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that t: ere exists a very slight systemic, chron ic tcxic e:fect c: sr:zoke con_ensate applied to mouse skin, as ;•_dged from the sur- vival of the test anima?s. The average body weights of t:e mice steadily ir.- crease_ in all groups (see Figure 3). As early as four weeks af:er the beginning of treat:-ier.t with test materials, the animals of t:e two contrc: groups (Groups B and C) were slightly heavier tt:an those c: t_.e four other groups, and t:.:s difference became pro- gressively more marked during the re:-iainder of the experiment. The bod; w:i¢l:ts cl the ani:aals of all groups leveled off towarc the e nc o: the oroiect. Because of the extrerr:elv ciose s:milar;.-: of the average body weights of the rr.::e in Groups A, D, E and F at any givea t;rae, t_.e data of these four gro::ps are represented as a sir.gle line i.n Figure 3. For the same reason, the data of Gro•.=s -5 a-.c C.:•e7e cozr:'=ined into one --..-, It is apparent :ror-n the results in Figure 3 that t: °_ s: :a: ._, s:,nifi:ant chronic toxic _..ect of smoke condC nsa:c aC at:atic n to t: e skin of mice n:an-'es:ec itself also by slight:: red•,::ez. G._. =e body we:g: ts. T: is systemic toxici. : was exac::•: sa-.e. •s::et*-er the smoke condensa:e had been co::ected ir. cc:_ .-a?s, s~ •-ra1 c.:s to several u•ecks r tc tne ex_ eri--:• en:a1 an:mals, or was dire:tly ceposite-' or. the skir :_ t: e....c- _r ~... fresh smoke. a1s •Nitn --ross-; vis:b1= pap:::o-: as exhib: zc•ara_e :-= %.ei;-:s -A•:.cl:.,ere, __r ai. _rac...al -?oses•: _.- sa..._ as .:...s_ =e:er:r.ined si....ataneo_si in ...ice o_' _._ sa:r._ SrL= .;_- t skin lesions. Conse,_. ::1;, it is -.cs: , psc:`_r.-.a f:_-:::at~on was cornected .v::-., or fol:cv:ei tec.: ::ei;_e.•iat:ng signif:cantly frer.: t.e ..:cans. lesions %:sible by gross e:;a:r.i natior. Papillornas - The cumulative n_:nbers of anir:a:s wit: grossly visible skin lesions in the treated area at the ti:r.e c: teru••.i.-iat:on of the experiment are listed in Table IV for all six groups. In accordance with our definition of a papi'_'.oma (see atove), these da:a were divided into several categories depending on (1) whether the lesion was an established or a questionable oapiLlo=---; (2) whether or n ot the lesion had regressed (partial:y or comple:eiy) and : ad n c: reappeared and (3) whether the : ost animal was dead cr r^ ~ "~ r cTR c(]NTRRCTS 00~3435 11225076 CTR ~`°~N 4~~ G'~~ ~

alive at t^e time :.f terr..ination of the e.:periz:ent. It is apparent from these data t:.at the incidence of pap:L'om-as (estab:ished papillorrsas, colL.:.r. ii) is considerabl;: higher in the group of :nice treated with cold-trap.precondensed smoke condensate (Group A) than :,-t any of t:.e groups of anirr.a:s treated with instant smoke condensate (Groups D, E, or F). These dif;eren :es are highly significant by statistical criteria, i. e. at coriide^ce levels of p S 0. 01. ydr^-r.istration of lanolir. to t: e treated skin area of t ne test a nir.:als, j;:st prior to the applicat:-na of :nstar.t s:r.o:ce con :er.sate, did not alter the response of the ani:: a:s, as seen from a comparison of the papillo: :a incidence in Groups D and E (Ta- ble :V, coiurr.rn ii). On the ot :er hand, application of acetor.e, the -•e:::cle .,: co:d-trap-precondensed smoke condensate, to de- posited .ns:a::' s^:c:,.e condensate on ...