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Inlroduction Dcvcli)ptitvllt and Orgazzizat[on of the 1982 ]lcport The content el" t]tj~ ]~el~it i~ "the wolll of nulncrotl$ ~icntisLB within tht~ I)l~l~lrtlllellt ill" I]cltllh arid IJurlt~ln ~t'rvicL+s, tL$ WeLl ~ ~civatifi¢ expeit~ oulaidc tile oiguitiz~lLion, hldividuJzl m;intisci'i0ts wci'e reviewed by eXliOr(~, birth out~ide lintl within the Pub[it llc~hh ~ci vice, lind I]lc CliLil v I~f~lltll t wll~ i.cvjew~d by u [iroiid Ililscd ]lallt~[ of 12 di~tllzguished scieliti~t~. M;my of tile~e ~ciell/ists life, or Ilave broil, dil'ectly involved ill re~c;ll¢:h on the health el'fw'ts of sillolling. 't'llc 19~2 l~epl~rt consists of a Preface ily the Surlfo~n (~caoi'~l, a Foicword hy t}le A~si~l ailt .~ucrctzzry ~lc | [/.ll[Z]l el I hc [)e]ltti lllleiit ill" I le~l~ll end I Itlln~fl St~rv[cc~, zlnd live P~trls, tl~ fill h)w~: ~p pt~l.t [ [ritrolitlc[ioll ~nd Conclusio/l~ ¢~ Palt II. llioliledic~ll Evidc ac'e f~l l)eter mirliilg (?;itlmd ity Pitrt III. Mechaili~ilt~of(~alcinogeltesia • l~alt IV., lnvolwiLtil y ,~Hiokitll: luld I,u al~ ( !ltllec r 4~ P~rL V. (~ILJoIt el Slnuklng I lislocie.I Perspccl(vo 'l'obilcco use wzis li~sociatvd willl I]l~ po~ible d~velop~ie,,t ,,f eaileer as early us 1761. Acc(~rdhlg to oily mvdical hisloriall, I)c. Johll [Ill] (17167 17751 ~ht~uld lle credited with th,~ lii~L rep~, L d~Icii,ileiit ill{~ lltl tt~ociation between ~lbacco I1~0 ~lld C~IICCl loll" lii~ iVtll k ()lJicrs ere, lit SI~UIIIIILCI'IiII{~ Ill 17!)5 li,{" il~>liil{~ ;i Itl;lliOll~[lill all ll~ociidio!l b~Lween lie;ivy ~llitil¢ [ 1114 lind CiuIcu r ill {,<cii~ i ;11. Mllilel ;,lld ~¢haircr ((iOll,llany) iii i!);;O aild 191,l ,cspvctivcly, a,l~l |)oitvr i~lll{Itl~ ]tln[~ Callt~'~.*l" puliell{~ Ilkuli ~tiliOrig 13Oll(fOl~, TIle ]ilB~ In~lj()l" ,l~vvlolilileni~ in the tli(~dut'll lii~ t~i'y ill iilve~tig~aLioa id Lllo ell'uvl~ ~*l" ~ltil~l[iill~ lll~ he~iltll llt!t~al'r'i:d ill l!lFl¢l wilh Ihe llul)li(rliiltlil ~)l" de,Ill" ictiOSllO~tiyv ~tudlc~ oil ~illoliilig {l~il~il~ (;f lulig c;lil(er llLIlielll~ alid ¢',~llilOlS in the [Jliitcll .~lat,~ hy ~iiruk eL al., I~1i11~ ;lrld I'lliler, ]Ar~ill Ct Ill , alld Wyllder lind (]l'{ihalll Hath ill tilt:SO lll3[(:d il cl)li~i~tviit~ ~taLi~ti(:ally ~it~liil~caliL a~iicial tioii bcLweuil Ulilldlilig aild ¢'aiicur ,,I the luilg, el llor ill ve~til~l [ll[~ [ll~lccuded Lll [ul liiel ex;itilinv Ihe ruJ;ilil~/IshiD J~y initi~lliillf lli'aspeciJvc ~Liidii~s ill whi(!h llirl41! Iliinl]lel~ Ill [l(!illLliy II[!l~(itl:; %~t~lo ll~ll()wod livl,i lilll(~ illld llildl" ~ll ll~.qllerl L ill[)l.t ;lliC~d ii{l((~ll.

hli: ill:4 ll,~tll~l I,IL,.I,.~II~. :,iiiii, t11,~,+lll,.t:.SJlll~ lig(;il ;irlq4 1:111 ~ spec'Llit+ ,ulpllalHy iv+is i,dl+:th,d hi Oclol~t'r l!II~l by t)l)]l tlltll llill +u /In+ thfited l~h~d~.n zuntm+; 40IO(X) JhiG~h phy~iciali~, lhinm+o,+d m,I }loin [olhp,.+.t+d II+++.t)tlt) nmhm Ippp++tlrllll~ +ii .)nlltlttt+y ~!)~'1~ III I~i+] lJniled ~l:llt.3 rrIH,~O +111d 15tlbP+t'41LII!Ii[ Itl+n:q.~cLive ~;[tldiPm COlldLlt'It!t~ in the UnihM .~lidt.s. ,Swotlen, ('ilrIildtt, ~ilitI JHIiiin, ~()I)lld llIl~ l)ril~ that ~+lnl)llt!rB IlIIVt+ mfl~,~tJmlial]'/elevMed cancer lllOitJlJi~y I+llt~, hut I'+iIi,~; t]++l+e+zr Ira+ beerl lhe t;uumnd l+tlliJtirl~ 4!,'llim~ or ~[qtl.h im f.he |Jniled Hlnlrs sinee 19;17. Provi+i<mal vital ~lnliMic~ tltlLa fro' Iti+l() intlietlte ~:tllt~',t,l ILCet+Lltdetl ft~r tllm¢lsL ~1 pe~c+l+L oF all d~u~hP+ i+t the /hfit~!d ~I~+t~'s. Tliim cmnTm~es to ]? percer,L ol nIl de+ill+ in 19711 t, nd 14.R pmcent ++f ull doMhm iv+ 195(). Vnrh+w+ invo+li~alo~ Imve +ilg~vsled +lilI~. ~2 (O ~l~ pPrCell+ ~f theme death~ can he atLribtJted to smokhtg, and l~lI+l'+ for P. Iil4~ polenH~ll~ "n v~firlable" if smoking did not exisL t~s II hulllIIII hi, HI tlVioP. Sil+c~ I ~51), the nlTe ~ll[it Iml ~d ore I't+] I vtlllCer death llll~ hn~ chilllJ!('d li~l?, wil/.ri];iR 111~ I1111,I~ C~III;OF de[ith lille }Iris IIICl L+llmt+d di illnltlienll3, I'~r both illil]l~s +ltl[I I~,llltl lull. 'l'ilO lU[lh~ tq~t:+mljslMed lllnl~ ettllt,tH" l'ii[e Jll~i'+.+I1,~'~+] ]~2 permen+ dtith+g Ihe i+eiiod It150=1952 lhrtl I+Y]~ J[}r~8. Female lung etmeer tl+'Ii(tl I+ll(~ ihllinl~ ~]li~ 5IIlIl~ p~tir.I hlel'~ll~l~d evei~ m01e: ~(~3 ciltlC~l th++llh JllllO+ll! /lltlIP$~ i11 Ihe lllliled ~t,'ltt~s, nnd if pl%*Sellt ll<:lllI+ COlll+lllU', will b+cI+111o the 14~RIIIJII+t cmu~4~ of c[InC+l" dealh in fi+tmlle~ dutirlg this tlec~tle; the age atliusled fenmle lung cancer deitt[I I~lt/" i~ i+l'~jeeled to p+~mibly +tlrpnss +lie deilLh pIl~ flip I}~eil+~ I-+IIIC4~F n~,~l ~G+tll'. 