l&m research

8/8/2019 L&M Research

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- ;--pt:Fations of Possible Xethoda for the Reduction of ther,og.ca1 .ctlvity or Cdaratte 5sore (Cancer), pp71-96.1 . Methods of Approsob2 . Paper Studiesa . Rand *Papersb. Other Paper Treatments3. Pfrolysis and Other handassatal States. anea b . Slow Pyrolysisa. Flash Pyrolysisd . Cbesioal and Biological Properties of Tarieas plrolyCte s1Tobaae _..__..~,Cellulose3 Tobsooo Piss J16Qit21J1a+ Fv+Z .- ; ;.4 9adacad,prssJf~e: ~-a. The aural":,TpalatOat tfies-

`i4. bdJit. zffsstiria"Sltrasiia~~-~,~esesa a -.4. bd taatiss eC' P:ralts3a - ri .y --

1. Oeaesrl tphas.aeole0a. B7draisa Gram"3 . CL11arr Ytiti2T4 . Inhalation Staaiaea . AcuteD . Ch ooio5. Sumsary

II. Flavor StudiesA. C16arette 6-A (now Chestertleld), pp. 306-10O.

1. General Cbaraotaristiss2. Smoking Paosl xwatloea

4. - ita~iaa.ea ~bl7~,t

D . 3 = s "sSs1sttoaa

's- -Future wort as Qaaaer4so0las, p., W.F. other I f t e x a O s s i too-am

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=T_n; Ctrricterietiee of the CgaretteD.ke o Durban, pp106-109-

MEngineering Studie sA . Nicotine 8edaotioa, pp. 11l-i14.

D . AW .F. - L and N latest Intsrfereaee, pp. It?-lit1. General statue2. Chroooloa of teeete

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;r-At influence which health 'rrnraineament$ have '.d onI .'.-n;ryin tNe . .act sev.rs1years and ocause of the emphasis

~~- 1~ rA:~yhits pcad on research in the oio1o.1oal fiela, it-~-E -c=r cri :-to spend the reJerity of the time ailottad to this o n--rer d aouxalne this eapeot of our war... Cur Intention is to pesent,

in mlnai:1 fAmhion, the .rirus portions of our wnrt which have coonc PPp1-t-d or are in po,ress, the a no1.'ons wP1eh may reasonaaly oe drawnfrom our results and to discuss tt.a direction ano rationale of proposedtutor. nrtSae orisiaal Iapetus for car aielosloal p*raa was" .i,en bythe puolicatioa bf a ipyll~aaars .i~a+s aoas:ronit~ar

.~

xes_, e~ntom. r.Ia. 9e5 (1,'e ), rh;oarepae'sed=-tbaL altars is s~s.a'oisaad'emoare 6i a larp"~~ a~proportlob sr- Sbeir exps~~s.ailApiaisSecomm af- Ylsis -bazian}n- and --- __try.. _ . ~ ._s"6a:=~41:~~ 7r ;;tneiPpart a sef -tbo ~reaye" 1b2f3,xl~ayWlT W a~ W4t isOCn0O!!eaT~-~Raa~~sssOf err vnehsa $b3 Stast3mss fad aa~esta assdbo disersea6 . tot 2essae!~KtMrf: ' ter "";~~4 "_4 -"

s Toawsalj preifir.Qiasassiea'of this OROJest lst.$ 70 ab`1mAae~stain, 1Wsr srssaMatboa. i.Q~s3ire+risri-in me Fiala of study;

4aoh of the poatsrisl in this section fad the tollewine srot.ons is treedfrow }ri-D10.2In e*aluatlon 9L Caroinc..nic kazard rl=1U2CR.o MitiTestuft rroteotion Coswittse, rood an-Writion eoard, aatiooal hassarahCouncil, Dec. 1669; and ai hod itry QL Cnoer ay Jesse P 4,reenstein(Ac dvale mess, Inc., Mwtart, i964).

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- :--I-"t c th livine ,ultioellular orgaAiso . ThisF : r:s 'r Ta single fertilised e" cell poceeds through

: :F:-- a tc cu.tlo uppimtive aroucs of cells wth vnryiniaparenco snu functional potentiality . .St continued growth

_.rrupof c.tls t-etr s~arate ehnracterlsticdiverse wore and noes-rich ether. these roups of cells, wth continue) cell uivisiea

developinto diatinsalshec1e entities and are Balled tissues. At the samtire thrt these tissues are developiAi into physiosl entities they are also

or example,. one ripofev.loP1nd sPeolalised phyaioloaioal function. ftissues assumes the oharactsriatios.of 2iveree12s, smother droua Yidney .cells dad seenthrorih Lh. srW,e;r$pioialisid.tssues Mood" for ... _"4r~"re! e~~_E12TSi3 ..r-L..~7~-ar .:...Li a cr+wDlste Began .- sure_~s se-mss. ~ravp_za~+sY.o~~sysaaaa ryas

s am_hTsieZp~Sab htaptie~es '3rnM:- sli , psstlaila4=..as t1R sa=isus ;d. r.. of Oltlresat2stles .1tbi.:a1smties =

=~ - '?he_PMStTyo*;tips is5.Zreai_~s des ~eii tai:7biL$- vtitt is . -...~.- . . :::. h"a"m.= .:. :~li ra des a -dal nlilmat J-ea amsr*sebpd. Par laatasoe, shed 'all,partisos;K -meld ors rssewd, .ths'.tiadss-lylni layer prodnees sere' eridsr~al dells. ;=Vwwer aos+r1 siravstames .there is s!rsts .of Lreardown ef'tissw with a suosekusot rsfsamrmtion by.call division. Usually tha reoeneratlon resehes the maximum allosahlg limitpotentiality of any tissue is usually confined within detinite limits mywhich is eharaeteristlc of the adult ordnnism anu %hen asases. the growth

cell division out of the fartllited odd to the attainment of the adultcmtrols which are exerted oy the ordaniw itself . From the eeiinnusr of

re5ener.tive oepacitles of the tissues are iraduslly aialnlsh.d at ratesnut the ere-ter p.:t of tee life span of the ardanims. alth 'old ad.' thof every ether tissue

. t~s coordination is apparentlymaintained throu+b-elate the uevelops.nt and irnwth of each tissue 1s onerdtn.t*d with that

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r.rrF: : :atence of the rultiosllular orsaniss is, thsrotore,

coordinated with the drnwtb of sarsal :base is eallad a jam= er a peo21* .Tueers are usually di.IAed 1Ate, -faisie~elets:~SQ~a s~d.~t..Zt Ssy case t+ea not progress after the stlsaalus which caused it is rwewad.t.n a onnrril wasa of tissue, tbw. &1X'mrth of which exceeds acid soots'. a lncr'l ara is e.11e1hlyerflla ia. Hyperpasia tends to regress, and in

h aacnrdinatinn of the capacity of the tissues for j~th to_ : . :e%eneand calanoe of the orsaniss as a Vbole. Occasionally, a

-se -AY cane oynnd tho normal 11-Sits of the 61)&eftian.So-h n nvre'rw%h if it results in an increase in the nuobwr of cells

possible ,

usually nonwiderad in tbres satsinsisa:-(1 n.rein"a -a Lower arlsiai .remepthelial sells i.e., tbeee se11swhich form a ooe.riad ssrorane fors . ordaOor a emend of a oavitr;(Y) MAMMA - w town! wrialud fr' ooeaeetlwe or supportive tissues; and(S) noe+nl wsma of the lymphatic or the blood fofeini tissues.rho general tare cancer s:pies to all smt.nant tuners. the particularcancer wth -hieh we wll oeat onnown*4 is oaroinnss.

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and duration .i.d intans.tye+f eaPosrtre to oertwto sxtsrrnal stlnall.

r : . :-:rr thoresumad r..ercianoe or Lha early irwth to tae sbapa of arrat . Usny tbines era knn.ra to have on effoot on the inoidrase of saucer is.nie+le r+r in ann. Some of thess are: toastios or heredity, cis, sez dirt

.r.=-r t.' boon rcn,nitd for over 4,000 ys.rs, And Was so DMwd by the

the rvid.noo is clear that ienetio factors runt p3.aJa Inns rule tocancer inoiuauee. Yor iaataoos,,is oertala sn:rains of aloe iacs of the

6

is

animals rbiab live to a osrtalasri Aevslvp-Danvere at a par$isalar site. Oe-UM .otber bane, sasaive treatansl".'if, etbirir aoI -4 vita naafi .aloes tae eaacnf.o! aaatarials want ~~~~~

- ~'l biest .

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. . . . . ~r1etj of suoetano.s h+ve open shorn to w relatively -.n .~;-rimntrl anlnals. taroisioeenio activity Ii also

tr r ..:e: Woun_n,s, aoraslnns or irrltaLons or and trauma. ; .r+, .ea1y cr.na _nto calnd a healingpocess. e+eoentl7, specific

:,:e or s rr n.opaes In aege animals have been rather definitely :! CLLta Cle Ln viruses .

Thu, alt!i .uoh the vener .1 chersOteristios of cancer have been known fnrxi lone ti-"e and although many stimuli are known to prniuev cancers in ran wadin e:r.rlmental animals; a general tbenr7 of oercinodeaesis is cot tame a.

the stosoitio eau" 4f !seat aw~arallYnd therpfnre Doeta~'lmj oeelowre, may.. " 'cregains unknevn._ i :v~=Z's~: acChem1~rniroa.neeim.S;s::,__:

'~'" M 11[ h:le there As 11tt1 ariebf l~.Z-sabL atsal~iisas:aeal ~eae! oeessiaoils aree, arawa~-eherssoareinnyrms,. (a narsisiVOK." 'i laOri~ as'i~+sswr~aT'+At ii ~3Ti~swm~- J,

. (Dancers is .s leant Doe s,ssles:ar:asaLa eE ~mr laalaI moireKsro 7aaT-et~wamaterials which have aeon report" to 00-seseeiao,asas of stiah thews is e+tewdouct use their astivitl. L the~masa of the materials listed scare, arather hUh iacidsaoO of wooer Do me ootalned is a numcer of apaaiss s7treatment With rela:ivel7 Beall doses. In the Wont or deuctfal ear+eia*,eeaathe iasia.mes of tumors to relative37lar even after treatment Withrelatively iar0e amounts of materials for extended periods of time. .iththose materials the .:;eerlmental difficulties in seasurind tumor fortingability are very lard*. uret core gust be ta.en to control. such rperi.pntaldetail' as the rh7sioal state of the c-tarsal; the species, strain, end se=of the test animal; the diet employed; the m.thol of e.veinistarin{ the agentthe urtien of trpe.nrlm.nt; the passielorasenOof earcinndeniec nt s min.nts; and the ptheloeto1valuat.on of the lesions.

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~~- :-r u -1 : . s' rdlwss of the atpohanias inolran, how*ver, oxpwrleants~ .~ lr . :ic-tra F?-NC o-rtlnuous pzposare to a oarcino,4ani6 want is not a

re . ulr--nt :Mr tnp rnreRation of Cancer calls. interaittent exposure toc&rc :nc,pns l;reIen. hazards vrloh as c;uits diftersnt from sisilar azpoeurpsto toxic awtwlals which aces resellydatoztiru or ezareted opthe Coot.In irneral, the azporisental dia frcai aalaal etadiss inoieate:(1) that thre ta always a ralatleely loos pwriod of ties oetwewn theapplication of a oarolooaeu an* the apoearanes of tumors. This is refarrsdto as the latent Dotted.-t) that for rv~t:d sr s>:rasi 3h!a~


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P R O D U C T IO N O F S KI N 7?JMOP . 5 iN / - ;PAINTED WITH DIFFERENT CONCENTRATION' .3 4 -B ENZPYRENE IN ACETONE

PER CENT 3,4 B EN ZPY REN f IN RCETO N E


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cf Tuaora with Vartpu,2`Clmtte Smoke ~n~enar,tea_L!.e a t c YynGe . -0afym=e r .an,Tested Mou e Per Cent mor umaer St a 1. omaa Gareinomas

A ::heaterfisld 112 CAF, 40.0 18.5F 114 C A F a 44.6 15.4114 C A F 1 51.4 23.7are- M 122 CAF. 41.8 4 . 04rperlment started on ?taj 31 19b4 and ran for 2years.Bset on number of animals apes at first tumor or ICmonths rflobever was first

.29.09.17.725.67.218.ZCasstmtiele bc%100 biss16e+4=Cbsstmrfimt (l[amtso extr+oted) 60 arts 19.662arts Cidarstte Ayer (!'Tre1 )toCe10045JtCite ow C are bO!rise 615382 Used on number of animals alive at Bret tumor or 22 moataa Ybiobever time first.

f-( ,26-x, "~

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tP rrwth or lun, tumors in won which may have boon irLitlatpd=,.t. ._ct as .ir pollution or oooupatinnl hatarda. Aso, chemcal._tbt.-ir-s %''ich wll posoto t.wors in snimols have been rw,:orted inpossible pomotingffaot of oidorwtts swots on tumors initlat.d by34-b.nt,rrne. In some instanoos a 9sa11initlatind effect has wen found; inothers on inhlbitlnd affect seems to be apparent. Al in all the results ofthw.e .spria.nts have not boon noteworthy.