- ski.n o: the test ar..-na:_. sligl:t:: increased the papilloma ....-__n ce, i. e. _'ro=, 17. &._ -.. ?=: (compa: e f:b,:r _ s for Gro;:ps D and _ i:. cc! 1:-=. .: o: Table :V,. , Y-io•.%-ever, this _ifferer.ce is :ar from bei.^.a it shct::^ _=!sa be noted t: at the :ar:'.ioma i-c:dence .: _z.:. J, E' an:~ _ ..h:=.. •.c•as ca:.__- by apol:ca:io:. of ir.s:=n t s^:o::e condensa:e to rr_ice, is signi_i:an::y cifferent(ps :. 0-) frorr .: e abser.ce of papilloraa occurren ce _.n the two contrc: cr c ps .I Ea:: _ :.ate app°arar.ce - Cr:ronclog:c rec.rd- i: ..- t:^._ papi:io.^.za -..c.ce::ce, when ptot.__ ._ a -cordtna:_ . ..... c: aa ro!:abilitv scale (ior the papille::.a c_currence, on t::e cr__:.a:e. - s a lin.ear sca:e (time, on the abscissa), yie'._s a r.ear strai.. ;:or these two parameters (see = ig---e 1; Exa=.'-r.-_- tior_ c: these data s:ows that precondensed sz-.:ore condensate (Gro;:c :. nc: on'.-i causes a much higher incidence of s;c:n :rs:crs in t::e an:- r.:a:s than instant smoke conCen sate (Groups D, E and F), but ::at th° forr: er s:r.o:ce condensate (Group A) also affords a conspicuo:.sly steeper slope of the time-effect relationship than the latter kind of smoke condensa:e (Groups D and F); the data of Group E are sit ihr to t: cse of Gro•jY D and were omitted from F4-_-re 4 to preserve clar itv of exhibit. Regression of oaoillomas - The r.::a:Sers of an:.rrals -10- ~ ..C L!1 L11 C.n CTR CONTRACT S 005336 11225077 C~°R ~"'~~'`'~ +~~ ~ '~~ ~

a /h wit'rh regressed pap:licr.:as are shown i: colum.r. (ii?) of Table IV. When these figures are expressed in percent of the total numbers of mice in which papillomas ever appeared (figures in column (ii)), it becomes obvious that there were considerably fewer regressions in the a:.ir.:als treated with precondensed smoke con=ensate (GroupA), i. e. 21. 1Pa, than in two of the three groups o: animals treated K•it'r. instant sr :oke condensate (Groups E and F), i. e. 66. 7% and 61. 5"0, respectively. The regression rate in the third group of mice treated with insta nt smoke condensate (Group D) a•as about the same as that in Grou: A, i. e. 25. OTO. Questionable oaoillomas - Alt:^.o•_g!: r.:ost of the estab- lis'ned papiao:nas, listcd i.^n column Sii) of Table IV have, at one time or an:.ther, passed through the stage of a questionable oapilloma (for definition, see above), very few lesior.s have a::_allv remained a: this state for an len_ : of time, as seen fro:n the cata in colur_ s Civ) ar.e (v) of Table i:'. The decision as to .v:et::er or not such 1e- s:o::s were significar.t was left up to the outco:ne of the histODatLoloSic s- '_ies (see 5elcv,). Fer this reason, such histc::_:c studies were per::)r^:e_ on the skirn of a_1 surviving ani::ials with cuestic na~-:e or regressed c,uestion ab:e papillor: as, as well as on as many as p:.ss:- :,1e of t.._ mice that die? y.:e-^.zaturely, provided :at the sample -.as -z: lost ...rous : auto:.:s:.or cannibalism. Multiple paoillo: .as The time a: U•:ica the largest n. --ber of establ:she= papil:cr :as .vere