoke. In addle-ion if we. are able to determine that nicotine has a direcU actien at the cellular level ~;e plan hie-. ( chemical studies to date---mine the nature of the interactions ~rith enzymic comoonents ._nou~,~ to be associated :-~tn the acid secretory mechs~'., ism. PRINCIPAL INVESTIGATOR (reed,col, g,eduate, e~c.) John G. Forte, Ph.D. was awarded a grant for a period of three"years beginning February i, 1968 with a total budget of $78,621.00. The approved budget for the first year is $32,175.00. 50207

September 8, 1967 INFORMATION MEMORANDUM SUBJECT: A~ Release on A~-ERF Tobacco Research Program Attached is a copy of a news release from the American Medical Association on three years of research sponsored by the Project for Research on Tobacco and Health of the AMA-Educatlon and Research Foundation. The tone of the release is shown in the second paragraph: "The best estimate of clinicians and scientists in the field is that clgarets are a health hazard. But they admit they don't have the scientific data yet to establish why and how." (p. 1) ~'~ Other statements of possible interest: -- AMA delegates "made it clear they did not think" the 1964 Surgeon General's Report "could stand alone," but "needed facts to back it up." (p.3) -- Acknowledgement of the tobacco industry support of the program (p.3) -- Comments by Dr. Maurice Seevers, Chairman of the Committee (and a member of the 1964 Surgeon General's Advisory Committee): "While the medical profession and tobacco industry have somewhat divergent reasons for promoting tobacco research, both are commited to basic scientific research as the best means of developing specific answers to questions raised by our smoking population." "Certainly there are no scientific data that would contradict the basic tenets of the Surgeon General's report...l believe very few if any, of the scientists working under this program would advise anyone to smoke. Still we hope that in search for facts, we can retain an open mind." (p.4) cc : Senator Clements General'Counsel Ad Hoc Company Public Relations Representatives 5020 7 7~ t~8

THE AMERICAN MEDICAL 535 North Dearborn Street, Chicago, Illinois 60610 • • Area Code 312 527-1500 ASSOCIATION FOR IMMEDIATE RELEASE THREE-YEAR PROGRAM STIMULATES TOBACCO-HEALTH RESEARCH CHICAGO--Is smoking a psychologlcal addiction with deadly over- tones or more in the nature of a bad habit? The best estimate of clinicians and scientists in the field is that clgarets are a health hazard, But they admit they don't have the scientific data yet to establish why and how. The problem is one that must be answered at the cellular and molecular level• What effect is produced by the molecules that con- stitute cigaret smoke on the molecules that make up human cells? For the past three years, wide .anglng research into many questions at this level has been sponsored by the Project for Re- search on Tobacco and Health of the American Medical Association- Education and Research Foundation. But direct and incontrovertible evidence for a cause and effect relationship between smoking and dlsease--including cancer, respiratory and cardiovascular dlsease-- is difficult to obtain. The answers are probably still years away. 5020~ 7BS9

-2- Nevertheless, the program has already met with a degree of success, according to its architects. Explains Maurlce H. Seevers, M.D., Ph.D., chairman of the Com- mlttee for Research on Tobacco and Health: "For one thing, the program has helped stimulate an interest in laboratory research on smoking." In the past research into the effects of smokinghas often been retrospective in nature--attempting to correlate certain diseases with smoking patterns on a statistical basis. There was, however, only spotty interest among scientists in laboratory investigation of the questions posed by the statistics. Dr. Seevers, professor and chairman of the Department of Phar- macology at the University of Michigan Medical School, said grants provided under the AMA-ERF program are designed to change this by making it possible for scientists to undertake long-range studies. "Our goal has been to stimulate such interest among established researchers," he said. The decision to include cardiovascular and respiratory research in the program along with cancer, he explained, was based on the fact that certain respiratory and circulatory diseases show much the same statistical reiationshlp to smoking as cancer, and at the ~ame time are more prevalent than cancer. 50207 7~50

-3- The Project for Research on Tobacco and Health was initiated by the AMA House of Delegates as an adjunct to its educational cam- paign to discourage the use of toxic materlals--includlng tobacco-- among young people. The indictment of cigaret smoking as "a serious health hazard, was restated following the Surgeon General's report citing the statistical relationship between smoking and lung cancer and other diseases. At that time, however, the AMA delegates made it clear they did not think the report could stand alone. It needed facts to back it up. They indicated that statistical tabulations alone were not enough to dlsuade smokers from their habit. The role of smoking as a causative factor in death and disease--the mechanisms by which tobacco smoke attacks the body and the chemical agents, if any, responsible for the damage--also would have to be defined if any educational campaign were to be successful, they said. Much of the support for the research project was furnished by the tobacco industry itself, which pledged $I0,000,000 over a five- year period. Industry interest was in settling once and for all the question of whether smoking is or is not the cause of certain .diseases. Furthermore, the tobacco firms wanted to know if smoking $0~0 7

-4- was Impllcated in disease, was it due to some specific agent or agents in the tobacco which could be removed from the smoke. As Dr. Seevers explalned: "While the medlcal profession and tobacco industry have somewhat divergent reasons for promoting tobacco researdh, both are committed to basic scientific research as the best means of developing specific answers to the questions raised by our smoking population." "Certainly there are no scientific data that would contradict the basic tenets of the Surgeon General's report," he added. "I believe very few, if any, o~ the scientists working under this program would advise anyone to smoke. Still we hope that in search for facts, we can retain an open mind." All grants awarded under the program rest with the AMA-ERF and the research committee headed by Dr. Seevers. Other members of the committee are Drs. Richard J. Bing, professor and chairman of the department of medicine, Wayne State University; Robert J. Hasterllk, professor of medicine at the University of Chicago School of Medi- cine; John B. Hickam, professor and chairman of the department of internal medicine, Indiana University Medical Center; Paul S. Larson, professor and chairman of the department of pharmacology, Medical College of Virginia, and Paul Kotln, director of the National En- .vlronmental Health Science Center, Chapel Hill, N.C. 50207 7~52

-5- To date 79 grants have been awarded, including four in foreign countries, and a total of $6,090,886 committed to research projects. Goals and guldellnes lald down for the awarding of grants are centered on "efforts to encourage and support studies to determine which significant ailments might be caused or aggravated by smok- Ing...those mechanisms by which cigaret smoking might affect health...and the particular substance or substances in smoke which might be the causal or aggravating agent." -0o 915167 50207 7~53

November 28~ 1967 , , INFORMATIONAL MEMORANDUM ~ ~-~ ~ SUBJECT: American Medlcal Association on National Interagency Council The AHA's House of Delegates in Houston Tuesday referred to the Boar~ of Trustees for study (and probably report at next June's annual meeting) a resolution proposed by the Colorado Delegation that A~A become a sponsoring member of the National Interagency Council on Smoking and Health. A reference committee reporting on the resolution recommended the action as follows (note reference to a 1968 report on the ANA-ERF tobacco research program): "This resolution seeks to have the American Medical Association become a sponsoring member of the National Interagency Council on Smoking and Health. The resolutlon states that the National Interagency Council plays a vital role in the dlsse~inatlon of information on the health hazards of cigarette smoking for the pur- pose of reducing the incidence of the habit in America. i '. "The polily of the American Medical Association recognizes the deleterlous effects of tobacco on human health. Efforts to educate the publlc to these dele- terious effects have been a continuing project of the Association for many years. Many pamphlets and other materlals are disseminated annually, and physicians are urged to educate young people about the health hazards of cigarette smoking to deter them from acquiring the habit. "The Amerlcan Medlcal Association Education and Research Foundation has an established research program under~ay to clarify the exact relationship of tobacco to health. The results of this program will be presented at a scientific session at the annual convention in June 1968. "It is apparent to the reference committee that the goals and efforts of the AMAand the Natlonal lnteragency Council on Smoking and Health in these educational efforts are comparable. Since Resolutlon 49 would have this Association become a spon- ~ sorlng member of another, addltlonal information about the costs involved and the pllcatlons of such a sponsoring membership appear to require addltlonal study and con- slderably more information than was available to this committee. "Mr. Speaker, your reference committee recommends that Resolution 49 be re- ferred to the Board of Trustees." Resolutlon 49 advanced by the Colorado delegation reads as follows: Whereas, virtually all physicians now believe that cigarette smoking is harmful to health; and Whereas, the National Interagency Council on Smoking and Health is playing a vital role in disseminating smoking and health information and in endeavoring to reduce the smoking of the American public, and k~ereas, official health actions by the A. M. A. have important Influence upon the American public, therefore be it, Resolved, that the Amerlcan Medical Association become a sponsoring member of the National Interagency on Smoking and Health. cc: Senator Clements, Ad Hoc Committee, General Counsel, ~0~0~ Company Public Relations Representatives

I'~OT FOR PUBLICATION OR PUBLICATION REFERENCE NOTICE OF RESEARCH PROJECT SCIENCE INFORMATION EXCHANGE SMITHSON IAN INSTITUTION $1E NO. AGENCY NO. SUPPORTING AGENCY:Amerlcan Medical Association Committee for Research on Tobacco and Health TITLE OF PROJECT: Analysis of relationship Of selected characteristics and smoking habits of University of Illinois freshmen. Give names, departments, and o|ficiol titles of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the project. Dorothy F. Dunn, MSPH, Ph.D. Associate Professor of Health Science University Student Health Center 1109 South Lincoln Avenue Urbana, Illinois 61801 NAME AND ADDRESS OF INSTITUTION: '' ' University of Illinois, Urbana ,. Illinois 61801 SU~V, ARY OF PROPOSED WORK - (200 words or less.) - In the Science Information Exchange summaries o| work in progress ore exchanged with ~overnment and private agencies supporting research, end are forwarded to investigators who request such In|ormotion. Your surrn'nory is to be used for these purposes. In a four-year (1964-68) longitudinal study of the 1964-65 class of University freshmen, Urbana, Illinois, further study in 1967 of additional multivariables for smokers and nonsmokers includes student dropout s, 1965-66 cumulative grade point averages, a study of illnesses and chronic health conditions, and a comparison of the 1965 oumulative cigarette exposure for light to heavy smokers. To learn if campus smoking policies for the incoming freshmen dictates to some extent his cigarette smoking patterns and to learn the place health occupies in the students basic value system, three groups of incoming freshmen and their roommates are to be studied. In addition to a control population methods used will include practices of non-Social acceptances of smokers and the use of intervention process techniques. ~ Dorothy F. Dunn, Ph.D, one year beginning May $9,019.00. SIGNATURE OF ~ ~ " PRINCIPAL INVESTIGATOR ~ ~ .6-~9 t~u.~_~---- PROFESSIONAL SCHOOL Department of Health Science (medicol, g~du~te, etc.) v~s ~de~ ~ 8~ ~or~ ~e~o~ o~ i, 1967 wi~h a ~o~al budget of

,*¢-,;*; .cv. *.., NOTICE OF RESEARCH PROJECT - ," , ..-~. ~C|F.~C~'- INFOI~M~TION . ,.- ~ ~uca~ion ~d Rese~h Foundation :LOCALTZATION OF~ H3-NICO¢]~E IN At~'O~O]~I"C GA~GL~ CCM;i.~A1ex~Alcarez, Bloche~isc, Psychopha~cology Special ~ucposa Labs., V.A. ulvcda; ~llf;; Eskll ~nsson~ D~ Ph~colo~, ~yal Ve~eri~W ~ll¢~e, Scockhol~, 90031 • .ames; dep~,men~;~nd oi|i¢iol lilies el PRIHC~PAL INVESTIGATORS end ALL OTHER PROFE,r>SIOHAL PERSONNEL ~=t:'W;~Earle~ ,Ph.D., PrLncLpal Invr'sl:tgat:or, Sr. Lecl:urer and Chatrr~.~n, CC~i!D~V~.~ijT~/~uoka~.," Ph,D.'~ Co-¢nvest:iga~:or, Research Associat:e,. Dcpt:. of SIGNATURE OF PRINCIPAL INVESTIGA'[OR PROFESSIONAL SCHOOL (medical, g,oduote, etc.) Robert W. Earle, Ph.D. was awared a grant for a period of two years with a tot'al budget of $33,325.00. The approved budget for the first year is $18,515.00. R~e grant begins August I, 1967.