A rather large Dancer of other experiment@have been run primarily totest the doso response of uo twat aaisala to ol,,arette+seas and to know

c :,,rtt. a-o..A numo.r of lon,6terme:imisents have been run to studyth

materials and t0*otat& sober rata Whiat.1s nsslnl IS latsspraMMA& the results

Atto b1b.10 :wisemesas %*61Js Msaetiallj the ssandard test forskin eaaslee~*alailti t'~~ .'W-be" too" -es sz bsast oba otherailwal~2a e~dl iw=ip fas_fri~Cttir:$ooUa pst~tie wee ohreslatests OR Abe. _basii'aC.ji!s olts fer tai jse9ose. M sees is not a true toot!ae eareimen,W is- ta0 Jews that the rsaerimssts i: sssallj tws.s.. SMb.far eaeers are fersi4 She test 3A pates od is mush the Seep s nner asthe sousw toot in that the test sasssameh is painted onto the shaved book sof the toot animals. the and oolot of the twos is reached rhea be of theaalils have d.velep.d were than ewe papillowa. fte relative potency of as.terisl is lunged t17 the lwndth of Us* required to produow .ultiple tumorsis 00% of the anirals. Year rabolts arm usually chosen as the toot soup andthe Si.. required for a test is somewhat shorter than that required for thelong tors souse test. In general, the results of the smoke and awoke frac-tions have wen in fair r-grewsnt when tested on the sloe and on the rabbits .Table 12 shove some tjptoal results from a rabbit experiment.

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a

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:r. L :" :~ me : :,n of our report a rather brief surveyhas boon made ofi Or in t vs of the areas which may relate to lungoamoer and

. : .'arette aaoktng. Atrief osaoripion has been liven of the pbenosc=eo

shorn that these data are confirmed by experiments wbiob were run in ourwill cause skin cancer in laboratory animals has been liven and it has beent.ave been given. Base of the published data shoving that tobacco sacks

cancer, chemcal oarcinogenisis and carcinogenic testing. base of theatatletios vnich indicate an association between smokingand lungcancer

arc laboratories.been tboodl+ statistioal stills. ?anaes prove a'oauaal rslatioaship

between amotiag and Inag maser; eat the aoaortalatUN and difflasltias ataztrapoLtlag .frasf4sbaeatasy-$ tanimalstoastia are psarallT bsaepted .

Ys ftbs dtiatLas ss is~s f-1rasWb3a.y all rs+geesT&w*.ris petioles. "Its-H~M2i il: that 1i s+easrat3sastiMS_38s mood:ha4atisaCeasittes, (hmtl! r{l.ns'-Np of tlsaattosa3 ~Wsiq it tsissf~os, istiwlasaarah Coussil. Dsossoer,:lam) are rather 11-mbelt; partiaQ3arlyamong govermseatal advisory and reprlatart prrrsonnsl. lbsse geoaralisations

'L If a sobstssas is shove by adequate tests to US oarainmgesue taras. aamaliaa spifesies, it is probable that it is oaretaa solo for many,bat net o'aessartly far all ethers, although quantitative differeaeestetween ""too may be marked.

'3. There are non-tumorijenie levels of exposure to carcinogens forRven ezwiwental conditions, but threshold levels maybe affected byanueber of factors associated wth the caroinogenio pocose

difereooes associated with mute of adainistretion are evident.

92. Caroinogene are likely to be active when administered by any ofseveral, but not necessarily all routes, although noteworthy quantitative

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e,-tone of tr.1a report will deal with psaifio attaapts,~ .eFary ftctual lnformetton to 6 *&1 prop.rly with ther-~1ch faces the tobacco Industry

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A - 2E -TC; TTH CAnCIhO:;ViICIT OF CIOnitETTt SK0[

a considerable number of reports speculating_an the-.tttirs rich could be responsible for the carcinogenic

c:,rr-te sm;~ .. The s ajority of these reports have deal: wtha-omotie hydrocarbons (PhAH's) . Numerous studies hove been

:s ed re~_ardind the presence of certain PNAk's in cigarette stacks . These

assomata oof :theee .~tarialsaisb tea Daass reportedo date, when takes eitherslam or in concert; are inad.gaate-to-aosount.tor the off vote of the smokecondensate on souse skin. (~If one doubles the a.ounts of these knownoaroloooens, to account for possible lasses in the isolation; assumes thatsnob is active as beaso(a)pyr.e.; and that all of the activities are additive ;the result is about 1/90 or the observed activity.) We are thus lift withthe poblemof findingadditional oarCnoento materials or pomoters ofsufficient strength to increase this activity many-fold

Additional compounds of the PMAH class are present in cigarette smoke .These contain aliphatic substituents of a wde variety. The estlaatedamounts of these compounds are of the order of 6 C48 in the smoke from1000 cigarettes as compared to loss than 2 age for the unsubstituted PNAH's .Al types of PNAHs thus make upa total of about 0.03%of the total seekscondensate Tne poblemof identifyingand povingthe structures of *act.or those individual compounds is an insurmountable task . It is for thisreason, doubtless, that relatively fewreports referringto the pesence

he teen summarized in Table 1The compounds of this class found bytheLggett and %yere laboratoryare listed in Table 2. Most of the unsubstitutedPNAH's reported do not stow carcinogenic activity when tested in animals byvarious means, includingthe long-tere skin test. Those which have shownactivity of this strt:are listed is Sable 3wth a aeaiquantitative indiea-tion of their relative aetivitlas toward arouse sliII.:

Soon the strong :advoeaisa_of ths. thsory_.i bss Ps1B' a are the as.oroarelootgenis -aatarlals =tsi aisi.tte rota 'i i11 readt17 await that the_=r+'?,r ~a,. : + , - ^ : - _.F:, _-cry -. ---

RC- 602-67-00

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;or

or

It

C F.ruI C'CarDen hf,.,ort.a In C1are%t. awokeKcro6aas par1bOOri~aretLes

Ic.ra,.hthene'cn-pntilen 4185nhwcnn@race6anttr ceneS6110c.rt (a) anthrao ne2SCo.nt( ao phenannyene3b noj fluosnhene6b noYfunanhene6b.ntoano)flu(%antAane1-11 R- D.nso(a fluor.na11 Ft-b.nsn(b fluorwnebanso a)naphthweanebanoi hi)pryeew16basn a pAwsantbrraebennpp+WX18Dense a y7reM- .;--243ohr7eese.-06-6oe:eswsr - .. _ beibss+-!t)asaraeese~: 0541311-4Lbase a,l)f1. iee'eae .' ;dlbns >as >s+tpbtawe/ae -. , r= "diersse ~ awpes>>.eas . -"b"ase n4 pvaaatb""d1,1praas:dboneaMs"rs0dioasoai p7eae00efueraahase1680tluareasf' ,1'-naphtbc-1 1.tluorasep+~aa3p> s.aaa terenepyr no5437triceas(a,o,a)aathraoenefhe asounts liven are the lowest and hiabest valuesreported. Consideraole variation In eaokino teohnit,aeaana rethods of estisatiao these materials v,-ula accountfor the wde ariwtlon In an.o of thpr..ults.

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nr.t"'. ne e60-~~ 78."yr-no 40. .+nr-nthn. 30

bnt( .).nthr.one E 7r-n-o(& )orr.ns 10

loa.wltearrri-iglu b..1so3.f es. Y!~: Gareiao.aaie ro1*nuelasr ~hL1~-wt1-i*Sr,Ncaertitis. tiww se.a ~ati.iess~ si -3~1 Diana et ttlCra~eislstwasraslai"SsS.asiil.s '~OSCMiieos 1f.ee open appilad r

bn-~(orrn.ant()scphnanthryl.n bb nnj )fluosnhaea311Rb*nzoCfuo*ns1011 P-banso(a t1.or se b1.3.aso(k)flogr+n ~ .4!' ,1 ,-aotttae-l,~pi~.04tripewa~l..e--. 0!7 B-oasm+(o)tlrnrnts-ad.so .s'ss~D?r.a! i~~"z" ~-4r ~;. ;" .01-.

uarela.*sie,vaey

b.asIsantarao.e.wns .) seepbesasthryle.awase(J)tlrorasthase .Casso(& h,i)peryl.sb nsoappesanhonee.nssa ptrofteoneapraneohrya.nadib.ns(,!s)anthrao no.13 R dib.nso(a,i)flueraneAlbnso{(a h)pyrn e

b nok)f{uonhene1tb.nlo(a,1P7rne~:tbntn((A,1))prr.ne ...

Ind.x of r1ati' activity to.nunr skin: hi&h; w+d.r.tv.ak; Yrr weak; t not t.atd ad.t,ut.lr or uu.stion-b1

c

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smoke have appeared. To give an exampe of: :s p-otle. it may be calculated that there-are possible,

66dimettyl- 220 trimetbyl- 495tetromethyl-and,-- .:~cnt(~anthracenesAdditional possibilities would than be

tyveryin,t the nature of the aubstitiant groupthe total numbert,csatble compounds, already astroncalcal, would then need to be multiplied

:y a factor related to the total possible nuclear types. In Table 4 are:fisted a number of substituted PNAE's which have been reported present incigarette smoke byseveral investija ors. It is our belief that the evidencepesented in all of these oases was insufficient to sstabllah the nature othe substituent on the PRAR-.t7ye, :aadin coat-oasis t..a location of thesubstituent 1s very tasttetiv

Thu findings at ld ggstt and 1~ers .raga:diag'mnbstituLsd Pll~i~s toc10rrtte smoke bees lees ~namaris7sd-in-Table 5.- uZbottr~t w have notidentified these eosyossadm oomplatalj,' .T" ba's.,obtalaed iafornatioa regardingthe wassailer weights and .aolubtlitias M3eh AL -a ewhmt Rows dgfiaitsconclusions regarding the nature of the eliphmilo substitusots. The lackof adequate model eompounds with which to compare these materials has beena serious hindrance to their identifioa:ion.

With regard to aarclnogenie activity, some f the simple alkyl-substi-tuted derivatives of certain PNAH types are soon the most active eareinagensto mouse skin, known. Rgher siLyl substitution epolar substltuents.bavein general been found to decrease oarclncgentc aett-ity although somecompounds of this class Ave also very aet .ve. Since the structures of thesubstituted FKAH's present in ei.,arette a15te are not known completely, itcannot be said whether these are active cv-ctnosens c-not

Arsenic is another material, pesent -n tobacc. Li;d in cigarette smokewhich is suspect of oarcinodenicity to man. The cont.nt of arsenic inco aercial c1urettes rose fromato-+t 13rpmin 1919 t. about 51 ppa

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~nL4 i__r +r,,cLar fo~atic MYCrooerbnne L.oartd in_y~~arete as

~ I i

-.thylt~rt(a)anth= ~oro,1?-dl~thy2DMZ(a)anthr .Cenet-dihydra-l-g-bnzn(a)ol7cloDwnt(h)nnthraopne1~,11-dihyiro-B-H-onto(a)cycl*pent(1)anthracene1-r. thyl-llN-oenzn(w)flunrPna5--.th71e.nzo(e) phenanthrone?-Fy u rj't.nzO(a)Dyrene?-+th1 cengn(a)Prr.n.01'7,8-,ihydro1.nso(a)pyrwn99-sohyobyen041-sRth7lobr7.o. ~..vt t-di.t 71sAr7ua. .r.. .8-.etlt~flueraatb.o!,t-tisoth~tl+~orast~oY,b-dis.t2tylpbaaatbTaa. . ~ ~ .~:'.t ~T-diwt2tlye.aatL~!Ma ' . ~4-.s thslp72 s a60

slb. idootirtoation of all of tbs l aatertal. 1sMla...d hitbl7 q istioaa0la.