actua:l;• in e:•aster.ce st:r:'.:1- __.e~ occ•_rred a: ter...:r.ation e: the exper.:r.er . e. in a.:,tal :_ =^ ar.i: :als in all groups corzb:-ed (see col ::~', in Table ':i, a:ti:ougl: a considerable n urr.ler oi iesicns : ad a:ready disaD=eared, e::'r.er because of sncnta neous regression (co-_: :(:•:) in Tab'-^ V), cr pre-^at•,:re death of the host an :mal (column (.ii) in Tab'_e `: ). Gi tce 40 r-..:ce with existing papiilornas at ter:ranaticr., 75=ro had sint:e _esions (cc:ur:•i:. (vi), Table V). All of the :n•.:lt:_'_e '.esior.s occ;:rrr'_ t:^e grcup o' anizr:a'_s treated with precondensed smoke conzensa:e (~roup A), and one of t:esc znice even exhibited three or more'_esions (columns (vii) and (viii)). Survivors without established papillomas at terrr.ina- tion - There can be no doubt that questionable papiliornas more fre- quently regressed than established papillotr.as. This may be due to the fact that many of the questionable lesions, small by definiti=n, could have been ca--sed by factors unrelated to the skin applicat?c^ o' smoke condensates, although no questionable papillomas have been CTR CONTRRCTS 00~1323? 11225078. C ~°R IIN 042363

observed in eithor of t-.,e control groups. The number oi s-:rvivo-s without established papillornas, as judged by gross vis::al cbse:•ra- tions at termination of the experiment, would then cons:it•,:te a::c:her meaningful criterion for the biologic activity of the various smoke condensates. These data can be derived from the sun:s of the f:g•.:res in columtts (iv), (v) and (vi) of Table IV, using the n•.-bers in parer.- theses, and can be expressed in percent of the correspor.ding effec- tive numbers of anir.:als (colusr• :(vii) in Table IV). Thus, only 12 o•,:: of ;3 animals, cr 14. 5°je, exhibited no papillor.:as in Group A, as cpccsed to 82.2?c, 8C.4cl, and 69.8;0, in Groups D, E and F, res?ec- :?•:e'_v (i00'o in each of the two control groups, Groups B and C). :iistonat:clo5ic studies c_° skin sect:c=s All an irnals surviving at te:rn i:.atio= of the experi- ..._-:.aere s=.:.r'.ficed and autopsied at that ti::.=, and histology of ..._ treated area o_' their sK:rn was s^_died. ; an i-als __ Gro•_? A, 124 o.' Groua B, '!- of Gro• _ C, 43 ..- Grc.:p D, 40 o: E, 4: of Gro•.:p F and 40 untreated and Lshaved con trol ani- ra:s, or a tctal of 4=E mice, were i.^.:estiga:ec irn t!as manner. L: ac~:t:oa, the sii- from a total of 60 anir`ais, that ha? died (sponz- : eocsl}• o= b;• sac: ifice) pr.or to :er^:ination, •:.as preserved :. - st_...es. Of these, 13 .:ere ....:e c..... ec:ablished pa: _ :c-as (existi n5 z~: regres:ed a: the time of dea::^.) and had bee= :-. ci:dec, t:erefere, irn the correspondi:~g effec::ve nu^:bers. T:e re:::ai.^.ir-2 -r2 a..;=als :.ac died spontaneo•,s:.: eit^e: «it^c_t g:css:v .... ia 1_s:c_., _. a: cuest:oaab:e _e_.n::s, ar.- t: , hac I-- : under the exne::r :eatal condi:ions for a: least iG wee'r.s, „_ ..-s.:.patl•.oicg'.c s..:dies revea:ed e:t_her a ca:c.no.:,a o: a:ao:1:c: a. _ .-._-ty, hist~,logic sec::o-s were orep_-re_ on ..._ ani: :als which c.ad d:ed after less than 90 weer.s of trea:-er-:; :_ : a=-i1c -as ~r c~.rcino:nas were detected histc_:;_ca'.•:y ...