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03. 1T'9,~ TUE 13 45 FA~ ................. :},(--~*z> ~)..~:>.~,~ [4~01)9 May I~. 19~0 L A. Cause or Cau~e~ Positions/Questions OutlLne No ont know~ the cause ar causes of lung camcqr. C. Multifactorial Disease Studies zeport I~g cancer to be statixtic~.lly .~ociated ~a~tor~ ~cl~di~g r~ce, ,t~icity, religion, sex, on.potion, ~i~t, Epidemlalogict/Evi~.~ce Stu~i~a r~pozt ~ statl~tica/ a_,ao¢iatlot~ ~ztwt~ smo~g ~d l=g c~¢~. Howevtr, ~tatistlc~ studies ~o nat estab~h a causzl relationship. Rath~ ~7 yo~t ~ t~ nte~ for c~ntc~ ~4 labo~tory re~=~ in o~er to determ~e ~e prec~e.relation~hip- Cau,ation v~. the Constitutional Hy~othe~s The reported ~atlstical association between smoking amcl lung c.;mcer ~ ~etter e~lained by a constituti~l or genetic h~ot~esis (i.e., the smoker ~d not the smoking Is ~espon~ible for the a~ociattoa) ~ by the cig~ette ¢ausation h~othesi*- C. Methodological Weakx~e~ses i~ Prospective Studies The subjects Ln prospective stu4ies ~-e sell.elected a~ to smo~g, 1-,-, the subjects decide for themszh'es whether or. /[~/~ not to smoke. Accordingly~ re~I~s of ~ch'ttud~cs ~o not elimiuate the constitutional or gtnetic h~othesi~ (*¢e above}. -1-

03,'i7 98 TUE 13:45 FAX ~)~ only ~mo~u~ rather t~-multifactorial [i.e., examining the Unxepre~mo tat ire tire of ~t gener~ population. Far example, iB Hammond'a U.~. populattom Mcthodologi¢~ WeakB~r.~m~ G-t IZetro~pective Studies b. Co~y mad C~ Compa,r~o~, Dif£erenc~ ia lung ca-~cer mott~3.it~ in v~Jou~ p~t, of corruption. ~e~ diff~en~e~ h~ve be~ shown to exit f~ co~t7 to co~ty~ from ~it~ to ~i~ ~d even withi~ ¢itie~ ~acial ~i~crep~clea Difference~ in lung'¢~cer mortality betwee-B whltet black~ c~not be explained on the ba~i~ of ~g~et~e con~ump- t~a H-e., blac~ smoke fewer Cig~ctte* ~ white~ but have hi~her lun~ ~nccr mortality). .7_O

So Lung l~',~Hgious Disc~ep~cies DiE[erences in the ~cide~ce 0£ I~mg c~ncer between Se,=ish a.nd non-$e~ish popul*tions in Montreal, Pitt~b~h ~d else- where c~not be e~lained o~ the b~sls o[ ~t~e ca~sump- tio~ M=le-Fe~ale Discrep~.ncies For many years there has been a wide difference (&:l} ~-~ the incidence of lung c~ncer mortRlity ~n males c0~pare~to ~em~ R=cen~ studies report ~ ~e ~ r~tio is d~cre~- ~g duc to ~ p~k~g ~ ~e ~ence of I~ c~c~r ~mo~g ~a]~ ~d ~ concomit~t ~e~se ~ [c~e~ However, ~e reported ~crease amoog fem~ ~ l~gel7 adenoc~c~oma, a t~e of c~cer fo~'~ studies not to be se~t~H~lly a~ocl- azed w;~ smok~g. ~ermcre, studies ~ the U.X. ~d that the m~Ie-~em~e I~g c~cer ~d c~g~et~e con~tio~ ~t- cau~ti~ h~oche~s. Occup,tion -axious occupations ~¢hie.~ ~e not explained by Y~ zhe e~'ly t960°s ,~ese~xc.l~v~ examin?d the lung cz~cer dea~ rates ~rom ~e 193D~ t~ough ~e 1950s ~d to~d k~ea~ but at ~ ~~g ~t~ ~ ~ ~t, they pr~dict~/I~ ~ 7 next decade ~ ~ ~o~ ~ ~he ~.S. ~ ~e U.~),.reach~g the~/ S~ud~e~ s~ce th~ h~ve ~pport~d the~ pre~ct~ (Le.~ ~e ~-~ d~ce of l~ c~cer ~ the U.K- h~ peter ~d ~c:e~g ~ly ~ ~e oM=st age ~s}- ~e c~r am~ ~.S~ [em~es is ~eported to be ~cre~s~ but the ~ __ t~e o~ I~ c~cer ~e~ ~e ~yorte~y de-elop~ (i.e., adenoc~- c~om~ ~ ~ t~ o[ c~cer fo~d ~n s~ud~es not to be Real versus Art~/act Ma.,~y scientists h~ve obse.~,,ed that the l~g cancer migh~ ~e]l bc due to increased diagnostic ac- c~acy. ~e probl~m ~ comported by early p~t of ~e cent~y ~ere w~ pro~abl probabIy ~ tendency to o~crd;~gnose

