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p:^ai iepo:_ Contract: C':Z-0030 SQ?N.A eZY III. CTR-100 (I-1c01. C0-C?IRCI\CG2:7S5:5 A:iD C'ROVIC He1L.dT.,,V C: :a CiGARiT':IS SM0X-7 The first c:salat:on study _':i:ed :ent_cky Reference 2a1 cigarette ssoke ~(tiiqh ;ar-lov nicoti e) a: a dose of "1 aq/tota: particulate =atter (':P`4) per day per co;:se lu::q. The experiment =ad _ou: rajor objectives: 1) to dete:m:-e the icpact of _;e ciqaret:e sroke ;ene:ation equi ^ent and delivery system on t~e test aai3als (3C3:1/Csa female mice), 21 to determine t~e toxicological ef:ects* of daily exposure to 2a1 whole cigarette smoke in 3C3?1/Cus -nice over a 12-15 aont:: period, 3) to characterize the susceptibility of 3C3F1/=- and C1H/anf C::a mice to l::ng cancer after t:ea=ent wLth inovn chemical carcinogens, and 4) to dete:mine the effects of _aily exposure to vho?a ciqaret=e smoke on 3-methylcsolant!:tene (MCa)-ind;:ced l::aq tuno:s. A total of 3476 mice were put on test :o: this study. Mice ve:a observed during and i=ediately after daily smoie and sham treatment. ?or the smoke expcsed animals, :rhile a certain aaouat of adaptation occurred, t`:e aninals never accepted the =oka exposure without some aqitatio.^n or struqqlinq in the holder. They also occasionally demonstrated some shallow breathing or gasping during exposure. Iamediately after exposu:e, ssice in the smoke exposed groups were :ethargic, ataxic, and hypothermic. The sham exposed animals also demonstrated agitation and struggling while restrained in the holders, but generally appeared normal after exposu:e. Cacboxyhemoglobin (COHb) levels in the smoke exposed =i:e averaged between 40 and 50% after each exposure session. ".`.e results ::crs the 2A1 smoke, sham, and shelf control groups uil: be presented f?:st, followed by the resu:ts ::oc the !!CA-t:=a:ed group. The i=pact of the exposures and :elated -anipulatio.^.s :esu::ed in "S0t of the animals dying in the smoke or sham exposed groups by 36 weeks on test. :Z addition, neck abrasions were cbserved lo both smoke and sham exposed mice. Two equipment modifications were recommended: temperature coapensated flow taermistors to monitor smoke/air :lov. _h:ouqa the modules and polyca:5oaate inserts to cushion the neck edge of the restraint. :t:e theraisto:s were designed, developed, and utilized. ?olycar5onate neck inserts were designed but their atilization was not approved. Data from all 6ham exposed controls shoved that the spontaneous incidence of malignant lunq :=o:s in CTR-100 (all alveolar adenocarcinomas) was 0.5%. Smoke exposed animals were observed to have no malignant lun,T changes during the study. The most frequeat lesion observed in the smoke exposed g:oups was pigmented alveolar macrophage acc,=ulation (PA!!A). After 20 weeks of exposure, the incidence of PA:d.a was 100=. Two other r. 2 CTR CONTRRCTS 029178 11248928 CTR MN 04,39EGS