- r.es_ latter 5-s sections, an= they were excluded __:a:ions, since ?t :nigh•. `_e reasoned that lesicns could i.a•:e __..:ed :.n these ani: :als if they would have surviv--_: lon,e.. Histc=ogic studies o: the skin, th::s, incl•.:ded a grand tot.al of 565 anir_ ais out of an initial populatton of 976 rnice (inc:,:d:r.6 the 40 untreated and u nshaved controls), or $7. 9`0 of the total popu- la`_ion (32. 0% in Group A, where the initial mor:ality had been high; 67.5;o in Group B; 60. 0°,'o in Group C; 62.5% in Group D, 5:.4is :Z Gro•:p E, and 65. 2% ir. Grc•:.p F). There were a tota: of 33 ca: cino- rr.as, eight preir.vasive carcinomas, 49 papaomas, 89 eoide:z-.:a: -12- CTR CC~~~TE~ACT S (~Q5~3B 11225079 CTR HN 042-3641

Ih /1 and/or de:r: al ulcers, 185 instances ef hy'oerkera::s'.s, 2. 71 cases of epidermal hyperplasia, 265 sections with dermal i.•lamrnaticn, 249 skin samples with mast cell accumulation an d 158 animals with normal skin, including both derr:is and epidermis. µi ith the exception of the nora:alc.: c: s'r.in, these features almost always occurred in association with two, three, four or more of the other pher.oraena, as seen fro-: ::e resul:s in Tables Vi to XII. Th_s, skin sections with carc:::orn as o:ten ex- hibited also papillomas. Ulcers occurred alone, as wea as con- cc,:rre::tly with either carcinomas and!or papillo^:as. Epidermal liyoerplasia and, to some extent, ::yperkeratosis coasistently ac- companied a:l carcinomas, papillomas or ulcers (=ables 'o I, IX, % and XI), but were freq•,:entl,v found also witho•.:t t:ese :::o:e severe lesions, such as in partic;aar in the co n:rol g-oups (Ta'Dies V:1, V.^,I and X_T). Dermal i:.`lat-unaticn and, to a lesser deg:ee, mast cell acc•,:m%;iat'-ern were very frequent ..c_,..:ences ... a_1 groupe, even in the control animals. Carcinomas - These we-e clearly r:al:r- .._..t lcs:ons, and a'_^zos: all were e~:?er rcic sq•,:a:::o•_s cell carci ..omas. Frequently, one or several papi_c:::a: -;~ere seen in a::c:- .-„- to a car...no:zia crn t: e same sect:o-. Alr..cs: a"-` _: t.ese .es:o=: were accor.:panied b•; :narked eplder-:a1 h•;peroiasia ar.dio: hyper- <e-atosis. ': arious degrees o_' mast ce:: accu.:.:::a::o:: an_ derr.za: _'ia = a:ion were present in most instances. e:. :as:v A carcino^1as .nvas?ve carci.no:nas ^nen:ione_ above. .:.ere -_re -,..._ i~stance~ -- ' cseudoep:t:elioa,atcus hy?e-plas:a" ::erc d:st:r.- :s : frorr: very early invasive carc.no:r.as and .•_._.. ..._s: be class.- .._.4 as "; re:r.vaslve" or llq;:es:ionable" cazc... ..:~_. Paoiaomas -':hese were diainose: cr. basis o- localized presence of hyperplasia of the epithel:v.•ith hyperkera- tosis. They were lobulated tumors a:ising from t.e ep:~_er::.is ir. a localized, ciscrete area. Sometimes they were r^ultip'.e, and alr..•=s: alway-s were they accompanied by widespread eriderr.:a: hyperplas:a and/or hyperkeratosis, as well as by mast cel: acc•:=.:aation and dermal inflar:.mation. Ulcers - A cor.siderab:e r.u:nber of sections showed dermal and/or cpidermal ulceration s, mostly tsgether wit: eztens'.ve :3- CTk CC1NT~2ACT~ 005339 11225080 V f R i i f 3 042365

