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/'MICROBIOLOGICAL /_ ASSOCIATES DeceTber -.:, :933 "!r . :'om Hov: '"he Coc:r,c:'_ for -obacco =2sear_::-U.S. ;. . .r.c. 110 East 59t.1 Street `2W York, Nea Y:.:X =ea: yr. Hoyt: ~enaewpr,,a ..soeul.s A 1Jn.l el wn.nno Geree.eeen 5221 a..., qele 6oI/N.es M1M.ne ja1G 13011 {SlZ f.N. Ne ty4793 =..c'osed is our prooosa: regardiaq campletion of tne manuscripts a_soci3`ed with the chronic zmcke inhalaticn study. As s_a_e•? .•n the proocsal, :+2 recctrTe^d :hat the s:_dv be =.res:^,t2d in :oL:: manuscripts, the first o! which ycu r8ce:-ed ~:fl ;.eceT~r.r 1, :?83. The second arid :`ird mz::uscri?ts, -..:l::::::c a 3esc::~-::.:1 cF ter-i^nn- pa:zo2ogj, ::ave been scae9uled :3, :?94 The :ourt': :nan,usc:,:r. -c:t =na' 's:s :f ==:- -:^^ :he second and third nanu3cs zts. A :2ya:3:= :^St._ z4 :e?l:l=ed `Or this prz-?ct =..:. 'v i1= ^e =,:a---==3 :._ _ ster ....:e. j~:.-.°t-, ..'.. ..~° ... .^.7: r2^u:red 3t thls _-me a.^.d7 .n.T= .:$•L.n. 5:.::?.3_-°-~. --.`.s a_- .~tf. •'7l:tiJl_.:at:9n :°es. '--_ _==tr 3.^.C cc=~ tc- =_-xe .:IIv! =Le~ . C---° 2 _=s_ ::r ...:s ya J'Z9, 754. w? :=-1e':2 _..-s =rr'.:53_ 3C.!=2sses -::a r°'.l:a:~:1C :0:2c-= d.°.s::=d -°t : ^R. : ! ;Jo:. ':3': e Z _ c1:a5 =:cfa . ^'_-.as9 -:' n7t CTR CONTr~aCTS 02684 z CTR NN 0444904."

f• :^E ?:oDosal :ece^aer -, :983 FOR ':-BdCCO-U.S.:.., :'7C. PROPOSAL :OR CO`1PL::':ON CF `!AVUSCRiPTS FROM DATA GENERATE'~ JNDER "..C:1TRAC'. -= .`!:CROBIOLCGICAL .1SSOC:..:'ES '.`.e c::ron:c smoke :nzalat:on stu3ies orovide the data ;or a fair:y complete evaluat:o:: of the biological activity of whole cigarette smoke in a model animal system and could provide the basis for an updated ::sk assessement analysis of the effects of cigarette smoke in humans. Four manuscripts describing these smoke inhalation studies nave been outlined and given the following titles: 1. Chronic :ahalat:on Studies in Mice: I. Facilities and Ecuirmen: fo:-Nose-only Exposure to Cigarette Smoke 2. Chronic :nhaiat:o:: Studies in Mice: *_I. Effects of Lifetime Exposures to High Tar, High Nicotine Cigarette SmoKe :. Chronic Inhalation Studies in Mice: III. Effects of Co-Treatment of Cigarette Smoke and Model Chemical Carcinogens 4. Chronic Inhalation Studies in Mice: IV. Comparison with Human Data The draft of the first paper has been completed and on December 1, 1983, was sent to C'"R, Oak Ridge, and Process and Instruments for review and comments. a revised working outline of the manuscript describing the lifet:me study is presented in Figure 1 of this document. This paper will focus on three issues: 1) a description of the :og:stics and procedures :nvolved in daily exposure of over 3000 -ice to cigarette smo. Ke. 21 a descriotion of the oert:nent =at::ology :n these mice, and 3) analyses of the types. :::c:dences a..d :atenc:es of _es:ons cbserved in t::e smoke, sham, and snelf :OuCs. T.`.e _::ird -:anuscrip: :s outlined in Figure 2 and desc:ibes t'.^.e :esul:s of c::ronic smoke exposure in animals pre-tzeated with ,odel chemical carc:noaens. 3-meth,vlc;olanthrene and oenzo(a)pyrene. This =aper will include tasults from exoeriments C-i01a and 1-100. This paper will describe the types, :ncidences and :atencies of c3:c:noaen-induced lung cancer and the :esult of daily smoke exposure on tne expression of these lesions. c i R CUNTRAc?'S 026842 C,Tti VIN 0444wj1