03/17,9~ TUE t3 45 FAX Ad,,a.'aces in Diagnostic Technique~ The principal techniques for diagnosing lt~ng ca-ricer ray, bronchoscopy and tputum cytology} became widely available after 1930. ~ere was ~ot e~en a ~ecific I.C.D. category for l~g c~cer ~til 1939. Accord~gly, at~emp~ to comp~e l~g cancer ~ the ¢~ly century with l~ng c~ccr today ~e often mislead~g. Inaccuracy of Death Certificates Studies of smoking and lu~ng c.a.ncer often raly upo~ death terrific:ties in determL~ing cause of death- How~ver~ m~T studies have fo~ death certificat~ to h~ p~tic- of deat~ Confusion with Other IRe~-piratorT Conditions ~ o~Iy a small pert=hinge (i-e., about 1-5~) of ca~es ' ~agnased ~s tub~los~ ~ othar ~fectlous ~ea~es ~t app~c~t ~crcas¢ ~ l~g c~c~= ~ce ~e tu~ of the ce~y ~ould h~ virtu~y aliminzte~ d. De~,ection Bias smogars in e~ua~g ~ medic~ situation, smok~g the ~se~e itself. ~onfusion of Primary a~d Seconda_~/ Studies Fred that ~he main re,son Jar d~ath certificate ~nac~a~ wi~ r~g~ to l~g ~cer is due to ~e inabili~ to dist~Is~ prim~ l~g c~c~ (Le-, l~g c~c~ whi~ ~es ~ ~s lung, ~rom secon~7 ¢~cer (Le.~ cance~ whi~ m~t~st~izcs to ~e I~E)- M~y of the met~tatiC l~g c~cars ~e from ~s not even statistically associated ~i~ smok~g. Population quali~ies Age this cent~'-y has rcs~ited in ~ older population ~oday. perhaps ~tth ~eaker l~gs, which is p~ticularly ~sctpt- ible ta ~r~nic pulm~n~7 disease~, such as lung c~cer. Furthermore, ~tudias, of c~cer ~ diHtr~nt countries age ~t~ctur¢ of the populations f~d that the total number of ¢~cer deaths ~ a given population is relate~ to its age armature not its environment. 2S2023470

03 17 !}8 Tug 13 ~8 FAX . [~,I b. ~ohort F[l'ect ¢~ncer ~ ~llke other a~er -- d~d Aot ~orrelate ~ith ~c~ea~ing age but ra~her it peaked in ~hite ~ale~ ~ the latter half of t~e ~i~ decade of li[e. ~ey lh~ ~nding to a ~eeable ¢ohor~ o£ men ~i.e., ~hose born a~d the ~urn of ~e certify} ~d postulated ~ this vu~er~ble cohort grows older ~d is elim~ted frnm the ~opulations ~e incidence of l~g c~ccr among ~hlte ~a1~a wo~ peak ~4 £ina~y decline. s~udiea conf~m ~he accuracy of their predlction~ (i-e., in the U.S. l~g c~cer ~ ~cre~s~g ~Iy in the ctdes~ catego~ ~d ~ ~he U.K. it h~ peaked. ~al the age vf incidence of l~g c~cer dae~ ho~ ~epend eider up~ the age at ~hi~ =mo~g ¢~mmenced o~ the duration ~f smok~g or evea ~hether or not one smokes. The claSm t, ha.t smokes ~ho ~ale ~e more ~hle co c~c~ is ~¢~n~tent ~i~ ~ ~dings from one pro~e~ive Ce~ati~ of Smoking W'aile most a~ll-smoker~ c/aim zhgt a~ ~x-~moker°s rL~k for developing l~g c~cer ~pproa~ ~at of a .nonsmok~ y~s after ce~ation, at ]tgst one claim~ ~at ~ ex~oker's r~sk for deve~op~g I~E c~cer ix ~onsi~tant with the constitutional 4. "Tar" Yields The peaking of lung cancer in ~hite ~ales /s more llke]y the re~lt of ~e ch~ng ~at~e~ ~f the ~seate ~h~ ~e decrease in "tar" yields of cig~etta~ during ~e last ]5 years. ~ the c~ly 1960's rese~chers excreted the l~g cancer death rates from ~he 1930's ~hrough xhe 1950's ~ fo~d ~em t~ be ~crea~g, hut at • decreasiag rate. As a result, they predicted that the male death rate f~m I~g c~er ~ould level ~ff in ~he nex~ decade or so ~h0th ~ the U.S. ~4 the U.K.}, r~achtug thclr conclusion ~ithout r~g~d to lh~ ~ok~g h~hits in the population- -5- 2023 ? 1