a /h epidermal hyperr'-asia, without'r.o•.vever ex~-.;bitir.g the char>_c:er- ist'-cs of a papilloma. Not infrequently, ulcers occurred concur- rently with either carcinomas or papillor-:as. A conspicuously large number of ulcers was seer. in the untreated and "uns: avea" control mice (see Table X1I). Since the animals were shaved aftcr sac-.i•fice, these lesion s were probably artifacts.. Hyperplasia and hyperkeratosis varied considerab:;: in intensity from onc sectior. to another and these graduations are not ;r.dicated i n the accompanying tables. It should be etnphasized, however, that the instances of hyperplasia and hyperkeratosis ob- serc•ed in the control animals, i. e. i n Groups B and C, and in t:e gro•.:p of untreatec and unshaved mice, were nearly exc:::sively o: the mild variety. Severe hyperplasia and/or hyperkeratosis o_- curre: in ani:nals treated with smoke condensate (Groups A, D, E aa_ F), either with or wit: eut s:rnultaneous carcinomas, papi:'_or as o- ulcers. De-r._a'. iaf:a::-~.-rLatic:. - =h:s _nomenon occLrr-c .: a great number of animals, both from : the ex; erir-.ental and con- t_01 grcups, and varien in severit;: c.er a w•ide range. .: v:as fc•.:n? t: uch less -reouer._'.v and was much w ilder in t:e trc•o ce-:-c: (Z-~:=_ps B and C) than rn the fo::- groups of animals treate= ....rn s^zo::e condensate (Groups A, D, Z' and F). How•e ver, t:er e•.,as a rather high incidence of dermal 1aFia:-L-riatior. :n the untreated and ,.r.s :aved" contrc: a::irn aa (Ta::e X*"), where this type of was -::)=e-a:e1}• seve-e in many ilsta:lces. Mas: cell acc_:^•_:atic.^n ranged :.n deiree -r on-. a e: e increase in the number of c:soe::ed ceas in the der mis :_ .ise existen ce of sing:e and even rr.ultiple, w•ell-defined nccuies :- c!•usters of :nast cells. Like dermal infla.:r.:a:ion, mast =e1: a: ._.. l;laticn was more freqsent and r::cre pronounc-'_ in a-.- ^:a'-s trea:e'_ with smoke condensate (Groups A, D, E ar._ _) :.._n in the control m:ce. Lz contrast to dermal infiar.^mation, mast cell accun:,aation was rare in the untreated and unshaved control ar.:- :nals, and whenever this phenomenon did occvr in the latter group of mice, it was very ::zild. Normal skin - Ar.ion5 all of the ani:nals treated witn smoke condensate and studied histologically (a total of 218 :r. Grcups A, D, E and F), there was only a single mouse with nor:::al ski :(in Group F, see Table XI). However, 92 out of 131 mice ir. Group B, -14- CTE2 CaHTRACTS 005,540 11225081 CTR MN 4~ ~~~"~ G~

a /h 54 out of 117 animals in Group C anc 11 of the 40 untreated control mice, i, e. a total of 1-5' oL:t of 263 control animals exhibited corr- pletel;: nor-•ial skin, oc:h with regard to the dermis and the ep:dermis. Y.istopatcologic confirmation of gross:y visible ::nd:nss - Out of a total of 53 animals irn all groups with grossly visible papi'_lor.:as, irn existence at the tir: e of death or sacrifice, as many as 43 r.^.ice, cr E1. K',, exhibited carcinomas and/or papillomas by aistopathological criteria. On 1v seven of Lhe 21 mice (33. 3%) with regressed, grossh• visible pa?t11cr-.as showed carcinomas or papillomas. This would in- c.icate tc:at in about one half of t:e instancos of regression of gr;,ssi•; Visible ?a??llcr::as (b:. 1 - 33. 