MOT FOR PUbLiCATION OR P~LICATION REFERENCE SUPPORTING AGENCY: NOTICE OF RESEARCH PROJECT SCIENCE INFORMATION EXCHANGE SMITHSONIAN iNSTITUTION AMA Education and Research Foundation . #)_----," './ Sl E HO. AGENCY NO. TITLE OF PROJECT: Effect of Cigarette Smoking on Pulmonary Ventilation-Perfuslon Relationships GWo names, 4eporlments, ond official lilies o| PRINCIPAL INVESTIGATORS end ALL OTHER PROFESSIONAL PERSONNEL lngoged on IF.o proi¢c|. Wiili~m H. ;underson, M. D., Chief, Section of Pulmonary Disease J. Bruce Willia~s, M. D., PuLvonary Fellow Fe~.mndo~o,~ Jr., M. D., Pul~onary Fellow Tno.~s Stephenson, M. D., Pulmonary Fellow all in Department of Medicine AND ADDRESS OF INSTITUTION: University of Louisville School of Medicine, i01 W. Chestnut St., Louisville, Kentucky 40202 SL~'.~,~ARY OF P~OPOSFO WORK - (200 wo,ds or less.) - In the Science Information E~chonge I~mories of ~,k in pr~¢els ore exchanged whh govcmmcnt on~ pr;vote ogencies supporting reseorch~ ond are fo~orded to inveitigetori w~ requeit iu~ ini~mati~. ~our iu~ory is to ~¢ used to¢ l~ese p~rposes. The acute effects of cigarette smoking on pulmonary ventilatlon-perfusion (9/~) relationships will be studied in normal individuals, those with obstructive .ai~ay disease, patients with diffuse pulmonary disease and with acute infections. The method of studying 9/~ will be the determination of alveolar-arterlal gradients and percenta$~ venous a~vixture while breathing 40% oxygen. It is planned to do these, studies before and after snaking, both at rest and following mild exercise in the above patient groups. In addition sir~lar studies are planned following the smoking of filtered cigarette s~mke. The potential modifying effect of bronchodilator medication prior to cigarette smoking will also be studied. Since ~/~ abnormalities are the primary cause of inadequate gas exchange in obstructive airway disease, these studies may pro~de evidence of the mechanistic relationship.s between smoking and obstructive air~:ay disease. In addition, this type of study may be able to serve as a humanmodel for the evaluation of effective filtration of cigarette smoke. SIGNATURE OF PROFESSIONAL SCHOOL (medical, g,oduote, etc.) Medical~ William H. Anderson, M.D. was awarded a grant for a period of tw6 years with a total budget of $34,155.00. The approved budget for the first year is $20,~00.00. The grant begins August I, 1967. 50207 7q 58

• ~-s~£-~a~cv.~'aa NOTICE OF RESEARCH PROJECT . ,- ," " SCIENCE INFORMA~ON EXCHANGE "~'~'~'~"~ ~ ! ~MIT~ONI~N INSTITUTION , ~ .~NOT'~OR PUBLICATION OR ~ ~PPORTINC AG£~CY: ~.~:~ ~ ~ ~uca~ion ~d Rese~ch Foundation N_co,~ne a~.d Sz..okLns: ,TL¢ Or p~Oa~C,: Electrocnceph~lographic Effects of ' .... :~ As~e~v.ent of Additivo, Antagonistic, and Surrogate Actionz of ;.~dol Ccr.~und~. ;~:n~.es; dei>om.en,s. =,d ~ilici~l fide| el PRINCIPAL INVESTIGATCRS ~.d AL~ 0THE~ PROFESSI~AL PERSONNEL enpged on ,he proiec,. C~-I C Pfe~'for- Ph.D., M.D., Co-~nve~tigator, Head, Neuro~co!o~ Section • AMF.,AKD ,~DDR£$$ Olr INSTITUTIOH: . - " N~w J~rscy Mental Health Research and Develo.~ment F~nd 'J~UARY OF PROPOSED WOR~ - (200 ,~ods o. • r ~e~ pu~oses. , The. project ~Io~ c~ter t~c-ser~ f~qucncy ~ys~ of ~e elcctroenceph~o~r~ ~~ objective ~say of" the ~tio~ of ~cot~e ~ the central nervous sy~e .... Noel ~ ~ol~teers, ~th s~kers ~d nonsmoker, ~ stu~ed. The effects of model net~oph~ ~colo:ic~ ~ompo~ ~ as c~fe~e, ~phe~e, mepro~te, ~d ~enob~bi~ ~tu~ed for ad~tive or ~go~stic effects ~ ~ok~g ~d ~cot~e ~d for the~ ability to substitute p~cclogic~y for smo~g dur~g abst~ence ~u hCa~ sxokcrs. Effectc of nicot~e ap~ ~o~ the complex acti~ties ~ssoc~ted ~-ith szokLuZ c~: b~ sep~ated cut by us~z non-~cot~e (Lactu~ satin) cig~ttes versu~ or~arj ~pplezented by ~ujectio~ of ~cot~e verbs s~ pl~ebo. This ~-r~ also help to ~stLn~!sh Cue effects of c~bo~h~og~ob~ ~d meth~oglog~ caused by th~ snok~ z'~ ~ our ~ork so f~ ~ been ~t there is a rapid st~l~ut effect occurring ,~tP~u % ~econ~ after ~u ~alation of szoke. This se~ms to be t~quick to b~ due to ~.blood borne p~cological effect on ~e bra~, ~d ~tead is zorc l~<ely to b~ result cf a re~ex action, ~ossibly. ~a the va~s ne~e. This ~ tu~ ~h~ " b~ cau~ea s~oly by irritation of the bronchial ~ucosa by the smoke. clariP# this possibility. Our ex~erL~.ents should ~.~. o PRiNCiPAL INVESTIGATOR - ' PROFESSIONAL SCHOOL (medicol, groduote, etc.) Henry B. Murphree, M.D. was awarded a grant for a period of thr&e years with a total budget of $60,000.00. The approved budget for the first year is $20,000.00. The gran~ begins .... :~:i;,~... August i,1967.~.~ ........ .~ :: 50203 ?~60

HILL J~ND KNOWLTON, INc. June 27, 1967 INFORMATIONAL MEMORANDa4 SUBJECT: American Medical Association meeting, June 18-22, 1967 Followlng are hlghlights of the American Medical Association Meeting held in Atlantic City, New Jersey, June 18-22: 1. The AMAnow has on record another resolutlon on smoking and health, which is a substitute for two separate and stronger versions proposed by delegates from.Ohlo and California (See memo dated June 22 for more detail.) 2. Copies of papers mentioning smoking and health are available on request. None appear to be of great importance. a. Labay, Peregrlna, and Boyarsky, Saul: "The Effect of Topical Nicotine on the Ureter." b. Porles, Walter J. et a__l: "The Treatment of Atherosclerosis with Zinc Sulfate." Co do Pe11, Sidney, and D'Alonzo, C. A.: "The Prevalence of Chronic Disease Among Problem Drinkers." Kershbaum, Alfred, PapaJohn, Douglas J., and Bellet, Samuel: "Effect of Smoking and Nicotine on Adrenocortleal Secretion~" Another paper, by Dr. Lee Farr, on noise pollution and other pollutants may be of interest chiefly because of his statement on page six where, in discussing smoking and respiratory disease, he said: "But, prior to the development of specific disability, it is impossible to indite a specific indlvidual as one of those who will, for example, with certainty, develop mallgnancy." Copies of this paper are being distributed to the ad hoc committee. 3. The Natlonal Clearinghouse for Smoking and Health had an exhibit in the scientific exhibit area. It consisted chiefly of three panels with text based on the attached handout (headed: "Physicians have stopped smoking. Why haven't their patients?"). Among the other material distributed from this exhibit: the diagram of a skeleton with diseases indicated (headed: "Distribution of Diseases Associated with Smoking); copies of "Medical Bulletln on Tobacco"; and copies of Clearinghouse antl-smokln8 literature.

4. It was reported privately to our observer at the meeting that the National Interagency Council on Smoking and Health has been trying to persuade AMA to Join as a member. The NIC, he was told, seems interested in getting a $i00,000 year gift from AMA for the NIC budget. There was no indication that AMA is considering Joining. 5. Dr. Milford O. Rouse, Dallas, was installed as AMA president. Dr. Dwight Wilbur, San Francisco, was named president-elect and will take office next June. / 6. Dr. Alton Ochsner was one of three recipients of a Distinguished Service Award from the AMA house of delegates. Just a few days before, he received the 1967 College Hedal of the Amerlcan College of Chest Physicians~ Ochsner recently announced that he would not do any more surgery. 7. In a meeting also held in Atlantic City, coinciding with the AMA, American College of Chest Physicians elected Dr. William E. Adams of Chicago as president. Adams is a long-tlmeAmerican Cancer Society official (director at large) and a member of the lllinols Division's Committee on Smoking and Health. He was also llsted as treasurer of the 1st International Congress on Smoking and Health, which was promoted by the American Temperance Society in 1965-66. 8. At the meeting of the National Association of Science Writers, the executive committee turned down -- unanimously -- a request by Emil Corwln, public information officer of the National Clearinghouse for Smoking and Health, that NASN Join the C1earlnghouse in sponsoring a survey of the smoking habits of the NASN members. Enclosures cc: Senator Clements General Counsel Ad Hoc Committee - Farr Paper Company Public Relations Representatives 50~03 "Ttt 62

National ' Clearinghouse for Smoking and Health PHYSICIANS HAVE STOPPED SHOKIIqG. WHY HAVEN'T THEIR PATIENTS? The sharp reduction in cigarette smoking among physicians shows " that the physician is aware of this real threat to his health and is doing something positivd about it. In 195~, over 50% of physicians smoked cigarettes.. By 195~ the proportion of physlc£an.smokers had dropped to less than 30%. , Many physicians have stopped smoking because they know that the death rate for cigarette ~mokers in comparison to that of nonosmoker~ 70% higher from all causes 500~ higher from chronic bronchitis and emphysema 1000% higher from lung cancer. Those in the medical profession can be an important influence toward 'changing the smoking habits of people by: Instructing all their patients about the health hazards of cigarette smoking; Participating in com~unlty programs to help adult smokers give up smoking and youth not to start; Recognizing the importance of their attitudes and actions as non-smokers in ~ettlng an example. DO YOUR PATI~I~TS KNOW AS IdUCH ABOUT THE HAZARDS AS YOU DO? U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service Bureau of Disease Prevention and Environmental Control National Center. for Chronic Disease Control "

HILL .~D I~NOWLTO.~0 I~c. INFORMATIONAL MEMORANDUM SUBJECT: AMA Passes Smoking Resolution The American Medical Association, by vote of its House of Delegates at the group's annual meeting in Atlantic City, approved a resolution on smoking and health Thursday. The resolution was a Reference Con~tttee substitute for two proposed resolutions (#22 and 6.4), which were more strongly worded. The text of the report of the Reference Committee follows~ "Resolutions 22 and 6~: The Reference Co~nittee considered these reso- lutions together. Several speakers spoke feelingly and infor~atively of the problem of smoking and health relating to the effects of smoking and approaches to improved health habits. The Reference Committee believes that the best interests of all concerned will be furthered by the following sub- stitute resolution~ Whereas the American Medical Association recognized and continues to recognize the deleterious effects of tobacco on hwnan health, and urges physicians to engage more actively in intensive education programs regarding smoking and health; therefore, be it Resolved, That the AMAreaffirm its policy regarding tobacco and health and vigorously continue its measures for corrective action." Copies of the two proposed resolutions are attached. Enclosures cc: Senator Clements ~eneral Counsel Ad Hoc Committee Company Public Relations Representatives 50207 7~16~1

AMERICAN MEDICAL ASSOCIATION HOUSE OF DELEGATES Resolutlon,- 22 Introduced by: Ohio Delegation Subject= Smoking and Health Referred to: Reference Committee £ (H. B. Ande~son~ M. D., Chairman) Whereas, Cigarette smoking has been established as having a causal relationship with death and disabillty from .lung cancer, coronax~y heart disease, emphysema andchronic b~onchltis; and Whereas, Death and disability from these diseases cause needless pain and anguish and millions of dollars in lost wages, medlcal expenses and hospitalization; and " Whereas, The conclusion of the Smoking and Health Advisory Committee to the Surgeon General of the United States Public Health Service is that: "Cigarette smoking is a health hazard of sufficient importance in the United States to war~ant appropriate ~emedialactlon."~ ther~for~ be it Resolved, That members of the American Medical Association, officially recognize their opportunities and ~esponsibilities in this ir,portant field by setting an e~ample as regards cigarette smoking, and by paeticipatlng actively in their practices and in community p~og~ams to influence and persuade people not to smoke. 50201 .1~65

THE COUNCIl, I~OR TOBACCO RI~EARCH T0~¢60 ~NDOFI~¥ P,~.4~OI 633 THIRD N~W YORK. N. Y. 10017 March 1~, 1967 Mr. Henry H. Ra~ /~ "'// Vice President an~eneral Counsel R. J. Reynolds T~acco Company Winston- Sal~ ~orth, Carolina Dear Henry: v i Thank you for sending me the Science Information Exchange abstracts of the AMA-ERF grantees. I have checked these against the reports I have received frc~ Ira Singer and find that, of the nine you sent me, five of them refer to approvals at that organization's November i, 1966 meeting. The other four are the ones approved at the February 9, 1967 meeting, as indicated in the attached correspondence. I have talked to both Drs. Little and Hockett about the relatively small number of applications which are being received by the AMA-ERF as opposed to the increasing number being received by The Council. We have not been able to account for this as yet. Perhaps we m~y find the answer in time. Hope to see you soon, Sincerely, W. T. Hoyt Executive Director WTH:ek art.

