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(` sIIinm cy wa? USiAM with e®phe-sis upon ?OSSIET? C'.?kDa- S F'ROM T:1&ACCO ~ Exh'bi 109D Data DR-lID A Cn?::=E AD b7 C1aud• F.. Te~.,qwe,qwe, Jr. 2 Fsbrvarrr 1953 J C/J7 7 Hl l 043168

(' IlM 2F 22MA-M I. JGS ~L`f . P&P 2 II. ~ $~SC~Og• 2 a. ?ol~;~,lea.~ -oma 'c pz3zrocarkn.e Lad ml.at.A Het,.r2oycli4 6 B. Q a~ Ca: cinoa.nic a a. 9 d Seterocs4lia C.omnouid~. l. Ali~hatio ~~ 9 , 2. &r2M Lic Lx:a+s• 10 3. X1sceLr.ma.e r"a. 10 1•• ivJpiV~IJ hNJ 4•l.ny,~~ Arid~I • . 10 A. StaLintiGal S 'es. 10 ., . ~$L'.,udi e s vi t.h lo Dncoo Ss~ as ~a noe a• 22 C. :z. -en;s I9er.tiilc3 Lg fob°eM 2aLxjARM. . 12 , D. Cr_-_-po :ae-a soi ~.~s o ,~~stancsa g~' + L'4esibili~ _o~ 13 Cs.-~no;-~~a a ri a:.n¢ Tbesi.. y. '41oDa.ooo Adi ; inj. 14 i4_ J+?hT. J 16 -1 - CTR MN 043169

!'h. ob jst of i2sis report is to g,tvs a bro.el, general s¢rr.7 •f oanasr r.saarch, with -iapbaais os •tuiiss artoallar or poteatiallJ r+Lt.d to careimge3ss Sron tobasoo. Pertinent xe.fsrsnoes are sit.dy whero possible these are review artieleu vit,h oosprsbenaine oonrage anr] bibl.iogr.p2q. Ib attsayt has been mede at oo~stabsss of oaverage of various topios or oo+L;Ilet.- n+ssa of oitction of orig•i=al .vciroes. II. '~T "MMIOg Caaosr ia one of the aost aaeieat of b=Ln dis.ases and its ooairrence is not.d in the earliest reootd.d history. It is on. of the srsat universal and eosron of all dia.asss and attacks a11 foss.s of lif., including plant life. In strict sedierl naaQei eenaoer' rafsrs only to saligmnt tmors s.r± sinz frsa epithelial tisane, that is, from otlls sontained in the skin or coverin= stuoosa or ssrous sbesbransa. Kalignsnt taors of non.pithelial, modified, oor.n.otiw tiasae are knovn aadica117 as saroosds, aW various other ar.zss a-_e ap;tlied to other intraaite, sialignant growths depending on their origin. ard ahsraot,aristiea. A arsd.ioal 42usifioation of Lusxa, both aalis-- aant and banign, is given in Table I. To the 2tpz,an, •canoar" haa, through long asags, oose to be an all-embraaiw tera referring to a11 fo.rzs of ral3.gnaat, invn.ai.e tusora, and that nsap Yil: be followed in this discissioa. As used in thi s di sau as io n"earaino geni o" xsans oanoe: -givdncisg, a nd a •ca=roinogen" will sser.a a oancer prodsoing ageot, tGss" being gsuerally aaoeptad ;iaszss. S~ I Cle.saifioation -o_° Tumors _ e:Az n M-alirnan 3c sot in-Tesive Inrasir. S: ov grovi.z~g Rapidly growing Jo not -.etaataaise lieta.taaise "~o not intarf®r-s vitz hsalth Det-imntal to bsalt:, ofLen fatal 1. CMNb..^?IV_'- 2ISSGZ TMcaS A. 3anigns 1. M.roma, co"sad of fibroas tisaue. 2. Choadrova, oanpos.d of cartilage. 3. Cateossa, coa,xssd of bone. ti. Lipom, composad of Yat. J B. Na1lgna-- ts Sa:-cama, a cellul.er tAmor cxon?os.d of any ooaasec'.ivs tis..i ealls in d.lsar'!a_iy a.r.^a:gnacnt. 2 I t- U 0 ~ W ~ ~~m R ~"~~~ 043 ~ ~~ ~