'J'od+l~, i]01~th+ I'1~111 t:tlllCeF or ~ll~ Iuil~ ~-~pi(,~PliL +lilly Oil+ qtmrL+r ¢1~ IIII ~l~t+kh+ <ltle to c+ui~er ill Lh+ Uniled ,~tatc+. In ]!)G~, Lhe year whon tim ~uigotm (] t'nerai'8 Advisory Colnmitlee on ~ln,>l[in~ +lud I hmlLh lipid++ n deliber~ntin~ the e'Hdence pi'csen led in Jim hmdmnrk t(!pot L, sllglitry mote Lhtut 4 l,OI)O lie~3ons died of rung t::si+c~r Imlttmll~, +m+ll~,ir~ t+ IP,,3t~ll Itul~. ctlm!+~ de~ths ill I~3F+O, 1;+ ] 9tL2, I be Americarl C:In¢~I' ~ocieLy es tilu;itv++ I l I ,P~ )f) ~lneliCimm will +]i+~ O[ ]Un[; tiIllt:e~, ncnrly tt Ihree-fohl irlcro~ ill Lh+ nliltlh/'r ol denlhs in a 2(I-y~itr Lint+ sl+ttl The Advlsuty (klttllXdtLee'+ Rel~+rl of I!)G4 ju(h~ed tim enusal sigriil]cancv of the association of t:igilrelle smoking ttnd di+.'nse by Iigitl ctJrtqitl, iio Olle Of whieil tllOllO Wits Su~eiollL fop .51 cat/sal jttdgrnenL The el+idemiologic criteria ilmluded: n, The eonslstency of the association b, The mtreng Lh of the +e+sociation e The spceificily of the associatimt d, The teml+m al relatieilship or" t he amociaLion, and e, '['h+ coh~+enct~ of ihe tt~+~+<:itxti+m I' LI;P.TO 9 4 ,I IIIIIIIIipI~ Itlili t'llllt'l h lit,ill Ii I t,lil< [i,ii( f!+ ~iltllilil'ii+ll. lill+liliolilil p~l,il,lllil]L, ovitIPnl.o lillllhiff +iillllltllilt In "~ttl~t!l'l , I1+t ~'+t'll 11~ I<~ tll her I ~ll i:~t't'~l-t +,l~l t,~l tli~t!n!~t<~, lla'~ ltvt xllnllhlh,~l ~ilit,l! Ilif: i[llllilit'l+ +t[ Ih:l# Ail+iSOly (~llillilliltl,i,'+ [IOllilil iu 19i;t Mulh of Lhls hnF+ lgt!l!ll t'lJlh,vli'd, It!ViPl'4Pl]+ III1<1 litlbli~;hod hi IIIiiiiiii1 iel~>l,l+++ liy IIi1~ ] )l,lulll UlOlll of I IP+lllh ltlU[ I ]lliltilii ~l,llSil:l,l, The" Iltllll+++o nl" Ilil~ lil'liill{ l'i III It+vi~'w ili IhLpih Iho IIl~ltl'i~ ~IIIII(I'R Ill P+l:il!nllPli+ pvill+!liCO Idilllul~ cil~llit,ttt+ ~,nllllliiil+ Io t,iwh +,itlll,l,i liy n lilll olni(" +iIo, lUld to IwII hlllt P I lliPi evilh!il< p by t lip ~4filll r, i,l'il t,I ill f}l gl e+hillli+hell by tile Advimlny (Inllililillt!l! lit i1+ 19GI Ih!l~lll, in~ lliclilqt ex pt,i iintqllil[ Cll i't i Ill lift' Ill'+ i~i lilid h iiillil n e iii< h>ln il>lol[i<: ~t liillt,,~, Conclt~slons of the 1982 Report Overnll (~nneer iMm.tnlilv , I. (~igiu'oll~" ~llu~kel~ have nvel(ill illur hllily t+ll<,~ muh~hlllti;lllv ,~rolllOl. Ih3rl till>m(! ill¸ ilnll.qlrloller~+ I)vPinll ci,tlcPr. +h,;it h i:~l~,:~ irr inll[~- Ritlltt<(!l~ ~l.p ilrllllOKil)lill(,iy <r4111111t* lilt~!+(, tll lie}lib;ill+ill o1+~; ovora[I cllnc~l¸ d(,ll~l /lllf!R (If" J'l?nilll~ ~lllO[ll!l~ illt! lll)Vll(l~l tu;ll(!iy 30 pereenL ]llh'h(,v I hlli} nnnsluok0r~, lulq[ nil, iilt, r +.~t!~il~l~ I )w,Fll[I (,iii1('~ t. itlol lll[il V I lllt!H ii111o11~ Rnlcll~l, f.~ flip 41<1~+~ 14,111h ql ll~ rlll!~l~tJr~,d hy Ihe ilqllllllPr Or ciglllt,llt,~ Z;tll+~hr,l~ pi,i ehly. Ile~lvy muokers (~Jver +~irv ll~lell [~r' dllyl h~lve iuole Ill:ill Ihl<:l! llnte~ |llo OVel llll clJ iic~i¸ lh~lLh rnl 0.ol i] (ill,ill,lit el ~, ~. ()Vel~ll cnricer devil il lilies d~c]ille wil ]1 Ih<! lllllllher +lr vl~llr.!: olr ¢il~atelle~, llllpr(llichilll[ the ile+lLll I~lle +If rllm!;ut<ll<ei'~ wilh ir tcI eil~inl{ dtlr~lLion ill¸ t~l.~+ll ir ~rl. Sile-Spe¢if[e Cnllcer Ml~rlllllLy l,lt tl~ C¢lttl~!t l.(~ignlel,to mnokhlg i~ Ihe In+~or ~nuse rlF Itlitl~ ~lltr~<.r" hi fht' Ilnii.d Rhde~. 2, Itllll~ CllnCel" lllOll~llil~' [ller~,ll~,~ wilil ilXCi.l*~i11~ (Jql~tll~r~ uf filnolte ~XllOsIIr(~ lit~ II~¢!;IRIIrl,II by lll~ iilUiIT~(,r" ()l¸ c[iT~lr<!lll.~ ~ln(iklnl dnily, Ih~' .hllnLioll rlf Sl]lokinlL llrl(] inhnlnihlll I~+l- tpi tiF,) nnd i~ ilIve rsely v/~hlllyd |rl ~tl~e ~1 lu (p<l hi !;inqlll<. ~UlOl~l!r ,~ wiln c~,l~Ulne Iwr~ rll¸ lill~rl* i~lck~q oF eil~;ir i,(fe~ dllily II:lVl! lulll~ i~llll ['(!1- lllnl ~lliity i ~tl~,~ I,~ Io ~,,~ [illle~ iuonll!r Ihllrl nllll~lnohr~r S 3. (~i~il" llill] llille ~nl+l~ ill/! n i.e Illmo ¢~lll~til ~lClOl ~ ~n¸ Iiirll~ (.jttl (.(,l. }h~wever. t|le I~liOrillt v t~ In~ ellu~,r int~lltl~ily hi Ilie ~llllt~,<l ~1 ~tl [,B i~ (Iu~ I r) (:iglir4~l Ii. ~nlllkirll[. 4, (~+~al h>n ill ~ul+lklrll~ reduces +lie li~;k ill lunf~ ~lrle(,r" nlol f illily crllnll~UOd to t]ln[ i+[ Ihl, (!tlllLillllillg Rltlllkl!l¸ I~nlril~!r ~illt~ltr,l~;