Amevican Medical Association 535 NORTH DEARBORN STREET • CHICAGO. ILLINOIS 60610 TWX-- AREA CODE 312 910.22 t -0300 827.l BOO COMMITTEE FOR RESEARCIi ON TOBACCO /L~D IlEAL'Ill RO~[~T J. HAST[ILl[, M.D., C~i¢~lo IlL PAUL S. LAlSON, P~.D., Ric~mo*~. Y~ March 2, 1967 Mr. W. T. Hoyt Executive Director The Council for Tobacco Research 633 Third Avenue New York, New York 10017 Dear Tom: Enclosed you will find a llst of grants that were approved by the Committee for Research on Tobacco and Health at their February 9, 1967 meeting and another list of grants that were rejected by the Committee at the same meeting. Sincerely yours, Ira Singer sk enclosure 50201 71168

Flarc~ 9, 1.967. Executive Dlrector~ The Council £or Tobacco ~e~earch o 633 ~t~ ~vo~oj ~ York, ~ York 1~17. Dear Yo~: As proa~s~ I ~lose copies of ~ abstracts the research projects recently approved by the Cos~ttee £or itssearch on .Tobacco and I~alth of the kser£can Medical ~ssociation Education and ~search Fonndation. These wore received by me fx~m Dr. Sfn~er a few days a~o. 81neerely. Enclosures H. H. itsstm,~ Vice President and General Counsel, ~0~07 7~7~

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.~IoSIE-71~A: REV. 6-64 I, NO~" FOR PUBLICATION OR ~ PU B'~ICATION REFERENCE; SUPPORTING AGENCY: NOTICE OF RESEARCH PROJECT SCIENCE INFORMATION EXCHANGE SMITH$ONIAN INSTITUTION AMAEducation and Research Foundation • 1 E NO, AGENCY NO, TITLE OF PROJECT: The Biochemical and Metabolic Bases for the Effect qf Component.s of Tobacco Smoke on the Pulmonary Macrophage Givenomes, deportments, ondofficioltitlesofPRINCIPALINVESTiGATORSon~ALL OTHERPROFESSIONAL PE~$ONNELengogedontheproiect. Gareth Green, M.D. AssoE~ate in Mediclne~ Harvard Medical School; Physician-in-Charge, Resplr@tory Diseases Clinic, Boston City Hospital Edward ~.'Kass~ M.D. Associate Professor of. Bacteriology and Immunology, Harvard Medical School; Director, Department of Bacteriology and the Channing Laboratory, Boston. City NAME &ND ADDRESSer INSTITUTION= Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115 SUmmARY OF PROPOSED WORK - (200 ~rds or less.) - In the Science Information Exchonge summaries of ~rk in progress ore exchonged with 9ovcrnment end prlvote ogencies supporting reseorch, end ore forworded to investigotors who request such informotion, Your summery is to be used er these purposes, ' small amounts of tobacco smoke inhibit the capacity of alveolar macrophages to kill. bacteria in vitro with no concomitant effect on the viability of the macrophage. Since alveolar macrophages provide a major defense mechanism against inhaled bacteria and other particulate material, this finding may be important in the pathogenesis of lung'dlseases associated with cigarette smoking. It is probable that the inhibitory action of cigarette smoke is biochemlc$11y mediated. Although preliminary studies of isolated components of tobacco smoke have not yet identified the active substance (s), the active component is water soluble and labile. ~ The present investigations propose a three-fold series of objectives: i) to isolate and characterize the active water-soluble labile principle in tobacco smoke that inhibits the capacity of macrophages to kill bacteria, 2) tb gain more insight into the metabolic effects of the unknown substance(s) in tobacco smoke on pulmonary macrophages, and 3) to gain more insight into the biochemical, physiological, and anatomical characteristics of the pulmonary macrophage system. PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL Harvard Medical School (medicol, groduote, etc.) Gareth M.• Green was awarded a grant for a period of three years beginning February i, 1967 with a total budget of-$-1~74~.- The approved budge~ • for the first year is $31,078 ~.- ~-~o 50207 7.7~

HOT|CF-. OF RESEARCH PROJECT |$~ SCIENCE INFOR.~ATIO.~" EXCIiANGE SMITH$ONIAN INSTITUTION NOT FOR PUBLICATION OR ~ AGENCY hG. "PUBLICATION REFERENCE su~o~,.~.o~.c~e~ican Medical Association C0~,i~ee fo~ Research TITLE OF PROJECT: "Some Effects of Nicotine and Smoking on Animal and Hu~.&n C-asi~oin~cz~ina! Gi~e names, deportments, and of|iciol titles of PRINCIPAL INVESTIGATORS oncl ALL OTHER PROFESSIONAL P£RSO,~NEL engogec~ or, r;~ pc,ice;. Jeremy H. Thompson, M.D., M.R.C.P.I. NAME AND ADDRESS OF INSTITUTION: Department of Pha~m.&cology UCLA School of Medicine LOS Angele$~ C~.].ifo~D~a SUMN, ARY OF PROPOSED WORK - (200 worcls or less.) - In the Science Inform~tior, Exchcnge summor;es of work ~n prc~re~ ~rc exc;,cr,~¢C govemmentondprivate agencies ~upporting research, ondare forwor~edto invest~ctors who request such informctlon. Your sum~,ary is ~ beuscd -thesepurposes. The effects of nicotine and re!a~ed drugs upon ~he sqor.es ~owel sero~onin, associaZed enzymes, and seroxonin synZhesis in rats be de~ermined. Under controlled in vitro condiZions ~he effec~ of and ~elated d~u~s will be dete~minei or, the incorporation anl ,e~e~ se~o~onin in bowel mucosal slices f~o= both ~azs and man. [~ is to measure ~he levels of se~otonin in various ~umo~s s~icai!y " E~om the ~ast~oin~estinal t~act. These levels will be co~ela~e~ wixh s=okin~ his¢o~y, blood g~oup s¢atus~ family his~o~y~ and Zu=ou~ his=oLoZy. SIGNATURE OF PRINCIPAL INVESTIGAT~ • PROFESSIONAL SCHOOL'~I (medical, gracluat~, o;c.) ~ J~/} ,,-~,~. I~ q~ : "=. re~'~y ~/~.. ~'n-Smp s o n, .~':. D LA_~noo! of Medicine Jeremy H. Thompson, M.D. was awarded a grant for a period of thyee years with a total budget of $54,408.00. The approved budget for th~ first year is $19,464.00. The grant begins February I, 1967. 50207 7q75

.I NOT FOR PUBLICATION OR PUBLICATION REFERENCE suPPORTING AGENCY: TITLE OF PROJECT: NOTICE OF RESEARCH PROJECT SCIENCE INFOtlMATION r~XCttANGE SMITHSONtAN INSTITUTION .___ L/ NO. American Medical Association~ Committee for Research on Tobac:~o a~.~'i ?4~alth Mechanism of Secretion from the Adrenal Medulla Norman Kirshner NAME AND ADDRESS OF INSTITUTION: Duke UniversiW, Durham, North Carolina 27706 SU~VJ~ARY OF PROPOSED WORK - (200 words or less.) - In the Science Information Exchange summaries o~ work in government ond private agencies supporting research, and ore forwarded to investigators who request such information. Your summary is ~o be used ' these purposes. Studies on the mechanism of secretion of catecholamines from the adrenal medulla and the metabolic requirements for this process will be carried out. The release of ca~echolamines .~ , in response to chemical stimulation by acetylcholine~ nicotine and Bar-.- can be cor3.pie~ely blocked in the presence of both 0.1 mM iodoacetate and 0.1 re.k4 potassium cyanide.~ but neither alone has any effect. Further studies using other specific inhibiZors of giycolysis and oxidative phosphorylation will be carried out to further delineate the source and requirements for metabolic energy for the secretory process and to obtain infc.:mat~on ~o indicate whether this energy is requiredin one or more discrete steps in the secretory process i~self, or whether this energy is required to maintain the cell in a functional state. The role of membrane lipids in the secretory process will also be investigated. Studies on the incorporation of radioactive lipids into the storage vesicle membranes and the plasma membranes in resting; and stimulated conditions will be conducted. SIGNATURE OF '" PROFESSIONAL SCHOOL. (medical, graduate, atc,) ~edical Norman Kirshner, Ph.D. was awarded a grant for a period of three years with a total budget of $48,518.00. The approved budget for the first year is $18,296.00. The grant begins February i, i96~. 50207 7t~76

$~.$tF.-7'e~; R£¥, e-64 NOT FOR PUBLICATION OR PU B~.ICATION REFERrNCE SUPPORT|NO AGENCY: NOTICE OF RESEARCH PROJECT SC|F.NCE INFORMA'I~ON EXCHANGe'. SMITHION IAN INST|TUT|ON AMA Education and Research Foundation Sir NO. ~ NO. TITI.~ OF PROJECT: The transmission of nicotine across the hemochor~al placehta Give .~me~,, clepertme.ts, e.d ofticiel titles o! PRIHCIPAL INVESTIGATORS end ALL OTHER PROFESSI~AL PERSONNEL engoged on ~he p~o~ect. Dr. Albert A.. P]entl Oe~rtment of Obstetrics and ~ynecol~ Ass~te ~o~essor AND ADDRESS OF INSTITUTION: Columbia University College of Physicians and Surgeons, 630West 168th Street, New York, Nc~, York 10032 SU~'.~ARY OF PROPOSED WORK - (200 words o¢ tess.) - In the Sc;ence Informot;o=~ E,=chonge sv:nmo~et o( wo,k in ,og,~ss o~e exchonge~ w;~h govcrnm~l end pr~vole og~cie~ =upporling reseotch~ end o~e to.ordeal to invesllgoto~s who request such in(or~t,~, "(our sundry ~s to be used tot ~he~e purposes. The transmission of nicotine and ~ts metabolic products is to studied on pregnant rhesus monkeys. Tritium or carbon-14 beled nicotine will be used for th~s purpose. The proposed wo~ k begins with the study of isolation procedures from body fluids and analytic and radiochemical correlation usin~ commercially available nicotine. Syntheses and degradations will then be ex- plored to introduce specific ~bels of h~h activity. Similar studies w~ll concern themselves with the major.metabol~tes of nicotine. These procedures will then be applied to physiologic preparations for the purpose of qualitati.ve and quantitative estimation of the transfer of this alkaloid and to evaluate poss~le differences in adult and fetal metabolism. The in vivo collection of fetal urine, blood and amniotic fluid will make it possible to study these path- ways under essentially normal, undisturbed conditions. In a simi- ' ]mr. manner, measurements of acute changes in vascular dynamics of the fetus in response to nicotine, its metabolites and other drugs will be made. ' SIGNATURE ~)F (.. (.'Z'~L /..(, / ('_. /, " !/./(.L...,.....'~_-.~ PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL Colle~e of. ~hysicians ~ Surgeons (medicel, gre4uote, etc.) Albert A. Plentl, Ph.D., M.D. was awarded agrant for a period of three years beginning May i, 1967 with a total budget of.$ 213,990.00. The approved budget for the first year is $82,002.00. • ~ 50207 7~ 77