03/17/98 TUE 1.3 46 FAX ~x-p ~im ent al Igvideace A. Anim:al Studies I. Lung Ca:acer and Laboratory Anim~Is Despite a~ enorraoua research effort to produce i~ the • ted with smokey, resear~cr~ have fa~,d to produce a. Beagle Dogs Several yea.rs ago a researcher cla.i--c~l ~hxt he had~ produced I~E c~cer ~ heagl~ dog~ e~osed to ~resh, whol~ ~moke. ~s e~er~ment received a grc~t de~ of rese~ ~d a great de~ of trouble ~d~g a scienti- fic jo~al ~at ~Id p~b~ ~e ~ud7 be~e hi~ con~l ~ ~d other ~e~od~ogles w~e ~ade- "e~l7 ~mo~ ce~ bron~ c~c~om~," but h~ pi~ t~ o£ ~e~ ~ppoaedl7 ~x~ve ~i~a do not ~ow eider ~c~oma, or ~v~ion~ ~ ~y .evenh ~e re- se~er's ~m ~at he hxs p~uced ~ dogs ~ t~e o£ l~g c~cer ~at ki~ hum~ has ho~ me~ ~i~ ~cre~-J ~g s~epti~sm ~d =ou-accept~c~ Some of his dogs~ ~o~ ~ose4 to smoke ~d ~t ~ ~po~ did have statistica~g ~oclated wi~ smokey. ~stead, ~ey ~e hellevad ~ he ~e re~lt of • ~1 ettvlo~. b. SF~i~ Golden Hamsters Syrian Gold~.~ hamsters have bee= • populaz model ",.he experimental produc*.ion of lung cancer hacause their l,r.~o~n capability to develop *.he disease cape:sad to a cancer causi~ agent. Nevertheless, se~chera ~ve ~fformly ~ailed ~o produce ~ h~msters expose~ to gze~, ~hole cig.are~te ~mokc the k~d ~ ,c~ce~ reporte~ to be stat~tically a~ociated ~ith ing. One life time study reported ~at h~scers to ~woke gained le~ ~eight th~ the non-exposed ~als; ho~e~er, ~he expo~e~.~nimal~ lived longer non~xposed controlg -6- 2S2023472

03 ~7 9~ TUE 13 " 46 FAX. ~nd Other ~odents ~e~plte ~n ~normoua research eIfoct, labocatory tests ~ole ~m~ke h~ve tailed t~ produc~ the ~d o~ lung ~7 c~cer reported to he atati~ticall~ a~cfat~d ~t~ amok- ~g. ~d, ode ~cent ~p~imc:% whi~ ~xam~e~ ~e potengi~l of tobacco smoke to act with other chemlc~s~ ~lu~c~ atther ~ fncidenc~ ~r ~e la~ea~ of I~io~s ind¢ced ~ mic~ -ith a laharator~ carc~o~e~. c~cer on the skis o~ ~im~s p~nt~d with tub~cco smoke ~lav~ t~ ~e ~m~ l~g ~c~ ~rob]em- Am~g ~e re~o~s given £or ~hi$ ~iew ar~: . The rel;zttvely enocmoua closes o~ ":ax" used. skb-, painting experimenLs. l~mg tLs~e, i~r..hadLng va~ima~ cle~ct~g mee.hma- frex~ ~hcle ~g~ette ~o~., ~~ers have reported ~e p~ductio= of l~ge~ c~c~ ~ h~msters ~ose~ 10 to~co ~oke; hc~ev~, h~ ca~e of ~e pe~li~ ~hy~olo~ O~ ~e hamster (l.e., it conc~trates ~e ~moke on a sma~ ~a ~ sk~ p~L~g th~ t~al~on te~ The posslble role of v|ral agents in sk/n paint/ha ~ ~ Other Tachniques ~Impla.~tation, I~.srtLlati~m, etc.) ~l-~ents or in special media such as w~m bees ~, tmpl~t~- tion phlle~s, ~c. Some researchers have claimc~ poaitSve~ results; ocher expcrlmentx ha~e resulted ~ negative findings -7-