rllI ~s {}lIly ~lighl]y J]bov~ thine flJr I LQIIIjl) tlJl[u~+lt la j)[lll L L%q/o Lizlle~ g~uutul L 'j'h~ [u~idual ri~l~ of d~w:l~qfi.g hulg clmC~r is directly jjl41jldll'liIHild ~ll overall lifo -lilllu ~){P()~(lle l(j cj~l.~|l~) ~;lllok(]. |"illul'ud Inw~r lar Cig~l'l~l~ ~u]uIluln huvu a lower lunl~ ~'~u~(ur libll Ctili)lHli~d ILl Iliiilfhl[L]rt~d, hjl~ti~r {Izr Cil~IJl'C~o ~l]Xol{d~l~. clev~fl~d zig JoV~ Ih~ I-i~k of nonsn](lliu£ ~ g ~ine~ lhc ~:i~lly ](JS(l~, lung cancel ]~a~ been iho leadiag cause I~malc~, IIm lung cancer deaLh tale i~ accelerating and will likuly ~ll'p~zl llml of bl'em;l ~ancul in LIra ] (JB()~. ah]~ II i~ c~timated that in 1975, lung canccr coat f~3 8 billion h~ lull umnml~, $3795 milli~ln in ~hoi't-L~rm hospital c~at~, ~md $78 millh.I in pby~i~ian fuc~. Illat ~,~ I~le~lit I~f iUlI~ calIcO¢ nlo/l~iity ~OtlZd |lave b~url ~wdd~d ff imlividual~ newt look up ~liulkjng. Furthermore. z~uIp~/IlIIIizll l~dtlC~il~l~S ilX i, he IIIillib~l" el" del]th~ fr4~lll ILltlg ezn~:er ¢t~lhl b(~ uclxiev~d if ~ Ilidj{il [z~zlioll (~[" Ihl] ~l]]ll~ii]g lmlmlaLhnl [pro Licularly young P~r~on~) could bc p~rauaded m~L h) ~01[4J]{~, ],lz/~)lll~l~ld| (~lll('d'l' !) ( 'ig4 Idol [~ ~Jllui(ilt~ i8 the major catl~e ~1" laryllgeld Ca slc~i" irz I1~o Ihlilc~l ~11~1~, (~igal¸ and I)i[)~ ~llll~k(~z~ e×l)el.ietle~ a I,i~k ~)r ILae yi]g~n J c~ll~z" ~iali[~l Io thliL Id" z* i:iga r~l(t] z~lnl)l[er. JO 'l'litt ri~ll ,,I devi:lopg)g I~l'yll~U~l c~lllc¢r ~lll:lU[l~s with in- ~,n~d~e~s havu huynguul CUIICUJ IIIIII hdity ,i~l~s 2() ~) ~[{I /ilil~ ] [ (~¢~iJ(i(ll] OI ~lZl()ltill~ I'12dllC~ II)~ i'i~]{ (g" I~lyjiguai CallCOl Ilalll~dily (~mlpm~d h~ LlizlL ~)~ Ilu! HIIllhillhl[[ ~nud{t!r 'l'llu hJlll:t:l ~l iglJIl~r Slllokur is ofl cig~lutlu~ the iL~w~!I" tii~ ri;g~ lar yilge~ll (:illlUU [" I isl~ Ihmi IIm~' whu u~v tinl~lte~t~d highl~¢ tan IB 'i'gt: ~t~ (If ~tll:lilir~] in conlhiil~flilu] w[lh {:igUlt:tlu ~lllllllglg ~lnJn:;us {i' art ~YJ~Ul'gi~(icaily I~ I~iually hll:tea~ Ih~ Ji:~l~ ripr C~II)G{~I UI Ihu lill yllx, I}llll I'LIcL(I*I" ~ ( 'ii:U HI I(! ~nudljilg is a major czuJs~ ~X (:nncers I)f I h~. (Iral cIWity T:9 TOG9 experience a risk fvr oral ¢liitcc r ~imilar to tlmt of the cigarette ~Liiokul*, |5, Morttdity ratios for oral ~uncer'iimrease with lira numher ~f eigar~tte~ ~,noked daily uml dimiJ,i~h will, cu~slltion of ~nmk i[,g. ]1] (]igaretle smokillg and alcohol uso act ~yner~istically Lo inl~rea~ Ihe r~k of I~ra] ~uvgy cu ne~r~. 17, ]~Jllg term tl~e of 611tt[f ~l)[)ear~ to Im a f~zclor ill IhrJ d t!v~lODJllell ~ ~ ~tlnct~rs Of |h(! oriel cavity, i)ar[icii]Ul'ly (.zlllcel ~ of th~ cheek and gum. E~ot~hageal Cancer 18, Cigur~t Lv ~molling ia a [z][zj~r cause of e~q)hag~a] caill!er il~ the [hlitwl Sta~e~. Cigar and pipe ~,nokvr~ e×[)et'i~lL¢~ a ri~k of esuphageal ~ancer similar tt~ Lhat af cigar~ttv ~m~k~Js )9 The risk ~f e~ph~geal caaccr increases with increased s,nukc ~Xl)n:i~zr~, IIs me85tlr~d I)y t]l~ n~mg~r t)f ~it{~lrt~Ll~u siiioJ~ed daily, and is dimini~}md by ~lisc~ll tir~L, ing the habil. 20. The u~e of a]~oiloi ill ~o,]lbhLa tiu[i wiLh ~ m[ll[ing aet!~ aynl!rgi~,Li c~illy to gl~uLly incleil~ I][e risk I~*r e~o[~hag~ll c[Jn,~r mortality. Bh~hler Cuucer 21. Cigarette ~moking is a ¢oJ,t]ibdt~y I~mh~r i,~ lira devtd~qmu~nt ~f bladder canccr in the Uniiud Stat~. '/'hi~ i c*hltio~lMlilJ is n(~t 1~ lstrong ~s LJlat noted I~)r [ht~ zl~s(~l:i~liil~ll I~l~twl,(~ll ~lllolliiLl[ arul cancer's (}f t he lung, l~ryn×, (~lal ~ J*Vily, and ~l)i~a~t~l~. The t~rnl "ctmLrihlJ~ry li~l~l~lJ¸'' bY tit) l,luan~ exchi~h~ the. i]d~Mbili ty ~l¸ a cz) ~1~ I rol~ Igr ~nltlkinl~ ill (!lillc~!J s id¸ I his ~;it~ Khh.?, (~rm~er 22 (;iga[~ite sm~ki[ig ia a e~mLilhuhlry I'm:tier in Lhe d~velopnmnL ol¸ll hh]t}y ca]lcer in I he Urldud ~lat es. l'~xlrcl¢,zli¢ (_~(llll'¢l' 2;l Cigale[t{~ glll()killg iS li ~(mh'ihuLI)ry Jhteti)r ill Iht: th~vehllullt!lll of i~:~ZlCl uali~: cancer in Lhe I JJui~d .%ta Les. ,~;t.m{~ch (:am'er 2'1. I':l}idenli(doglcal sLudies have nmed ;Ill usst,ci~*tion I)vlwe~m Ci~JI t d][ 1~2 hil]iilIcing lJnii hh)l ii iicg Cil ~11:(~, Pl)h{! ~lNSlhL~i~ i~ ilill i~ ~llli[]~

iii l'l,lllJl[lll~lll WIIII lhill llll11"d Jill ~lllllI~ill~ ~lllil ~IHIII, iiI11~,I Illerirrt! ('i'ttrix (~tt,'i'r 2~'~ "l'heI~' :~te ~,nllicl inf." rt~lllls in sl ud i~.~ pllblish(~l Io dnU. fill I11~ c~islurlce oF ~] rt.l~dionship h~lweq.lt sla]oking 111~II c~.rvic.~11 ~illee'l'; fllllJlcr ii.~e~ll~Jl i~ ni.¢(.~ll.)' [o d(!line wJlolJli!1¸ Zlll t1~o{'kdion e×i~l'~ nnd. if l]o. wht~lh~.r lh~iL ZlSso¢iILLioJl i~ irireel. t)r¸ i1111it c.ct ~|echlmisrtts (ff (~nr(:ino~engsis '~'11~ ov(!l-,Cit!w III.L,~(!I11.~I eVill(ql(N) ]ln(] o~l,%f~lyHl~illll~l 011 I(I1)II('P() emn21t~l)l~en esls pliall~Lrily rh,velnlJl~l ,~inc~" 1~)TB. I. 'rio(! Ili(Jl~lj~ic~ll ~lclivily of wh~le (,ij~l i,iI ~ srnolle iind ilt~ hit iii]11 I~lr tl.acliol)S c;ul Ii(iw ]~t~ inl!~l!~lllt,d I~y irnptoved ill])zlJ~lLil~ll ~lS,,~It~,t~ irl ~ll~lliJi~lll io 1#2b(~ ft~l¸ qtlJil~ll..illili~l~ir~g~ [Llnlo~lJionloL* ir i1~, l~nil (,ot,~l t ei noip211ic ~lq:l i ','ilil'~ Iltl itlr;llS~2 ~kin 2. !