NOT FOR PUBLICATION OR PUBLICATION REFERENCE SUPPORTING AGENCY: I$:E lqO. American Medical Association Education and Researcla (Committee for Research on ToSacco a;~c, NOTICE OF RESt-ARCH PROJECT SCIENCE INFOR~tATIO,'~ EXCHANGE flMITH$ONIAN INSTITUTION TITLE OF .PROJECT: Location of Nicotine Receptors in l]~e Nervous Syste~n. Give nomes, deportments, ond officiol titles of PRINCIPAL INVESTIGATORS ond ALL OTHER PROFESSIONAL PERSONNEL engoge~ Gn :.qc ;,rG~ect. David A. Brown, Lecturer in Pharmacology, Department of Phar:nacology. (Principal Investigator). NAME AND ADDRESS OF mST|TUT~ON:~edical Co1!ege of St. Bartholomew's Ho~):t~l, eharterhouse Square, London, SUM.V, ARY OF PROPOSED WORK - (200 words or less.) -in the Science lnform¢t;cn Excbc, nSe s~;mmcries o{ work ;r. prc;r~; ore government ond privote ogencies iupporting reseorch, and ore forwarded to inves~;gctors who requcs~ such ini~rmction. Ycur ~ummory ,r these p~rposes. The object of ~e investigation is to locate reff~ons and neurons r~i~in C-:~ nerv~u~ system containing a.high densi~ of nicol[nc receptors. The approach v;iii consis~ measuring ~e accusation in ne~ous tissue of radioaclively-label!cd nicotine of o~er drugs which interact wi~ nicotine receptors. Conven~ionai ~,ei~ods of ing ~issue radioactivity will be used, and dqe c~l~. 1oca~ion of radioaczlvi[-.; examined ~ing a high-resolution au~oradio~ali~ictechnique s~table for v.,a~er drug location. Initial e~eriments will be mnder~aken usin~ d~e syrnTathe~ic ganLilon S~sequenNy, Comparable studies on dru~ u~ak~ in different re~ons of ~ adon regar~ng ~e probable sites of niCotine aCtion d~riwd from o~e~" ~ods SIGNATURE OF PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL (medicol, graduate, etc.) David A. Brown, Ph.D. was awarded a grant for a period of beginning February I, 1967 with a total budget of $15,120. approved budget for the first year is $13,070. ~The 50207 7q78

NOT FOR PUBLICATION OR PUBLICATION REFERENCE SUPPORTING AGENCY: NOTICE OF RESEARCH PROJECT SCIENCE INFORMATION EXCHANGE SMITHS, ON IAN INSTITUTION Education &nd Research Foundation TITLE; OF PROJECT: +~ the Alarm ~eaction. Effect of Nicotine .on Vascular Cor.ponen~ of Give n~mes, deportments, and afficiol til'les of PRiNCiPAL INVESTIGATORS and ALL OTHSR PROF£S$1ONAL Ralnh R. Sonnenschein, Professor of Physiolo,%,, Department of PhTslo!o~ Fred N. ~ite, Associate Professor of Physiolo~ Department of Physioiccy Eduardo H. Rubinstein, Senior Research investigator of the Los ~geles Heart Association ,,~ *NO*~OR£SS OF ~NsTiVUTiO,.Department of Physio!o,~,,, Center for the Y, ea!~h Sciences UCLA School of ~-[edicine Los ~eles, California c',)99h SUh',V~ARY OF PROPOSED WORK - (200 worcIs or less.) - In the Science in(or,mo~;o;~ ExchanGe summaries o{ w~rk in pro~rcss ore exc~,cr,~eC w.~>, -r these purposes, The relative roles of the renin-angiotensin system ~.d of iirect ~t~mula~_o,. of the vasomotor innervation in the vascular response to o = " -~ ~. " hypothala~ic alarm area, and the effect of nicotine in modify, inK the v&scular response, will be evaluated in anesthetized mud unanesthe~ized ani~ais. SIGNATURE OF , PRINCIPAL INVESTIGATOR ...... ~ " ' Ral'~h R. Sonnenzchein, ~.~.D., r,~ PROFESSIONAL SCHOOL (medico~, grocluc~te, etc.) SC~IOOI of :~ ---" -" Ralph R. Sonnenschein, M.D, Ph.D. was awarded a grant for a period of'three years with a total budget of $64,931100. The 9pproved budget for the first year is $23,80i.00. The grant begins August I, 1967. 50207 7~80

George l.l.. Co*hran~ Ph,D, ~ Department of Botany, Profess6r of Botany and Plzn~ J~es LeGra.~da Shupe~ D.V.~,, Department o~ Veterinary Science= Professor.ot Ross A~ Smar=~ b.V,H,, Department of Vetecin~ry Sc£ence, Assoc~ate P~o~e~or o~ Vc:~£~a~. ' ""-" ;'~ Science NAME AND ADDRESS OF INSTITUTION: Utah..State" UniyersSty ~ Logan, Utah "g4 321 ~ ~e~ pu~ose~ Developing ~icken ~b~os and new-born hamsters ~ill be inocul~ted with various natuzally-occut'~Ing developmental fo~s of ~obacco =o~aic virus Chat have becn ~soia~ed from systemically infected Turkish tobacco plants, The inoculated animals ~ill be #~d~i~iced and s~udl~ fo~ the development ~f pathogenic conditions that can with the ~fec¢i~ vl~al fo~, Attempts ~£II be made to det~rmlna the possible sites of vl~ infec~lo~ an4 =ItIpllcatlon In the animals, Any evldencus of carci~ogenesls will. be ~otod, The ~o~ and fo~ of th~ In~ec~ivlty recovered from .th~ £noc~lated. an£msls wild,also:be no~ed~... ..... .,,: .... . . SIGNATURE OF '= PRINCIPAL iNVESTIGATOR .... PROFESSIONAL SCHOOL ........ (m,~;col.'~,~o~e,~c.) Colle~es of Science and Attic=]:,.:re George W. Cochran, Ph.D. was awarded a grant for a period of years with a total budget of $39,150.00. The a:eproved budget the first year is $19~575.00. The grant ~e~,.~,~ Mav i, 1567.

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Comments and Critique by the Coeenittee for Research on Tobacco and Health Conference and Workshops for Rese~arch on Tobac,~co sued, Hea,l, th Abstracted from the minutes of the meeting of November 3, 1966 in Colorado Springs. Dr. Richard Btng ex~pressed disappointment in two of the reports given in his workshop that of Ntcoll on bat wing circulation and the Oser grant on air-way resistance. The Nicoll grant had already terminated. The Co.~ttee discussed the work of the Oser group and expressed dissatisfaction with the progress made. The Committee directed that in the final year of this award the group restrict itself only to a study of the 8uiuea pig plethysmosraph. (This has been doee ~ndDr. Oser has chosen not to request continuation support. Th~s project is therefore considered terminated.) Dr. Robert Hasterlik questioned support of Dr. P. O'B. Montgomery and stated that he felt the motion picture shown was not new and of little relevance to the objectives of the Co,~tttee. A discussion followed concerning this award and also the London award. The Co~nittee agreed that the time had come to reevaluate these projects and suggested a future site visit to Southwestern Medical College to do SO. Dr. Hlckam felt that the level of the papers was up and down, some were better than others, some hadn't progressed very far. He thought that the Committee had the right, when the situation occurred, to direct the investigator's attention to the fact that objectives of the program had not been met and that the investigator should be ~lven every chance to do so. He expressed pleasure with the meeting and opined it was a fine thing to have happened. Dr. Seevers stated that he was a little worried when he first came, but was now confident. Most people he had talked with said they hoped it would be a continuing type of operation. This, of course, would not preclude an open meeting. Dr. Larson suggested taking a specific area and getting the people involved together. 50207 7~182

-2- Dr. Singer added that in about a year an extra day might be added to the Co~nlttee meeting and one group could be convened at a time for discuss~ons or workshop sessions. Dr. Rites polnted out that the Coas~ttee had been handicapped by a finite amount of money and time and a lack of clear-cut objectives. He suggested that the Cow, tree consider itself a permanent group, and that he thought funding was assured for some tlue to come. Further, he felt that there was an opportunity for the Co~n~tttee to enter other areas. He cited the period when few people were Interested in virus diseases. The subsequent stimulation of research on such diseases--by a grant from the National Foundatio~ to the NIH--focused attention on the problem and provided for a man- power pool. At the first meeting of the Co~nLtttee attempts were made to identify areas of importance, and now, after this conference, another opportunity to name such areas ha8 come. The Consatttee might consider a fello~ship program and the assignment of people to definite areas. The Board of Directors relies 100~ on this Concretes. The only problem ae hand is to try to define new directions for action. Dr. Rites further mentioned that his opinions had chan~ed about some of the grants. Some were far better than he expected and others were not as good, but on the whole a favorable impression was made. Dr. Hlckam remarked that the NIH have a similar Job to that of the Conx~ttee. They regard themselves as a group try/x~ to reach certain ends; in 8o doing they must identify the areas which need additional study. The hard part of their situation is to try to attract good people iuco these areas and not to put people o££ too much by giving them the impression of completely directed research. Hany people are so attracted by n~ney they don't mind direction~ but they like it less when they are told exactly what to do. The problem is to try to identify the ends you want and keep good investigators attracted to the funds. Dr. Biug indicated his feeling that it was clear that there is a place for basic research and that the Comnfttee has followed these lines very well. If the Co~nittee were to fully reevaluate its position, it would not come up with anything different. He suggested that as Dr. Kotin becomes a more active member of the Comnittee, greater interest will be found among applicants in cancer research. Dr. Seevers pointed out that Dr. Bayne-Jones had said that the cancer area had not been given sufficient stress by the Commttte~. 50207 7~83

Remarks of Dr. Stanhope Bayne-3ones Confe.r.e.nce and .~,orkshops for I~esear.ch on Tob,a.eeo and Health Dr. Bayne-Jones expressed appreciation for the honor 8ivan h~n through the invitation to preside at this meeting. He said that this conference had great human significance because such a meting brings a mutual interest group closer together and gives individuals the opportunity for association, conversation, argument, and for making new friendships and consolidating old ones. He was impressed with the integrity both o£ the comnittee and the investigators and~rfth the abilities o£ the committee. The first grant was appro~-ed in 1964 and since then many thi~gs have gotten under way and many projects have even been completed. He considered this a significant accomplio~ment having produced sufficient material in so short a time--to Justify the confere~ce and workshops. Dr. Bayne-Jones mentioned that risks were involved in some of the projects using radioactive materials. He hoped that the committee has asked grantees to comply with federal safety regulations. This is important for the American Medical Association, the committee and the individuals on whom the experiments are being done. conclusion, Dr. Bayne-~ones thanked the AMA staff and the participants. "A good beginning is the secret to success, and you have done well." S020~ ~n8~

Remarks of Hershey H. Block, Ph.D., H.D., !~apvortevr Wprkshop o~ the. !~elati~s.hlp of Cerclno~enesls and - --.I._fect[on~tO To.~.co use-- - The ~xper1:ental =esu1~s presented in this section could be classifled into t~o general categories: (I) epldeatolo~Ic studies atte~pting to relate p~lor Infecti~ or e~os~e to tadioleot~e8 to ~e ~e of to~o ~ to t~ t~tde~e of c~er; ~ (2)s~dies ~ t~ ~ts l~dt~ ~ t~ d~el~nt cf c~cer, i.e., the pre- dict state. !. Epid_ ,e~to.!.o~tc The t~o genero]L categorLe8 /~veetiSatad ~era o~~o to i~tL~ a~ to r~L~ctL~ ~I~L~ ~ redLoactL~ 1~. ~id~ of pr~ pstt~c~io ~ecti~ v~ st ftre~ f~ tu ~tiente ~ ~~. ~, pres~ly d~ to ~ rec~t fell ~tiento. H~, ~r ~~e to psittacosis m r~e ~ pati~ts ~~. to ~eI ld~ti~ ~ to ~188u ~J~ ~t to ~ ~t~t o£ est~s~ a ¢~stl~ :ole to ~se tA£~tl~. relstL~hLp of t~o ~e to t~ l~cL~nce o£ these ~tL~ ~s ~~ ~ ~~ s~~ 18 relatively £req~n~ ta patients. ~nteresti~ d~te v~re presented on I~)-210 and its breakdovn products in t~o pl~U, In v~t~ stages of the ~act~i~ pr~ess~ in c~ettes, ~d In cigarette s~ers. ~ c~tratl~ of ~-210 ~ ~e sir varies ~dely In the ~ited S~tee. It is ~S~st In ~ ~e c~l ~ b~ In ~rge ~ts. ~eto of 0.2-0.3 ~/~ ~re c~ist~tly ~o~d In d~stl¢ c~ettes, a ~eat~ ~t ~ f~ In t~ ray leaf. ~t II~ enters the I~ In t~ ~i~e~ ~, ~ ~a~ swkers ~crete &-~ ti~s es ~h ~-210 ~ do n~-s~ers. ~e~r, abeo~l~ of ~-210 Is also ~nd~t ~ ~ dle~, ~-210 bel~ f~nd In ~ In ~e t~ of ~er ~ ~la. ~ yeC there Is no I~~ re- ~t1~ ~-210 ~o 1~ c~cer ~ ~ ~e co~,tra~i~ of th~s Isotope In the t~s~s ~d excre~a of patients ~th t~g c~cer.