(N II. II I. Ma.a TL45U SiMTR9 -- B+aigns Rjvssap eorposd of iaooth sms41e tissu. , Y:- ITFffi.IIL tQNOW l. beaiWu 1. 2. AsFil.Zom, acx,xse!d of sarrtio* spittxlims, Adsn=ti eaa~asad of glanQnlar spitbalita, $. . Nal.ignaat: 1. 2. Epitbelioss, sqt:aasors •pitbalia; oella in disordecrlJ ai-rsnQs-eat. Carc..'mwa, glanhul.ar spitheli.al Calle in disorderl7 arrntszeaent. 17. RK~Ir..~ 1~. ,IlL ?uMIRS A. 3cnigas 1. iiamaneioaa, oam:-oad of blood sas.ls, 2. ~~, oa"aed of lyaph ? sasnls. B. ?~.alianant i Sr--Iolholiam, an?oaed of •ndotbali.ai oa11.a in diaordsrly a..-ranCessnt ?. Piao~:?D 2UW,)3S A. 3enign.i Sevu.a, a r-izaecrted sals . °. ?+_w 6-n&at: Mel.a.ncaa, Pigne-rtd t.z=oi darired iram seolo. C&=sr bsgins as a sizp14 body eall or group of o.lla vhiah s7a&..nlJ s',s..--ts to W.i1Li,^.ly vittrnxt restraint. In •aposrtaaeons" human canc5er this au?+ 4 ;1!.ontion is initiatd by nDkaovn csnae or oeusss. s0ooupationnl• aanos~s is :.-l,.e reau:t of p:rolong.d axposure to imovn oaraiwg*alc agents, a.s radio-- actiws cs;.c.-ials, z-.remT, ooil tar, aad others. aRxperiseat4l" oanoes' is the :eaul ;, of dnlib-sruta snd often, repeated, applicatioA of oaraimgsnda agents for '. ;a parpoee of produaiqq canoe-. T:w unrestrained aad nava]ly si;id milti.liaat.ion of oslls takes place ind.pendantl,y of the reat of the aodr, servizg tb use11i1 bodii.y Panc'.:=; ar-i iaRdsa the surrounding tissuss er o ras r.s b7 :i rsdt agrea.d. Jiagm r•ed aod treated at thi e s tsge, usna117 by :adiczil erarzsry or radS.ationi t.he oanoer "y often be rsov+ad or aads to s._bs±de before the aatire o-,,4r: i= =r-olaad. A].loved to proeeed unchsckedg the -T~ovth a,r^s eads throuot,oat Uoo body. ':lxall groups of o.lls ba aak off from •..ba pr'..--ary Zy-ovth a-nd :sc by tbs body fluids to distant tissnes vhe re they i n turn pr->du,e~a grr e*.!-~- - i.=Uar to the priea,ury tn.4 _r: It i ~e+.-~ ~,~• c ~:1+: : S ~'a ~.ic ot s`t2'ea.Cl o.^ :6 3tasc,r:..°'c33~ i1 3t dittiOgLtia~ s ~g~t •!"" a benig-i, tumor, CTR 11N 04.~ T"I

(I In i;dte of obae.rwationp rsa.eroho and theorizing for the paat 2000 yrars, tbs awas+ cf spontaa.oess bmean eanorr is sti]1 unkncva. By obsavatioa end Ly oorralatioa of -qlinio.l data vitb ooaypation, ea.irosaent, and the lik.# s.rv.ra1 at.ete eLvA a8 ooovp.tioeal aaa4ar Oave bwa diavo.rtd. ibovgh know 1sd=. of Mv or vlq tb.se agents att is v.rr 1a4arql.U. Ear1y in the present oant=7 it w r*aUsad tbat wrlcers in o®mpatLona insoltiaR prrolAag+d az.pome to ooa.I tar products sboV.d an a.bnor.alLy high inoidsam of W-n oaao.r. In 1915 Zssisiya and Iobika.a dlseorsred tiAt. as edaAaz of tbs skin sould be prodzsosd by painting the sars of rabbits vitb soal tar. D.tailod infsatigatiou into the aature and ia.satitT of the earcinoesnic agenta in oaal tar indi.Qat+d that the ageats wers proDahly poly- noclanx s.zoaati.o 2qdr-..sarborsa, probably alated to D.rsanthravev.. 