~[udi~ urt srnlflle irthllhltiorl w~lh IJ]e Ii~lllts[er now tel>peal' ~iil~lhle fi~J r:sliril~]t~n~ Ihe ieh~llve Imnori~llie IioLer]Lk~l ill" Ltamor il)dtlcLi~ln in [he a'e~l)iralltty Itlt~L is bes~ a~hleve~l b~ J'l~ll!lilm;l(iqlr]~ rlf Itlr ~md I)y ~i~;lly'; ilrl iiiotJ~e ei~ilh,i nlis ~JI(IL ~,lel illitl~ Ih(. I~1~ ~lrld ]l(llent'y ()t' f.lli~ ~3 rci 11o1~21]t~, Itl Clllll~Jirl~l. lira1 wiLh blo(:henlical le~l~, n]ilu~e ~kitl ~l~.~lyS sk1~i]d ak-o aid ir~ t!vlllllldjll~ (Jlc: ~>os~,il~lf~ roJ~ ol¸ rliel)tlne ~1~ ~ ~l~calC~llO/~eii, ;].'J'JtL! idl!nlilil!~lrion, fo~'nll~tiOl~, ~l]]ql itlu~llJ[~lic tlt!livlllion or oli~zll~..,qJ~ciJi¢ (~ll~'illOl~erl~ Ji~tve ))l,4!n sLudied wJl~¢Jl hl!Jp ex- i~J:tin lite ilit~l(!it~ed risk Lo cil~llrt,l~e ~l)lokeltl OF ¢l~ncer ol Ihe t!~Ol)~i~ll~ll~, i)~ln~r.~tls, kidll~y, iIIIr~ ilrirlliry I)lllri(Jt,t', Jn ~111dJLion h~ Cl~ll:tiri tll'om~lLi~ iiit1111~.% (oll~lCCt3-SllUcific ]~.lliLrosIiillirll,:~ ~lr~l~(~ll¸ [o ]~e 1111 ~ll~por[[inL I~ro11]) o[¸ o1~1 Sl~Ci/]~ c111~i11¢)t~,l~ hi tol~ilCCO [lltd (nl)~lcu~ t;rllolge. Li[~le i~ ktlOWll of t.ht~ il~ i~ll!t~ J~ll iil[iLil~ll o~ or~,t~ln.~l)l~i [i~ Carpi illtl,'t!n~ Iron1 Ili~oLirl~ Jlnd o~ller ll~:liv~l~iOrl Lo uJl in~ll(e czlrcitto~elliC i~1"111~ i~t!lts [o I~ explore*l ItS/eJl~nlopl~.v~llLive a[tprolleJle~. (:ig~lr~'(It. slnokirlff sh0u[d be inw,~li~nLud more firlly, rL h~s bl~l~n known [~r ~orne Lime ~Fl~lt iilli~ll~l(,iOll o[ llll),'leCO ~ln(ik(! ~lc(ivnJes enzyJties in ~)le l)lllcl!lll~t altd fol.tJ~ and I~L~ Cllll:~e- i(ll(,~c~s of ~;iJ t~ h cJl~l rlb~L.s ile'et I |o Jl(! s~lJ (Jied 5, TJ~e (~l~llnuit~ modificaLit~n of US. cil~arell~s luls letl L(~ chamois it~ Lh~ q~al~LilaLiv~ atttl p~.lhal~3 tll~ Lhe quaUtat~v*~ (~llrlllJo~i(il)ll ijJ" |~le sln(]ke, 'J~hi~; on/~oillj~ tt(!veJoprnl!nl, ii.qllir~,~ H , t,llhlirl~q J iiitlrllh ,* irll~ ~,1 rrlt. i~1~ r( ~lllll i ;~ii Ii~o!~l nl(' i,li, lit ~;iJ rd G The i:h;llff~i's in t'i~at i.l[i. ('imlllI]si[iml h.nd l;i.m.l~dly [o l(.dlll l.iI (,1111~:si~lll o[ lll~liOl II):~iI lllllill~Jll!Hlll ~lll[llIl' l,or1~Jihl(lllS :i~ 111l'Jl~llt1'~I ill 11tlrIlvii~:ll lld~nntmi~'~; lllHh'l Iil~lhirlI'~m~dlil~r! c~i~diliims. ~illl~ ~lllO1{(q.g ini(.r)~iry pull villmnl. I~lld ,h.Ilt~.~..d ildl~d:illorl whnl~ Sllmliirll! zs h~wtr yi~.Id ril~;, I'll('. Tlff.~(.li~.. il ~l~I~Idd I~! ((el~'t'tl~ill(,<l "~lll~l, ~f~,¢( ilil(,II'Id li'~'lllli(lllI'!I zl( ~I dil~lli,n ~llIl i]IftI~lilm h:tvI' in eomlri!iIulilq~ lhl. im~i.;u~d ~.rlli~hI! e;~llO~lll (. lh;ll i ~.s~dl~l floln infe11'.ilivd ~;nl~IiirlI~ |nvoJlllll~ll-), ~11141tlilll~ ~llll l~lllll,~ (~Illll'l!l" L ~3ill~treFlltl lind ~itll'slrI'111Jl ci~i1relle ~111iil((! ('olllnill ~hllilllr chcnli~ ~I eIln~liUlerd:~. I JMair~slteam slnldII~ i~ ~im~ke which llm ~;llJokol" illhld!s Ilitet:ll.v d~lliIl~ imllinl~ .~.ilb'slti.~Irn '~nlt~ke i!~ ~It~i~Iie enlillo~l (Ioln a ~moltle.rlil.~ ci,~ati!Iti! inlil lhl. ~mlhh.td ilir.) ~rhl!~e l:flll~til?11*lll~; illl:llI(~(' kl1(l~n lY~lll'illol~I!ll!~, ~(Jlll4" IPI whkh ~u~ p~I'sellt in ll~gl1~.r ~.Xlm:i.iltt111ion~ il~ sid,,~ih~.m~ lhlm ill lll[lillF~(.l.l.[llll ~tIlllke. pllsrive or illvOliiill:ll~ SlIHIIIilII[ dflliq~: I'r(llll "~olulllllr~ CiI[IIII~II[, ~lllr)kill~ Wiltl te~lll'(:(. Ill II1~' ( II151"1,11 [tIlJi[~ll I~f ~lttOJce ('o111(Io11('11l~ inhalell, tJ~, dllNlliOll I1111~ Ill' [llll!11('~ 11[ Sllloke @x jlO~4lll ~,, 11nd I lm p~lll 1,iii (i[ illJ1~iIlll iotl 2. Two ~!llilh!miIllo[!ie shldie~ l~0ve [ou ml 1111 irlcl e~l~I'rl I i:~k ,l ht~iT cii[I¢~r in lll)I}~]nTIllli111~ ~/~Ve~ of Rt1111kill~ J111~Tl~111ri~ In l]it.~.~. ~ludles. the nI~nsttlIllclrll[ wi[e'~ rirk ol rurlt! I:an(:~.r bli't i.~i.d in r(,l~iliotl to L}IO I!xlI']]l (~r i)le Ilti~l]nlld'~ ~,rilnllh~l~. lli ~t tlfir,I fitlldy* the risk ~f ]ll/ll~ I:1111/'1!r ;Irllorlf~ Itrtrl~Hu)rlhql wlve~ 111' snlokilll{ hll~hnlld~ WlI,~ (i~[lI irIqreilsed, blll lh(. dilllql.llcF. WII~ noL slalisl ic~*lly silli~ilicanl. 3. AllhIlu~h lh~ cllr/elllly llVlliJ;Ible evfik.m'i, i~ rl.f sllllJ ('ienL i~ I~OIIC1111](! Illll1- prl~'~ive I)r IIIV/IIuDIIII~ ~ItlOkilll~ l~lll~l's hlrl~ ~llll~'er ill ndlrl~411ll)k~r's, the. evidt.u,~ d~.s rliise ('lllli(.lll IIIHHIt U pil~ ild e: ~I!r i~Ir p,hlie hI'n II h Itrrdlh'nl. 4..~es~alJon I~l ~nlo|ttnl~ I. J~irlely five lff.r~'erd ~if i hllr.~ who Ii~i'.'~ (llliL SlllO]linf.~ b;ive lJil?l~. ~Ii Wil~)011l LII¢~ llld Ill till tlp/~lrlized ~111oili11~ ['l,S~llklll J>101~111711, [llill I110~[ ~'llrrl,lll, ~in(lIil,IR (tllJic11([' rl 1)r'(~[i,rl,rli¢• r.l qllillili~ r~otl lfl t, lllpr nrl o1 llillllzi,d, l,~ ii1 lllr (,11 [,t l~liv4~ pl Ill!r ~ii11, 2 ll1'.'.elir¢]l ew/hl~llh)lt~ or ~ellLi~elp nid~ h~lve 14'Jllllll'r] ~;lll'l'l'~ III~('~ llp h) .~() peri'e111 ('~.~:lliilll al i.xh.niIi!d roJhi~qll)~ {(i In l!i t11r~11111~). ~IIsL eslirni~h.~. Jli]w~ver', Fall bI'h~w lhir. lttmlml ~ In ~0 llercl.rlL.