?iaal Repor: Contract: C-R-0030 SG' W a Y lesions were associated 'dith smoke exposu:e, squa=ous -e:aplasia of the t:acaea and :zi-:tis of the nase. T:eatzent of 3C3?!/Cua aice with MCA zes::d ted in -0'2 3il:=esent :ocbiaa:i:ns o• `sistooat`:oloqic diagnoses in the lunq. alveoloqenic ?esic,s we:e classified i.^.to 4 cate:::ies: alveola: ,ype:p!asia (ii)r al•reolar non- co:np:essi-q'^..odu!es (AYCY), slveo:a: coop:essi-q :9u:es (aC;t), and alveola:adenoca::incaa ;A aC). Sq;:amous lesi ^s were classi::ed _.:0 3-_.eaocies: squa.mous =etapiasia (3M), squaaous ceoplasa iSYI. a^d squanous cell carcinoma (;CC). The other carcinoTas four.3 ..^!__ed poorly di==e:entiated ca:c.-oaas (PDC) and a va::ety z f aixed csrc:::ocas. The ca::i::ccas metastasized and even:•:ally caused the death of the ar.iaal. The proq:essive nat::re of tnese :esions was documented and a scheme depictinq the evols:ian o: these =ali;.^.ar.cies was posts!a-ed (see ?iqu:e 29 and Sec::oz %nci!larl s:ud:es with other inown carcinogens and o:"er strains of zice suggested: !! C3H/anf C:La and 3C3: !/:-za sice were idenc.cal in :hei: s::scepti5ility to ~lCa-induced __c:q _a^ce:s; 2) a dose :esponse to MCa .-duced lung t;:~o:s was tse:ved; and 3) the carcinogenic activ::y for lung tissue was =ete:=i::ed to be yrea:est :o: MCA, =^lloved by 7,8-dihyd: -7,8-dihyd:oxy 5enzo (a) py:e::e (3a?-', 3-diol) , both o: uhic:: •:a:e -uca more active than :,enzo(a)py:ene (3aP). Daily exposa:e :3 2A1 cigarette smoke did :ot alter the types of MCa-iaduced p•::3onary lesions observed -__oa:ed to sham expose•d mice. The:e we:e slight variations in the incidence and 3ist:ibution of the lesioc:s as a function of 3_:a:ica of sao:ce exposure. analysis of individual lung lesions s:"owed that the `:Ca-shaa exposed ;:ouP ::ad a 1iqher inci3ence and/o: sho: te: :a:eacy _°oc all ca1:?::a.^.: 1u.^.g t=ors than the ':C1-szc)cs exposed g:ou?. 3noie exposed _ice developed a slightly ..i;::e: .^c:denca of wC:1, AC:1, and/o: Sythan the sham exposed,aice. analysis of the develoc.^.ent of either these latter lesions o: =aliqnant :esions was also pe::,z:=ed. Daily ex?osu:e to 2a1 =iqa:ette smoke did not alte: ~e incidence and/o: dist::~:ution of t:.ese mCa-i::duced lesions wnen compared to the saaa exp:sed ccn::ols. iY. ':R-101/1. CRR7y:C ZX?OSCeZZ CP 3C3:!/CC?S `!:CE °0 2R1 A2?T"E S1:OiC3 This second :csa:3:ion study was the fi:s: fes;qc:ed to use .lonq-tera or "lifeti:e" chronic smoKe exposu:e. Future studies .ere to address suc.'h variables as specie sensitivity, smoke exposure regimen, smoke dose, cigarette type, and d•s:ation of exposure. However, after initiation of this second study, it was decided not to pecfoa any other Lonq-te:a smoke inhalation studies. Thus, the main objective of this second inhalation study was to deter_ine :::e potential biological ac:ivity of daily 3 CTR CONTRRCTS 029179 11248929 CTR HN 0439-66-