-2- Tobacco mosaic virus (T~V) is • com~n infection OCc~rrin~ in pr~asa~ed In ~ ~~e chick ~~ by ~Ik sac i~la~i~ o~ its r~llc~ f~. H~ever, pr~ati~ ~ ~t ~n ~,~rs~ed ~ ~l~tcally c~en~ hl~r vertebrate. ~ the c~ee of t~e 8~les a ~ oe~ttive ~say t~q~ fo~ t~d moleculsr blolosy. A series of coaj~md~ ~ere st~Sied capable of inducinS increased be~~e. R~r~ v~L~ el~ r~i~o ~re f~ ~ ~o ~t~eet/~ ~~, ~ Is 8o c~, ~y ~ s ~e ~t~1 field for i~eJtigati~ of n~ lesds rs~r t~ ~ a ~ of i~Ibitlng c~c~~esle. Another paper Luv~stIsated ,l~eratlons in ¢o~cen~ratlon of ~H leoz~s In ~~ tles~, ~d In fled ~dla ~d cells of tissue ~l~es of p~~ tt8~8. ~s~e of cells In tlJs~ cul~re to s~~ ~ 12 r~ted in a ~uor ,Mft in p~tttl~ of tsoz~s.

-3- A beg~nnlu~ was made on analysls of the h£stogenesls of oral cancers by biopsy o£ the ~ucosa o£ patients ~ho vere heavy smokers, of nonsmokers, of heavy smokers vith oral cancer who contim~d to smoke after tesection of their lesio~ and of heavy smokers vith oral cancer who ceased 8mokin~ after operation. An ~ntereetLug and promlstn~ approach was demonstration of iuhlbltlon of nueleolar and cytoplasnlc KNA synthesLs by & nitro- quluollne-g-oxide, cos of the slnpler carclnosano. A~ least for cy~o~l~c RI~ synrJ~esis, this inhibition is mediated through 8n itd~tbitio~ of ~'ensfar Jt~. ,Ill. $~_e~esttons.,. ¢C~¢, ~ez~t~ ~ Future Ori~en.tatlOn of. ,,R~earch Techniques ~t be 8evelope8 to uore fully unders~ ~or~al respiratory ~i~11~; (1) ~ It ~tl~ in ~ of ~1~1~ biol.; (2) ~t ~e ~ ~~terietics ~ sep~ate it ot~ ~i~l~ fle~s in reKard to s~etL~ ~ ~tt~ of cilia; (3) ~~tl~l ~l~is of ~ ~~r ta~ of r~plrat~ epit~l~al cel~ 8~Jec~ to i~ec~i~, tobacco

Remarks by E. F. Domino, M.D., R_=~p_orteur Wg~kshop on the Pharmacological and Psychophaz~nacological Action of Tobacco and Tobg~O COmponents Benedict R.~chesl, and Charl~s R%$chus.t~r~.Ph_..D_. This s~udy is designed to determine the role of nicotine in smoking habits of normal volunteers. Previous investigations which attempted to assess the role of nicotine in smoking suffered because the patients wanted to stop smoking. Furthermore, the patients frequently had a variety of disease sta~es. The present investi- gators took elaborate histories to assure tha~ the subjects were normal. The subjects were under ~he impression they were being studied for the effects of drugs on performance. The investigators had to es~abllsh the proper dosage of nicotine, but when they were successful in this there was no change in any of the behavloral measures. Essentially it was shown that there are physlologlcal and psychological components to cigarette smoking. Approximately one-thlrd of the results were from nicotine and two-thlrds were from other substances or were psychological. Gerald A. Deneau, Ph~D~ This study has many ramifications. I~ is essentially concerned with four elements of drug dependence: tolerance, physiologic dependence, psychogenic dependence, and antlsocial behavior. Followlng nicotine administration to monkeys, there is tolerance development; no physiologlcal dependence or withdrawal symptoms; clear psychogenic dependence; and no significant antisocial behavior. Nicotine is therefore a habituating drug bu~ is not truly addictive. These effects are apparently not due to catecholamlne release. lrvlng Geller, Ph.D. Dr. Geller described the effects of drugs on the timing behavior in anlmals. No data was presented on the effects of nicotine. Dr. Domino thought Dr. Geller needed pharmacological help and thinks this workshop helped him in this respect. $020"/ "/~ 88

-2- ,Cha~r!es J. Ke.nsler, Ph.D. Dr. Kensler used reasonable pharmacological doses of nicotine equivalent.to those a human being gets when he smokes. Quite remarkable in that they were able to show, depending on behavioral situations, nicotine as well as other drugs affected behavior in a variety of ways--either stimulant or depressant. Dr. Domino was impressed, that in general, nicotine was like amphetamine with a clear-cut stimulant effect. Studies of the interaction of nicotine with caffein were especially interesting. Combinations with alcohol and other tranquilizers should be studied. Nicotine and caffetn potentiate one another. Professor Danlel Bovet Dr. Bovet studied the effects of drugs, including nicotine, on acquired and innate behavior. He pointed out the importance of strains of mice. Nicotine depresses learning in smart mice and facilitates it in dumb mice. .C.arl G. Schmlt.e.rlSw, M.D. i_ Ph.D. This research by Dr. SchmlterlSw showed how nlcotine in mice and cats distributes in a variety of tissues especlally the brain. This clearly indicates the importance of the brain in nicotine studies. Most of the work was with nicotine and some'of its metabolltes. Herber~_McKennis, Jr,, Ph.D. The purpose of this study is to determlne.nlcotine metabolism and what happens as it is converted by the organism. The bio- transformation of nicotine is an extremely complex problem. They emphasize that nicotine is converted to many other things. This is good work and it should be continued. Charles H. Jarboe~_ Ph.D. A sophisticated approach was presented because he was trying to understand more of the pharmacology of nicotine and related derivatives in a quantitative manner. He is making hi~ own nicotine derivatives. Dr. Domino gathered that he frequently had problems • such as getting resins. Dr. Dominots impression is that he needs an organic chemist to help him but what he is lookinZ for is a selective nicotine antagonist. 50207 7m89

-3- Herber~ McKe~nls, J~o, Ph.D. Dr. McKennls Is. trying to find better methods of measuring nicotine. We need to know more about how much nicotine is absor~ed, how it is distributed and metabolized. Excellent work and should be continued. Carl C. Pfelffe~, Ph,D...,. M.Dt and ~en;y B. Murphree. M.D. They used extremely elaborate electronic and computer techniques to measure and quantify brain waves. Measurements are very precise but would raise the question of whether they are viewing the trees ra~her than the forest. The work done to date is good but the results presented were extremely preliminary. Humans who smoke clga~s and Inhale show a mild amphetamine effect on brain waves again showing importance of brain in tobacco studies. They did not relate this to nicotine. They will study nicotine soon. Gerard L. Gebber ~ Phi. D.~. This work is important because it has shown a new effect of nicotine on autonomic ganglia. Gebber achieves facilitation of autonomic ganglion transmission that lasts for hours. Roy D. Hu~son~ Ph.D. He may be getting at the antl-appetlte effect of nicotine. Georg~ B. ~e.~ss, P~D. Dr. Weiss is studying the actions of nicotine on muscle con- traction. It is very interesting pharmacology. Saul Boyar~ky, M.D. The study of nicotine is a side issue. Ureters have been thought of previously as passive tubules. In reallty, they have a fantastic mechanism for pumping~ dilatlng.~ etc. Eventually this will lead to the s~udy of patients while they are smoking to determine what happens to ureteral action.

-4- Charles~ R. Zcht.L M:D~ and-Richard W. Stande.r~ M.D. This was a clinical study showing that when women smoke during the end of gestation the.uterus is more irritable and the babies of some of the women kick around more. R. Frederick Becker~ Ph.D. Dr. Becket has done a large amo~mt of work. He can duplicate in rats what we know happens to women; heavy smokers have smaller babies. The question is what exactly causes this. The importance of this study is that the investigator went beyond nicotine and measured food and water consumption. Rats that don't eat and drink ~mll have essentially the same problem as female rats on nicotine. 50207 7qgt

Remarks by Alfred P. Fishman, M.D., Ravvorte~ W_0rksho~_on the,. Rel.at£or, shtv Of Pulmonary ~r0 Krumholtz end C.~R. ~oolf. H.D. Drs. Krumholtz and Woolies papers were dlrectly related. Dro Krumholtz extended studies done for a long time using previous controls to assess what happens to chronic smokers. A remarkable thing about his observations is that if a chronic smoker quits, he shows dramatic changes in pulmonary performance in a period of 3-6 weeks. He intends to continue observations up to two y~r$. Dr. Woolf, who studied women with a somewhat similar technique, found heavy smoking causes no change in pulmonary performance. Dr. Fielunan raised the question that if there is no change, how can it be reversed in 3-6 weeks? He dldnWt think a change llke that can show in three weeks. What would help here Is--(1) a clear definition of "what is a smoher?"; (2) how many subjects had bronchitis clinically?; (3) did they all have somewhat similar lun~ function tests? I think they and Dr. Yrayser would benefit fromtalking to each other. This might help others by defining some"sort of standards. Regi.na. Frayser. p_h,D. As a result of accidental observation of oxygen debt during exercise, Dr. Frayser has embarked upon measuring concentrations of all sorts of enzymes in blood. The key questions here are~ ~ny is this piece of work being done? What is one looktn$ for? Whae does one expect to find? Dr. Flshman is not at all certain about why they are measuring enzymes. Jerome Elia,,s,,Cohn! M.D. This is one of the papers where technique is being set up to analyze blood flow and ventilation. There is nothing really new about the technique because it is fairly standard now to use the substances cited for these analyseso This will be useful to general physiology.

-2- Dr. ,.Te.mple (Paper Was presented by Herbert O. Sieker, M.D.) Dr. Sieker gave a very interesting approach to analyzing blood flow and ventilation in the lung. He probably will do little as far as orlglnal objectives which probably would be to determine minor degrees of abnormality which you get in bronchitis. Instead, Dr. Fishman thinks they will come up with a method which will be useful in detecting gross abnormalities in blood flow and ventila- tlon. ~B.enJamln _H. Le~Is. M.D. This is interesting research in pulmonary physiology. Obser- vation is quite slmple: there is a pattern of breathing in the normal patient which is different from the abnormal. He used a computer to solve the question of why but it really does not have much physlological meaning at the moment because no one knows whether what the computer produced has a1~ything to do with wha~ the anlmsl produces. .Kenneth_M. M,.,ser~ .M.D. This again is a prellmlnary kind of statement of what wil! be. It is very much accepted now to use scintillation cameras to obtain pictures of ventilation and blood flow in the lung. There is a question of whether one method has any advantage over another. One problem in the use of sequentlal studies is that the radiation dose becomes important, Several questions from the audience were dismissed rather lightly but think that this will be a very serious problem in scanning, Dr. Fishman recommended to the Committee that they be rather careful about the amount of radiation given to patients. Dr. K~Iburn '"(Tak~ £~omvr. Herbert O. Sieker~s grant) His work was presented as something new. Actually it is not new but it is quite good. It was first done in the early 1920~s with a frog lung. This is a direct outgrowth; better with the frog lung than in manna allan lung. Nevertheless, it could be an important way to look at the lung.