15, ~IIC('(~ Ill qtlitting incJ caavd with the inlmber cJI elloll~ ii/;idc: tdl~ut 455 I~errent of ~h~le~c~nltt who k~pt tiyillg ~¢v~ntLmlly ~tlcc~edct], with alJ¢}~tt hair Ill" the su~c.~es tlcc~JI t illg ~it ~1" lh~ t,~t~ot id tly. |(J,~lllokin~ IllOv01ttioll II~OlJlillll~ tLr~ t]~iluble ~llt~ln~lljvl!s to fichool [RL~I], ]I~t.U~J~ ]IIIVC t;]lown ~1 ~f) i)~tt;oll~ or iJll~l~ i~dtlct[~r~ itl stiiokil]~ oll~L.

PART II. BIOMEDICAL EVIDENCE FOR DETERMINING CAUSALITY 13

,I IN'rI{ODUCT[ON Pruvi~iaJlal mortality d~llii t'or J980 indicate tirol cancer was r.+~l)on~ible for approximalely ,lI2,fl<)0 deaths in tlw t/aiLed Statc~ (199). It is estimated that ia i982 t her.. will be ,13{).(l{l{) deaths due h) cllncur, ~33,00() Ilnlong Inert alnl ]~?,0~l(I alllOllg wozll~n {~). Various inve~tigatol~ (70. 78. 106) imve mLqgesled that 2~ t~) 38 pelceut i~f tllv~u de;~tll~ can b~ attributed to ~m~king, and Ihotulbte llJo (x~tentiully "avoidable" if ~m(~king (lid not exist as a hunlml hehavh~r' - A relatianship betwven smoking and cancer was IiJbt stig~csted for neoplasm~ of tho lung in scientilie reports floJn thl. 192lJ~ and emly 1930:~ (203, 266). Muller (19D m 1935 and Schah'er aml Schou]ligel (237) in 1943 reported that allot hlng cancer patients were snlolier~. Snhs~qutmtly. 18 nmj~r prl~spcdive studle~ and zt~ot~ tinm .rd) t~'t~OSl~tive studies tlave exumlned this r~latioru~ilip lit 1!)61, Lhe Advlso~y C~mmittee to tl~e Surgeon Gcncrtd of tim L].S l%hli¢ lleulth Service (272) pub]i~hed a cuulpr,.hensive Jeview of the Ihen availuble data. They concluded IImL "t:i/~arelt.e ~loltint! is eau~a]ly ,elat~l to lung cancer in me,i; tl.. iilagllitud~ (~l th~ eil~:ct of cll~dt'etto ~nloking I~l' nuLwei~;h~ all (Itilec factol~. Ilala r(ll. ivon]eJl, though le~ exten~,ive, pomt iu the smue directhm. The risl¢ ill" develolfing lung elul/.~r illcl.e~ WiLJI ~he dui.atil~n ()l ~lllflkif)l~ ~l]~tl the i]tmlhcr of clgaretle~ ~m0|tulf pet d~ly trod i~; dimilli~hcd by di~contiauing ~mokingY river Ihe h~t 17 ye~lrs, thous;nlds of ~:ienliric inw.~*i~;iti,ns Imvu ctmiirmod tile Conlmittcc'~ clmclm;ion ml,I i/iovid~,l ~,hlili~nlni evidence callc~vniug the i~.l~lilm.~hiP o~ cigal.t:lle mHd, i~lH i~ hlll~ h~ynx, lind cavity, and (:~aldnlgns, iuld a~ovin h~d willl t~;nlct~ td liln II[il)aty lliudd~!r, kidney, nnd I,am~l'eas. This is tht~ lil~t t~pul't devoted I!xl:[tlSivuly to ~l corail~Ji~herl~iv~ ll~!s~lln!lll of lh~ :*~;.ci;I- tioo~s rel~ot.led b~tweou ~mokillg ~hild w~zhms emlcvt~, hn the I~dh~w- in/~ ~*etion~ ifl" this J~ait ~t Ille IL,,l~(,it, Llte natule ol" Ihes~ as~l)cialions is llllln~ised in Iht~ li~,,ht i)l" eurrl.rltly uwiihddc Itiit)wJ 6 Lt' T069 15

|,]|'|I)I,]I~II(;'I.I.}(;IL~ ~.#Li I~I,;ILi/% I*(.miL L~ALI~L\I.II ~. The ~¢lneqPpL i~i-+~lmsi~lily h11~ beoi~ ill.b+tl~[~ I~ ~LtliIl'nt~ of Ilhilo~l+- I~l+y sil+ce IILe dElyS ~F ArisLolle. I)n'~id Tlqltne {1711-177(i) +m,I +b~hn ~ttlaiL Mill (1~1r;-1~7;I} ~,tt~ ct+.~lilc, I wi+h t+mj++r cc~tlLl'illl]tiolts to cl)ntt.lnllc+mPy inl~ip~llL ;toni til('ory ol` c~lus:lllLy. Mor~ re~u~llly, niPitl I~lS +~l¸ <Ira Aslvi~+,l~y (kJnllnlillec to Ibe ~;lln~t~ul (~nerlll 1~721, Ibll .'.,'ielll'e~;. 'l`~l~! ~ll+illty to IolnL]iy cr*lllt,~l Ihe exi;erinu!t+lal etlvinlll~- Ill(:llt+ ~(i i~lild<mLi~ t!llttl~ur~, lind It) iil(.~l~tlrl] Ili..-eetel~ i~lj(i?<~illt+~ lllhtw~ II cb.lll¸ ex[>~.l.inl~nlli] d~lllOllslr+lli~tn ill Cllll~.'lliLy. llowev.2r, Ibe ++l~l}li~t~i+~n <~f lhese r'i~kl ]+ll~ol~lltl~y lecllniqlm~ ~t' eslal~lishing c;itls~lbly Ii~ ~i(! ~;lll(ly ~r czlnec~r In ]lllnlllnS i~ c]etlriy irnlltl~.q~hle The ilb!tl oi" i]ximsin~ hLitll~lll ~tli~l!l'l#] |{~ l~+~t<!tlti~llly cni+c~l'-i+loc}ll~iil~ il~unf~ ill t~iller Io e~Lzibtish c~llns+tlily i~ mllrally iltl+l eLhic~nliy un+lt:<:c~l~l~lble+ Tht!n'Pl`~a'e. i]lher cril~ii~l h~v~ i~e~.rt dl,vel+~l>l.tl L<) t~ln~l~llsh c~tu~aFity wilh +L "~en3* hif~h ~lt~l~t~e of" ~clenLific prl~l~lbiliiy (~ 11~ 15'#. 2#;¢#. 272. 281~F. Trs ii+lnt:l ict+, el~ill+.llli~ll<+i~ic nleth(}ql~ biiv~ ~n[!(!n e.lllllt>yed to sttidy ~111<~1. ~ii Ill;Ill. rl'h/-a~! ~tll{ri~ I'esulL ill <~h~;el vlt~ion~][ d.-ita ~ll~lL iIiny (..sl;llglis]l ii ...~l~Lislb'?llly b~nifiClllll, a~socktLiOll ]}~.w~.c.r} ...J~rlilble~ (}r 'l'ht. pl+~.ilgibl~ (~1 till ~lrLil`~ltllll {or ~ltllrio~ls) rl#~ulL Cil/l be el~llllntlL+ • 211 il¸ Iht+ ~h!~tl ~llld clgnl~llCL of the ~l~l<lil!s tirE, Jltl~qltgll.e. [11111 if F;I titli[!~ ~'<~litblcll~cl ill dil{~r~tlL L[t~l~r;119}~ic~+~ tlrcti~ DIId allll~ll~ iI~f~el.- enL i+l~l>lllllLitlll ~ttlUl;S igi~l(Itict" Lh~ F.;llllt! or I~bllilzir' ~lilLi~llt'.'l~ tbt i.t!l (~lnl~lll) phi! Jbm<l<~mi~llitm i~ aul atLempL to +~limbmte the ~rfeet of nil vliliplhl(!~ i~lilt!l¸ Lil~lrl Lhe one Ilnller Slil<ly. [Io'..~t]v~r. ii l~lz~]lllll i:h+~i~ I~t!li~lvi~Ji. ~lrch li~ slnoking is inll]{l~$ihl~ IT. rl/lld~rlliz~ li.o.. LI1 ~li~l~tle ~nll~lltit~i~ beh~vior). Ther~h~re. il~ i)n<ler L~ esl~lhlisll t}ltlL an t i'¢~q~(.~;~l i~lll it~!l xvl2t!n ~]liol(in~T I~n<l I1 di.