3= 47.81N), there was complete caa:- pearance c: the lesions, as judged by histopathology. The number of a::ma'-: with questionable, grossly vis:- ble• pap::lor.:as, studie_ l:istolcgi_a:1}-, was srnall, .. -. only fc;:r -_..co ..:e - wi:-. :ionres-essf-r' q_es:ior.able . _-p:_lo.^.:as and 11 •.ci:h rey-esse--* tio na'cle papillcn:as in all gro',:?s. I:istopathologica'-a•, there ..==2 ... ( 5C'•1 and t: ree 177. 3T,) instan:es ef carcinomas er oa=alomas, re- so ec--re1~ _..ese ;gures are tco small to be ef a:, sig::'-icanc_: the a.^.-..._-_ grossly .is:*D._ skl_ -__.:n .. . .C :arc:..:-..._s 5a n.= s:x 7a.'+ ..~..-.ai ...t::OLa CarC..._...a_, ..E. a o' 1 lesions, were ..e:ected by h:s:oiogic stLdies. Wher. these ::g-_re: a:= co::oared to the nu•^-zbers o: :nice without v:sible les:on s i: .:.- exper.-.e-.tP.: (_-o'.:t)s (Gro•_:s A, D, E and i.e. a tota= ar..:::a'_s, the ....c_ g:cs: •.:-:bie lesicns , eld o-. _. _..- .:-cg:ca:iy c'e_-..-: oa...omP.- _.._%c: careir.o::.as. -iI:s f:g•_--- c•: e:=n ^:uc:: smaller :f t::e an=.als of tae cor.t-c. _roups ~ce=_ ...- c: in th?s cor.siderat:o.^.. It :h::s appears t=a: :::._e wit'-- quest:~-.ab:e a-.= :- :_ cre:_ed les;ons a: e 3ar more 1.*-ely to : avc a}:sto:ogical:•: de :: n- s:rab:e :arc;r.cr..a o- pao;llo: na ::-.arn anir:a:s wahou: an•: .:si_:e _..... lesio.^.. Numbers of mice with carcinomas or paoillomas by all means of observation - In e;ra:::a:ing the biologic response to ad- ministration of cigarette smoke cor.densate on the sxin of test tn i- mals, a decision has to be made, as to the definition of such biologic response. For this purpose, only the appearance of carc:r.c.:.a.s an =/ or papiaomas wil: be considered a resF'`nse to smoke condensate ap- plication. Irn order to cor:putc the total number of animals u•i::-. car- CTR CahtTRACTS 005*314 1 11225082 C~mR MN 4~~-~~6f'`

a /k c:nomas and/or papil:o: ;as by all means o! observation, it has tc be taken i ntc account that histooathologic sttdies on animals wit :- out grossly visible lesions were limited to three categories of mice, i. e. (1) aniznals s;:rvivir.g at termination of the experiment (10z weeks), (2) ani.-r:als studied ristologically which died prior to ter- mination, but w: ich had been exposed to the experimental conditiors long enoug:: to sufficiently minimize the probability that a lesion would have arisen in the event that the animal would have lived to termination ; this limit was set arbitrarily at 90 weeks, and (3) a::- :r-als which died prior to that 90-week limit, but where papillomas or carc?n-_:nas were d:tected histolog:cally. SnEr: a:: v,•:Lh erosslv cisioie lesicns that had never reached a 2 m.:m diameter (cuestionab:e papilio-nas by definition), or with regresse'_ ques:io:able papi:lo-:as had been shown above ..3 have a cor.sicerabi,; :':: er incidence of histopathologieally de- r.o: stra'cle car.--nor:as ar.d''c: rapi'_ioz:as, i. e. 50c'o and 2. 3°'~ r~s::ect?~•ei.•, ..._...-.icc a:;tnout grossiv v:sible lesions `:evcrtbe.ess, -..e cocsicer_tior.s concerr.:n_c the cor:putati7n o_° t^e total numbers of an::nals .ca:: car;._no:: as and/or papillomas arc tine sar-:e as .-, t::e caee o: .-..ce .;•i::..u: Erossly visibie lesions. ..-e n u:-:e-s c: all mice wit^ .as a- lo~:eal:; c-:,•.