?:.^•al Report :3nLrsc=: C-Z-:O3G SVnVf7•!ZY exposure to Kentt:cky Re!e;"ce :a1 :ga:e:-4 smoke .`•::;.`, _3: - •.l'1 ..:cotinel under one soeci::- se: a: exMe: -en:a1 ---d: .. s.a secondart objec:ive was _;ed_:e:mina::on of t..e poss:b:_ ,e::ec: 2: d a i : y e x P o s u : e : j s : a < e 3 ~ :en:o(a)pyrene-ind,.ced "ne .1•=be- 0: :z:ce an :esc .__ .-? s_cie s-an aad siel? qroups -as::3'a^d 439. :esrec:.:e:y. 3a? :as _ :en int:at:acaea:lf :o an :.`.er ;:aup of :^•:ce. --e ---be: ~: oice cut on test :ar .-e 3a? - saoke, 3a? - s-a, a-d Ha? - s:.el: ;:oups was 320, 257, a:d :30, :es;.ec: vely. 3a? :as ;• :ea =h;ee ::nes at b!veekly .-sr~als and smoke/s;:a3 ex::s;::e ~:as initiated one :+eek after .;e :as: 3aP t:eatxent. Smokz ex:cs:::e concinsed on a daily basis :zt 1:0 weeks. The :.-se ~f :R1 :;arec:e smoke was dete:=:-ed :o be 0.2 =q '°?!i -er day =e: =:•_se ^q The results :ro3 _"e 3o<e, sham and shel: v:1 be p:esented :::s:, :oL:.;wed by the :essl:s .-:?. .-a 3a?-t:ea:ed groups. The major cl!nlcal si;ns ia ^e smolce exposed, s-a: ex?:sad, -^d sae1= =ontrol mice :+e:a as ::1:ovs. 1) The -'asc::s ::r o:e~1 =eath of t:^e 3ice vere ei-.`.er =^di:.or.s that randa-:.y -2- nai-aLs P:cm the study S!.e. smoke cr sham expos:::e--ela:ed, ho:der-:elated, or doc=ez:ed ai' or smoke flow :....:e.2s1 , or '_evelopiaq diseases that litely :ed to the death o:.ne aa::al. 2) Rate of weight gain vas sl:ver in the sham and s.:<e ;:..-;:s -c=_va:ed to the shelt :^:::::-s. 3) ~aily COt•tb LeveLs sve:s;ed :7.2%, 1.4% and 1.81`:r :::e smoke, shaa and :espec=ively. - Among the shelf ocn::sls, 50% o: the -mice =fed Z: s-:ca -eo?las;fc diseases as -e=a: -.oietic cancers ;-33t) a-d j b:osa::o3as ("13:), -dhi:e 40% 3:ed of non-neo?1as::: :asi--rs s::ca as congestion/pne•:-oa:a neph:itis a-3 a :nriety of incidental :esions ("23%) . :hes.e sace ::pes o: :esiozs were observed :n :'.^.e smoke and saaz axpose3 ..i:e. ~atailed analyses of '::e `:1:owin? :esions vere -,ade in r_o~ce and sna3 exposed animals: cancers, 2) zon-le:?:as:ic :espi:atory tract lesiols, 3) other ::on-neoplastic :es::-s. 4) all maliqnancies, 5) head and neck :!brosarco=as, an3 5) ::ecatoaoietic t=ors. all lung cancers obse:ved in the 3C3F1/C::3 -.=e =ere alveolar adenocarcinccas ~aAC). ~to squa:ous call car:::::=aa o: other pulmonary carcis:mas were cbserved !1 the s=o<e, s,am. a; s:nelt control groups. A total of 19 AAC were observed 2u: Z= a total of 978 animals at r:sk in :=e smoke exposed .;:ou=, wni:e 7 ;aC were observed out of 531 s-a.z exposed animals at ::s:c. :a:a analysis (see Section :7. i.) ia :our different ways i-d'._3:ed that no differences vere »se:ved between the smoke .. snaa exposed groups at p< 0.35. 7.:e :acidence of l+AC was ;:ea:er i1 the saoke exposed qroups to the sham exposed ;:o.:ps CTR CONTRRCTS 029180 11248930 ~ CTR N 0439-6:~P'?`

?:na 1 Repo: : Cont:3c:. _-R-J03J 5:.F.-.AtY (p-0.17) and tie Latency of expression •:as dec•eased :n :=e sn o<e exposed g:c::?s ccepa:ed :o t::e sna= ec=ased ;:oups Occsrraace o: avCY or aC!1 vas 38/973 :c: sr:oia exposed ;:oups and 21/551 for _he shaa exiosed ;:o::;.s ;;.•J.5= (:acidence): p0.33 tl3tencY)!. T::e occ_::ence of ei:"e: ,aC o: \C4 ;(:elded -e =a:;est 3i::e:e::ce be:veen the s:o~ce a^d s,s.3 erposed ;roups. :'he _°.nai inc:dence ot XAC or ACN :as :9. ?'3 :: . .ne s~oxe ex • c?a:ed posed c.." :a 23/53i ia ` _^e s:naz ax:asad y:oup These ~a _z:ide.