~l~a~l] i~ IlOt i~llO Lo tl coil figtltltl in~ v:ln.i~,i,le. +m elltlte belly of ~l~tn mn~l e~ist to ~'~;~ ~pecific jml~mt~t~L 'l'l~t]s, when a ~clentific jud(gnl~llL i~ 0]n[ttJ~ LImL u]l l~btusiblc~ ccmlbllndltlg wlrlahlc'a Im~e heel1 cotlsidered, ~in a'~s~l¢iu Liorl Innly I>e .:llilS~{ll~rt~li to ~ge d ] i.L.~l.. Fn Ilni~ I{t~i~orl, lbe slime dofinil`io~ of Ihe Lerm "cmns~" tlll,L was t~sed ill t)~e ~t~l)Ot.L or i~to Advisory (~ommil.tee Lo t~lo ~l]r~.'eon (ieneml ill J!AI;4 Im~ been n~lollLed. "The wol'd cause is the one Jn .genl!rtli tlgllF[I] bl c0nlleCLiiin w]t]l IrnTILLet~ ~'onsidereLi in Lbi~l ~lll(ly. ~llld it i~ CI~l~l+te t~; cotlve~.it~g lhe n~timl ~f a sllgtliFiC~l~aL, efl`~cltml rl]ln(ilmsbiI) ~gq!lwo~ll 4in itl~ll~ Illld £111 ll~OCklt~d iI~ml)l~]er Or (ti~le~i~{+ in Ihe JI~+~L" (2721.¸'1'11o lerm "calme" ~;hotild nmL be constrll(*d Lo O } F TOG9 ~"{c'lald~' lllht'l" ~ll!C'lll~ :i'~ ('lllll;,'~; I;ILhq!r, il i~ m;r,,I bi Itlll ll,4'll~liiliotl bl thi~ Ib,llell t~ tl~ ~l~ lhl! elan lil~r oll,', tht' Zll ( I iblllillll Ill' "{ ~lll~ll ~il V" Ill II cli~c;,~e-IISSllckl(~'d wlpi~qhll' {tit;, ~nll~llilll!) bll'h]dl'~ l`llll tt,~ iif!lli I~l'~lllll, ~, IHIII1Flf,r of el ilel i~ p9111!;I hi! Illilizell, illl imp, ~F wbkl~ ~ im [I. Th(! COIl:~i!;I e fll~ llf I b~, ~l~ill,kll il)~l I 'rhr~ (!l~betence nf tile ass~¢:i~f i,lll" 'l'be~' ct'ileria tire utilized hi, rein for evllrllllli,)rl lie Ihe It'llr,/r('rl bl htlm1111~ 'l'l~is crit~rilm illnl~|i~,s Ibllt cllw!r~e ?nelblll}~ of ;}l~ltrllal:)l ill Ibt, /¢'qlliri!~ lllnt Iho ~ockllk~ll }r~!.l'l!jle;~t~ll~ ilb3elvl,d l)y inlullil,le ill ~'~liiIIIl(It~, bl dlfFt'r t'tal I~,l tlilntl~ and ~iL/ml iltllS, ~1 diffbH~nl ri m~"~, lllI.~hIl<II+l+ll~y I~t" t~lll~iecL sele~!li<tll, ~i+1<I lhlll it is +rot imli+I<l ~hI+, h+ ~ml [<~llllllin~ 'mrial)les such l~s dlf,I, <~tl[llll it)el, t~l ~PIIl,I it7~ ~lr~m~lh of the ~.~oclnlioui r+,Lio of cancer rate~ [or ~11149114~r~ to Ih0 I'1~o$ ~of I~(mS/ll[~]<l'l=~ 'rh<! rc!lllliVe risk ratio yields evid~nc~, on tbe ~i~,¢ (~r Lhe e[l~l'! nf a l`n~ t~r OI1 d~l~ll[;~ oc~tlrre~l~e ii/itl whk!h, even ill the ~lr<!~nl:¢, 19( ~lrmlber tls~;ocin tel~ l`n ~tm' wilhllLll cml~ll I el`[~cL bill eol]lcilleel t wilk Ihe ['ml ~lll ii~erlt, will 11o~ be obscured Ily LbC~ iir~rl~ c)l` LII~ firm cl/ll~l l~ellt A rcb~tive li~k r+~li(~ nle#lglll (!~ tile t~l"rent~th +~1 ntn ~:4s<~ri:~llon ttllll pi~lvirb,~ tm t'vnllmli<ln or Iht~ iillltortanco ill" tblll I~lill>r bl Ill+~ I~rodtnctioi~ ofn disettse. II Ilia CI~Se~ O~ [h~ tllseil~e initial" ~lJdy, bLIL nolle fPf ~h¢? Cr)lill'4)]~, ]l~l','e n ili~ory t)r ~IpO~llre ill the ~u~pected eti+,l,~i,,i~' ;tl~elll i)r chtll'ttet~ii~ti¢ (~Iiii]1}~ lh~l~ LIII ll+lequnl~ mlmlter {I~ etl~t,~ itt~i C[]l~l i'lll~ exisI Jn Lhe 11Olgt¢ Ill I.k)ll IJ rld(~r @till]y), g o11(! I (} retiE! C[~l.rec{p()ll hyl~oi hl:~is wmlht }1~ credible. I~l*~L digerl~es are inl]~letlc~'(I I,~ I~l:my

ftl/lor~, h{)w~v~r, alld tJHqt.~foro it ullu to oll~ celrl.t~lx);idullc~ wotl]d tl0t i~o exiluctud, tJ'iiL~ Ml'l!ll~[ll lit" ilia lis~oeiulion i~ llIciinurud i~y let.live li~k ratlo~, incidenc~ rati(~, t); nlol taliLy ratioa. The greater Ihu i~l.lliv~ link ratiu or th~ nmrlalily r.tio, Ihe t.tlonger the i~Jzd hm~.hip b~lwuen tile ~tiuloglc ugunL amJ tile ,liseuae. P~ oapective ht.diLa haw zdiUWll tila[ [hIJ dea{]l rldu ~ioni cancer (d" the ]ling lttlt{ill,~ cJgultdlt~ ~lnukers i~ Upl)i.xiJnalely tO fairies t}lC t~tl~ ill IlUlt~tilnkel~, m.l the rate in h~avy cigarette fil]lUkt~r~ i3 2{) It; g{) lime~ glulllcl" than ill nouamukura. 'l'o a¢COLLnt fi)r micll high lelative rink it~ tcrlna of all indirect a~oclutiun would require that an IIIli{nliwiI cauaal factor bY preseltt at leaat ID tillt~b nl{n~ I'rt!ClllCli~lg ill th~ ~laokula and 20 to 30 tilnes lllOl'U frequently umuJig he,ivy t~Lnulit=r~ Lllan unloJig rlonSlllOk~ro. ~llell a ¢onfoutlding facLor ~hotlhl be curtly d~Lcctabl~, and iJ" ~L Callllg~t ~a detecled or I~a~olmbly il d'ut t cd, the fiading of ~uch a l~t/ung u~sociation makes a conclusion. eUllC~lning can~ulity more probable. Importunt to tile strellgth, as well au to tim e.herenee of the associution, is the preamlce {ff u d{~se- ic~pllli~u i~hunonmllon in which a I~'~ilive gradient between degree af t~x[Jo3tll~ tu tll~ a~ellt and incidence oz' I1501 tz~lily raLes of the diaeuse ¢'UlI lie d~lllOll~tl utcd. Hp~cificlty of tile A~soclaiion 'rhi~ c(incel)t calinoL bu entirely di~uclaLed from th~ conc~llt itll~:lt~llL in the t, ll'en~th of file us~u¢iati~m. IL inlplie~ the iwecisi.n wilh wtiit:li (ilia ci)nlpun4~nt of an ll~(lc~ult~d pfiir cun b~ utlliLt~d Ltl i~i udit:L liit~ occllr i'ellee of tiLt~ triller, i t~.