•e n car,:::._ ::i. and/or pa_'.lioa:as, w: er= Sress ha4 reve=led eitr.er r.o lesions or only q,:es- :..,-:abie :~a::Uc--:a ~c--:a~ ,==-esse_: or not regressed), were a~ae: io: eac~ g:.,.:?, a::~ ...:sc Lr_ sh:.... ..n colu:^.. able -.__. -_ t:ncse _~_res were added the au::bers o: a-.:- a1s wi:: "e=:~ss_y vis'~__ ca=:!'c ras, ..._e=e : e^t_;: ofec•-e::er _r no*_ t.-_se iesior.s rac :e~r~sse~, ar.i regardiess of .ehet: e• .. ..:.- t:e sro:s .:n_:ngs had bee.n con`in-::ed cy oa:..clog,:. : ce res_air.3 fig~res, ind::atir._ .i:e t::;:1 r.c rbers _. aYi:na:_ vriti: ca-_-r.o:-:a a-:/or oao ac::a b: a:. r.:ear.s o' c::ser :ati:,: , are s:own .., col,.=-n (iv) c: :at'-e X:il. T:.:s _-c- cedure appears because over alre o: the nonregressec, grossly observable papil:c.:,as could be con:irmed by histology, while only 53 of a total of 70 animals in this classification were available for histologic studies; the others had died prematurely. It remains unknown whether t:.e sarne proportion of ccnfir:nation prevailed in the 17 m:ce with grossly visible papillomas where no histologic studies could be performe,_4. Slt :cso:^. the proportion of histologic corfirrnaticn CTR caNTRRCTS 0053412 11225083 CTf"!it l I i i 0 "T .Q .. ~,.~ i,,..a 8

was coneiderabl.• s-laller -: animais regressed ~api:i ^ias (33°0) than in those with nonregressed papillomas, all of the m::e vviti: re;:ressed papiLornas were included in computing the totai numbers o: carcinomas and papillornas for the following two rea- sons: (1) In accordance with the definition, a papilloma is a non- malignant lesion, and the regression o: a papilio^:a does not i::- ply, therefore, that it has never existed. (2) As in the case o: mice with nonregressed, grossly visible papillomas, histopath:loEic studies on animals with regressed papillornas d:d not izcl;:de al: c: ti.e animals with such lesions, because of mortality prior to ter- mination of the experiment. For this reason, the exact n,.::nbe r o` mice with histological:y cor°irmed, regressed papaomas is no: lcnown. Since t: e figures in coi ..:-r. (i• ) of Table MI_ inc:_ce some ani:: als which had died before terminat:cn of the experi:::e-::: w:thout grossly visible oapaomas, :.`.e:r numbers are not in t:e effect_ve nu^: bers. To adjus'. _ne effect!ve nur::bers acc_-~- inglv, the n.:r_zbers of the corresp::.di:.z a-i-: _is have beer. co:-.- p_ted frc::: the figures on the las: l:r.es of Tac:es Vi to XI and a-.e shcv.z: :.. colu u: (vi) ..: Table XIII. _:^.e "ad?•_stec" effective .,ers in coiur.:n (vi'-) are, t=•.:s, o_-:zine_°. Finally, c_ .._^:5er_ __ a=.:rr.ais wit : carcino:::as andJor papi:io::•sas by al'l rr:ea ns of ctse-•._.tiens were expresse_ in cercer.t c: th= adjusted e:fective ;co'-um_n viii; =_ Table }~~). -hese z- res are, --. o•_r ooir.io-., .:._ z::o,t .^.:ca::. -,:1 expression o: the bi..-og?c acti'. :; of t: e var.,._- test .-.c.=-_als. =nei- -._^^-erical val~es and ._ .-_ rclative or---_ _:on :. are .,..:er _......=r to ..._ ecrr-=s.ond:-:g oc--_- _c .-. :: e bas:s of Eross %:sua: cose-<<tic:: a'-:)ne (see ::; ces .n par=.. :.. > >: col.:r :n (i:) .:. = ab':e I'.'). Carcir.ogenicity o: test :-:aterials a°c r.iali<r.