1A asrDer of oospocmda related to b.nsant2iraotrA were pr.pared and found to be oarainogsaie. Conai.-re.ntly, imnsatigatar9 wrScinQ on ooal tar iaolated j,4-bsaspyna.• tonnd it to be idsntiaal +dt.ti aynLaetic 3.4-b+nspn'sae, aLd shoved that both onspound.s had identiaal0 poaitiw aetivity. R.oent work has shown that ooal tar oontaiar other potvnt cmrcinoeeme. By 1930 the work of the Lond.on sc3ool under Keisaaw&7 and C*ok bad t-~-orouz,hly estahLahed the fact that oarrtain Pctre, synthetio) pol.ymaal.ar a.xomatie oom-_poands ~,~ere true carcinogens. Ls a rssalt of wor3c of this tse=a, to;;ethar vit?: tfia'.:;o.° A2-- :aesrioan group b ead.d b7 Fi.asz' and Zat.b...nai it was soon found that a la.-Z* a.aDa~ of polyirclic aroaatio , togethar vit2: ssa.q of their Itixtional derivatit+esp poasessed carcinogaoic aativitr. Later work s3oved thzt anb3tancea skis to po2ymaolear arQba'.ie bjdzoc~na b:.-t eo ntaining he tero a tocs al so po s a+s scd carcinaecs'e c a ati ti ty. i s re se.."ch activity e.z;~snded sierera_l otber ola.ass of a.~onsYis vere fomi to be {~ oarciaogeni.o. Those reoeid.ng moat attention he.yd been tse sustar+ds, rari-Als a.ro^...at,ic anlm coapomds, and oa:ponnde related to 2-4.ainofloarene. Mup o: :er classes of orn,-ounds have bssn investigated and asnah work is oarravtly Dai.og doae on this bhase di the proDlea. / / 3aw~a1 seet-hods hire been used for testing of tb6 o&rciaogenie gf_ sate of +ea.rious substances on amixt . These test netboe:s are accsxxtep '..hough rath_r alov. Waa,7 kinds of teat a.aisdls have bein usad, too~ pazn strain eiae seem to be used most widely. ?u.re strain mios abov ndar27 Us arme a~copti bS1i tr to ehesd oal aarcinogs ai e i s and are ot .e ry siad-~ir gene ti c oonstitution. S4isoeptibilitJ ms:: vary oonaiders.'u17 from etz&in to jtaz!n, in one test ssat':od a dilute solution of the carcinogen in inert so:rent is B-ppIied to the skin of a test anisial. Application is sade, tdd.r; :+eekly, for a-period of aeversl veeks. Aftez a more or ieea p;'v7Ja;ed latant pe r? od an a ati ve onsti~no a-e n gi fes ri a e to a ca noetti+us ~-.~ of f be ski.a. ~ Another method involves injection of the agent su?+~.ite *~aso: intz•_`- pe:-;toneally into a test aniadl. The quantity in,jeoted ;:z„ solv.nt is oftea used, ard. more than oAe injeotl.on is aosetisisa >ade. k:.~6t''•iw car- cino;en.gives rise to a canoer of the oorsmeoti.e tissue, ,-;`~ti at the o_ i 1 j= ot.io n. Kar;y o:L-s...- te s`,.a ha ve baen na ed. Exps ri =:~aad ik^..hai dp e.ra 3ale to detarnins within a day or tvo the t.ime at vhic--', a U-:ek°n-ing of the t.iss:be is indicativv of tunor forzation. PRSthological z;-~~ss e-2 used to e:,t,ab.lish whether or not a tumor was aottLallJ present. - 1 - C• / V 1  ! ! 0• 1!' .A `/e-e2-C