-3- .Ian T. T. Hlgglns~ M.~. Continuing the tradition of the British eptdemio!ogist who gets himself a little town wlth a Salvation Army depot. He is using the same techniques used in mining towns in Wales. It will be very well done but not very much new will be learned. He and his group have a fiendishly clever way to create particles of known size for distribution to the lung of both man and donkey. Because of this, they can predict rather well where the particles go. Dr. Fishman was disappointed that this group has not attempted ~o examine the lung microscopically to determine if any iron oxide remain. They admit some do not come back, especially the smaller ones. Dr. Fishman has some reservations since they are also using radioactive materials. (Dr. Domino mentioned the new PHS rules for studies involving the use of humans. He wondered whether the AMA, in an effort to protect itself, should insist that all grants go through the human use co~nlttees now in existence at every center using PHS funds°) William H. Anderson, ~,D... Here we have a poorly designed experiment as well as a poor performance. He starts with a new histological technique which involves using lOOZ CO2 to prepare tissues for examination and then exposes rabbits to hearty doses of smoke in a system which allows accumulation of carbon monoxide, etc. Dr. Fishman thinks that no one can ever m~ravel this. ~errill A. Bender~ M.D~ Dr. Bender is doing external scintillation counting using NaI crystals as detectors. The test substance is p-iodobenzolc acid labeled with 1132. Involved in a very interesting, compllcated electronics system where indlvidual counters feed information in such a way to computers that he gets both a dlgltal readout and an analogue readout which is more representative in time. Entirely in the developmental stage. He has to develop more instrumentation to record rapidly enough to get serial film of events in the lung. Dr. Fishman thinks the work is good--skilled electronlc gadgetry with a direction. 50207 7~9~

-4- Gar.~e~h M" Green~, ,~.D~. This is a serious and impressive piece of work. It will probably succeed in identifying individual components of smoke that may have deleterious effects on the behavior of the two mechanisms. ,R,~bert G. _,L, opdon~,' M.D. Dr. Loudon is doing interesting work which may hoe be closely related to the problem at hand. He is studying systematically patterns of a cough and its acoustic components. He has a lot of imagination but one could quibble about some of the data he presented today. ,T,o~e ,Dalh~, M.D_. It is a curious kind of work. Dr. Fishnmn thinks It may be interesting but it is not the kind of work he would enjoy and does not know what conclusions you can draw from lt. He uses a pharma- cologlc rather than a physlologlc dose of the agents and his results may be subject to debate. _~ohn J_, 5_a!len~er, M.D, Dr. Ballenger gave an interesting and ~amattc approach. Dr. Flshman is not sure of what ultimate value this study will have. OsGar. K. Reiss,,, He has shown by elaborate techniques that the black pigment of the human lung occaslonally is something other than carbon such as ferritin. ~Dr. Richard Ehrlich's grant) He found that tobacco affected mice's resistance to infection. 50207

-5- s mu.el T. J. Gia. . ,ona , M.D. and Watts R, Webbo M.D. Both were concerned with surface active material in the lung. They used different techniques to obtain materlal and both agreed smoking modifies the surface active material. There was a little disagreement about exactly what it does but both are agreed it may be in part responslble for the emphysema which occurs. Dr. Fishman has serious doubts about this interpre- tation and thinks Dr. Hickam does also. One does not know how much surface active material one needs to get the "anti" effect. Dr. Fishman also thinks it is very fashlonable and will go on forever but will not end the question. As such, the studies are well done but will not answer the question of whether the surface active materlals are seriously affected by smoking to the polr~t where they are involved in the pathogenesis of emphysema. 50207 ~96

J ~..,.,.,~,.~v.~-s, NOTICE OF RESEARCH PROJEC'I" Is,"~'o. " SCIENCE INFORMATION EXCHANGE [ " J SldiTNSONIA N INSTITUTION NOT IroR pJGLICATION OFt * AOIrNCy NO. J p, ¢. ~..ICA T ION R£FRNrNC[ SUPPORTING AG£NCY: AMA Education and Research Foundation STUDY ON THE ]~ECHANISH OF ACTION OF NICOTINE ON PLASF;A FREE FATTY ACIDS Give heroes, 4eper~ments, e~d officlel titles of PRINCJPAL INVESTIGATORS end ALL OTHER PROFESSIOt~AL PERSONNEL engeged on the project. Principal Investigator : Silvio GARATTINI, M.D., Director Co-Investigator : A. BIZZI, PharmeD. .*Mr ANO*DDRrs$ OF Is%ituto di Ricerche Farmacologiche "Hario ]~egri",Yia Eritrea, 62,MILAN,Italy SU/,'.V.ARY OF PROPOSED WORK - (200 w~rds o, less.) - |n the Science I,|orm~tion Exchon9" summories o[ ~,k in prog,ess o,e excho, ged with (ovcrnm~t end privote og~cies sup~rtin8 reseerch, ~d e~e io~orded to invesl,gotors who ~e~est su~ info~ti~. Your su~o~ is ~ ~ us~ • ~r the~e purposes. The purpose of this investigation is to obtain more information, about the mechanxsm by whleh nicotine increases the level of plasma free fatty ~FFA)in experimental animals. Experiments will be designed in order to answer a number of basic questions : a) to establish whether the effect of nicotine is the result of an increased lip61ysis or a reduced utilization of FFA at the level of the peripheral tissues o~ the metabolic conseqe~nces of this increased level of plasma FFA c) the role of the central nervous system ~ d) the importa~nce of t~e ~d~eaals (medullar or cortical) e) a possible direct action on adipose tissue f) Drugs which may prevent the effect of nicotine~'~I~: S~GNATURE OF PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL (medicel, gredue~e, etc.) Dr. Sil~io Garat:ti~i was awarded a gra~t: £or a period o~ fi~e! years beginning Nove~be~ 1, ].966 wlt:h a ~ot:a]. budget: o~ $75,070. approved budgot: ~or the £irst: yea~ is $17,225. 5020 ? ~t~ 99

t~OT ¥O~ pJDt_ICATION OR NOTICE: OF" RE:SEARCH PROJE:CT SClgNCg INFORMATION EXCHANG£ IMITH|ONIAN INITiTUTION A/4A Education and Research Foundation TITI.£ OF PROJECT: Effects of Smoking on the Fetus in Utero and After Birth Give names, deportments, and o|lic|ol titles o| PRINCIPAL INVESTIGATORS ,nd ALL OTHER PROFESSIOHAL PER$OHNEL e.pged ~ the proiect. Thomas H. Kirschbaum, M.D., Associate Professor of Obstetrics & Gynecology, UCLA School of Medicine, Los Angeles, Calif. Nicholas S. Assali, M.D., Professor of Obstetrics & Gynecology, & Physiology, UCLA School of Medicine, Los Angeles,. Calif. o~ ,.ST,*U*,ON: UCLA School of Medicine, 10833 LeConte Avenue~ Los Angeles, California 90024 SUmmARY OF PROPOSED WORK - (~0 ~,ds or I,s,.) - In ~e Science Info~o6on Eec~ge summerigs e[ ~,k in progress ore each~ged with ~ovcmm©n! end private eg~cies eup~rting research, ~d ere Io~erded to Investigators w~ ~e~esl su~ Inl~moti~. Youe summe~ is to ~ used • )r these purposes. The proposed studies are aimed at investigating the effects of smoking by the mother on utero-placental and fetal circulations and metabolism in animal and h~man sub~ects. The animals to be used are pregnant "sheep, monkeys and cats. Maternal and fetal arterial pressures, uterine and umbilical blood flows, maternal and fetal pO2, pH, pCO2 and carboxyhemoglobin will be measured in control, smoking and recovery periods. In a series of chronic experiments on pregnant sheep, maternal and fetal circulatory and respiratory parameters will be measured in the conscious state in control, smoking and recovery periods. In the smoking period,.the sheep wili be placed in a specially constructed chamber with the atmosphere saturated with cigarette smoke. The human investigation will be carried out on pregnant women in various periods of gestation. The effects of smoking on maternal hemodynamics will be recorded. The time for initiation of breathing by the newborn will ~e recorded in the smoking group and compared to that of nonsmokers. Fetal ).food composition will be analysed in infants born to a group of smokers and compared to that of nonsmokers. PRINCIPAL INVESTIGATOR PROFESSIONAL SCHOOL (medico|, g,.4uote, etc.) UCLA School of Medicine Thomas H, Kirschbaum, M.D. was awarded a grant for a period of three years beginning August I, 1966 with a total budget of $60,252. The approved budget for the first year is $19,490. 50201 7500 I

• . .... ~-~,~;~v.~.~, NOTICE OF RESEARCH PROJECT I=,=NO. i SCIENCE I~FONMA~O~ EXCHA~.GE I kOT FOR PubLICATION OR IMITHIONIAN INSTITUTION ~ PUE~ICATION REFERENCE SUPPORTING AGENCY: AFLA Education and Research Foundation TITt.E OF PROJECT: Fffec~ of Nicot'ine and Smoking on Animal and Human BIo~)d Vessels. John A. Bevan, Associate Professor, Department of Phacmacology Ove A. Nedergaz~rd, Assistant Research Pharmacologist~ Department of Pharmacolooy AND ADDRESS OF INSTITUTION: Cniversity of California, 405 Hilqard Avenue, Los Angeles, California 90024 SUt/,MARY OF PROPOSED WORK - (200 words or le-s.) - in the Science Infom~ation Exch~ge -u~mories of ~ek in pe~geess oee exchongeO wi~h govcmm~l end private oo~cies lup~rting research, ~d ere to.ordeal to investigators w~ retest su~ InJo~ti~. ~our ~u~a~ is to be used Mode of Action of Nicotine on the Adreneroic Stores in the Wall of Blood Vessels. Nicotine and related drugs modify neuromuscular transmission from postganglionic sympathetic.nerve terminals to vascular smooth muscle. We plan to extend studies already initiated into the mode of action of nicotine at this site using classical pharmacological and also isotopic techniques. Our ultimate aim is to gain an understanding of the home- ostatic mechanisms which control the release and uptake of the neuro- humoral transmitter in the adrenergic neFve in blood vessels and the way in which nicotinic drugs modify these. b. An in vitro Study of Human Blood Vessels. It is proposed to study under controlled in vitro conditions, various physical, physiological and pharmacological characteristics of human blood vessels and correlate these parametePs with their his- tology, objective evidence of cardiovascular disease and smoking his- tory. It is hoped that significant and suggestive observations will emerge that will lead ¢o a subsequent definitive investigation. SIGNATURE OF PRINCIPAL INVESTIGATOR .. . John A. Bevan, Assoc. Prof. PROFESSIONAL SCHOOL Med i c i he' (medical, groduole, etc.). John A. Bevan, M.D. was awarded a grant for a period of two years beginning August i, 1966 with a total budget of $49,766. Thd approved budget for the first year is $24,250. 50207 7501

hOT FOR PUBLICATION OR PUBLICATION REFERENCE SUPPORTING AGENCY; NOTICE OF' RESEARCH PROJECT SCIENCE IN~'O~.,,,~ IIO.N SMITH$ONIAN INSTITUTION Education ~nd Research Foundation ISlE NO, ,AGENCY NO, TITLE OF PROJECT: Radioisotopic Studies of the Effects of Cigarette Smoking Upon Distribution of Pulmonary Ventilation and Blood Flow Give names, 4opo,tment=, and otliciol title= of PRINCIPAL INVESTIGATORS end ALL OTHER PROFESSIONAL PERSONNEL engege4 on the project, Kenneth M. Mo:;er, M. D. Assistant Professor of Medicine (Responsible Investigator) August Miale, M. D. Ass;slant Professor of Medicine (Co-investlgator) NAME. AND ADDRESS OF INSTITUTION: Georgetown Unlvers~ty Medical School, 3S00 Reservolt P,.oad; N.W.; Wa_~hlngI_on; D. C. 20007 SUt,'J,~ARY OF PROPOSED WORK - (200 words or less.) - In lhe Sc once nformcficn Exchange summarietot ~rk in progress ore e~chongedwilh £ovcrn~cn~ and private ogencie~ ~upporting research, and ore Jo~orde6 Io inves~ ;otors who eeque~t ~uch inJormoti~, Your ~u~oty ~ Io be ute~ ~r these purposes. This project w~ll comb;ne radio;sotoplc and pulmonary ~nctlonal technics to determine: (a) the effects of acute and chronic cigarette smoking upon the distribution of ventilation and blood flow in the lung; (b) the corelation baleen such effect= and alterations in =piro&etrlc pedorm~nce and arter;al blood gas values; (c) pharmacologic and other method= which may prevent or reverse the effects obsewed. PROFESSIONAL SCHOOL Georgetown University Medical School (medicol, graduate, etc.) Kenneth M. Moser, M.D. was awarded a grant for aperiod of two years beginning November I., 1966 with a total budget of $50,966. The approved budget for the first year is $24,167. 50207 7502