^•ces were ^ot de:ent (pv0.59). -== _;e :=ocs~ •:pea. d =ace ;::.:k:y in .-e s~c;ce exposed ,:o••p p=0.:?) -. A total of five ::on-neoplas:i: :espi:ato:y _:ac: :esions were analy:ed: ?At*.A, congestion, ati:is -edia, snd oti:is exte:::a. The overall incidence :: ?iIKa was :5t dzi-a is considerably love: than that obse:ve3 .- the previous =i;a:ec:e smoke study. The nuxber of ?XYAs inc:eased with exposure, hu: only :eac:led 35t durinq the :ast 4 months o: ezposu:=. Congestion was a:at`er common '-esian in Soca the smoke and s=am exposed ani=als. The occir:ence of conqestian was greater in :-e sham ezcosed ani=als compared to the scc. Ke exrosed •_.ce !c0.02). The :i:ia1 incidence of rhinitis was noc different ~e:veen the s;noRe and sas.-a exposed gcoups (p%0.97), but the lesion oc_u::ed slig::;:y =ore :apidly in the smoke exrosed =ice (?-.25) . The latency pe:i.d :o: otitis media was sno::ec in saoRe exposed =ice p< 0.01) and according to one aaalysis, the final incidence o; t::is :esios was also higher in s-moke exposed ani=sis (p-0.05) . The final .-.cidecce of otitis extecna was Zot different between the smoke and s:a3 exposed groups (?0.iS). Hovever, :he:e :re:e i:.dicacioas :::at this :esion occ::•:ed with a shorter late.^.cy in the s3oke exposed q:oup compa:ed to :ie sham exposed ;:o~; (?'0.10). The ot-er r:on-neoplastic lesion chse:ved was nepk::? :s, a•^n in::a=atc:y :esion of the kidneys. '=ere were no d:::a:ences becveen the smoke exposed and sham exposed ;:oups. A comparison of the occa::eace of all aali;nancies demonst:ated a 27% incidence for the smoke exposed and a 29% :::ci,r .er.ce :o: :`e sha_~ exposed animals. The .. ._idence and/o: :atency was not different between :he two ;:oups. One oartic,:lar type of t_eaor, head and neck :i5resaccoca, was obsesved with a higher frequency :Z smoke exposed =ice ccmpa:ed to the sham exposed mice. "=ese t:LZo:s were aggressive and metastasized to tiss::es far removed :'-e .primary site. A total of 29 head and neck :ibcosa:c:=as •Je:_ observed in the smoke exposed aice. c:apa:ed with 8 in t:^e sha3 exposed q:oups. This difference is hiq:z:y significant (p< J.05). 7zposure to smoRe was associated with both a higher inci3e^ce and shorter latency of head and neck :ibrosa:comas. The zec::anism cy which these :--=o:s developed is unclear. S ' CTR CONTRRCTS 029181 11248931 CTR MH 043966

*:za1 Re?or: Contza_-: C'3-0030 Scli`,•AdY Hematopoie:ia = nphosa:c:-as. ce:' sarcozas, and =ysp oc; ::c c: : yapao i3 :euke:a ias . The :o t3: iacider.ce of :.`.ese _was 131. :d '-he s-o:<e exposed and :91 :~e shaa exposed an._als. ~s:ng `ouc d:_`e:e::_ ,e:,od s : a^nlysis, -he .-c:de^te .;: _-ese =ocs :as :ea:e:, and =~e =3=e.^.^y ; er.-:d was si:..: _e: :1 .'e s:1am ex--Csed ._Z~a:2v t3 e S73oRe eX?zsed aZ:ma/5 Acalfsis a: _~e 3a?-t:ea:ed ;:ours :as 'a z::j :-;ed as desc::bed above. :he ..,.:dence of PAMA in tae Ba? - smo<e exposed ;:oup was 513. For _::e aaimals axposed :o :R1 s-o<e without 3a? .:ea:=ent, :^e _.._i:e::cs of PAxA -was less than .:t. ._ would seea :.