f` Caroimgs:as s..rr oonaideraDly in potanq and taiaors app.ar in traated aalsnls only after a aonsidarabl• latent prriod. This period irari.s iroa oaa to two srrntas for very aetirs eoepoand.s to two or .ars years for fsbl,y active ona. k3dle the test a.t.hods dire very good qvalitatiw rssulta as to tbe aarcinoC*aieity of oompouadsp a*outat* qsxntitatiT+s rssalts a.s to r.].ative potstaiss are ditTisnlt to obtain. 3ersral systeas lsavs ae.a devised for rating eoapotmd.s aa to .araizoCsaie a.otiTit,, bat atw s*ms to be entirely satiate.etorT. Suoh systeas nsaall,y ta]es into aooosuit dosaV l.ewl# dosW periad, latrat period, and p.roant of ani.als d.valopins active eaoosrs, Witb tb,. Yaowledge that spsaitia, pur., organic oo.qoaads could in!uoa .acpariaarstal oanosi sim33ar in every respect to apontabemsa oanosr cxam natuY.lljr an atLwapt to aorrslat+ spontanwm hsaman oanorr vith the prss.aAe of Ynovn ch4wical oaroino"as. ihils s•aores of potsnt ds.mdca.2l o..rainog.as •ure m.r Irno%rn tkwro is m dis+st eTidaaes that tbV ars indssd rsspeasible for epontansona Aissn oseoar. It is possible that tbea" ah..daal odraiao=.ns say ba proc:naed in the body by abnorial prooss"s, bat substantiating evi.d.noe is 2. cdd n; .'• o da te m hvn c3emi cal oarcinafe n bas be sa foand i n oanoei+otu tiesi:.a or in body flni*ia. Fiosmr, sneh an agent xs,y have aet.d as sa ia- st±3stor of aali3na•nc7 at an earlier itage in the lif. of the organisai being present in vaniahingly azsall e.9o=ta at Us t•7sw of attempt.d isoLtion. There is much czi..-rent reaeareb aod apeonlati.on on this phass of carainotanisis. I t i a a1 so po s s i ble tha t s po ntansaus carrxr aay bo Caus.d by ext.raal c:aseiaogenic ageats, such agenta a=„ering ths body with too3, during respiration, or boing aheo-bed trorn the body anrtdoa. Sose such ag-~ata, as ooil tar products and x-ray, haTa indezd been aho:rn, by esaa`_ nation of clinical data, to oamw an abnorr,a.i.l,y hig.h rate of ine-ridenae of oszoar (oocupational ") in persons BubJeated to lone and repeated azpoa:,=a to thsa. " other external ag*neias hcTr beoome a3spect, and considerabl• rese4roh haa been ddw s.nd is in proirsss along l.4sae 1Leas. Several atal.istioal stsdiea, based on elinioal data, on eanosr of tbe reapirai,or.T systea hare bc~en cads, and t.bsse etad.iss indioata an s•bnots.l ix-ease in the inddQnoe of e,4ob oanc5ara, paxt.loalarly among aess, dzzrizg the :_aa t a ava...: d acades .: has e a t:xii ab i ndi ca t. tba t soasa Qaroim gsn, either ain bo: n or ar'..::ia_ally inta•oc?uo.d into the raspirator7 eyeta.t, is responsible for canoar of the respiratory systea, sad taat videspread expoauro to tb. aar- ;s=.