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q9 . 5AP-597., . .z .. :r:r +LjL!m . -r4 I Xd. . 1200

: r~ wnd Lndsay, Brit. .i, n r , 8, '2P6-301r wry: Ln(lsry, 'r;~7g1260.126-r Lnsw; .n i teller, Chem-. A410 ;1 . 1418

Cair.L11 weal Cccrrr . SAeL. tu Ing. 64-5.;amen nd Avor- AALSAnnual Matink~. Atlanta, Dwc. 27;,or-r an:- Llnu.ry n"IL. Cancer. $ 304-309Le : .rr and aa 1n, j~t~+r+isaena .~;,; rr~n, i,Z, 210Swrl .op, j,. LamUntrraueh. A. Yun. 3 518-22

i 9 6bnnnr t sna WakowNrl . a.L & . 211724-33Ga:don, k1vord, at g., jrjj . 44ncer lU 485-97uilcort ann Lnusoy, erlt. jL C-ncer, , 642%o1lowrt and Lindsey, ba". A., 646-618LatarJet,, Ad3 .figGnear. M 12096Lyon Q_R i .;h t and Ws r a r,,,=.sumBu. g, 1691957 Bonnet wed Zwukomm'; elerSw:L~11129 'Campbell nab Llmsa7 a - L.I n~~USA"Lien., MLh AM - BC2- 3s;1i= 2==L""and Johnston; jam~ G.ffiit. 1Lfeukosw MW bm%w4- , Strom"%bg aml.; . 1,

W"'Pr, . iii: g.. -I-, ~.a. . ar . z andWes: j sm 1Q 5-2-271 2t.363,-370lobe bAlleanln d . rotaez a RL~2biel. g~ 4 Ia. a7sz-9obyna e~cn . &44 2C orona, febeges , 4s L4 j: lit1'o)zonne ay and L na .,y . . M1U1 lit1 24 - 1 31Lyons, nature- 1 B = 178arr1a, VaaDuuren feoak, Bolen. Sobaitt. ~~ ~jpL ., ,5b?-8611959 eentleyan, Berry. hesearnb tapers No3 . The Constituents of rooacooSookr, an AnnotateC biolioeraptiy Snoacco Manursoturere St.n..it4Co.aittw, London.Dikun and Chushtln, Voer. Onk0l. 17). 34-e

Hoffean and Wyn ..r, ACS Atlantic Cty, SepJohnstone and Plisnsar. Q= . a, 8e5-936rlrttsch, I-hsr.alr, u, 466-47aynarr, AL". tel . . 317 April 10-13yym,rr and Koffman. t=As. Cane, lnet. Atlantic Cty1=Ac 4offman amtiynaer, ~~cr -. }~. 295

I- if"ssos M a t W W Ia44Soas~ellY_tl ,n-d Baluoci. . 22211MIt l innJn~5,._n_eal. 424-426Van Darren, a,. 1GAQg= In"., Ej 1-16Van DYUren, L. X"tr.OOC=. M, U623-030Von Duuren anu Nelsen, rroo. AACli j, 353kynasr, aright and Lan, AACI Reeti.na April

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557-5E:

c co

: :IIVHype VTyoe V IType VIITypo VIIIOther unidentified types

Suostituted chryseaet,De Itype 11Type IIIOther unickentitied typesSubstituted pyreoeType I . -Type-IIType III - -ryps ITT y"T' Type T AType T7Type VIIOther unideotified typesSubstituted bene(a)ent'hraoeneType IType IITypo II IType IVType VOther unidentified types5uestituted 1111 beneo(a flunrene and11S bento(b rluoreneType ITyoe II

1787783200178+102113IPSO1787850178 597920

178 302201.78 7390176.6411650178.160 2.42245

Substituted fluorentheneyp6heunLentedtypes2Suotuedcennaprrenes1(e) The values for molecular wei6ht were detervlned by dirfuElon thrnuLb esintered a1sc. the first n,.eoar is the h: of the parent oonpouna era heaecnnd, the suostlt.ient. The ouscorary error is eecut 110> . The Kv.luarefer to the rol.tive aelluoility in hexane vs.84} Sethiunl%&q.), . hiehvalue is lndlotIve of more ncn-polar sueatitution sock a lowvalue, ofless suoatltutlon or of ;solar suostituents.

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"da

I . .1 (Continued

:.es were eetiir,teu on he cask or UVacsor:lion intensities::. ;nSUbGt:tutee cr'auounue. Mny of the sae;ies are relativelyan(: therefore the rF:1"a Led uAntltles may oe too high .(o) -he compounds listed In the table have been grouped accordingto alascr polynuclear. each compound is given an arbitrarydesigaation ofTypes I, II, etc. on the basis of differences in UYspectra. aoleoularweights and distribution ooefflcisnts.

f . L

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- . . . . . ;en precipitously to about 6 pps. (FE.G . 5"11 Jr., Tobacco 148, 20 (?gb. a . 1

7-ese fleures reflect the usedo of arsenic-containinginseo-: . ..-tscco far c . raringthis period. For Cgarette tobaccotc~t pps of arsenic (7.4 eicrodrsns per cigarette) 03 micro-

r c1EFrette Is transferred to the smoke (EC. Codbill and X. EHobbs ,:_ acco, 144, 24 (Tob. 6ci. I, 68-73) 1957). Go-Alden at &I (F. OcQldon,

L . K -naway and r. E. Uquhart, Belt. JCancer, 6, 1 (1962)) have reportedthe pesence of 0.06aicrograss of arsenic per cubic aster in air, on thebasis of average values for sight cities in kgland. On this basis a persomight inhale 0.6 aiarogres of arsenic per day from the atmosphere.

The general con.snass-of opinion in sedioal circles appears to be thatarsenic snot be cussed as an sxagences caretnogen having a low order ofPLtency. This is bard largely on-aa aasocLtSon of Aaaesr with oertaiaoccupations Involving lamps usage at $rssalaals. several attempts to producearsenical caneere In laboratory animals bee been unesosesaful. perhapspartly doe to its high toxicity. On the basis of this information it hasbeen tentatively assumed that man is more susceptible to arsenic than thelaboratory anisals used thus far. It would appear likely on this basis thatthe carcinogenic activity noted for ciaarstte sacko with respect to souse skinis not due to arsenic.

beryllium eosryounds have been shown to cause cancers in laboratoryanimals and have been associated with the incidence of cancels in men engagedin certain occupations. (ON. Badger, artt .J.Cancsr, 10 330 (1966);J. Schubert, Scientific American. 199. 27(1968)). Analysis of tobacco bythe Analytical Research Section has shown the presence of beryllium to theextent of 0.03 ;pa. No beryllium was found in the amok* from cigarettes .The sensitivity of the detarsination would pace an upper limt of 0.001microgrees of beryllium In smoke per cigarette. Adiscussion of thes

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i

-c,=*.sended tolerances of the ABC and sasriean n- ~:-n was pesented in the eteport of the anal,ytioalcr -4yere nesearoh Uepsrtment for 1969. It vat oonc1uded

; sufficient aounta of berylliumcould be carried:e eroful. It is not believed likely ttit this materialble for to. carcinogenic activity of the cost active

. :s clrarette smoteSevere: investigators have measured the free radical ooeeentrations in

- : ;.rests smote. These materials are cbesioally reactive tome which have:ern poposed as possible cancer causative agents (K. Jrose JT. atbooaand D. JS. Zn~ss, tub, 1Q1 io (1961)). The sase40068010 aotiftty of

'moke condensate toward sooty skim bias prom to be relatively stable sussit can be stored and beeped torMsaiders'pericds~iritMat ipipsrsstdeterioration. This fast ea~s*tsi 3nbt, 's~3lsGitjh"fsbssstiaals eight arm-,tribute to the action of we sS tthedvir ,'tlbfn friOU-ladled, isw omu---w - ;7seaa unlikely %bat it is this _tTpi'of sstar e:11hisb is PA~sible far tbo "; ~activity toward moues skis.

It has been suggested that the earcinaisaio activity of cigarette smotecry be related to tba content of radioactive Garton, 04' in plant eoastitoeate :(J . R. Chojoawski and A. Derabialaka, .1 SM. JgJ-lattres I&"CLsse TV8, 5 pp (1957)) . Tbsrs would boss to be no basis for **lootingtobacco as asource of C". Al pants, includingthose consumed for food, vould beexpected to contain comparable amounts of the radioactive isotope .

The majorityof reports concerningoarainoiens in oikaretti smoke dealtwth the identification and, in scab cases. Quantitative estimation ofcompounds in ciarette smoke which have been shown . in other studies, to becarctnogr-lo. The criterion of carcinogenicity has been. most often, wthr.epect to mouse ss;in Mother appoach, which s aypovide useful information

;c determne the carcinogenic activityof substances known to be pesent

in tohthesetobaccbowevesoreenA rcptthe urfor itpsinteEach twishesthe a

IVe ri o.eonJ ecvery

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I

Each test is a or undertaking even for the whole smoke; and if onepointed with cigarette smoke condensate equivalent to 15.000-20,000 cigarettes.for its carcinogenic action . In the routine long-tore tests, 50 sic* are

t~ :ikelycoavcnents of cigarette smoke. Whenc-- ally acailatlo or are readily obtainable fro.e, the long-tore souse assay uan be made. 1t would,

e d.e:rable to mve some less time-consuming and L,trdensome way ofr .r . s_ :!% cn-cpounds to present a complete randomness of the approach .

-c , :d b:olo~eal screeningtest is an absolute necessity If one is to study. e unknown chemical components of cigarette smoke which might be responsibl e

wishes to test fractions of smoke, the operation is further oomplioated t othe extent of tbe .aboaloal a .nipulations required to,obtaio these fractions .

The state of Unowla6gs roga.Kting saaasr tattiation is .admittedly poor.

e

various theories bow . wm propo"ALUt aces ire proms and Most are shearconjecture. DadouUtad>>,' a aesb - of factors are loweleed and theme may

reliably predict, in a reaeonably short ties . whether a liven agent i sfor these reasons that It has been difficult to devise a test which wllvery to some extant with the adeut. :the boat amd the site of action. It icarcinogenic. Several s etheds are beingstudied in different laboratories

organisms to study the mutagenie activity of suspected carcinogens;method for earcinWenii materials. these Include: (1) the use of aicro-with the object of devising a simple, reliable and reasonably rapid bioassay

salamander; (3) the study of changes in explants of human foetal lung ;(2) hyperpastigsnio reaction of the epderms of the leiton, a type of

and accentuate the reaotin of a weaker carcinogen or pomoter; (7) photo-sensitisatSon of Pareseeiu by earetnogenie agents; and (C) changes in theuse of initiation treatment wth s potent carcinogen to shorten the tim(5 variation of mtotic index In an organ or in tissue cultures; (6) th(4) chemcal changes In tissues treated wth carcinogens or to-carcinogens;

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.elands of mce after brief exposure to carcinogenicnave been considered and several of then evaluated bypersonnel for possible appication to the assay o

t c.e fractions. none of these methods are in such early stagesthat their merits cannot be poperlyevaluated. Others are

cdapable to the types of materials tslleved to to involved in the:br=inc.enic smoke fractions. Anumber of investigators h+ve shown that when:ne stn of mice is painted for a short period with pertain oareinodens(PwbRIs in particular) the sebaceous glands dageosr.te in about four day.the epderms because thiokanad, and the hair is loot to about ton days.The total lipid material of the spiderats was feued to deerseso by as wpbas 40% in only 5 days-after a atng1 appllaatioa of a ettglaboLathredo, apatent caroiaosse or the 7m a'ss '(Yiaks sad gustier!, ,j. tW6~geg. 1M.

eI.te6(29+t)). sins dottrustioa of the $*boom=$ gla+ a ty the esrainog.ooemrred at the alas of the- lesrlose is -totma-Uptt; Oarls% Sre (C~gg in.2ebb-68 (1950)) felt that the-V= yreems work el00el1 aaoesiated. Ilkssisenewborn (e-7 day-014) miss, whose'skis tiMsdevoid of sebassoua glands andretreats" to oaroimopsesis by.t~/labalasthreao, had by values for totallipid, lipid phosphorus and ahalastsrol. Xtoe at 14 days of age developedtun rs as the result of a single spplioation of sethylobolaethrsns. Forthese mice. the contact of total 11pid, lipid P. and Cholesterol. in thabsence of oareinodans, was that found in the adult souse . Development ofthe sebaceous glands could also be observed at this time. Thus the responseof the epidermis to ssthylohsbantbrens was thouyi to be linked with th edevelopment of sebaceous glands and possibly with their production of lipid.In tae mouse. the sebaceous glands are destroyed and disappear after a singlepainttna wtth sethyleholasthrere, whereas in the rat theyhave teen showntie persistence of the sebaoeous glands in the rat *Mn has been lined t_

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._ . asthjlonclanthrene and dimethylbsnsanthrecene inexistence of a physiological barrier between the glandsr

r. r.us at to suggested59urtisff and coworkers (V. 8untaeff, i. TCovdry and A.tr.~r, Fencer Research, 26. 037 (1956)) reported that cigarette tar

'c.G_aet erects on the epderms and sebaceous glands of aide vhioh weres :m:icr to the effects produced by methylcbolanthrene. 5aith 2111(W. C .Sai:n, Z . Cooper and Z . L . rynder, ?=- A L L . ARM. Goner aesearchy

n3

45 (1964)) reported tbat the sebaesooe glaetdeganeration tact was in Agreementwth the long-termBaits teat is that calf those rr.stig. of tobacco smokeoondenaate which gave 6asatloratio~=it tide aehmeseoa tea. save nativeoaroinogsaieal3y is tie long-terms+oasi tast 8mntadl, AB. Crooiagsr.r%~s. ._'_ ' : - FewL.. Mader. $. r c o .ars as s = a .~ ~.e!rl: rs14. s a l )). isvas on the beats a[ 4hO" eomtiiiii~bs- use Awat&m4 $o anise tidetest to fellow t~i .'t stiasttia~'rCadpu~sttt adore -,------t. Zwas hepedthis the esrreLttss~etwss .tie o tLes f!f to OReebaesess glas41 andthe prodostins of oseowe on mows attn Vealt b valittnroaC- *ta.fractionation.

The L . aberstcriee devised a relatisaly ibort assay proseaare %seedon the changes to thieknese of the epidermal layer and to. depaeration ofseboooare glands brought about bj:the applioatioa of test subesamgee tothe skin of mice. This pregednre is as followt(1) Tarr White mine of a censer-waeeeptible stain (Cif hybrids) are paintedwith 100 agog of an acetone solution of the test material on foursuc..eesive days. The solution 1e applied with a brush to a shavedarea of the back. 8 gas in are..(9) The sloe are asorifieed on the fifth day and the skin in the test

area is excised, stained and mounted in a paraffin block.(3) Vertical skin section, 10 aicroaa in thiotnssa, are out fromtheblock wth a alorotome and these are ezaained mcroscopcallytodetermine the epidermal thickness and the degree of eebaoeoue glanddegeneration. Twentyheir follicles are examned for sebaoeous glands.