`.a: t:ea:=en: wi::z 3a? aodi:°ed the -ac:op-age :esponse :esul:ing in h:g':e: .::cidence of these p:,:.en:ed ce1:s in ::e _:ng. Dai'_y expos:::e :0 231 _iga:st:e saoke !•-.-::g _:ze __ce 3a?-i :3_ce3 L_-q .r.ors ,•.eveloced did ::ot al:e: .-e .•.c:_'ence o: :a:e.^.cl in _,e 3a? • scoke ^,:oups c0mpa:ed :o _::e Ba? - sc:a= ex;osed q:oups. V. C:R-1113. EX?:SGR3 ^? 3C3F1/C:?t `S*_CE '0 2R1 5 !0KE During 1979-1980, aa exposu:e reqiaen was :eveio?ed that :esul:ed in low toxicity for botl 2R1 and 3a1 _i;a_et:e saoke. :hese expcsu:e coc=:::oss allowed the se'.^.eduli::;, o: a:onq :erm study whe:eby the S:ological effects of smoke '::= bot:1 _i;are::e types could be s'_mu1:a.-.eously evaluated. Suci a:ang :e:3 study zcpioying ::zis saoke exposu:e :egizen was p:oposrS, a?proved, and .ai::ated d• -ic:g the :330 contract year. :a Ju'-y :930. -oweve:, ._ vas deci"ed that _...s s:,:dy saould not :e and that saoke ex?osu:e ua!er -hese newly defined -d-iors •:oul3 be _:~ited to the lea;::: of iae durir.q whici aai_a_s in C:R-L0LA :+e:e to be exrosed to smoke. T`:e exreri=en:s coad•:e:ed in the ..:R-10:3 were desi;zed to evaluate =er:aiz sio: -te:z _:xi=ological endpoiz:s ;at may be :elevan: to !e:e=:•^.:^g the po:e^:fal Siologi:al a:tivity of whole ,.igare::e s-oke. ;he smoke exposu:e :egi-en :ot in this s:u:y did not include :est periods between' successive ciga:et:es, •:sed an exposu:e pe:iod of 15 seconds :er minute, and contin_ous exposu:e for :7 •':uns" in 140 micu:es. This :egiaen :esul=ed i1 -30 •.:g :'?!t deposited per day ;er =ouse Ls-q, an averaqe C:e?b of 13.9%, and 3reater than 95% i:%cf=ence of ?A.'iA by 15 weeis of daily smoke exposure. The following assays ~ere selected for :hei: ?ocen:ial =o predict or monitor L:ag-te:M e::ec a of _:qa:e::a s;:o:<e: 1) inhibition of pulcona:y :NA :epai: in vit-oi 2) s:icjla:ion of pul=onary DvA synthesis in vit:ol 3) iaduct::n of pulaona:y a:yl 5 CTR COh{TRACTS 0229182 11248932 Cf R PIN 041"3969

?inal Repor: Con:ract: --TR-0030 Sa;'..--IAAY hydrocarbon i:ydroxylase (aHH) activity; 4) induction of orni:hine decar5oxylase (o0C) activity; 5) aug:aentation of the DNA 3amaqinq effects of particular lung carcinogens; 5) induction of sistar chramatid exchange (SCS) In bone marrow; 7) alteration in certain physical -aaracteristics such as Lung weiqht (wet and dry), body weight, and bioc::emical c::aracteristics such as DNA, protein and iydroxyprol:ne LeveLs in lunq, 8) alteration of i3mune c^iPecence, and 9) alteration in rate of atre:ia (i.e. oocyte =oxici ty) . Osing the discontinuous exposure reqi:ien as defined in CTQ-L00, inhibition of DNA repair capacity (e.q. unscheduled D`tA synthesis (ODS)J occurred within 13 weeks of •daily exposure to 2a1 or 3a1 cigarette smoke, but was unaffected by exposure to 2Q1 cigarette smoke for even up to 52 weeks. Osinq the continuous reqimen as defined for CTR-1013, no DNA repair inhibition :+as observed for either 3A1 or 2R1 cigarette smoke even after 52 weeks of daily exposure. Thus, the inhibition of DNA repair (QDS) by cigarette smoke would seem to be dependent upon