~ li41w Ii ~:{lll(:llLly th~ lll'u~211¢e ill¸ ti[i~ wllilil~le will llr~dicL, ill tile ~ilin~ hldlvldual, the In'u~llee tg> ilnl)l ht~r ~;1~ iliciLy iulldie~ ihaL u cauual ug~nL invaliubly leud~ Lo a ~illgiu ~l~:lilic lli~t~il~e, lin ~vent rululy uil~clv~d, A lllit:-Ll~ ulit~ iclaLhiJl~ldll J,ci II i~il t I~l: ill t~(:llCt~ ill arl eli(ihl.q ic ul4uliL UL/d di~eu~v w~nLhl ll:ltl~l:L il (:illl:.it I i t:lu Iillu~ hill, I hlwvvet¸, ~V~li~l ll~iill ts Lnlt~.L i~ IlupL in nlilld ill illlt:il~lt:tql[~ ~l~t~il'ici£y ill ld(dlqlicld ~y~tulll~. FII~L, Uli zl~nl Jll;iy ht~ ll~(Iciuled wiLli ILiulLildt~ di:~en~l:a ~et:olld. inilny le~.p(lllsu.~ {:tJli~iti~l'l~d ttl iu~ disease ~l~ltt~; h;iv~ illillLilllt~ CallS~H. t!(~lll{elliLill tli[iilillliiu{ion:~, I~I, (~.~Ullllll~, r~itlt I~tllli lli~nld~l lltdizdioil ii~ well ii~ Jtlml Niliie drllgfl ~ldlllii~isturud dUliJig ]n~gllUlll!y lnld olliel" llu hll~ Vuiillli(lil~ in the re]ttLive I'i~k id dlne~l~U may he Jn~ldtJl:t~d lly vat inl illlla hi liit~ n~liubcr (if eu u~ill zlt~t~ll{~ .i~ wvil un hy tlzv nlll~t!ilieil ~' i,I¸ ii i~JVt!li I:illi~Id al~l~nL Third, i~ ~iliHl~ lllll~ nidl.~t~lllt.l~ hi tllt~ t:JIVililUlilt:ht Jll~ty lllt~llJt:C zl ntlJnht~l. (if dillS:reid, di~:~l~t!~.. 'i'h~! ux I~L~l ilUuiil~d llr(idilr Liuli ill ,'1 V~l i.ic I y t)l¸lii~eu~t:~ ill adl:t3 I~y ex i )41~t ii.t~ Ill X i'uy~ i~ il i~(md ~xuJnllJu (if Ihi~ I,'~l[ll Lit, U ~illgle I~ici~ll" iiuiy I)l! Ihl! inixluJ~ .I ~uvelid Lhou~und indlvilhllll cllJl~lit ~lOiLI ~, lind tJiul t.l~ll ~: iL WtlLihl lllit lie mll'pl'i~hlg to I]ild t hal I hi!~l! divl:l ~t~ sLdlst~lllcl~ ale ll[llu 19L T069 L ,. to Illl~ltlc~ IIIO[1~ lllun I]11e ildvel'~e biologic lOal~lll~l~. It ill al~O 11Ol I~Uil)ii~hlg IliaI. tlie~u~ coll~titnelil~ Intly have pos~ihle additive, ~ynergJsti~, or ¢onipeLiLive uction~ with each other and with oLli~r ullenl~ in Ihe onvirtinnient, Aiid Ill'Ill, lllere i~ no i'eii~ll to u~Ull/e ihui iil~ rclation~llill.q b~ lxJ#ei~ i i Olle 171clu f filld dil]{,ren L ili~nu~et lillY() ~indlllr /.XlllunatiOll~. The as~ocJatilm between ~inokhig ullil hlllg ~illiCOl+t fur eXfillllileI is ~onnldeled dilect lllld Cail~ini> wheFeil~ that bet wt'~ll cigarette smok big and cilillo~i8 of tile liver 19 t Ilol~gllt to i)o illdlr~ct, i'~fiecLing the ~oso¢iatlon nf cigarelL~ I~n/o]{illg alid li~nl'y a]culi(d tl~e by ~OIIlO scglnt~rt t.~ Ill tlio pOliulathln. Ill ~tlnlmary, despite tile [act that the denlon~itriitJoll ~[ speeificily iD lilt IISS~Iu lion nlakea tl causal ]tyl)utllesis iilUl'e acci, llizlblo, lack {d" Sll~eii]ciiy does not negate ~llCll all liypolhe~i~, l~iiice iliilny lliol~gie lllld cllhl~nli~logic llspects of the a~aclalioli nln~t ll~ ~ll Ji~i[lerl.d 'l'~iilllllrl~l lletattonship of lira As~ocillthln In chronic di~asea, in~Jdhiil*~ lill~l~L lnld llie hick of ICllowil~dg~ uf pl'~¢is~ induction perials auloJll~iticaliy llre~eilt llrol)l~nm oil wiiicii l'ali/t~ fh'st--tils suspected ugt~liL ill tilt! discus/, IiI ally i!vuhl~itiojI of tile sJgilil]eance of an assocla li~/i~ eXl*~Ul'O to all Ligln i t ilrenilnied Lo lie causal Inu~t precede, ll~lnlioi ally~ tile on~eL of a diseii~ wllicli [L is [lln'llol'ted tO p rodlike. Tile erJiei'iOll of telniloral reialiiln~llijl requires Ill;it UXlliiSili'~ to the ~ll~lleCl etiologic factor i]ll~[lll~ Lilt! di:~ell~, Tenillorulily i~ iiiofo dirficuli to e~ilibli~h [llr dis~un/,~ ~villi hlilg hlli, nt'y ilelilnt.~, ~llC]l 14~; I~ali('t~l', lq'ospc~tiw studies iilJldinizl~ tlq~ dilticully, al[ilOUl¢h t:Vl~ll In'o~il~ctive ~Ludie~i do illlt ~;{clll(l~ lile iill~dlililv ililll Ih~ lii~t~i~o Wll~ iii,l~st./it. ill tin tllidoll~ci~d lllllU [liiUl I~1 t,l~llil~lZl/• lit iht! illllnl IIi~l.lrlgic evidence delllllU~lllilillg iil,l!illlilil~lllllll rhilill~l~~ iiltlOilll itidividilldS oxllu~etl |o the iil~Olii, bill illll Hiillllll{ Iiill!Tllfl~l~il { lUlhlll~' lii'liviil~/~vldellce limt leinllol~llily i~ lli~,~OliL Iglllll~liiill~lll;ll ~liiilit:~ illily ~ilsli ll~lilOll~i rule li I~ lillllil id zinnocllilillli, (~o]loi'~liCe of tli~ A~so~iatlon q31t! i]nui criLeriiln l{Ir tile Ulllirai~al of culi~iil signil]t!ance lif {111 ii~litilitiOll ]~ it~ c~llelellf:e wiili I{liown fucl.~ hi llln li~tul~d hi~liny lind IIiuhJgy Id" tin! dint!il~e, (~{)h{!l/~ilcl' leflllil'n~ tilal di!~il!rilllivn ellid~liii(lhil!h! i,l!~llll~ eli IIi~ii~ {l~CUl-lUiic~ corr/qaLe wilh Illt!ll~illl'l~ ill I.XltO~tlle [O lile nU:illl!¢lld iigeilL Pel'l]ail~ Liilt iiill~l= JlilllUllitzlL coll~Jd(~l-;iLiilll hl:l,t! i~ lilt. i)h~efvaliUll lif ~l dllHl~-ri~lliiil~t! leluLion~hill Isl!lw(!t~ll ii~l~ll[ illlll Ilia'list5 tllUl i~, the In'ogl'~iveiy i lllll i~U~Jllll~ Ill ('tl rl i~liCt! lit tli~i~a~ iu Jiicit:UniliEly Ileavily expo~d iflOUll~>, hi ~iUlll~ {!filet!h, liligiilli/, illl!~l ~>UlL'~ III ll~ige arc i~viiJlnldl: Tile IlZltlll;ll hi~hll'y llf llJnisll~ WnLltd JIwlllde tlllSl~l'Vll{iOll~t on Iile liltlt~lIX'~.~iinl uf dJneiln~ wilh /'lllliJlillilil~