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c' stin thickening (hyperplasta) and the decrease in theoebaceous glands associated with hair follicles is takennative estimate of the activity of the tee; substance.l epdermal thickness is 10-15mcrons. Cctr..e bypsrpasia-eFLi:el in akin thickness as great as 57 aicroas It hasLeco-. C:1Rtomaryto report the results of the sebaceous glandde .neration in terms of the doss in sides ehicb wll door.... thepercentage of hair follicles wth sebaoeous glands to one-halt thenarnal value. This quantity is termed the IDsos vtloe which hasalso teen ueed extensivelyin the Dag. This is the doss in agesat vtich 45%or the hair follicles have eebaoeous glands.

. . ,s r, ~.~vy 1i~ars~o,r, i f .A6e}W4Yy

A nuaLsr of studies have been reported in which the abort-term stirsthickening s od sebaceous gland affects on souse .tin prodnoed by testsubstances have bees eospared to the long-tarm production of oaaoers withthe safe test embsto s. Mbsvs .sallab stsd with the 1. psrsosnai inartiag ssristl at ts:e *=PON" 1Wiii t-tt~psaesdars. in an effortto dateir*A stile teta dst- a.r iii aetf iatorsiatia regarding the.r ~'Koiwwa~'!~

~tbs< .~Oei ~.aatitativ. . . . "a'ay' 1 "'fit , . --; . ti' _T : ::~..-%-w- ytS ~ .d

sited

p3asta .(sleiaihI .nt a i tbs 3. i1at iid" they are ettestive against~lNd~:N~MOYa aOLSi ? . OS1 IaQa''sbOw ='.Z.tiveUtl bypw~F==?'tiserreLigiaar t*.s. a _-, . _art the Oefte ivesoss inssbseoess g1as+Os. !ss.eat .skits earsiae#sna of this .eriss-?,l2-.iaetlpi-b.os(a)aathras.ase *O.antbllebalaathrsaa. 6-.stb7lbenao(a)p~rwe-esusedMge.ars%Is@ of the s b..eme glands at the iciest test levels. Camino *nsof istersedisto setivity required higher,to.* levels to prodoos this effectwhile p14 's which are coo-eareinogenic gave little or no effect on

saris* of subetituted'bsos(a)anthrso.aes that the affect on asbaooous glandsroughly paralleled the souse skin carcinogenic potency. The data availableon the short-term effects for aromatic b7droearbons versus their earcinoeenieactivity to given in Table G.

an d A . Mind, Cancer bee rev }e eel (1958)) found for a rasher sazsnaiv eebaoeous glands at r.ietiv.l,y himteat levels. SO" and Mnd (TG. sock

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A

-3+-

r-f ~~-ArrSSoKjooarDOn

,.r,- rirIA:,n+.n.:olu.npo-G:chlornr .ntPDet.tr~lniouncylbenrenet.trahydrosoenephth-lneo7oloh*z71D~nsanw

Two Dentene rtntan.vhthal.ne2,3-Ciaetfi1napbtt+aleno1,6-di*etb,2.S*tba1, .26-4lseih7laap~tbaloet236-trim*tbt7lAapbf a

GlibCSR.C.H.C1sCLOBs .CLSRseCIPRI.C$.Ria

Cn!Dar-ed .o C&rctnoA"aIeitFeported51 -.ort Sera lo-u: rarcinr+-u/S s t a:e+- n1r Z

1584at 100 heBook ua6.at 100 No71at 100 mBook nag.at 100 sobook n .at 100 soDock nei.et 100 soBrooks /-at bo0 so0101boat aaa.at 2CsasLe 11179 .t 1CIOiyay 18/'2 wt .1--Cox :. 11/t0 as.10Cea=se. : . .13/68 at 10,: O.~a~ Aoek ,mnd. at 30Ca boot aoo.at 1

Three Dan:.eia riala-+- =.fir' . r_~:~: -E-abaeaat~sre .. *~4 w1 ' ., Wis . :y 1~M:'_T ie -al~.att-ewtLplLpt~aosa ttrraa! . _a a s A. 12 atO b3-shspafaaatlteM? >- ' asaps. 33att~t4 , 6-arath 2*"Pbe+stbeor . . ns+rz14/t0iat - 019-arrvapboaaatbala - --CAbeck peeat 33reeae0ease1453a 06aatbraa~eea9-.tet~iansar.oaosiluorantbaae-tR7lriDaraatseaot,3-oeacrlrerrae1,9-baasrloerase

Pour haliasll rieratripbeWlroep7r.E-e.thJp7reoe4-aetP y1D7rone1-weth71P7reneebryeeneDent(a)enthracene7-aet~y1O.o:(e anthreoene5-ar thyl Dwnt (a .n thr&oene6-aethylcant a anthraowD.6-awthylc nt a aothraoane9-arttqleeat(a).n%hracene11-m.tPJ1tnc(a)antpra4ene2-a.thylc.nt(a)anthrao.ne

CsagsaCsessoalga..CsiztaC1*8taCues.ClaRioC,,R,aC1nr.C,,HiaCsaBaa

13179 " 0.6boot ar


32/145

i

.ri Rr::.morn.A i ,c :ithrwoene) ant TS 4 o. nocns.(a)anthr.o.ne-ci~thyl0.r (~)an:hr.oene

2-~tt~:D .n~.o(o ph.nanthrensS-m.thrl0ntc(c pbPoanthrone6_r.t!I1Dnto o ph.naathreo.,_w.L?y1Doto a pb.nantlsrea.4-s.t)ylc.nto(o pEroantbrsaenaphthacsnooeoso(k)rlnorsmtA- s

die.esfa~~)antnraoeaepert' Pasbens e)pyrene6-.wt)7loPozo(s)pyreneo-phervlenep na

bock pos.at 13ttpAu.b"ck pos. a t 3.3 sObook pos.at 10 so0onk poc.st 10 soboat neg.at 2nobook ned.at 1Wak28/15 t 0.06Srooa266at 0.0020/46 at 0.01Ca,Ra book at lb .OakC1 .Rts book at 18MadiaaC1s114 book at 16 :*&k0 10R14 book -at 1.5 WeCest boat - at 1.6lacales/, book - as 0.5 soO.a.. 1?/14 at 0.0 seaTana at o_odYsa as a...aOJss We as '0.!tbd1a atoadw1s/a3 as fl.1stronas'so"m

U--Z. 04/80 ass0i . ' *aweoda- /07 as 61.1/@3 as 0 .07.!8

Css1a t0/13at 0.008 Stran16/al at 0.01817/88 at.0.0017/69 at 0.001C,.X1a 2a/93at 1CsR a 14/96at 0.1 sa,es1, 66/19 as 0 .1 Strong16/46 at 0.0516159 at 0.0es14/76 at 0.01Oas81a 2615 at 0.6teaCo oe La book - t 0.831C s o R l. 17/53at 0.1hCR1. book at 0.1SronV-saN1, 2G/Y,8 at 1 .. T2175at 0.5

LG0021641


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I

5-R thYl-1, 4, 8,'.--dibansPyre n.5,1CL diath771-5,4,8,9- ib.ntvyrenob .n~o(c; .h, ilperylene12-2,1-antbrao. onthrao.n.ru bonaiolantbraa0pyrantbraescornnanetb.i */% .Oaom aamd. as a4a.K8001o ipusa. Mst easati.oa

C ..AS. 14/64 at 0.1soC..H&15/89 t O.21C . .N1. 19/64 at 0.1xdiu15/56 at 0.117/76 at 0.05C,R119/93at 0.1MediuCOOK a 14/84 at 0.1waC.Bi boo -a 1YatC.ae.a 19/96at 0.1toCa.Ba BCOk -r.t 0.9M0,21BO/68at 01CaoBs. 1694 at 01C.SBN1682at 05

tbe results of tb asset-tsm test= are r.orIMaWe"" (j1 or. qpi WV sal*oar positi?a. S.odiasts a 4eors.e at.t Toast No 1s aoou a'laad .lnd.lo.t eo" efeet an sosooon Shoos at Ow ap dooyo sadio.ted.at sas ~*a de.~LG0021542


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-L.F~.~':.:moo.'.. -_---as~~-Nf1ev.:~=:k..~::-?i-;..; `^5 *~terrcycilc compounds are among the

; :rr rd . *.cus sgin. when a series of h-heterocyclicf-r epdermal thickeningand sebaceous gland effects,

e :e :onnoundm were less effective than the PMAH's . They:,vp_paata at the levels at which ae:aoeous gland

was s1gn1'1car,t. rho strongoarcinosen, 7,9-dlaethylbenZ(c).- :tn activity only slightly lose than 20_sethylcholanthrens

red 1C-SOtia-s as such material to poduce the sass degree of deterio-ration of the sebaceous =lands. It would appear, therefore, that theheterocyclic carcinogens night be detected by this test but their doselevels vould need to b* sooevbat.higher ba for the IS" 's of eoaparobisoaroinoggataity Eaj short-$.i data fortbaeeoasyowl" are given inTable 7 along with their earaimegeoia aatlvitj.:-'!ha tebaooo allnlaida,nioottDs. sposaiae aa4 :alsot rtsri:rQiah aso:rePr.Natatives at the betero-cyolio Glass of eeapeeata; a t~iatamed!o-ig_eft elaodealetoaardmoue akin (1t'eoch i4 s1. Zwo An' ARM. %a. all. L 903 t%907)) .Vynder and Mattawan have recently reported that proaotiag activity he.been established for the nioetiae-free saute fraction of oliarstte smokecondensate.

A number o: oaroinadena, active at mites other than the skin, havebeen tested for their effect an the skin and eebaceoiie glands. Those resultsare summarised in Table B. No clear-cut relationshipis obvious althoughsome of these materials do appear to exhibit destructive effeota on thesebaceous glands.

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4, F-Colli'llne`~:cotiRlac~! ak, t'1e2-wo tryllnonle1-me thyl-P-otwnylinanla5- wTlRO-1, P , a- trlasnle1-r.tyl--ph nylinool*owroasolpa-rthyloarba=e1M4-asaDyrrnw2- a sdlsrorwet*wea7-asarluer.tt haewP.,S-brntosrbasl'l.12-basoarbasela6t-as.o~awes3,4-dib74ro-E-4saobr"3-aac r rsasr4- as so-15. 4- QMXPYr*M1P-bwasaaridit -3 ,4-brns.orid1r.7 9-cisrthylbres(ofaoridlo.7'10-itt .t!ylDwcite~aoridles1 se t tyrl-6, 6.- baosaarl41ae10-.att,Tl-7,6-o.as.ariaioa1, 2 ,10is ise t h?1- 7 , 8- bsas aor i ill e.alDees(a,tS)aaridiaaGio.as a,~ aeriaisaReport.d preaeet in tobacco or .sots .

e.AN15/!4 at 1! .5C,K.H13/69 at 19.5..KLN14/61at 1' .6C1OH14Na 11/75 at 2C HNi/45 atCHm1 /t5 atC.6.N2290 at 1C,.Ha$ 1695 at I

NoNoNoHoNoN o

C.HN41394at I It2,.aias 15/9b at 1C1 .H.N14PSat 3NoCra,all 14/98at 3ZIaR*Y 12/93 at 0 .5C15sa 14/86at 05CsHaka 13/85 at 0.6C15R3a$ 15198 at SCaati834/10 *t 3wwakCargaes -. 28/59 at 0 . 5Cs+aaa* 14/81 -st 0.6C"Naa8 14151 as 0.6ca.8so4 17/60-at 06Css8sa6 17/51at 0.6l;~*iia.814/70 at O.bso0I9541a 1,3/26 at 0.6NCaaBtas t0/13at 0.5 strongC3aRsa120/9 at 06strongCaliaaa 15/96at 01NoC1910I 17/84 at 01Nwus%;Dousvx Lb/14 et 01ua,ea,~ 15/14 at 0.6 aedius16/51 at 0.5 w*alua14/63 at 0. 3

LG0021644


36/145

-44 -fl

Ufs"A LQr d 1 1 I I 1 1 1 1 ~ 4 n m u C % r A A 4 9 A X M {PaDAt-Ishort term tootMl at atito_

, .,it .~lrn-,it.Fnxld- nr. tyl nnl noflunrone

1 n- : hthyl 'a1naa-ihthyl-wine

2- nTlnnwnthraoenep-fl.m-thylwnontobentenaILtl-hytirep-roxy-4Woholeatenw-3-onsrte-(b-ehlororthyl)TetNyl-amnehydrnchlorldtrlt!-yl-ne,olaeln

1 .PQ-trlhy.lrnxyanthraoeneI'-hydrotyruinnl in,i--Prcnpoperlne-~rtlnotrInr-nlrhl.lne

OgKOO, oo+ok at 3 3O/a8 ..NOlook al.dO~apvMB, 11/8O,at 10109TO11, ; .lleok a . at 1

01089NO 10/7e atO,eall.s 1 0 /6 9 % tC,oNN,O, 10/30 at

c c '

akinliver, bladder, or-n"Ibladder, liver, ntherebledior, liver, othersliver, skin (sub.cut.)liveraub. out .