NOTICE OF RESEARCH PROJECT TheZffec: of lnflucnz: V,irus and :;~co:ino on th~ Nucl0~r Structure ~row~h changes where feasible. John J. Ballenger, M.D. with a total budget of ~.s $12,720.00, The grar, t begins ~;as awarde8 e 7:rant for a period of three years $38,160- The a-p~roved budget for the first year N ..... ~'-~ ~ ~966 S0207 7503

NOT FOR PUSLICATION OR PU~LICATIO~ REFERENCE NOTICE OF RESEARCH PROJECT SCIENCE I.NFOiL~IATION EXCHANGE ~M|TH$ON~AN INST~TU TIQN AGENCY ~0. SUPPORTING AGENCY: .... Educat-."cr. and Re~_ea.~ch Youndaticn TITLE OF P~.C, JECT: G;ve homes, de;,orlr..enls, ond of~iciol lilies of PRINCIPAL INVESTIG,~/ORS ono ALL OTHER PROFESSIONAL PERSONNEL engoge4 on Ihe Saul Boyarsky, M.D., Professor of Urology, Director of Urologic Research, Division of Urology, Department of Surgery James,F. Glenn, Jr., M.D. , Professor and Head, Division of Urology Peregrina Labay, M.D. , Research Assgc~ate, Division of Urology ANO ADDRESS OF INSTiTuTION: Duke University Medical Center Durham, North Carolina 27706 PROPOSED WORK - (200 words o~ less,) - In the Sc;ence lnformol~o~ Excnon~e summor;es of ~rk in prog,ess ore ,xchor.;e~ ~.,.~ on~ pr.vo~e ogencies ~u~porling ~e~eorch, ond ore to~orde~ ~o inves~go~ors who ~e~uest such inlormol~. You; su~ory ,s ~ be use~ purpose&. Nerves in the renal pelvis and ureter will be sought by chemical and biological testing, using nicotine topically and parenterally as a chenhical ~ti~,~alant of ganglionic activity. Peristalsis will be determined by eleczromanometry, cinefluorography and in vitro studies of contractility. Intravenous urograms and direct observation at iaparotomy will supplement these observations. SIGNATURE OF "/~ PRINCIPAL iNVESTIGATOR/ ~"~1 " PROFESSIONAL SCHOOL (~,~icol, ~,~oo~e, ,,¢.1 Duke University,School of Medicin~ Saul Boyarsky, M.D. beginning August I, was awarded a grant for a period of one Mear 1966 with a budget of $16,062. ~ 5020~

FOR PUBLICAT;ON OR PUBL|CAT~O~ REFERENCE NOTICE OF R~SEARCH PROJECT SCIENCE INrOa,,,A ilO,~ k;XCIiANGE SM|TH,~ON,A N INSTiTUTiON Su PPORT lh, G AGENCY: ~CA Education -~.d R~,~..~o~-~'ch Foundation. TITt.E: OF PROJECT: Relation of Pro-Cancerous Oral Epz,,,',chal Ch~mgcs to Tobacco Usage AG[NCY NO. Condict Moore, M. D., Department of Surgery, Associate Professor of Surgery (Oncolo~,~5') Fe Isis, M. D., Department of Patholog-y, Resident NAME A~-;D A~,RE$$ OF INSTITUTION: University of Louisville School of Medicine, 101 West Chesh~ut St., Louisville, Ky. 40202 SU;/.'~AkY OE PROPOSED WO;;'K - (200 wo,ds o, less.) - in the Soence InJo,m.atio.~ Exchonge summode= of ~ek in p,ogeess e,e e~chon~e~ whh Jot lhe&e purposes. A study will be made of the relation, if any, of the earliest microscopically detectable changes in the oral epithelium with smoking and ~ith mouth cancer. Living human 'volunteers with grossly normal oral tissue will have biopsies done at the same spot; six groups will be selected: (1) healthy non-smokers, (2) healthy moder.ately heavy smokders, (3) smokers who quit over three years previously, (4) smokers who have r::outh cancer at a site other thab that of biopsy, (5) smokers surgically cured of mouth cancer more than three years, (6) smokers who quit after a diagnosis of cancer. Each of the six groups will be matched as to age, sex, dietary and alcoholic habits, oral hygiene, and smoking histories will be as uniform as possible. Comparisons will be made of tissue and cellular abnormalities among the six groups. SIGNATURE OF PRINCIPAL iNVESTiGATOR Condict Y/oore,-M, PROFESSIONAL sC~OO~universi~, (~,~ico~, ~,o~o,,, ,,c.) ,~ of Louis~lle - Medic~ School Condict Moore, M.D. was awarded a grant for a period of two years beginning August i, 1966 with a total budget of $16,643. The approved budget for the first year is $9,021. 50207 7505

NOT FOR PUBLICAT|ON OR PU BLICA TIO/'~ NOTICE OF RESEARCH PROJECT $MITH$ONIAN INSTiTUTiON ~,.~ Educaticn t.nd Research Foundation TITI.E; OF PROJECT: The Cellular Basis of the Action of N~eot~nr. in_S~..ooth a~d .¢~riated Murc]e . Give names, deportments, and ot|icioi titles o| PRINCIPAL INVESTIGATORS end ALL OTHER PROFE$SIONAL PERSONNEL engaged on the proiect. Dr. George B. Weiss - Department of PharmaCology - Assistant Professor NAME AND AD;~RESS OF INSTITUTION: Hed~c~l Colleg~ of Virginia, Richmond, Vir$inia SUh'.~ARY OF PROPOSED WORK - (200 words 6, less.) - In the Scicnc, In~ormotio~ Exchange summo,les ot ~rk in p,og,ess o,e exchon~eo wi~h ~o OVCrnmcnt and pr;vote og~c/es supporting research, on4 o~e iorwo~oe4 ~o investigators who reguest lu~ informati~. Your sugary i~ ~o be used r these purposes. The aims of this project are to delineate the action of nicotine at the cellular level'in a number.of d~fferent muscle systems and to obtain data indicating the points at which nicotine acts in the excitation-contraction coupling sequence-in muscle. Preparations to be employed are frog sartorius muscle, frog rectus abdominis muscle, rabbit aorta, and longitudinal smooth muscle from guinea pig ileum. Experiments will be designed to yield information concerning the relationship of nicotine actionto ion movements (Na22, K42, Ca45), and to the actions of procaine, nitrate, iris, IAA, nialamide, high potassium, and pH. Emphasis will be placed upon-the measurement of tension and calcium ion movements (Ca45) as parameters of particular importance for characterization of nicotine actions. It is anticipated that correlations found between the actions of nicotine and those of these-other agents upon ionic movements in different muscle systems will lead to a better understanding of the mechanism and site of action of nicotine. (metrical, g,o{luete, etc.) George B..Weiss was awarded a grant for a period of two years. beginning November I, 1966 with a total budget of $24,241. TSe .approved budget for the first year is $12,082.

NOT FOR PUBLICATION OR PUBLICATION REFERENCE SUPPORTING AGENCY: NOTICE OF R-~$EARCH PROJECT Education ;.,nd Resea_~ch Foundation AG E~NCY NO. TITI.E OF PROJECT: EFFECT OF CIGAR AND PIPE &MOKING ON LIPID METABOLISM Give homes, depo,lments, ond ol|icioi titles of PRINCIPAL iNVESTiGATORS one/ALL OTHER PROFESSIONAL PERSONNEL engogec~ on the proieCto Samuel Belle% M.D. (Pr~cip~ Investigator)--Director, Division of Cardiolo~ Philadelphia General Hospital Alfred Kersh~, M.D. (Co-Investigator)--Assist~t Chief, Division of C~diolo~ P~ladelphia General Hospi~l Douglas J. Pappajo~, Ph.D.--Rese~ch Bioch~ist, Division of C~diolo~ Philadelphia O~no~! }~ecpita! NAM~ AND ADORKSS OF INSTITUTION: Division of Car~olo~, P~ladelphia General Hospital, 3~ St. & ~ie Ave. )f lhese putpo~o~. The aim of this work is to investigate the metabolic and pharmac~loglc effects of cigar and pipe smoking as compared to cigarette smoking. Comparative studies will be made of the effect of the different forms of smoking on lipid metabolism, hormonal effects and their relationship to lipid metabolism, and on nicotine absorption. In addition, isotopic studies will be made of the different types of smoking on lipoproteln lipid dynamics and synthesis. Their effect on adrenal cortical steroidogenesis, their relationship to the lipid effects of coffee, and their effect on the metabolism and physical properties of serum cholesterol will also be investigated, SIGNATURE OF PRINCIPAL IN VESTIGAT~)/R PROFESSIONAL SCHOOL-- (me(~;col, groC~uote, etc.) Director, Division of Cardiology Philadelphia General Hosp~tal _ Samuel Bellet, M.D. was awarded a grant for a period of two years beginning November i, 1966 with a total budget of $39,992. The approved budget for the first year is $19,997.

s,-s,¢-~s~.;~zv.,.~, NOTICE OF R~'£~'ARCH PROJECT SCIENCE IXFO:.....~ ,ION EXCilANGE /Lv~A Educatiox~_-nd- Research Foundation SUPPORTING AGENCY: TITLE OF PROJECT: Physiological disposition and biotransfor~.a~ion of nicotine~ G~ve homes, 4epo,lments. ond ofliciol fifle~ of PRINCIPAL INVESTIGATORS ~nd ALL OTHER PROFESSI~AL PERSONNEL engoged ~ the pto~mch Professor Carl G Schmiterl6w, Dept of Pharmacology Doctor Eskil Hansson " Doctor Gunnar Andersson " Doctor Torbj6rn St&lhandske " NAMr AND A~DR~$$ OF' INSTITUTION: Departmen: of Pharmacology, Royal Veterinary College, Stockholm 50, Sweden SUtV,V~ARY OF PROPOSED WORK - (200 wo,ds or less.) - In ~he Science i~tormofion Exch©nge s~mories o{ ~rk in prog,ess or, ,~chongeO whh ~ovc~cn~ ond privole o~c;e, luppo¢~in~ re~eorch, on~ e~e fo~o¢~ed to inve~o~ors who ¢eque~ mu~ info~li~. Your ~u~ory i~ to be used %,e following problems will be studied: I. Distribu~ion and metabolism of C14- and H3-1abeled nicotine in the bra~. Z. Distribution of nicotine in ganglia and adrenal medulla. 3. Bio/raHs£ormation of nicotine in the body. Autoradiographic technique will mainly be used to study the cellular distribution. 3 We have earlier observed a concentration of radioactivity in nerve cells after injection of H - labeled nicotine. Especially high levels were observed in the cellular layers of the hippo- campus. These studies will be extended to try to study the distribution on an intracellular level. Chromatographic investigations of extracts fgom mouse brain at various times after injection of (-)-nicotine-methyl-C14 show that the mouse brain during the first Z0 minutes mainly contains unchanged nicotine but ~ater contains mainly metabolites. Cotinine was the major melabolite found in brain, liver and kidney. The. studies of ~he metabolism of nicotine in slices and microsome fraction of liver will be extended with the use of nicotine labeled i~ 2"-position. It should make possible the identification of metabolites not possible to .. ntify wigh the N-me~hyl-iabeled nicotine earlier used. PROFESSIONAL SCHOOL (rnec~icol, grod~ ~u'. etc.) M.D., Ph.D. Carl G. S'chmiterlow was awarded a grar.t for a period of two years beginning November i, 1966 with a total budget of $42,100. The approved budget for the first year is $21,550. 50207 7508