-:n, va..a.-ly azoN nen,Lcs b+aa fairlq reaont and is inarsasinQ. The reoen t ra'.o of iac..-saae o' eanoe7 of tbe respiratory syatem rathsr alos.ly ;>azrnllels the racent int.rocturtion and rate of inomTsie of cigarette oonitmption, and Lhia, toge;har with the fact that until Tary raoentl,7 the vast wforit, of :;igaratte aaokara haro been sen, 2ms raised a wsJ oonsiderable quosti~ There appears to bo a groving s-.ust-~idon, or e-Ta.n ae~tano+, a~rong s*diaal men and c5ncer resers-obers that the xra12e1 inc-rease in cigarette oons:mption and inoidenoe o: oanoer of the respiratory ays',sm is core than ooiacidsaos. The atatistlor._ at.uies oontixms, and their iaplicationa 3save bcooze the subject of esucr n?.ec-sln:.ion. T'hia vork is disc+.iasad in more deta.il in a later section. Som wrze:-a have atteapted to p:vd:tioe txperizen:al ea.noers in t..at by a.ppli~L:on of lzrs obtainad fros tobscco, tabeoco =oke, and otb,47 _ 5 _ CT~' H~~ 4~~~ ~ ~ ~f`~ ~

a,ate±1a.le derir.d fr+oa tobaaao. ?be results of tbes" teeta, aoae atrong,l,jr posittiive and other ooapl.tely bsZativ., bsvv bsa iaooQCluaivo, tmoagII ronld tes to iadi.at.. the preseaos of earoioogass. Other workers hare atte.qt.d to isolste a+eraaaogena fzna plrcnlJtio -produota fYva toDaaoo, and the i,dsntiti- oation of knovn oheaiail oarad.nojeas is rsported. A l.at,er seotian will .ona.id.r this work in aorv detsil. Beonnae of the pouible oaaneotion betwsa tobaoco sooYi.ng and oaneer of the rwpiretory sratom it is rrs11 for aarsnfasture.rs of tobaooo produats to be aware of pns+t and present oa.aoer rsaearoh, Aooording1J, tLe re.aiaiag aeetioas of this disauaaioo villl r+-ri.u in .osw detiil tbe prs.ct st,.tua of caao.r res.a_rch tidth particular eaphsaL on statistioil s tudiss relating oanoer of the respire,tors sratsa to use of toDaooo, and on knoun osrcLogeaic ompounds aad their ral.ati.on to awyoands present in tobaaoo or tobaaoo saoYe. OM?a CAL Q RjRCxs= :.. ~l~oleer AMMU r 1pd.-ogarbou.e ind ".•gjajgd RejeroaPello QoZ2UWA. (1 - 16) A l.rge m=ber of polym}clear a.ronatic coupounds, togethar vAih suq related hcterocyclio ooapounds, have bean tounsl to be carcinogenic. on azr~ration end diacsesion of all suah ooapormd.s is obrioitsla baToad tbe ecape of tMs disanaeion. Reprtiaa.aesti.e ooapounda vill be oone-de.red;a very gcneralisdd eor^elation of aotirity r.ith strnctare vi:_1 be gissn. Cbol.anthztiane (I), 3,~--~eas?y:ea. (II), 1,2,5,^-c.'iber.santhraoers (III), 3,4--aaasa;-hexian:ti.-wne (IY), chrys.r.e (V), aud 1,2,3,4-d..ibentphecanth.-ene (PI) a..--e a11 car-,r-"m;; ans , and are re ;re sea ta tis o f the bns i c ring e truotur,sa found to sccampany carcimgaaic activity. II 111 J V 6 I a/ CTR HN 0431"A