37/145

La11uaeNOe too, ., . 'l

-46-llhla (Oontlnued)

-nrln-1?.4-trletole O,H.N.A- riaphthol C11H,OA* 'rblo cld C'F'O'1 . r-n htho, ulnnne C,eH,O,9 . Ifi-Anthrequlnnne O .H.O.rhAn .at),r'nenulnone C2 .H,O,Q--holretn-l-one l:e,N4s0netr ne 01.Hsea.'I,. nc ld C,,H.,0009r :lnnllo ..c)d HQ:H, COOK

e rt ten testJa , flitsn !11~11C1L113/94 at 1tbrrol4(t!0/06at 3ba*rooai(suo.out.)kftk -t 8.6subout .13/66at 0 wr.k (tier out.)12/61 .t 6weak (pAr out.)book 0 tlOO reek (per cut . )14/e6mt 10 suoout. .aemrery, .nd lympiw1666at it tamors t Rallyaltes,not skine2/96 at 12.6euoout.

22/86 at 26 sub. out .


38/145

in lie iasttasM~ tia -A'biabde~ lass .arm-sue - --1; .

and se.ab(_--Nssad- a it W.40st:+slisa at areotise as ~otlag- SJs~-.~ ; .~Ya4K.( ~L7si. yi"f~~~-r "('ice ~7.

reports (Yjrnder and 8ortaann, moo. M Mooc. Casa. 14s1 ipr. 8-20, 1900)fame 1 splloated the pbenol traction of oidaretts smote as an important;ronotind portion of tbs condensate. The tluwn oompounda of this class,

:ee been tested for aborttsrs aoti.tty. are listed in Table 9.

lla da, rwading and fsT less; a~sm act :isasatiirl attributos,of promoting .agents . These oospouads do sSar ski aA it b19tsr 1sn1s. asset

LG0021647


39/145

cln-nr-oauclnnl. - : ucroph.nc+1cr-oph.nol

1. o4ophabc+lP .ntabr,mophonolc-ntaohlerophrnoltrILrvsophlorogluoinol24-dinitroph. ofp-(t- buty1)phanolp-(t- outyl))oatsabol ru6ennlp-oetylph+ool

C 4, ONp-CaR(ORaa-CM (OA CaRa(OR aCaR(OB TCA((06 3rCR. OR I'sC.(0jC7 C l ytO 8 par&ca 1009911006)p-nn~pb+~el ~sCas~P-(1,1,3 3-tstlaooth1 outyl}pais~.~[i *s-p-doaeol1pbsaol - _wp~ ~si y_-1_----4s~rop3z i~o0s0atrooe . .-C - too"barel a.aapbtbal

roaoralaola.erseel4jusiaoelp-cresol2,4-dlaetky3.pbs*o1 { -oapbtbel0 31op-olaethylpbsoolo-or.sol2 4 6- tri.etbyylpbsael1, 6,. trihpdroyaatbrae.Mcastes (OZ)oa(CBa)eC.Reaaa .a 6acl~cu . -(CRa ++COs0ACa,B`0A)a

Cnspounds rc5ortod In tobacco or cook&.

~hort-tart .u/S a:12/64 at 115/80 s t 0520/3 at 0.514/73 at 6.25onok - nt 6book - at 1hook - - t 1019/58 at 116/74 at 143/4 st 12.6soot - a. 1016/94 as 6.253f/38 at 6.2518/63 at 6.2596/40 at 631/.16 at 389/80 at 327/].8 at 334/6 at 1.627/80 -t 616/54 at t99/76 at 6.2520/94 at 316/94 at, 318/98 at 316/84 at 326/74 at 313/90 at 3'13/96 at 314/96 at 320/92 at 316/90 at 318/44 at 3

LG0021648


40/145

gteo1" n-Oeaaisa and Liirlaq.,lritJ.Oano's . 3 001(1956) ..Garratbsre and Jowsto i 1~a~, 7e~t (1960)Clam Ilrr r~ , Amr-Le and m~'!.(!Mj-Ch4a . &. 1419(1953) .

**The" values Loolude Us aoooa'tbl dwimtit'o .

LG0021649


41/145

.lve

ulfe,:bmtbera2*481P~VowaWbeIt 18 Akio ad to test .sleeted te~aanda IC S phaael glass for

lead-SW" aassiaapa3a11j as rail ,Ming as21ttMr sbert term raarita obtainet at AOL tee a earns of asters at tatty

Betas lrsa been eu~arlasd In Tape U. Zt was noted that the aelaeeoasgiant asaeesration beams sipiitiesat for esters of at least 19 carbon .tossand was seat effective for those of about 24 carbon atoms. Beyond this, theactivity decreased again. Dijalfioast $ttoots were noted at levels down toabout 0.8 age. At the" levels the etfeots on akin thickness were relativel yslight. Introduction of unsaturated linkages caused a decrease in the

LG0021650


42/145

.r ... ., iIsirO110aI IO7 Nra 3

..... r0 Ar))r. 0 1 ;


43/145

eebaosous land activity but an insroaae in US aria thlitss as.' >i "o. of b,r types of esters, ineludlai dioarbe;gl1o. braoebsd, yetis' areaat%.,r.d isopronold,prored ineottvs (Table 22). Am smeeptioa VMS US Da1%taasg1-'phenyl gestate. The activity of this oeapound .as bs11eeed dsa to the free.~phenol, which would be expected to be readily 31be!ated. The Timms aboavdno seboosous land .'recta and e.sryind assross of akin tbiabaiod, sa rportad'9;by 5atal4. (L3talaX . Aho and L. Marina"". Natarriessaaanel'tsa.-~328 (1959) ; C. so tale. aota ~atboLkioroMol. 6gip~. U. 14M totM'T. Wong. D. S. Jags and A. V. 111salar, J.14st .0aneer Inat., !!,4!S (1

Aa an osaaple of tbe-aatRrifed taty-ai34 .stair shish we'se

~ `PotiKty. .Zhe taet~ ar_~(iS?~.ls~~ y ~ 1 ~I$tT',e &4 t s* use sat 1

1r 2 - s~ .'.rr~a'~fsue" -,a., w, 'iii-i:~--t is 1ei'tiiii~iO,t~s~aY aovs'=tt rates w~ as~i~ias ae-r_. . of speeifie ee.pesats ie laetiyOniahi ban reporter tb0 paisesse at -tbs

..ethyl ewers at lasrts,spsistts sal paisitit gelds (Ontsbl; Toaita aM

preeeas is teb S1 -:ad 3s"..sfa altbasgb dilisltiee oats si ,gavots`

Tvlonsod . Mg.MC.9hM.Ag. JOIN , $, L19 (2$a7)) is JapaaeN floe-oaredtobrooo. fouler (Egg~ . 280-1 (1959)) tall reported the presses ofC1,-Ose ratty soil asters to the ""At of about 2.o% In tobacco, Withpalsitio and 1lnolente esters probably predealaant. C3.eso reports 0.84%esters in tobaeoo.

affected by PKAE's. Sclsti (paturrlaeensohaftsn 45. 394 (1956) found olsieacid andSaurio sold it hi,9b oonosntretions to be affective posoters for

rho" have been reports tbat fatty acid . are Prosours of as-"'

LG0021652


44/145

. - -L. -. --%,w

_Yaes_~..R1Short Z8S Effects =SQL 1(iseallamecsts l

eolan..;l acetateclolestoryl stearatestibmast.ryl oleatethyl-1-oao-octaAeoanowt e6yeerylmnostearat

rsm40 my. -4_- a= :4. &Z t d.l9~~~f~_V.~ 1 a0titiT''~~f~~+ ,v _ '.~azy>~idyetr_aetat r -;t;! f~ss~r atai.: e '19/73 sus- .entyl starateni,asO~aallaolyl ofaaasaseC~O86.O000sass -?: 1873af 64.looty1pbtbalata ' -u,_0~~-?hs-].tr/it~f 1i"'"'~`lpitLaa' ~~700Q--~4-4sotrlstearlnpf-rtaerythrlty1ethyl aselatetryl oebaoatephenyl acstatphenyl stearats.*-aa. ~aJ ~.`.1 . .:?_y +iY~{Ti_-~C!~?{'Si~00 poRM r aart4 la -$. os0.! "- ".. % :.A

CH,000C HC,HssCWaasC ,RaCO00af49H (CO)000C, .,CHCOOL HtORHN)s(C,,E,,cool ,CH(C,,a,,000C ).CC,K.000-SCR, V-COCOs!(,C .E 000-(CE. aCOCO,aeC E D C O O C , R,OaeBseO0mBs

sl,oet ta:. tst 7-is 93 at 6.251L 86 at 12.516/86 at 5.12v/a6at 60 19/63 at 12.512/70 at 18.6lb/84 at 12 .618/71 as 12.613/64 at-6Deck - at 10

1 1

LG0021653


45/145

C :m+thjYI'oersantt:racene vhils stearic and palaltia aaide vsrs;,iaaatits. 2be i#s .`.ort-termaffects for a series of saturated fatty acids ars,sii riled =t

noonooamd CH10008 1690at t5deeanoosaid C5,,COOS15/60st Soundeoanoeacd C1saeCOOa2307r't-6ilauric sold C%22&&C006"c-- 25/weat 2trideoaaois said '. ' 021609001[ - 37/8O-at-,-!5 = -aaraanc, -acidstsaa-sadCV~ a~palaitieOaia - -c'sa sWUMW..,_, .. ,~seid .' r;.-= -a-. . ; ~~00~_"3a{-.. ~'+araeitieieg sdawaaO~t0hepanocacd CHs000H1780 at L5ocanocacd CA.000H1785 at 2vristta-aesd - _-~~aB..0000~- 1V~! st35~i-Y "

ROMbsaaeaa'

mvoawsdsit3;.aonoesis 32-1a v sum reasirsd 3t~~eseeessllaZiasC=ssert-tas7;tssts Ter a sari.aC."t~asatsratssTatl~ aaiaa may itss ta lsDls "

TA"14 -thort I 1Cffsots L Unsaturstsd lattr AM"

orotoaie acid**lei* acid11aolsie acidflinalen.lo soldbrassidle acidrlaino2elo soldoleanalla sold

l6ert two testa/S at as.C,B.000Hbeak - at5Ci,8..000 2295 at 125Ca4Ha1CM25/Sb at 2Ci,Hs.000a26?6at 125CaiaeaCOM2O/SS at 125H0Cs,8.aCO0B2205 at 2HCCe .B. 10005 14/70 at 2 b

LG 0021654


46/145

tims 1nA4 ~~ay_..ja ;n, no effect was noted on 51Daes0J1 $lssrie WAS. . . . . . .. WASinsattSiiest afrbs! edt.ese compounds has been tested to inbioate the optimmm melsenlar die Imt

linoleio are oert in importaaw. lalliarl as.rsportad the saaaee,ot,;0.2%,

note that the enhancasent of skin thickenthji effects was also =tad wthunsaturation in the aster series. The range of soleoular sisas_4or opimumactivity also appears simlar. Compounds of this type whieb have beenreported in tobacco or asoks are Sadioated in the tables. Ta1mtia and11nol,nio acid are the major higher fattyaai&a in tobssoo. . .$tearte amd

c :; or trose vith 18-22 oarbon atoms gave this effect. It is iaterestios to

C . .-C- aatarsssd fstb~sids-mad;A.C~.,ilistmrfii~atb~adi~!..,.- .q,-.~~.a-+?:.i..~..g~r~,~' F Asa:3nc+s ._~=lflg:i=

petrol..-other'O.80setroleums rtbsr 02-40a.hsaaas"esdodesYetetradeeaeeestadaasasoata600amrlsisommmeostasesaaedotriseontaneiseoataaeneapbjtadleseequalaaeB-sarateaeoyoloboxhae

! i{.k~ss -"=~D .vi 23/88all0sovaa 19/60 at.3i.5Caalae 89/61at 118CseSss 2660 as 628Coal" 2q/S9 as 626066166lb/ft at 6264068 14/43at 126cents 1661at 100O,Bss 14/16at 626Comase 14/88at 126Caalsa 19/894%620Colas 14/94 at 100LG0021655

a $totip Ortire offsets on


47/145

(

7T,v . :1 ze nc;eC that these compounds are relatively inefttstty

effects . Compounds In the 12-20 carbon straight ohsis-grwp'-~:re rest effective on.both skin thickening and sabaoeous glaeds. Th

hydrocarbons in tobacco sacks are prinalpOU of the--jtypes, :otallind about 1% of 'the smoke condensate. The isopsnoid

p .9 found in tobacco and smoke were not active bythe short termtests.~ese compounds contribute about 0.2ago per cigaaretts to the esoka. V

noted above, Horton (Horton, Doman and tress.t, Ca rNeyargh, L968(1957)) has reported that solution, of caroin"aaso p%ARs In aliphaticiydrocerbons of 12-19 C atoms iadaoed tamora &t :a mcab bSghtrrt_fae agiven concentration of Dareaopatdt!_id