~r.c :or.s - T: _. _ were a totai of 33 an?r:als w•:L^ ha:o_at:cla_t ._. Y-ove n, in vasivc carcinoma in the treated area of tic s::in. i:. tion, eight ^zice exhibited lesions which were c'.assif:ea by his:-- patno:egic criteria as preinvasive, ir.c:::di ng four cases in Grc-_= A. one each :n Groups D and E, and two in Group =; t:a latter w•er e not inc ;:ded in the follcwing considerations on the ma:ignan cy of tt.e le- sions. Of the 33 instances of invas:ve carcino-w, as many as '_ ( cc- curred in the group of animals treated with precondensed sme<e con- densate (Group A), :osr in Group D and one each in Groups E and F (see last two columns of Table XIV). When these figures are ex- pressed in percent ef t: e msmber of animals in which histologic -17- CTR CaNTRRCTS 005343 11225084 CTR HN 0~~~~69-

sn:dies of the skin were performed (see co'-;:a•in (vii), Table it becor.:es apparent that precondensed smoke condensate (Group A) is overwhelmingly and significantly (p«0.01) more carcinogenic than instant smoke condensate, Independently of whether the latter is administered with or without acetone (Groups D and F), or in con;: nction with lanolin (Group E). The differences in car cino- genicity arno ng the test materials of the latter three groups are :n sig nificant by statistical criteria. The maligna::cy of the skin lesions observed by _ross visual inspect:on was greatest in the case of noaregressed papiilo- : sas, i. e. 45. 3',', (see colurr.n (ii)) and decreased to 28. 6?•; i: or u•he:: t:.e pap:llc:::as 1:z3 regressed (column (iii)). Animals wi::h grossly visible quest:onaz:e and regressed questionable papillon:as ex'r.izited a very low incidenc_ of carcinomas (see columns (iv) and (v)). :ow- ever, two ins:a=ces of carcinoma were detected by histological s:.:d- ies in t:.s nin e surviv:n g m:ce without grossly v:sible les?cn:, s. Gr o•.:c A, nor.e of the 120 ani.•:~tals o: Groups D, D ar.c~ _:o:'r.- biaed, vvhicLh survived wi:hout visible skin lesions, showed a.;• signs of car c:nomas (see cci•::an (vi)). Even tv :en t-.e n•_^:bers of carci- nomas are ex:ressed in percent of the sums of histologicall;: --cn- firn•:ed s}::rn iesions, including invas:ve carcinc:nas, pre:nvas:ve or c::est:cn ab:e czr cino.:as and papilior..as, it is apparent t:.at :-econ- dcnse-_~ s:aoke condensate produced many more ma'_ig.^.an: 1=s:cns ne (62. 8~o in A) than .nstant smoke conden sate under P• o° e ccnditio n_ tes:e-e tr:::•i ::. 3 to 33% in Groups D, E and F, see colu::=. =aole ..:~';. A`ner::.a'_it:e_ cbser•:ed on autoosv ter-::.~:icn A total o: 452 anL-na:s were autopsied at of t: e expe::Yen:, .. e. after 104 weeks of treat:ne nt with cor.=e nsa:e or exoosti:re to control co nditions. At :ha: 2:' ob- ser.-ations of aberratiorn from the normal state were :ne::e in a:cz' of 171 mice, and t^ese aberrations ranged fror. slight discoio: a:ion s of an crgan tc the occurrence of tt:mors. All six groups of mice, as well as the group of un- treated and unshaved control animals were thus affected. It is note- worthy, however, that a markedly larger proportion of animals from the control groups than from the experimental groups were involved. As many as fron: 76.7 to 85.450 of the mice treated with either kind _18- CTR CdNTRRCTS 005344 11225085 CTR ~~~~ ~~1~~'70