cigarette tyYe (i.e. 2A1, 3a1 >> 221) and/or the exposure reqimen (i.e. 30 seconds smoke per minute >> IS-20 seconds smoke =ec 3inu=e). Replicative DNA synthesis (ROS) in vitro was stimslatad 2 to 4-fold after 9 weeks of exposure to 2A1 or 3a1 cigarette smoke, but not after exposure to 2R1 cigarette smoke using :::e hiqh dose, conventional exposure regimen. ROS was stimulated -2-fold in mice exposed to either 2R1 or 3A1 cigarette smoke ssing the continuous exposure regimen. ONA :eplication as measured by tritiated th 1-3 id:1e incorporation into lung cells in vivo (Labellinq Index (LI)), was increased 3-to 6-fold in lung and tracheal tissues :com 2R1 and 3A1 ciyaret=e smoke exposed mice. No increase in Gt was observed in bladder, colon, liver, kidney, or spleen. 7-vidence was presented to suggest that daily exposure to whole smoke (ei ther 2R1 or 3A1), while stimulating normal DNA replication, may induce unsc::eduled DYA synthesis or repair synthesis as well. Daily exposure to 2R1 or 3al cigarette smoke failed to augment the L: induced by the potent lung carcinogen, 3aP-7,3-dio1. Thus, both cigarette smoke and certain chemical carcinogens (e.g. 3aP-7,g-diol) were capable of stimulating DNA synthesis in pul=or.ary tissue, but these effects did not seem to be additive, synergistic, or antagonistic. AHH was induced in the lung after exposure to 2R1 or 3AL ciqarette smoke using any exposure cegiaen investigated. Pulmonary AHH activity was stimulated 4-to 5-fold after 3, 6, or 9 months exposure. Renal AHH was induced after daily exposure for 9 months. aepatic AHH was uneffected at all time intervals. 7 C.TR CONTRRCTS 0291e3 11248933 CTR MN 041397`0

Fi-al Repor_ Consraet: C:Q-0030 SIIMLKAR? Pulmonary 00C activity, a potential marker 'or promo-ian, was induced -2-fold within 3 hours after daily exposure to 2R1 0: 3A1 szoke for 3 or 5 months. zxposu:e to 2R1 or 3A1 cigarette smoke :ailed to cause single strand breaks in the DYA of pulmonary cells. Smoxe axposu:e also :ailed to influence the level of 0:1a damage caused by 3a? or 3a?-7,a-diol. Sister chromatid exchanqe (SCE) was induced in bone marrow cells of mice after exposure to either 2R1 or 3a1 smoke. The iad uction was -2-fold and was first observed after 1 week smoke exposure. Continued exposure for 4, 12, or 46 weeks showed no further increase ta the number of SCEs. Increases iz SC=s persisted after cessation of smoke exposure for at Least : week, s+het::er the mice were exposed initially for 1 week or 46 weeRs (p < 0.05). °xposure to either 2R1 or 3a1 cigarette smoke using the continuous regiWen resulted in an increase in the cellalari:y of pulaonary tissue. Daily exposure from 1 week to 52 weeks caused a time-dependent increase in lung wet weight, lung dry weigit, lung CvA and protein, and lung hydroxy?.roline. This i,crease in tissue 3ass was likely the result of increased cellular proliferation. This proliferation was probably a:inal manifestation of the increased DaA synthesis rates observed ia these ani=als. Daily exposure to 2R1 and 3A1 cigarette smoke 'lsinq di:=arent