48/145

I

Bhort taro test,0/% at No .*ehano COHOOHBook - at 100decano C%oH&&OH2378at 328undeoano CtHaON2660 at 125dodeoano CHsod 30/68 at 32btetradecano C1HOH3969at 328hezadeoano usohasob3478at 325ocadsoano CgasOH1389at 126dooossno CaHtC115/91at 128phgo CeOESeOB3203at 16solanesol CeDAVtOB16/83at 625vitamin C.QP3270 at b---aseortic maid CBa0r Book - at t' 8b-aitostarol Ca91644- 19/80 at 8 y-:cholesterol . -Cseaas0 at 2Gi fbaaa 3aloohol 1C~S QS2/bd at 618 ' `r : . .aM. . tom Iks~ebaeie W saes":

.~~ :rte?-,-'ec3,~?'="'!~3''7 .:~' '.~"% ZF'

xe?bs-Sso~eaoid_OOOpe~QoLaMOZ ;~t~bj!-1t'asllat~ to: ibs_~ct :.i1Cis~-oai saea-tl~lrXbe eaaMe and -35 a -sm ssiob ! ,:. --:10t1vf lrepae~t-teso' w.w.=~ealaepee

p-tol, was gatts.astive both with reapeot t0-Nbaeeoaa paO~:'1m!}il1i . _ithiesaeatng. : sterols have base soapeet of wrsiaod.mioity.at.atbee satesthem the odd. Tbege asopeerds tested, saes so iMiwtiaa;at .abeei-ses~etfaota. the .sttsatad sent of sterols is tobeeeo Is abest< 0.1-0.4

the loos-chain aliphatic amines, is particular she soeoodary aataes,are very active to prodooiaf sMs thieksmind and degen.rstien of sebsoeowglands (Table 17) . Inaofttoisat sos)OUutds have been tested to gsner0,119eon the opiaaa rise of the substitoent groups. The onlymembers of thisgeneral also* of eoapounds vhi.h dove been reported to tobraeo or eidarettswoks are the lover hosologues which would not be expected to obwc .rc1no6en1c activity. It Is entirely possible that toms of the bigneralkyl amines may be present, however .

LG0021657


49/145

CaH1,106C o$a1KEaClo8asaa.C,.a ,*Hrssa,Cioiis aC.esaiCi,&:i(Ci.R,i) sCuiCao$ovuooaas3e

Sable 10 are ss.esk1.d tbs fhas't-.vror ooapo a. %atq at ibsM1s i~tn-ootylaainen-docylasinth.sadeo7laai n.Qi(n-ooty1)aainedi n-d.cy1 aminetri(n-deoyl)aainepiperidinsn-ooLadsoylaainen-tatradsc7lasine

abort tars s.aY/% as.17/24 at 4.2632/40 at a17/26 at G.l046/49 at 0.5-sis/G at 1-11/96 as 6.2816163 at 12.0-. .gooks ./. ai~breoka %at a:S. for a seal C1Utp "''rte .

GsasraY alms. at eaap~osiadt;.arid=' 4p~oai as ~- Q-bas_ :..tared 1t iatasdas'sal inJesiiea:it swr Ot;ltisisf.:

'~:Tfr,:_-te

:- .~.Q.~ 1) ietss+lsai : {aias>s as *ats'eas ~tiss_ 1as's i:~w:si .a.-. -.. irc.saass:i1ssr 'or til is 1600- 1y94ted for :. 3eoloe6 npet aLo , 7s4 (low)). 1lsitbse attbesa sespooW ezt:ilisst MW srtes: M stii'the . .a Llsiskaoss Or selaeeeaa psta. Crtala OwOspsaidla Letssbora astiritW as sloe (11e4assoa, lotto aad 1a7.t, ftw4a.daaoo . Cass.E89(1907)) .

leaogninoas and 1,1-aspbtbepsiooae a" reported], reek saresaajsesand promoters for ?ttd's (2akissas. LM&W - AM &. JIMIL3(1940IIsin and Auob, Carrot AU., 1, 7dt (1944)), rsitbar of those oospoaadagave any indication of aotirit7 is the abort-tess mass akia toot.

Croton all, a stroni promoter of oaroinopossis, save oonalderabls skin'hicksning at low do age levels. Iodosestio said and ohlaroacatopbsaons

LG0021658


50/145

laebatrrateaaearmodrla = = '_a.=,[as~a'_:; . = :f{ .Zw~_____tsalaaa . sa 4 i Q..L{~i -. 1~de"it_1-.~ . .

'mow ., ~t-`~%,.:--ce-_~_]~=Pfjc '01 .1.0. 1= fB S as 10a.x.0. r6

lAdNMLMLMkAL&.. . ~j.. fir:. .Nal :M.7 u 'atrreaa ea1aa1,3 .(*,3-apesrpeepe&7)oeasaaaebel~etarol K-~t3Yeetyiaaa 1111+4

6-plasa as18e1 .11+0111. aoaosidadlerelopentdlene tiepasideLlb=atbjl etherdiootyl otherdidaoT etherdtho-tdwoyl atb*rd10ZaM

O 1.O1.000.46041.11.0C1e~11.0C1.Bs.001091.0.Ca.9a0CC.. a...

13/79 at 10030/66-at 6.25Y/68 at 6.2521/66 at 6.2512/86 at 100

LG0021659

1aat :.as -1 .lsl~t~d13/91 at dBeat - at 10Boat - at 30Boot - at 10Beet at 1016/17 at 11s/so at 626/96 at 6is/9s at 616/A6 at 616/96 at 6


51/145

Ald'" d= &L4 latma-a acetonew .tbyl lsobutyl ketoneundecylaldehyddodeallalde2ydsa7ristle aldsh7doctadecylaldetydsnooadeoaabbrltetrdeojlaldehydeSndanoos1,9-basantbrewad-Cbol s s toa-3 -ao.es-MalAstewb-eas .-OvODd1MA-1~b~Q100e . "~.

- agtLeiii~->-adI

ssdM_G" GOVOlin thlow*&lisse64'e31 ..tossas 1-42dtiesp~aibeeegsaiad-a"lodastria6-7a1odstrintrieotaaetah.7dreoertlse0tsrrrs.7oiaretsoee0701000tattraos ai1L1 e0alodoaostic said

CRa (CO C%CR,(CO))C4H.CseH.1 CO HCa,Ha 00 HO,.R,, CO HC 1 4 H ., CO HCHss CO CH.C,.R, 00 H0400OLH4sa00,150 -iCaa~a~s.; .

12/85 st 10013/91 at 616/69 at is.&18/so at 18.517/94 as 12.518/46 at 12.624/86 at 6.18area" / at 80018/79 as 0.26

As ar-MnstW.s.1 ./M;A 5 .1O -" *2.0.11/8 5'0.118/75 at 626look - as 2.6boat - at 10023/el at 601 6 / 6 6 a t a1?/94 at a1 6 / 9 1 a t 312/91 at 0 .25it/9$ at 0 .26"oak - at 100book - at 118/96 at 517/96 at 6Book - at 30Book - at 2Back - at 0. 5

LG0021660


52/145

i

SS

Luf en tensoqulnone1 . 2-napbthoq%Ll nonei,4-naphtbooulnoneanthranuinonepbenanthrenequlnone3-phytyluenadlone (L-1)-meth '1r aphthoauinone2-aaino-1, 4-napbthoqu.none

is- .Y. ~.,~wars taes testa/6ate1.3/85 at 6soot - at 013/60 at b1s/m at bboot - at 200Ss/96 at 6.029/10 at 6.022/94 at 5.0

LG0021661


53/145

both been reported to have cocaroinogsnio proprrtiss (II,Sia aad ,sseh,-mncer hesearch, 4, 762(1944) and both give epdermal hypsrpasta is thea uae. (frwynn and Salomon, brit. JCancer. 7, 482(l $))

A number of attempts have been made to utilize the short-ter! % *atpocedure for the evaluation of the coabined offects of two agents, eitherse synergists or inhibitors. The results of some of ;b tests are ssasarizedin Table 19. In general, this type of appoach has poven ansnosswdnl.Compounds which tight be expected to complex bsnzprreas, and therefore toreduce the activity, such as the oyolodextrins, tetrasathylaris soid. Pieriaacid, trinitrofluorsnone and caffeine Sienese pe sligh%-+o! ae-_sssslts Wsstested to conjunction with benz'pyrsne ~-fa tracta -of eaok. mlittle effect. Li3inali (Lotin,. !ale,_~.tZiae4 and, Zeebid.ster._1(l 6)) has reported the So bttiesrnf~Oessias a eRZtit~ et__.P~iiei-~sa:applied la thi .preserve -W _AL Zb tal4 ~iSNi ;ihslanrOPelaiec aaLer1als~c=e~en f~s:JWOM~~MU~$ 74

en,_ was- ssnvnty:or oenspFrsae was . MV smarameel6ilalslo anhydride boo been reported to greatly retard tbt oaralaepoie--

astion of P112's on scams stria (Crsbtrea, Cancer llsssaroh, b, 346(lpii))s1hsa this sosgosad use tested in conjunction with bsaspyr by the abort.tars preosisre, it had no effect on the sebaceous ilaod resat and iaarsassdthe degree of skin thickening.

lphstocopberal, w3icb has been reported to alsm pramotiad activitytoward PKAMcarcinogens, did produce isereased skin thickening but no effecton sebaoeous glands.

Sterols tested in conjunction wth benzpyrene were wthout offset.Some of the PRAR's, when tested in combination seemed to rive greater

effects on sebaceous glands than Wald be expected for each tested alone ata two-fold level. Included amongthese wre chyrsene, b,nz(a)anthretons,and the bensfluorenes. These compounds are generally classed as very wee k

LG0021662


54/145

i

.5)) .i .,rt-:rasd

cff eCt

c}c:c:~trln--=yclodextrint .treeyanoethy1neptocoph,rrl

1 .,'1at 0.25 15/73at 0.05 16451./78 It C.2. 15/73at 0.05 16/6

E-3:toeero 14e0aaleic4nhydrlde21/93enkefracionII4A90/39evoke fraction 14I 26/30awokefracion91P5pyeasa 417141221chrysefto S714 _a11340awokefraoion132441at 142118at 0.06222hezsat eau-a6% of tooaoeo : 2088: ai.3t:-My-." !t2/ . .~bf80s~_~fb6x,rit~'O iv:, ~R9 0dicric solo ' .: sLO/69easpyrsat 2 * 7i a01?"200619a.Oanspyrn Y a:2E1449at-0s0 168*COr -fij3~ :fAaspns "1,*.31a;>:. lb43as b:a3'l lb/58k at~06~'x+;X/16'~, rls~atlaiaona- 2843as;0 =: 3641Re0'~= :ice

..:a : e16i"ROT sLa11 va '.C-s4"3=siisaTl63~~DZrti~--~i ,~,-- -a~0~538F~~~=_._-ti~~ _ ,~ _ - . . ~ :rte' . htto~aookaaLE6---=a ,: ala r.2-atl-"'t . .aLsewar twl staarstea tipatareitriosuma "tristearia

19/39 at 0.12246at 6.25 1678At 0.05 26/5a 6a 0041891at 62355 at 0.1325at 12.52413at 0.03223at 12.5 24/13at 0.05 24/1at 27.8 2118at. 0.06-, . 2x/32

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. . .:ens. the activity Cr a si:Lure of mna Ph*'s, In tW$ee/eetieas,ir. citi.rette smoke, . was predictable on tae belie ofadtitiso of tbo

:,nt of tP'e results reported above for Ynown compounds subjecteds :cwt-tern teat pocedure, It may be soon that the interp.tatios

_ . :-.le test should be made with caution. Lcaaples hase been cited in +shiehrather good correlation has been found for load-tore oaroino6enicityandsebaceous and deterioration. 8owevar, Oaroloogena at sites .that thouthe skin have not always responded to this test .. Ctth s+apsot-to Promotingactivity the picture Is Partape'less *2 esp.':between hfpsrp:.$eta and proe T4w1Xkroxidof sebaceous gland degenar.tieSoeo' iir~jr 4essnw

s>f1-48d-relatively ineffective m sitber-

~o aleoi sosipoutda teas the wsioa Smetia ' ~asS~e?,T t~e~s=a.r.ft.gonia and prensati4c offsets.:;obi peinsiplsthe present Zi.s,= saws to ~s *ti"TsI1isri -aotive at sites other than tbsatta. mass sD te~q .gst~eg~a'bass the pile-sebasooa sppsesli o of the sbia, the. os@aais-~lsl iaissi isand hsaos the obosioal requiresoate of lbws agssts a diffsa's t'bs -UDS i-