:?yese ooapou.ads, toetKor vith their derivatirs, lu.e De+a studied raLaer =t*zisiv.ly. 1• saaabe.r of allql-# arrl-i 6.].Ag..ao-, Wa.no-, lll4'l*2C''-# and. Lydrwqmat2q1-de: irativsa of tbe parreat tyd.rooazboas ba.e p~ to be .otiw, often anre aotiw tban-Ua parent eoipaaad. Mozq ral.at.d bateroa7olie Oompouads hn.e alao Dsn sbo+rn to be oaradavgenie, rsprsstatatirv erasP2as b.i.ag 4,9-di- ostb71-5.b-bnnsthiophm,nth.-S= (TII), 1,2#'Sv6-dibensaari,dins (7I21)q s.nd 7i9-4i- met2yl-3,lv-beauorid:.ns (IX), ,j , . ~I . -I GZi I C N~ IX ConLsaction of the oaatral ri.cq of dibansanthrarxne or its iaolog (VIII ), as i•n 1,2,5,6-di8onsfle..orane (X) and 1#2,5,6--.'SDaasaarba.sols (z.I), disini•ahes Dut does not aDolish activity. The lower 1.init of moleoul•ar sise oo"t.ible vith cereimgenlc aativity ap- p,--:s-tD hase:beem reaahed in alkyl subatitxsted tric,ynlie hydroosrbons, of vhioh 1, 2, 3,l,-t.eL.-a-%ethyl pLlanszt.hreaa (ZZZ) s.nd 9f1C,dirsthy2a.nt8raoene (XIII) are ezaaples. ~ ~ '3a u, pe..r L•sit of sol.c.itar sis" is still wso*rtaLin, thossgh no ooaponndG having w; e than siz fused rings has t~ far bien sborn to be earcLooZeaio. 7yi--Ag at the a;)p&rer4. ttppar l.ialt of siolscul.ar aisa art hesaorolic oosyonnds sucy as 1,2,3,.4-dibarso,-jrane (XIV) and 3,4,8,9-dibersoPO'T+ne (2V), both extresa¢lJ po'..ent aas•cS.aoreas des;•ite their high s,olcculsr veiZht s•nd i.as9uMlity. i I .i 7 IN IV L.r T f'4 F iN 0 4 3 17 ~•

('` ?he oa+Qrusxie desarib+d abors servs to illnstrats the i"rtant cLss.s of aeraiaogealo yol7saolsar aroaatio tqdrvosrb=s aaS related oospounds. YAuV wazice.rt lxve sought to oQt7t2aU aarcivogsaio aatiYiS4 with struotttTs in this olass of oompouads. Ptr d.tail.d oonsidsration of stroctur+ 7+..rsss atLitiV ia a larQe namber of smh oo.Qound.t osttain Caaml oonolnsidas have ti.ea drawa (1 - 20). Dadgsr (10) has aaaaris.d ttye.as oooolasioas in an sxasll.aat review i-rtiC.2.11 • 1. Cartai.n triarclio, t.dj„rsqvlio-i psataqalsa and h.zaoTolic lyd,ro- ,vLrbonr or their boa,olop an eano.r groduaing. lfost of the aotite oor,wuac3a, Dut rot a1i, ars deriTStiyss of ghenanthrem. 2. lidny oloanl,Y related het..roeynlio ooapouads a."s aleo oaaosr produaing. So ars aerte.in dibensflmrenas. 3. The in',zvduation of ase'.2:q1 _rroape into beasanthrAo+na, bsnsph6canthrenss azx3 .b.:7aa.ae raozma11y 1ssds to enhanoed activity. 