d iscqlzt tln ued In oe(ler (o (!sluhli~h the cnherence IJr Ji slleciFic ~s~ocillLion, iHher pl~i[)i~ explamilhln~ ~r the Nssaci~ltkm inusl. ~Jc J~stelnfllic~il]y ~nnsidcr~i luui excluded or I~llt ell into a(:coll tit. (~kere ll,~p is c[e~lrly e.~l~lb]ishetJ wlmn Ihc actmd mPeilllni.~m oF di~eas~ iJrl~Jltction is d(!rint!nl (~l~hvrt.nee ex~sl.% nt~ll~the]e.n.% idt[iough or a le~er ma~]li. IncJ(!, wiltm I J~erl! i~ ~non~h ~vhlE!rlee ]o :~tll)POlL ii plau~il~ie mech~l- ni~m, LI~IL sol ~l (l(!ildred iznder~tanl]inl~, qlf t!,'lch ~[ep ill the chail~ of evenls Ily wlli~ll a ~iveJt eLi(d(~i¢ sgeJit lU (eh4(:(!s diseaso. Causality for Specific Forms of Cancer "Jlt~ Catlstl~ Sigldficclnce 01" l~ll a~oci=[llotl is ~ matter of judgnteg](, which ~oes beyond any stateln[,nt ¢~f sl~ti.tical probability, [11 Iltu ft)llowi01g sectitm, tJ=e relaLioushlp I)etween smoking mid H(!v~r~d ('a nc(!r~¢ iH I e=l pJ)nlised. ~Cpid~nl ~(l~o~ic~ |gBt hulogic, lind ~Xlgoli. IIIOlll~d d;tl;l ]i)lrll I[IO DJl~i~ f(3r reviuw, When a ~i~,rli~i~+#]ll[ ll$SOCi~. Lion I)utlw!~n t:iffurt'tte ~nl°kill~ find I~ ~9('[~][ic C~IICCF is ~ti)tO~, the Ilalur., ill" Ihe ~ls~ociaLion wns at~es~(~i hy nppiy~g the jadgme.t cJih.ria noted Idmvo. If all epidemioh~l!i¢ criteria were jUdl~'ed to be sntislied luld i,nllmlop~ical nnd expeeinlrHl~] data are supportive, the ~(!rll] r'e~ltlSUI'= i~ applJed to the associltikm. '['lne desi~naLion "major czu4se" is use,d whes tim relntive r~sll for the cnncer in cigarette smt~ke=~ is hilt'it "rke term "contributory factor" is used when time bedy or eviden(~ is less compe]lhll~L the relative risk Js Iower~ or the ~lnt~i]l;tr)' evldea(e {]lath~h]gic and (~xller.hlleltt~d dala) ~ not Stlffi. cieall for a j,dgm~.nt of causality. 'rile tt~rnl "contribLd.ory fllctor" by lit) ~l~etHIS eYX('ILI(i('~ ~he pnssibility of a Call,el loll, fur sTr~okir~ ilI C;III~jIH (>[" Ihl~. sites. The /~rnt "as~o~:iati(]n" i~ 115~d Whell ~t reh~li~,llsJ:ip ])ut We(Sl ~l~ln~ill[~ ~nd a c~] ncer ~i~e ex i~L% but Ihe data III'C inl~lk~Illltt(e ~or ~tll ~O~.~tllen~ Or thl~ character of that i'(.~ld.if}n ship 9 PCT069 2t) L~Id(H{II~(;II{I,~I,ATI~i) C/\i.~L~I,;li,'; II~, ,~;11 II; Ltall~) Cancer .'. lihirO(]tl('(]l~ll ~ince lile e~lrly 1!l~, llml[ c~ntrer h~ls I'~en Ihl. i~.:ldin~ ~'llqisq. r~f c~lll{!~l, ilcalh tll)~tln~ mlde~ in (h(, T.Iidll~(] ,~(~110~; I~rilonj! li.ni;li~.~, l ile hJni~ runner (]Path rnle is n~'r.eln,rrdinl! ~f,!r LImn Idl ~lt]u.r i'~1111'~,l¸ de~lll~ lares Imd. if lira,sea t Ii i.n(l~ e~lrl~inll]e, will ]iht!ly ~nnl i~as~ II1:11 ,~ I~,~mst eluu:er I~ the ~nid I !}~Os I?J(Fil~urn II. ILclween 1!150 and 1977 inl 1be IIuiLed ~tate~,' 1he Iot:d rsunll~,r t>f hlnll~ cm~cer deaLhs increused ft.m 1~,;113 in 1!)5(~ I~ !}O.~H i,~ 1!)77 (Ihe hf~ure for 1977 hlchndes I(~1) (Iniernnlltm~l (~ln~ifica~i~m ~lf Illl!r~ wiH he l~9,tH)O new i~il~l~ cancer c~i~es di~tl~lnlsL.d iln 1!~12 ~md l I1.(1(}~) dealhs¸ Of rids nund,0r, flf),(~}l) will I,e men r,l~l 31,1}110 wouuen, rl'h~ al~e adiListed hm/~ ennl:er uru)rlnlil'/ r=]ll, fur ilu. Ii,l~ll p~q~ndatinn r~early tripled, ri~h~p~ Irmnl Ill l~ 327. f/~ll ~11~' =ldimd,.d ,deal]l i.a[~, tJille~ sllded othel wi~.e, wnl~! dt~iiv(.IS I}.y nitl~lyiqiI~ IJn,' ell~]liler~tul] in ]!}~q).l Overnil hml[ cIl?leer nlml~t]ily I~IllL~ iti~.e~.;l~,,~l over Lhis I~riq.I nt a d[.~deualia~ price Thus, in ihe 1!)Sf) I!)!W Jntf'rvrd. ~he ~verI~,~ Einnu~l increase iFi ihe ~l~[l!.ntljllS( ~.d ~ll.;nl In e ;,f~ w~ I) 2 pereel~t; over t]ie next ld ycllr~, idle ilvl~r~l~f~ Ilnnu:d il~cle=lm. was 40 I,errent; and in the fined ](I-)'ear interval, I!~q~t.1977, ~l,e rain of increase was 3 1 Fercenll. 'J'hes0 ~px ii~reF[a~ed ~tlr(.~ [lltle di[feren¢l~ il~ Ih~ Iunl~ #:[im.l.i mnrtali~ { rem]s o[ msles ~nd ~emtdes {Figures 2. 3. =lnd 4 ) ]t~ qh~. ~tq year ileria(r from ]!]5() L~} 1!177, th~ nf~ adju~te.d Innl~ q'lmrcr r~l~ increas('d ahn~t ~()0 ilere(.llt ~l>r ln~ll alld itver ~54) [~t,rel.qlt [e~l¸ wmuenl+ The nt~t stz'ikitll~ aSl~!~l of Lids tlel~d is Ih~. ~ll:('q.l(.e~lt iflr~ h~ ] un~ ca nt!er mortnlily a IIl~)lil~ feut~tles The nF.'e-ntlin~h~d deal h 1 ~lt~ ~d¸ while ~lTm]es illcl~aSed [ly rll} nvorn~ of l(I ilerreld per yf,m¸ ],eLween 195/I and 1957~ 5.5 p~tcenL per year Ilelw~ein I!158 ~ntd 1!91;7. am] 6 7 percent per year between 1!)(;~] and 1977, ']']le c~rl~'~l~l~Lli]=l~ increrlses For all O~Fler ~lfl le~ wele ~ O. ~. I. lind I~(] 1x,rcPn( I~n,r y(.~ll¸ (The t~rll) '~Borlwhi~e" re]}rl!sents Ii1[ race.~ olhPr Ih~11 whi(e m~d ix u~ed in most ~raphics throughout this i~ei~iI [~>r th~ sr,ke~,l F,it.viiy ) ]rl c{m Lrast la 11ds (r~nd irl ~emldc~, [he r~l e ~i" incI c+~l~e slowed d,~lVil ill lult]e~ Annr (!iinlbiTi]~ nB avel'Bl~ of~.l ix~l(!eil] a yt.~lr¸ fillln [[1~!) to ~9,b71 Lift. rtite nlnoTl~ w]lilf! nl~di.fl ro~e 4t) ileicelll iinntg~llly fl ~lm ]!]58 to ]9~7, and 2.1 percent n year IYmn I!P(;8 to 1977 The I:~1~, ~d¸ ~ncrease amllng Jill other nudes fell frtlm 87 h~ (;~ ill 3.6 I1~,1 el.nil l~l,," yenr aver ihese inLervais Even wil]l this dec~l~ralillnl hn 110(! ~isinll~ ~ "~,*rl~l,~v F.,,~, I~i~ ~ ~.,,~i,,d~ Wilh H,,,,,t I,,n I h,in, ,I ~n,,t, ~ n~ ~7.¸ i:,~ F.,, ,i ,~ ,~i~.1,1~ ,, ~.. ,,r in,~.,la~j, ,~ w, II ,,. ~,, ~,]~ G~r ,~h,~ .n~ ,,~ • ,, 1.1,,~ ~,, .,,~ ~,,,~ el,,¸ ,, ,,,5, ~, ,~.,,,n., rl,,~. ,,i,,,,., 21