.ess of the toot with regard to prosotind agesta has fat to be sstabusba4 -:Athough tbore are obortooaiaga wth regard to the short-tars toot we

do not have. at the pesent tics, asf otbsr oasts of repdly eealeatiftmaterials Isolated tree tobsoso or sacks. For this reason we base utilisedthis test to followthe fractionations which we bass carried out. It hasbeen our hope that by this appoach we slgbt as able to isolate and ideatlfr-a:n-;cnents which are active by the short-tere test and then subject these

rta:s, perhaps obtained In adequate quantity cosserotally or synthetically

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:. ~~;':'FTGy

t

hezane-soluble portion of the tacks vad~gsats'~11~4Ed-S~.' lSe-ea=sy-portlono hnacvyv~-suppy and also Wth the object that, barringa division of activity betvewnmore then one traction, the tumor yield would be expected to remain constantfor successive fractions. The results of these tests are sesmarised InPicture 1aril Table O. The earolaaienele~aetivitj was concentrated. is th'- : .+ae akin. The three vrisary fractions were rsob tested at levels poper-tnnal to their ccnt.nt ii the awoke. This ve,s done for pactical reasons of.si. e-par.tra nto several fractions for testing by the leied-ters'prooodure enInd o r one pillion cigarettes and consisting of-aver 00 peaada-st'eoodenssta-ato the lonb tern souse test for subataatL a.a .-A 9s=p1a at iost~~lepeacss -

1_-&Pw:-_-. e*jW_:. , -itr-1aersL~-ussas~s_

. . Y 1 4 1 2 a

Pe"" at ui' of the : 1 o 4 .T:eslam!atit thad;weuld be ?Woad in Prehive Il-48A-17. 0isar po3yenslaer arasatis hydrocarbonssimilar to 1,4-beosopyrsas e"a3* be roved IS either !'1-481.17 or 15. Todetermine v1etb.r a pramotisi (eoearsiaagsatla) motion vas present in the lase

seedier is v tieb S,4-sa naps sup': rd otber .esuivioao tiers sSasd atvarious stages of the eboateal frsstiwsatias iaLisettd _ fast this seeterial

than would be expected had the 3,4-eeosepyreae been applied alone. This wouldnice. The activity of the treated fractions was either no greater, or lea s

active Proatias which went not baltaved to eeateia 34-banaepyrens, a knownamount of this substaaee was added to T1"S-9 and 13 . The.. treated frac-tions were then tested for carcinogenicitybyextended paintingon the akin o

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i

noun utreatezaotioa.titer extract Helaae "tract Acetone and emulsion(10 .6 d; 51 @ 1723 41; 34.7%) 19+46 d; 11.601W41BA6u{

to

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n

Frootlon % of total$c, oondenaat11 . 8DV510

FP-48A-6349F-w7166Fr-46A-9 183Fr-48A-11188rr-48A13106Fr-48A-16186rr-40A-17 066Fr-46A-19 , 38. 8

2 .07

RelativeTestIwtela4 .21.01.41.31 .52.01.31 .91.81 .5

Thaap flduras were arrived at by 61vidlnd :0e dosage level

;1.

.~'~R : ~tf711


59/145

carth:: : .eoe fractions were not promoting agents tar 3,4-bonspyrsns.

T':e activityof Fractions FP-48A-5, 7, t and 13Ms also datorainst by~~plica:S or. of 50%acetone solutions to the skin of rabbits over a period_5 weals These results were consistent wth the long-tee .case tests

.r ;Rat goryindicated no activityfor FP-48A-9 and considerable activityr 'rP-46A-S and 7. No activity was found for FP-48A-13. (table 21.

TA & 1Long-Tern Caro n is Aetlvity gff C e t Siiakeaclont isSinSLii

Aalatf Ntest go. of weeks to obtainTraction go. levelsSO%autt.a sot avths"-48A732p-4a&a!9 ; : f - aid 4st_ OiLtla ;s@ to M vssb - -_ - .:, : . --:Vi=i; - 't,~.. n '' , 'r.'.3s=A7 `8A 4*' sot - btalP t . . a m Q- - - =.f."?-a'~ :. , -;-ate

,#DO. {oal Duey 0So~Total smoke 00. 30"ioft*" fiaurss were arrived-at bF dividing the dosagelevel by the % of total ooodanwts

The short-term effects of the eifarette smoke ooedeneate fractions onmouse skin have been summarised in Table 20. It is not possible to draanyconclusions tramthe skin shiokaess sine epdermal thiokaningvas notedin oil fractions. Dstinct diflereooes were, however, found when the affectupon the sebaosous glands was compared for the different fractions. Interse of the total number of units of Nbaceoos gland activity froma tveaamount of total woke condensate, Motion TP-481-13ss3tibited the costactivity of any of the and-fraction. by this criterion, FP-48A-111b and11 were about as active as TP-48A-8. If the comparison is Dada in torus orthe number of units per unit weight of the individual fraction, Fractions-_4FRA-11, 15 and 17 are 2-4 times as active as FP-48A-13 and 11-18 time s

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i

sro-:d be remembered, bowevsr. that the short.ters attests Wto dwtocccarcinogens as veil as carcinogens, while the leas tore asas7psaeeabitrequires a carcinogen to poduce cancers.

:e;veen the short-ters streets and the lom .Sere seepis a*psselbla. It?be theaioal freotionatton of 7P-48b11 and 13 has been purasM *sift

Accordance with the pr+diotioas from our )Mlisiaart stones" a bsslYsebls .the short-term effects on the mauve skin of a pide to aetivit7. L

listed in Table s t aMb. . Us a iw.Afrsess 04. ebeieloss syadsror fieLumbar of PMI a bare been found is frsatioa, 4e141. ?bees-b&" USIa

maubetituted MMSO1!i 106a2liedbeaaassthsroe basttllsstae0.m"sows- ~- - = , , ,~ ,.y---acs-

eelaeeoms glands. d es.. eatselnis wre . . ~s+eeess ; Y s 8704mwb-Qa~ loam

i

tIdUMUS Of 0921 On 80tribvtM slsnllleaatlM H tar tetsi MWS-tees *$Uflb' or fASstise32 411.22.!MW 1mClv100sl esONVOIN!WN respesassaa see tms sutltt appear t a'ratbeeOwners". Distribution e0atrlateets to is thr beans we $$ Mtbasal

cigarettes) . Infrared and ultraviolet spectra whiob ers Obtained for tLisof crystalline metmrial were.iae2atcd Tres sae active treaties (lam saloondiatillstloo at 80% 18 hlsa waoasa failed to roLtilisa than. Beall aeountsto the strmeture of scat of these. ?bey mast be relatie3j son-volatile aloneof Polarity. M3atlv.it little sr be said as thr pewt tlas wth rvap5tpetSher vartatlson rtes chest 0 .5 to 10.0, taatss%$as a rather wide arise

material and for some of its tressfO1ation peodncts have not been sufficientto characterize it. It wll be os.MSas7to pepare additional material to

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i

y_ I permit further studies. Several eospouads toss been Led& l .at laastllist

as known materials which were available coarruL.lly 0! gstba$iaalyhave been tested in pure fors by tbo abort-tees awess teat aaa lousy to toinac:io both on sebaceous glands and vitb rerpect to on& tbiebsaiag. ODD

..,,.. groupof fairly well-defined materials vitb Lvalues fros 240 (0.13totalsmote condensate end activity of 28/13at S so per appUeatiss) bas bassfurther fractionated. Analysis of the asJor fraotioa 1adist.t as avengemolecular formula of Oe.Hsa06.9 soa (MY 420). The 2b spostrta ici1sa"acompounds. largely alipbatie it maters, with .stnr or sataaia aerbosll ;loupeand ooasiasrable.aUtiaSe exists flIst ~l ."Stan "710S.- -A0ttftrrSe- 'i+.d i # aaAPM44 a catiOa p3ersa. O.pRMNW .a- .---= wteasaatsratsd aaia'at:a4aisaissi ~wOott sas.talseaisi. Mtresstar

Li'tb. maid gaa .4atia.'>ps03~.3 s + a dal d~ 7F{ '" ~ '

ti.-.~~L.~a ~+J~!y Tri L.T~~i TT r.--to ?e:lai so". tatM1S1M" "T=hf ibs~4JW aiBifsrsua.rr ie i , wbish w a s lass ..ties IS - t a m 1 0 0 0- t.M. a .wmay :

tae. Tr.46L.211 bst'aessaieaa awe activity sa-t3r basis of'sti.amt sabs.eors &UFA at! to,, bas also loss sMttoa mbar -ostos+diaij sodatr.iso tin essayed.stiti.s respeesibi. tar ibis a.tieity. Tes ibistrasstot wag separated a group of weekly "LUG.tori*Lof.sells erpbasolio asters. This trap Of soupasMa soaatitnrt 0.3-0.4, of the totalmake .oad.asat.Uptw. Soaatel.iar!'eat tlatrLbatioa of these.trials,tbey were partially separated into groups aoeordiog to tbsir relativepolarity. The short-tort aetitity (21-28 u/5-5% at Sep) was spreadthroughout a vide range otpdar types. Al of theca ratrLals were largelyaliphatic in nature and possessed, in 4geaaral, similar IS spectra. weaklyacidic tltrable fractions. conjugate to saturstion, and oarbonyl groups.

LG 0021670


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sps

r

-ns

17

Analyses indloated that they differed @COMMa$ Lb 601P'e0 d sia~tiea sadr.uaters of functional groups. The sort astiie setsrials vesle tdied ratbareztensiv"ly In an &Zzeept to deterstAe their ahesisal mom".

,he elemental &nalyeas for the most active Shoup of read asidio materialsind.lcated a formula of Oj,H,.Os with molecular vt. Of MO. Soo-spasmstitration ave an equlvalebt weight of P78, indieatisyfi a siniia amid feastion.

C ata1Ttie arases'satlea Steas"srd3aa a~last ems iaalatsd 601d as bd121~ . _~r- : ass: c8-9 6asn1 s heeds ae4/or epsJ,3a assess tm .ai Phi phsaat . Is -13W solos"Loetylation produced a soao-soetate with the disappsareaaa of tae tparosl .Group and displooeeeot of the carbonyl dre" to ahertar wsve-lagttas tad.loa-tive of an snol ooetats. On the basis of She aail7is is sae ostia.tad that _ amd fire et~sas s>zish.%ss'asti tiS~~ast a'ttisr_-.paM_ eriih aasbes~yZ peed 3a.;,lst~s~satirssSZMviaTTtsaSsrS9~~-. . 7r 't a21Yl ~bM t2a4a~Zasf=i Omsf. __ _--, y no.am.a ti '~ -Pf tes alsi#-w.li~s47 iemus- ow" %a,$. 2t do" not w e a r. ' lT s'aat taa_ria -,tratom-. is 'tat f~active nateriale at tba peesest Uses, ladiats that this &Wsep at oaapoua(s isnot-at "WAS type vitl strmtares readil . dtaraisabie. It tbq Gas bersltM to asa bamsa iseq Of Ntsriala tie tact rill be aMa easier.

Alma p"e"t In vas fraetioe ?k-4U-3 .3 is a droap at ocegpeasds whirs donot contain titrable fametioms. Per this rwou we. have eallsd these teaneutral aliphatts sespoaads. These materials are astive by the short-terncriteria. Upon tractioaatiob, the activity is dispersed thro h a greatnumber of f-tractiooa e~ntainlsg a,a.a dtffsrent types of compounds. we haveboon attempting to detsrsine the structures of lAL.ividusl oomponents of thisaiZture.

n?s.ssi at an7 !!Itwr. - Whe si.eelas *s io Sa iatalit3idabpdsedasstles. The rsselte door strstsoral '.tadi.a as an vewW am"* . 7 .,

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i

- -psi-= - -x - = w ~ ~: .. .~ - _ -.7of the i-b.tereo7711e cams s L 4i4LSM *'hat WpeatWrto be ekatole, oarbasole. substituted oarbeso1 s, add sabstitatal bass-

6-

acridin.s. The simple sembere of these WWI" bare set boso fsmd to becarcinogenic nor aid theyshowanyshort-tern effects as a04ss aLa. thdependingupon the type of substitution, osrtain di mnd tri aeti i boas-bentoarbasoles and bertaorid.3nes are recognised as cast to atrbat oas oiaagens -

aoridlnes beingquite active. W have not pogressed far 000440 in thecastudies to identify the nature of US suastttucnt d"Ws MA therefwf oaneet

of

say whether these satertala are oontribatigt to tha.aet3Tt of tb soohom.n.ate. lheJ are-eertaialy_suapset."bow,e*4r.;-2adtvi~aal arabsrs of this

class of oesoe4sid art ieoseat_3a,abaft loll sae sw a as .i.aaw ldmaL !'iits:

13R7~y

loeepb~i wo.4las foorl'ds-lei Asea=iii!,r iasis eAe f~i!-~e/rlfL ]~e~ to~aebb aa~_agekar: 2wsr.3a.'r r"-4~giIo pait tlihs~aL . yy~Me3~h:-- _ -.w-.--. -. : . . .. . . .-the a+ativtt of 1h1a3!a t e~OSt1t9s0t or tOOasM. a-- -ttaas' to _$)baMilsotLeas . .Sl ,$ as1T .1aiar1s1aafVM .

~: vita ~ - . .