'h+o x*tbyl trvoQs or oore aciraally aat additi,nl,7. on the other hand therm sezas to be a lisiL beyond which the intraduation of tuz-'.bsr set2q1 groups doss not lsad to enh&noed aa'•iYit,T. The S.xzttroduetSon of sqtiql groaps into the angular ri--Ag of beasa.nt.hraeene dop not have this aft.ot't and al.' ezeoh caapon3da a_ro iaa.atir* or have only traot activity. L,. Similar rolntionsbips hold for the beasacridiaee, exowpt that the 1,2-bzasacridinas are much sors oarcimgsnio tha.n the 3,4-bcssaaridi.nss. 5. The i.ntroduaLian of xeth7l jsroupa in baaspr:aie ar.d diD.asasthraotns ia mo:v camplex. Ia aary cases this diminishss activity alt2'roagh the oppoaite sea be trus. 6. il.kyl gr+ar.aa other t,2a-- iethrl are yrograsairsly lese efteo'.ira as the mabe: o f aarbo n staas in the ohain i ac.tiaasa. 7. genrv ol3,e: suDatituRn'ra in "tavoraDle• positi.on. oan coarert aa in.lotiro paraat bydroca: boa into a oar~m4eaio deri~rstivs. Both elec?son at`.raotiag and e.ootoron repelling grou?s nay bave this p.-v~erLy. "Pavor3b.le" poaitions for aetr,yl gro" are e»ti nsaessari]y the saae es for other groaas. 8. rart:.a.l hpdzogsnation of a carvimg®nio ooapound soaetixcs but not aluaye de$ctiratea the substanca. f 9. Attempts to relate carcinogenie aotirity vith (a) shape anci sise of tuae mleau? a e:.nd (b) elrctron ~^-ge on the ph,enant,hrao9-type doubl• ban,3 present 3n wst carainodens have b-.3en only partly suecssa1u1. .,tudie2 of aot._+y±*_.- and li is reasomhle to 8uppose tbc t vi th ia: reased da ta and s t.udjr vil : e ome a mo re p.revise und e rs Land.ing o f t.s ftryiamental relations`sips. 8 CTR HN 043'-1fG

I in e, Ann&j. (1,3,12) ` '!be diaaor.a-y t2bet oata.in polTan4lsr.r a.ra.ati.o eoupouads are stisulat.d a s.arah tor-otber tLassas of ooayounds wS1oD tdght also yroTs 1bo kave asti.ity. While tb. pol.Tau:cl.ar aresatic 00apou.n3s hnn rro.iT.d the .oet atteotion, other st.rjatarall7 unxed.,if..d al.a.asq of oosspoarnis ha.e inrS.eQ ba;a aLown to be earainagaiio. The s.arch for otbar. exraiw`sm is tar traa oasplst.e aad oontinsasa to be aativ+aly qurswd. Compoutrds r.prsssatatiw of the var3ons alassss of earGiao;ens ara 7ist,.d and briefly dsasribsd bel,QSt. 1. &Utbotio and H4 gnan"+ xi troWn sastards (1TI) aad sn1tur. av.atards ZYII ooots`iaing two aotive oent8rs haie besn sbmm to be o&reinotvado, apper.ntly dms to their action as crose-l.intiaQ e.gtiats (21 - 24). Other snbetano.e abl* to aroas-liaic add groups by este: iS:--ti,n- azd bocvn to be ' g.nio ar* ontadians diepozid. (lE=), t,rimet.t7lnl aal,amina (XZZ), a.nd disarylglyools (YX). (1, 25) 1 C~~ C::2- C1 C3z C~ -"C1 , ~ 2 / ~ ~ S Cx--CH c:.2 C:?z C'_ ~ C?.2 C::2 C1 z 1 x71 ctf_ Ca2 ~0~ xti_I %,7III / ~ . _c-- .-- - c C C~OH c~ cHz o-soz c~3 ~ , ;, ~ F h CH2-cx2 0 --S0z-ca3 C ~ SE Cr.2-C XX Ot'm- a1ipha•Sc ca.-c:1no3er.a a.re certain •t2~ylensi,ninea (7.II), ana c..-ethaae (ZXSZ). (1,25) ~- - C -ti 2 2 2 0 CH zcHj- o-c-sx2 `•"-X I XZI I 9 CTR HN 04311 `~~