HILL AND I~I'qOA'VLTONo INc. Public [~elab'ons Counsel |73~ K ~TREET~ N.~r. %~I~HI,~TO,~', ~. C. ~OOO~ October 14, 1966 To: Messrs. Haas_/ Hetsyo ~ith Yeaman Enclosed are news reports relating to a statement by Dr. Charles A. Le~laistre at a meeting of the Texas Interagency Council on Smoking and Health Thursday. It is understood from official sources that local reporters somewhat overinterpreted what was said, and clarifying statements were issued by Dr. LeMaistre and by a Public Health Service spokesman. It is understood that LeMafstre was referring to research, soon to be published, that wfll report the identification of "another agent" in cigarette smoke that is capable of causing animal cancer. LeMalstre did not mean to fmply, he said, the discovery of any speclflc element which, if removed, would result in a "safer" cigarette, It is understood. Best regards, EDH:crs Enclosures cc: Earle C. Clements Ad Hoc Committee Company Public Relations Representatives 50207 75'13

PRELIMINARY PROGRAM Workshops in Research on Tobacco and Health The Broadmoor, Colorado Springs, Colorado General Conference Chairemn, Stanhope Bayne-Jones~ H.D. and 1'!4 First Day, Tuesday, November Is 1966 Registration of participants 9:00 - 9:05 9:05 - 9:15 9:15 - 9: Second DaTa Wednesdays November 2, 1966 Welcome on behalf of the American Medical Association F. J. L. Blaslngame, M.D., Executive Vice President The Education and Research Foundation and its relationship to the project for research on tobacco and health James Z. Appel, M.D., Chairman of the Board of Directors, Education and Research Foundation The goals of the project for research on tobacco and health and how such goals are being satisfied bymeans of current awards and the various llnes of research supported 14aurlce H. Secrets, M.D., Ph.D., Chairman, Comalttee for Research on Tobacco and Health ~ 10:00 o 12:00 ROOM A ~orkshop o~ the Relationship of PulmonaryDisets~ to obacco Use Moderator: John B. Htckam, M.D. Rapporteur: Alfred P. Flehman. M.D. Session on pulmonary function and the effects of s~oklng Participants: Each to present an 8-10 minute report on current Or completed vorks -- followed by discussion Kru~holz, Ross - Pulmonary l~nctlon Before and During the Course of Prolonged Abstinence from Smoking in a Group on Chronic Smokers 35 - Cohn - Effects of Cigarette Smoking on Xntrapulmonery Ventilation-Perfuslon Relationships 59 - Woolf - A Study of the Respiratory Effects of Regular Cigarette Smoking in Women

1~30 - ~:30 -2- 85 - Teuple, Pitcher, Sieker - A Study of Pulmor~ry Ventilatlon and Perfuslon by Isotope Scanning 85 - Kilburn - A Study of the Pulmonary Microclrculatlon in Situ by Cinephotography 97 - Frayser - A Comparison of the Effect of Physlcal Training on Pulmonary Function and Serum Enzyme Levels of Smokers and Non-Smokers 104 - Lewis - Effect of lnhaled Substances on Distribution of Ventilatlon 106 - Higglns - Chronic Resplrator~ Disease in an lndustrlal To~n Session on the Effects of Smoking on Che Respiratory Tract 38 - London - Smoking and Cough 76 - Dalhamn - Cillostatlc Effect of Phenol and Resorclnol 69 - Anderson - Acute Effect of Cigarette Smoke on Lungs of Rabbits (A New Eistologiea1 ~eehnlque) Bender - quantitative Evaluatlon of the Distribution of Labelled Tobacco Smoke 11 - Albert, Lippmann, Splegelamn, Liuzzl - Effects of ~un~ Igarette Smoking on Lung Clearance of ~artlcles in ns and the Effects of lnhaled lrrltant @ages on Lung Clearance of Particles in Donkeys 77 - Spurgash, Ehrllch - Effect of Tobacco Smoke on Resistance to Respiratory Infectlon 90 - Relss - The Black Pigment of Human Lung 88 - Giammona - The Pressure-Volume Character~tlcs of the Lung, The Surface Tension and the Fa~y Acid Composition of Pulmonary Surfactan~ and~Electron Microscopy of the Lung After Exposure to Cigarette Smoke 24 - Bondurant - Effects of Components of Tobacco Smoke on Surface Tension of Lung Extracts $ - Webb - Surfactant Effects of Cigarette Smoke 113 - Chapman - Tobacco Smoke and Airborne Micro-Orsanlsms 50207 7519

RO0~l B -3- 10--12 1:30 - 4:30 Workshop on the Relationship of Cardiovascular and Coronary b~sease to Tobacco Use l~derator: Richard 3. Rapporteur: Session o~ the effects of smoking on cardiac metabolism I00 - Wenzel - Effects of Chronic Nicotine Administration on Multlple Molecular Forms of Myocardial Enzymes 103 - Westfall - Catecholamlne Metabolism Follovins Cigarette Smeklng and Nicotine Administration 80 - Gudb~rnason - Effect of Nicotine on Incorporation of C ~ -Amino Acids into Protein 37 - Bellet - Effect of Cigar and Pipe S:oklng on Lipid Metabolism 15 - Brachfeld - The Effect of Nicotine on Hyocardlal Hetabollsm Session on the effects of smoking on cardiovascular function 26 - Carson, Goldhamer, Clements - Evaluation of the Effects of Cigarette Smoke in the Intact Guinea Pig I0 - Bins - Study of the Effect of Nicotine on the Human Heart by Coincidence Isotope Scanniug 32 - Long - Sympethomlmentlc Action of Nicotine 33 - Allison, Roth - Effects of S:okins on the Heart and Peripheral Circulatlon In l~an~ Measured by Blood Pressure, Pulse Rate, Skin Temperatures and Electrlcal Impedence Pulse Volume Determination 34 - Harshall, Hurlbut, Talbott, Kezkl - Cardloresp~ratory Responses to Smoking, Cold Pressor Test, and Tilt in Non-Smokers and Smokers 55 - Greenspan, Knoebel- The Effect of Nicotine on the Canine Cardiac Action Potential 40 - Nicoll - Notor Responses of the Microclrculatlon Following Inhalation Exposure to Cigarette Smoke 56 - Chevaller - Oxygen Debt Accua~latlon in Smekers and Non-Smokers 87 - Estes, Harley - Effect of Myocar¢ial Conterpressure on Coronary Flow 50207 7520

RO0~ C -4- 1:30 - 4:30 Workshop on the Relatlonshi~ of Carclnogene~sls end Infection Hoderator: Peul Kotln, Rapporteur: 6 - Hontgo~ery - The Enlargement of a Research Program in Cellular Physlology 63 - Bogner - The kcle of A~pha-Emltt~ng Isotopes in the Effects o: Clga~ette $~okln8 21 - ;~': ..u~. Leong - Induction of Tncr~ased ~enz~yren~ Hydroxylase Act£vity In ~.~ Lung ~n Vtvo and In Vitro 36 - Rees - Study of the Effect of Polycyctxc Hydro- carbons on Chro~osoaes 8~ - Sweet, Broun - Relatlonshlp of Respiratory Viruses and Other Intracellular Infectlous Agents to Emphyse~, Chronic Bronchitis and Pulmonary Neoplasas 78 - Foley, Aftonomos - ~hs Effect of Posslble Oncogenlc Viruses on HUnCh Respiratory Cells in Tissue Culture Carpenter, LeClalr - Characterization of the Virlcldal Fetter(s) in ~ua~n Serua for Tobacco Hosalc Virus and its Relationshlo to S~oking Cochran, Fister, Dhallwal - A $~dy of the Abillty of Tobacco Hosa~c Viral I~A to Hult,ply in Nuclei and Other Subce~lular Ele~ents f~o~ ~ni~al Cells 10.. O0 - 12:O0 ROOM D Workshov_ ~ on the Pharmacological and Psvehophar~aco.. of ~,ob.a~Co and Tobecco 8 - 10 minute presentations followed by discussion Idoderator: Peul S. Larson, Ph.D. Rapporteur: E. F. Doalno, M.D. ~esslon on the psychophar~acologlcat of nlcotln~ or s~oklng Lucchesl, Schuster, Emly - Effects of Phat~sacologlcal and Psychologlcal Varlables on S~oklng Behavior In Hen with Speclel Emphasis on the Role o~ ~Ico~Ine 14 - Deneau - Evaluetlon of Physlcel Dependence, Psychogenic Dependence and Tolerance for Nicotine in the Honkey 5020~/ "~521

-$- 1:30- 4:30 86 - Geller - The Effects of Nicotine on Timing Behavior in the Rat: I. Effects on Acquisition of the Behavior: II. Performance of the Behavior Following Withdrawal of the Nicotine 108 - Davis, Bronstein, Kensler - Behavioral Effects of Nicotine in Squirrel Honkeys 74 - Dunn - Research on Behavioral Aspects of S~oklng 39 - HcArthur - Personallty end Smoklng: An Intensive Examination of Psychodynamics 47 - Bovet - Action of Nicotine and Nicotine Derivatives on Learning and Retention Session on the biochemicaI pharmacological properties of nicotine and ~moklng _ 2 - Schmlterlow, Hansson, Andersson, Appelgran, HofC~aan - Physiological Disposition and Biotransfonsatlon of Labelled Nicotine 3 - HcKennls - Studies on 14C Labelled Nicotine Hetabolltes 18 - Hurphree, Pfelffer - Electroencephalogrephlc Changes in Hen Following Smoking and Nicotine 30 -Stetner - The Effects of Smoking and Nicotine upon Cerebrovascular Reactivity 50 - Weiss - Effects of Nicotine bn Isolated Hustle 89 - Hudson, Carlson - Respiratory, Cardiac. Gastro- intestinal and EEG Effects of Chronic Nicotine Administration 92 - Jarboe - Some Structure1 Aspects of Nicotine Pharmacology 61 - Echt. Stander - Effects of Smoking upon Uterlne .Contractility and Placente in Husan PreSnancy 6& - HcKennis - Quantitative Hethods for the Deter~Inatlon of the Distribution of Nicotine and its Congeners in Biologlcal Systems 111 - Becker - Effects of Nicotine Absorption During Pregnancy 112 - Gebber - The Role of Nicotine and Related Substances

-6- 9:00 - 9:20 9:20- 9:30 9:30 - 0:50 9:50- 10:00 10:00- 10:20 10:20 - 10:30 10:30 - 10:50 10:.50- 11:00 11:00- 12:00 ,Th~r~ Day, Thursdays NOvember 3. 1966 Report by Dr. Fishman Discussion Report by rapporceur of csrdlov&scular Stoup Discussion Report by rapporteur of oncology group Discussion Re~ort by Dr. Domino Discussion General susmary by conference chairman, Stenhope Beyne-Jones 50207 7523

~u~ust 25, 1966. Dr. Charles E. Untveroity of Austin. Texas. Dear Dr, LeMstetro: Hy attention has boon called to an address you t~t s~nee the ~ort of ~o ~rg~n ~ora~'s .~~ . ~ttee on J~~ s~dLes ~d been 1,300 published s~dlei be ~y ~ense to ~ppy to re~rse y~ for ~. I want CO t4d~ .this opporcunlty co con~raCul~co you. on y~r n~ assi~nt at t~ ~i~rslty. X ~ ~t t~s. wi1~ offer you a Sr~at op~r~ty ~t X ~p~ss ~t ~t r~ves y~ ~rther f~ 7~r d~ ~d devoid late~st In the operstLons of ~~ste~ ~dlcal~~l, I do hope that we may have the opportunity to. uloet again In the not too distant future ~d~on we can ones more exchange views on our mutual probloas, IOIR:W BC: - Miss Janet Brown Vice YresLdent and Oenerat Counsel. 50207 752~

By Charles A. L~4~:l.strs~ Hore than a year ago. with other members of theSurgeon General's' Advisory Co~mittee on Smoking and Health, I attended your first con- £erence in Washington. The .date o£ your meeting, I recall, marked the first anniversary, on January 11, 1965, of the Comitteees report. I assume that an important purpose of your meeting in the next two days will be to undertake a critical and thorough examination of the progress and shortcomings of action taken thus far in response to the Advisory Con~nittee~s report. I am delighted to participate in this undertaktugo At the outset, I would like to present my understanding of the task. The call to action two years ago was clear enough. The Judgment of ° the Advisory Co,~nittee, after a careful evaluation of evidence in more than 10,000 studies, is summed up in that sentence so familiar to us all: *'Cigarette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial action." The conclusions of the committee were sound and they have been confirmed, extended and strengthened by subsequent research. Indeed no conclusion has been refuted or even infringed in the last two years. * Presented at the National Interagen~ Conference on SmoKing and Health~ College Park~ MarylLand~ May i~ i~)66 5020? 7525