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- .. ~ ~r 6r72.h '.IG_,TION OF P033I$LE Nt'fhODS FOR THE BCD't e=0' OG AL A rTVTFY cr BTA'!sko

- eD f

taaturiad taebatamts . ' Is31~it'it#his j-i$ a+iama apparent that astresic2-4plttislaal'~traass~ilta'af-=th%sBGitios .~-tar~3~aDialsel4~te tobasea=rool4could be realized bj 11sad chai~ss"br Mica nriatiooa, in the new ah nano-

tie v--ceedin{ sections of this report, it has be-n shown that6c:!t 5- e can cause non-arltgnant and Malignant outgrowths on the baotsaeleced rtce when a+iplied under specific conditions. It has also been

_'nwn that such smoke contains minute quantities of polr elmar aroemiti o% droca-bons, which in :bsoselees can glee a simlar biologto.a response.Acigarette whose saolte did not exhibit these effects or did so at a greatlyreduced level would be e*lnantly daalrable. fromtba Mort reported inpevious sections it does not appear t y though 557at n ticsnt reanotion

-C Ve1T!~.~wMi-w4wT~ki~~~!~_ati:-~~>.rL~.~?~ .:

F. ~ .:.a:~-TJC ~; R isr_-l1 :iLf~~~.r~+~i l.~ ...:~.cp?: :east 4wream ;the aataleossnt A!-'ooh a: s1t- :bsia UM:'e7.lsShiial: .1tt>~ribiiiterisa:~a

sectton amasrisaa shasi aatiKtisc:" :4 - .-,t.-- T" a oaeMa JNw 8100. 0000 a tsaJa mnrc. Too riot of 1WG4 -eoasaeta::'e

Awith a subsequent eatimatioo of polysuclear content and/or biolaiieal activity.This approach, which initially eonsleted of a rather random selection of 'treatments, has now ds,eleped to the point where some degree of predictionof the effects of sons types of additives to possible. It has also beenfound that such cigarettes are of oonsideratle use in the more fundamentals:udtes. Simlarly, the fundamental wort has poceeded to the point whereITto of use in selectingadaitiwas. so that the delineation between these-ppoachee is becomngless distinct wtDthe passage of tins.

or as isr .stlptloa at the tuMssatal proeconea cesurrier darinj the aam-bnstton of a cigarette. the seoona or sapirteal approach consists of theuse at a variety of chemical and gab steal treatments of paper and tobacco

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e : : :rc: a.4, gas . these studies ware Concerned wth tbe,rsportsdpo.7r.cclelrc and b1o1061ce1activityin the make obtains&from

:-. -r,r-iros this start, work on treatments of paper and later!is discussion tends to followthe chronological order

ese :eve:coeenta .=e-er Studies

in 1954, an announcement was made by the hand Dovslopment Cosperq ofC1.eland, Ohio of the discoveryof a oaroinodsnio response of and thepesence of the polybuclear arosatio hydrocarbon, 3:4 bsn=py.sne, In thsnot obtained frog ordlnnry cigarette paper. The forthsr Claim ve as4a- :that a polyserio paper had been 60+sloped21loh t6 nsot:'sstribtt tbass; `properties. In order to vvfify tba. llan4 r.rlta, a -pia pran cf.- bmrnist : ;apsrby their to hntQne an6.istisatiM tbp;iaasp"ead coossot.wa.,staMad.,; Zl :Rnabmnn- o- a.6 ehniQm: oaea'Slss:-atDiistn,c:s-mda !s*bsr:,is':a ~3iaa

rlagmast aad e413aitla podurawing Aur through -the mol4m ~gravity settling in a selleetion flask and rater sooladssoaicayee..collected condensate vas generally subjected to a combustion of solventfractionation and repeated column chromatography on slliea gal amalmaanito isolate a benapyDe4 fraction. Yiuorssoenne spsetrosoopy was used edthese fractions to detect and roughly estimate the benapyreae content.Alternative methods swab as the formation of the aastaV derivative, solventfractionation with cenoontrated sulfuric aaid, and selective eomplasing withpurine compounds were also developed and used to provide better estimatesof the benspyrene content of paper Mots.

Aongwth these teobnioues, a pogramof biological testingof paperand tobacco smokes was initiated at the A-tbi:: D. Lttle laboratory. TheInitial pogrampimarilyconsisted of the peviouslydiscussed lon,; termlcloloelcal assays. At a later date the aWt tars sebaceous gland destruc-:ion and akin thickeningtests were Introduced :base considerably aided

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s was aroused to have a fail Me nor,. atioa lrithtbetern, teat in that most material/ which bad longtermtunoragsnla

e : !ic short termsebaceous gland and epdermal thlotento:me validityof this assumpion has become Increasinglydoubtful,

cc3MnKythe aalua of these snort Zara tests has dimnlabed, but atIre-ent time no more suitable subetitute test is available.

was 3Sler"Pramm =n1~1;1*~17i~". ,a m o n g s t - of laTaet+fremi pa'~Mta{g~1_ t"ilia rni*Riisetivs materials and $3t 040%"S-ZAstsar.+K`~O,~OStr.sstlaitgiiia_: ~~13 ss ,. .~i=:- ;> ss~-'-=tip'to oontir. Lhe original lcaat.plaiM ~m~ratokd.'4 4 eeatatn sie2mpteal2t of t!;-. oThe overall r+.aalt abtalaad.Trot


67/145

i

y7rene, bentpyrens . and other unsubatituted pol7nuelsare were inalodmd in ,these erDerisents. As noted in the pevious paragraph, the amounts Of prNaa-is 3 ;4 bentpyrene were found to substantiallyIncrease as lbs.p7rolysist,-persture is raised. It was found that the amount of ions per 1grinsCtr.rette increased from 1 alorogras of 5000C to 137 micrograms at 100000 .Similarly the amount of 3 ;4 bentp7rens per Bras cigarette lnareseed fro2 12 micrograms at 75000 to 50 micrograms at 1000C. Those data and thatavailable far gaseous products are summarised In Sable 1.

LAjU 1Zislde of Various $atertals free flash 10yrol7ses of Cheesarfisld_ atgarattee

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! .le the.t the series of reactions leadingto the forawtion of poly-or the biological activity is oomson to most carbonaceous

F .

're a-f.ivses 'or ;yrene, ant occasionally other polynuelears, have found.n r.e ecrl.,it.on cf adaltie treatments, since it has been

.rw : re reCuctnn c :y:ene, in the pyrolyeis smoke froma treated.rc :e, re eproeed to an untreated cigarette 1s well correlated with the--diction or short ter" biological activity in the hexane extract of thennrral amnke from suet, a et6arette. This correlation povides a pacticalchemcal test for additive treatments.

In order to deterntne whether polynuolears and other biologically activematerials were being formed In the gaseous or ooo4ensed phases. experimemts

The raaacoiog behind these experiments was that if the lssetioos wrewere initiated utilisinga flash pyrolysis at considerably reduced pessutrss.oocurring in the p aeoue phase, the reduced ooaoeotratiom of the reactattitsat reduced pressure should lead to a dtaiaisbsd yield of products. If the-reaction were occurringIn the condensed phase, sayon the surface of the-tobacco, the yield of poducts abould be relativelyindependent of pessure,but would depend on the surface area available for reaction.

Dtperisents were performed In which Chesterfield tobaccos were fleshpyrolysed at prssourea between I and 40 millimeters of mercury. lieduotiooain the amounts of ethylene, ethane, pyrens and snort termbiological activitywere found at the higher temperatures as Indicated in !able 2The Changein biological activitywas considerablyless than the change in pyrenecontent, suggestingthrt this activitywas formed byboth pessuresensitive and insensitive reactions. Some doubt remains as to the interpets-:'on of these ripsults, since the reduction in pyrolysis pessure also results

a dl"tnished residence time of the reactingmaterials in the heated-ac-Such a change in rsid!nee time could affect both gaseous and

-sd passe reactions.

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TABy2-roerison of Yields of Various Materials for Atmospheric and A daoedPressure Flash Pysol3ses of Cbesterfiald Cgarettesr:17Rl senp . EthaneAbsorbancyat 4250 oa-

EthyleneAbsorbencyat 1915 c. Acetylenebsorbaesyat 729.4 girtatm. Mta red a s zed_450 .0043 .00405 :-0 . 0002 .0024 .0056 .0024 .0137 .018 0600 .0072 .0061 .0112 .0051 .0616 .0669700 .0161 .0068 .0290 .0148 .161 .166600 .0210 .0126 .0496 .0273 .0230 .240

length pyrolysis furn.os. This apparatus abould all w ppss7.y see to be Sad.pyrolysis apparatus in which powdered. tobacco is slowly'sifted-iato a r testis

Pyre Osago/eig.J. rid

0.93.40618.9 12

To avoid this difficulty, sxpariaaats are blind started wtha

at such l war prrssurea. as.tesll Si at ataoiphario preivari. and siasi_, . .tbs effast_at abaa8tas't!aidsoso tiN;~boolll._.sidlarli,s'sAseod. tf-+sIr71~the soouet of swett tats?talla.tbe twesNat aq.t1at-ta great1tavrathis spparstua it sboal*Zbs pooible -to sbsnp-tbs sartasrasw asa11s1L:. `for re+stios by adding suitable psotin8 to the farness, and thus datsssim4

alloyingthe cigarette to burs, either wth puffingor freely to and pastthe thermocouple. These asasursaents show that the maximum free burning andpuffingteaperaturee are rather close and generallyrends iron 800 to 830C

an .ztresaly fine thermocouple diametrically across the cigarette and

procsee. One of the.e Is a sariso of befou nfa of the tespezatare pofileof a burning cigarette.- lbeas were mods in the usual manor of %brooding

production on rate of addition of tobacco.In addition to the pyrolysis experiments, several other types of

messureasnts have been utilised in attempting to understand the burning

prellainsry .Veriasats teed to indiasts a eoosidsrabls dspeadseae of Wrsasdata 1s avatlable which bas boon obtained by this teehnigss, alsbeaghits offset an the reactions occurring. At the pesent ties, as pe tiers

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are found at the tip of the burning cons. The temperature rapier tails - 1 ; k:r the charringtobacco in back of the cone and in the ooolias aah

'r:e r .'.Ctemperature fall wth ins datingdistance fromthe acme severely!trite the boundaries of the pyrolysis sons. Pros these measuremeats itrrrm.rs likely that this region only covers about 12centimeter of theC?,arette at anygiven time.peak teeperature of a free burningcigarette byabout bOC. This to thoughtto occur through an alteration of the boat balance in the oooe regiom daeto the pesence of added mneral conatitusats. At the pesses timoTurtborinvestigation of the beet balaame ib'aMsrwf. Pros prelimlmas~_ stmmereseste~it atwsars as tbom~=atgsassamLel7"a mil! "er ust imelD Dewri bT tktt ~toba

_46-sosibe.etlon ia-264i+siad is :Bros zOa moms . Shia" losesa 20 'Ibomg t i-. , `11F= Z9_ t ~ _ s . .;~;~.. ...: _,_. s u e. ,.s .-~:-,::. --,:..rs~-alpreaa.tsad aonw~emeter Yeer: ~s! aMSSIlimmt chieh bai:~omm-htO :aM{ tan Zsobltigsl~ e~ M

71

booted in a faremse either in air or an inert fie. As the fmrmsai amt imiplsthe %eigt of a small'poedered iediple of s~terial obits it lab 1

almost explosive deoomposition of stem materials at approximately 25000.and burley, and is very sensitive to stem content, the latter refloating theThe pattern dihlee for different types of tobacco, bright. Pettish. Maryland ,of pure met* -tale, and appear to be so for car-of ully selected tobaeoo samples.eor+e. Sheer cusses here been found to be highly reprodioible for weal.shish vkan suitably rooordsd fora a characteristic thermal 4eeompositi.os

It was found that a variety of additives rather uniformy redoes the

teepexeture increases, the sample undergo" weight dlsdnishibg ~ssoipodtions,

useful for estimating additive-tobacco decomposition points.changes in the decomposition pattern, a fact which sakes this techniquethe presence of additives appears to cause alight but readily detectabl e

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Temperature 00Differential ?hernial ?race of Chesterfield Tobaccos 10% Mg(NGa) ,

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The ger,eral decomposition pattern ecnaista of three relatively,distlaatwhich are thought to be similar to those occurring with3A the

.--nature and 200Cin which water and other volatile materials apparentlyrre distilled out of the sampe, and the rata of weight loss is relatively

. nd cigarette. The first of these consists of a region betveaa rood

cigarette. The tobacco undergoes extensive *barring over this teapsratare-

weight lose occurs at a fairly rapd rate and heavy acrid mocks is givenoff by the sample. This reginn is thought to eoinalds in temperature wthtt'.3t to which the bulk of the pyrolysis remotions occur wthin the borntng

slow. In a second region between 200 and 5OQ0C the bulk. of the Overall

rang. The final ration-is n v e- a pradnal.loss IS veigbt .AMto the tsos eombsetlat of the,tabssw almreeal 'iaaibasewr aeQp4 1a" .aestlalLKhisf'td[?arnses~-Mle-sda~saha~soal iie a aah 1a teas ;teat=i.tfl ea 1a -

'Isot~teslsaia~s, rela dCe-p~awa~s~ rie- ansysiaa ~atlah,'L~aboos me" to moors-diatiaetly estli. the daeoapositioo patters at eariep--toieetee both with and without sMitives is that of ditferesttalthssssl :aaa2reis. this sosydat of a measurement of the tea'psratare dltlesseseexisting behoves an .Werimestal seep1e and an inert sampL While bosh areslowly and equally basted is a ssmeas furnase. The tsapsratare pattern

the reactions ooeorring esa be Of both types at saw given temperature, theor ex

l&m research

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