TUE 13- ~6 but, unfort~'aately, little ~ttent|on h~ been paid to them. example, one such study found that condensate the trachea of test ~imals did not re.It ~ ~y c~cers of the tory c~cinoge~ c~cer~ ~ese ~trapolat~g the ef[ects B. I~ Vitro Studies Some studies have reported mutatioual b~ct~ ~d ti~ue c~turex e~se~ to tobacco smok~ condensate ["t~") ~ tobacco ~moke. How~, no one ~d~t~ ~e ti~e ~imal ~ari~, not ~ a ~b~titute 7/ C. Ca.rcinogeno~is The 1963 Su.rge~n General'~ I~.=port tobacco smoke t~ ~e~t a ~zzlin~ ~om~." ~l~ewh~e, ~9~ ~port .a~o~l~ge ~e compl~ n~ o£ c~og~asis.~ e~og~ ~ ~Z~ette smoko ~ too 'sm~ c~c~og~ic ac21vi~" ~ ~be~ed ~ ~e~ ~ gig~tlc ~roblem m~ ~d, ~ 1977 ~ U.S. D~m~z of Health bootee ~tlt1~& e~p~ment~ tobacco smoke c~og~es~ "~at ~us~ relatlon~hlp becwe~ ~ig~eCte xmok~g ~d c~¢e~ h~ he~ dcm~at~'" ~e booklet [~ ~dlcated that i~en/~cati~ O~ ~it~a~ ~d ~romotcr~ O~ ¢~cer [~ tobacco ~t~ficial to focu~ upon th* effecta o[ ~y one ~gredien~ or J ~t~up ~ ingredients ~ i~ola~io~ from the other~. It N~ loag~ ' ~ ~¢cn ~o~n, /or exampl% that certain smoke constituent~ a~t~ 7 */ 7~ ~ ~ti-c~c~ogen~ ~ test ~imals. Similarly, co~po~ds th~t~ ~e c~c~ogeni~ i~ test ~{mals, ~hen ~plled in i~ol,~ion,~ 7~-- -8- 2 2023474

03/17 TUE 1347 FA.~ smoke previously thought ~= he ]xck~g ~lIogether genlc ~C~ivi[T have t~ce~II~ ~e~n (o~d to be geni~ ~hen ~pplied with true ca~cinoge=~ ~ test product ~t is produced bg pas~g tobacco sma~e ~tly, stgdles sho~ that there ~e qu~tative, f~esh smoke ~o ~hich hum~s ~e ~osed. Tobacco smoke is a. h~ghly coml~la= m~x~u~e o~ so-oral thou- tobzcco smoke does contx~ ~ m~tc amo~ o( ben:o(~-~ ~7 p~r~e, it d~e~ no~ me~ tha~ It ~i~ be h~mE~ to th~ ~moke..J ~of~ .w~ sgu~y showed that ~ofers e~ed m conce~-~ e~o~ in~ed hy smokhg had ~o ~c~sed ~cld~ca o~ ~g e~cer. 4. Nit~oaxmi~s ni~samiaes to be present ~ cfg~cce smoke. Other studies c~¢et. However, scientists ~d goverum~ agencia~ g~-~ c~cer rem~s unde t~m~e~ ~ A. Cl/nica! Evldcttce -9-

03/17.'98 TUE 13:,17 FAX r~lq. Persons who have never smoked develop camcer of the lung Studies indic~te that a substantia.l number of lumg co.ricers ragi~ ~hich i~ the place ~ thn ~ most ~ose~ to tobacco though the trachea, ~hi~ i~ p~t of th~ respiratory more exposed to tobacco smoke t~ the Laryngeal Cancer Although the l~ynx, which ig p~.rt o~ l~eal c~c~ h~s remained Second l~:im azie_~ ~ILhough Lh~ce is no reach to ~ppos~ ~t there ~ a grea~ar ~po~e La tobacco ~make. at ~he site of ~7 giv~ l~g c~cer l~g~ ~ ex~emely rar~ c~cer ~d others ~ not. ~se who hold studies by gellerm~ ~d Sh~ ~hi~ reported ~t p~centage o~ ]~g ~cer patients had high level~ of ~d~cibil-) i~ of ~ ~zyme called ~yl hy~oc~bon Howcv~, more recently Dr. Shaw has reported that he could ~ot rep~cat~ his e~lier find~g~. ~ere is ~so puhllah~d~ c~£i¢~m of the Kell,rm~ ~ Sha~ study ~eai~at~g tha~ :he of the mitogen use~ Other researches ha~e r~orted production of ~amou~ cell l~g cancer ~imals, a ~ding which ~z conteg~y to the ~ech~is~ ~her~by ]~g cancer is -10-