exposure regimens failed to alter the immune sta:--,s of 3C3P1/Cua mice. I=mune competence was determined by .:e:-:e plaque assay. Veith.r acute nor chronic exposure caused i.:.munosuppression in either HC3P1/Cum or 3aLa/c C.:.,n mice. Rates of atresia (i.e. natural loss of• oocytes from the ovart) were also uneffected by chronic exposure to 2R1 or 3A1 cigaret:e smoke. While it has been suggested in the literature =::at there is a relationship between cigarette saokinq and early onsat of menopause (i.e. when the ovaries are depleted of oocltes) , oocyte toxicity was not observed in eC3F1/C.:.3 aice after 52 weeks of daily smoke exposure. VL. C.^.ROLL.IRY STDDIES: ?HAe'2lSOCORIVETICS CF IVHAGEJ The deposition, distribution, and clearance were deterrined :or nicotine, 3a?, dotriacontane (DTC) and catechol in cigarette smoke. Data showed considerable differences among these four classes of chemicals. yicotine. 9ap and catechol showed rapid zedistribution from the lung to other tissues and clearance froa t;e body. The half-li:e for internal :etention (tl/2) was ess a CTR CONTRRCTS 029184 11248934 C TR HN 04 3 9 ~ I

Pinal Report Ccn::ac:: CTR-0030 SIITSl4ARY than 1s minutes for nicotine, Less than 1hour for 3a?, and less than 20 minutes for catechol. OTC si:oared little :edistribstion from the Lunq, with a tl/2 of greater than 24 hou:s. The deposition, distribution and clearance of catec::ol as sinqle csemical aerosol was shown to be identical :o catec::ol in cigarette smoke -- i.e. the pharaacokinetics of :atec^ol are not altered by :ae presence of the other chemicals ie cigarette smoRe. 3reater than 901 of the izhaled cateqhol, eit::er in cigarette smoke or as an aerosol, was found as a beta-ql-.:curonidase- or aryl sulfatase-sensitive conjuqate in the urine within two hours of exposure. The deposition, distribution, and clearance was also detec:iined :or 12-0-tetradeconylphorbol-13-acetate (TPA) as a single chemical aerosol. The pharaacokinetics of aerosolized ;'?A was investigated as a potential promoter in a two-stage (initiation and promotion) carcinogenesis model systea sreci:ic for l:nq tissue. Results from two expariments showed that over 631 of the initial TPA deposition was found in the -espi:atocy t:act. TPA was rapidly cleared from the lunq via the blood, •aith increasing acc=ulation in the liver, stomach, and intesti::es ::p to 8 hours after exposure. By 48 hours, over 70% of the inhaled TPA was found in the feces and 20% in the urine. aerosolized '?A induced a specific biochemical event in the lungs, that is, induction of 0DC activity, within 3 hours after inhalation. TPA thus, exerted its effect i=ediately and was then removed f:om the lung. The pharzacokinetics data suggested that aerosolized TPA may have effects in the qastrointestinal tract, in addition to the respiratory tract. These data supported the usa of T?A in a tvo-staqe model for Lunq carcinoqenesis. 9 CTR CONTf2RCT5 029185 11248935 CI R 1 I 7 I 0439.72

CTR CONTRRCTS 029166 11248936 CTR HN 043973

CTR CONTRRCTS Q1g 180 11248936 CTR MN 043974