CTR ?:cposal I~tce.^..aer ", :993 The second aad :h::d pape:s 1:i: be prepared at approximately ::.e same ..-e. :t is , rcosed .-a: one wi:l be submitted by Febr_ar;~ _ and :..e o:-er by:ebr::a:y 23. Computer .ime and co:.Gute: c:oa,rassner ::me be :equi:ed to complete these papers. At ::.is ti:ne, no addit:o'nal statistician ::me is planned. ?ataoloqy support :+ill be provided by Dr. William C. Hall, in consultation %+ith ~r. Len 3i11ups. '--ot:: of wnom nave been associated :+it1 these pro;ec:s in the past. The fourth manuscript will be an attempt to correlate all of the results of the previous 3 papers, compare these results to data in humans, discuss expected and observed results, and to maice a risk assessment. Ho budget or schedule has been made for this manuscript. The basis for this paper will reside in tne data analysis from manuscripts 2 and 3. This paper would probably require assistance from a stat:stician or eptdemiolcqist. Dr. C.,:. Henry will have overall responsibility for coordinating and completing tnese manuscripts. She will have specific responsibility for draft:zq of the second manuscript describir.g the effects of lifetime exposure to smoke. Dr. R.E. Kouri will be responsible for drafting of the third manuscript describing the effects of smoke on carcinogen-induced tumors. They will be assisted in preparation of these two manuscripts by Mrs. ?atricia Harbin. The cost of preparing manuscripts 2 and 3 is 829.754. Costs :or art work, publication fees, pathologist's time, and computer programmer and computer :ime have been included. 2 CTR C0NTRRCTS 026843 CTR MN 0444902

CTR Proposai Decemoe: ", :493 c icure 1 Revised workir Out::ne :.._ C.`.ronic Study '!anusct:pt, ent: _:ed: "Chronic Inhalation Studies in Mice: II. Effects of Lifetime Exposure to Hich Tar, High Nicotine Cigarette Smoke" I. INTRODUC"ION A. Review of Li_erature on Previous Inhalation studies (search has been ccmpleted) B. Rationale for our Study II. METHODS A. Data Collect:on/`lanaqement B. Smoke Generation/Delivery/Documentation C. Animals 1. Inventory 2. Weights 3. Carboxyhemoglobin D. Necroosv Procedures E. Methods of Analysis levels :II. RESUL':S A. Exper:men_al ~esia,n 3. Surv:val of ":ce to High Tar. liqh Nicotine Cigarette S:noRe C. Observat:o::s of Mice during Chronic =xposure 1. ?hysic='_ appearance !e.g., weights, effec:s of restra:..:s, etc.; 2. COHb :evels 0. Histopat::clocy :. ';.pes.. :nc:dences and.latenc?es of non- neooias:__ :esiczs 2. "ypes. :::c:dences and latenc:es of neoplast:c lesior.s 3 CTR C0#~~K.RC~~ CTR H~~ #"' ~~. ~:~. ~. C°°#~~

C:R ?rooosal Dece:^oer ', :983 IV. DISC:JSSIOU A. Smoke vs. Sham Non-neoolast:c/neoolastic B. C. Effects of Restraint Competing Risks for Survival D. alternat:ve r.ethods for Data Analysis CTR CLIh{TRRC t q-. 02606451 M/' / I f / I I 4I 044494 •

.,':R Proposal December 7, :983 _icure 2 Worring Outl:ze for C.`.ronic Study Manuscript, enti::ed "Chronic !nhalat:on St::dies in Mice: III. Effects of Co-Treatment of Cigarette Smoke and Model Chemical Carcinogens" I. INTRODUCT:ON A. B. Effects of Smoke cn Carcinoaen-Induced Lung '"s-zors Description of `:ouse Model System 11. METHODS A. Smoke G2neracion/Delivery/Documencation 1. 2. 2A1 regimen 2R1 regimen B. Animals 1. 2. 3. Inventory Weights COHb levels C. Chemicals 1. Preparation 2. Treatment D. Necropsy and Pathology Procedures ~. Methods of .analvsis III. RESULTS A. Survival of 4ice _„ Chemical-Smoke Treatment 1. 2A1 smoke - MCA vs. sham • MCA vs. MCA alone 2. 2R1 smoke - Ba? vs. sham - BaP vs. BaP alone B. Observations of Mice during Zxposuze 1. ?hysical aooearance (e.g., weights, effects of restr=ia~cs, e:c.; 2. COHb levels 5 c R coN~,Ac~= 026846 C/ TR / l/ I S..n !. 6...i. L",.L. ~°"'~ 4-1'

i CTR Proposal Oecemoer 7, _?93 C. woes. :nc:dences and Latenc:es of Respiratory :'ract Diseases 1. Carc:noaen aione 2. Carcinoqen - snam 3. Carc:nogen - smoke IV. OISCUSS:ON A. Carcinogen - Smoke vs. Carcinogen + Sham B. Cotnoet:zg R:sks f-.r Survival C. Alternative Metacds for Data Analysis 0. Complete Carc:nocens vs. Incomplete Carcinogens 6 4 r CTR CC1N TRRCTS 0.4226 6 ~TR 1*4 0444~~6