Tobacco Documents Online

al \ ~p ASSOCIATES~ICAL 5221 RIVER ROAD, BETHESOA, MARYIAND 20816 ~,~hi__p, CTR COHTRRCTS 029167 11248917 E:XFi1BIT NO.-L S.N 0 CTR ~~~ ~RES

FINAL REPORT THE COGNCIL c'OR TOBACCO RESEARCH-U.S.A., :YC. CONTRaC';: C':R-0030 "SKORE I:1HALaTIOY STODIES IY !SICE" !SICRCBIOLOGICAL aSSOCIaTES 5221 RIVER ROAD 3LTItES0J1, MARYLAND 20816 PROJECT D[RECTORS: DR. CaROL J. HENRY OR. RICHARD E. t00RI FEBROARY 28, 1984 CTF2 CONTRACTS 029169 11248919 CTR HN 04-3956

7tnal Rapor- Contract: CTR-0030 ADDITICNAL CCYTQI3CTOQS TO ':!?SS^o ?ROJSCTS FROM SlICR0820LCCICAL aSSOC:a:'SS :VCLCDS :''iS eCLLCWI:7G: ti s. M. D e n i s e Av e r y Dr. 3harat 3hooshan Dr. Leonard 8illup. Dr. Rodger 0. Curren Mr. David R. Danaie Or. Marshall Dinovitz Ms. Sue Goanell Dr. William C. Hall Dr. [in-Rai Hwang Dr. Ren iC. Kanaqalinqam Mr. Rob Ryanko Mr. aqustin Lopez Dr. Ronald A. Lubet Ms. Cindy E. McKinney Mr. H. Doyle !!ull inax Mr. Raymond Hims Mr. Thomas Rude Dr. Carrie Whi"-t:e Special t4anks to Ms. Janet C. Stinnett and Mrs. ?atricia' HarSin Eor taei: help in completinq this report. CTR caNTRacTS 029170 11248920 CTR HN 04,39. E-55 7

linal Rapor: contsac:: C:'2-0030 TABLE OF CCNTEYTS A38RrVIaTIONS ............................ ...... 4ACE NO. i SCM!'.ARY ........................................... 1 I. I:1TR000CTION ..................................... 10 II. FACILITIES AND EQOIPMENT .......................... 12 A. Description of General Operations ............. 13 3. Description of Facilities ..................... 14 C. Description of Equip:aent ..................... 14 III. C:'R-100. (1-100) CO-CARCINOGENESIS AND CHRONIC INHALATION OF 2A1 CIGARETTE SMOKE ................. 42 A. Evaluation of SEi II Smoke Exposure Machine and Its Animal Containment Qnits .............. 43 8. Determination of Expected Mortality Rates With the SE:S II Smoke Exposure Machir.e ........ 44 C. Effects of Exposure to 2A1 Cigarette Smoke On MCa-Treated and Ontreated 9C3F1/Cum Hice.... 45, D. 3iological Activity of Chemical Carcinogen Induced Lung Cancers .... ....................... 52 IV. CTR-101a. CHRONIC EXPOSDRE OF SC3F1/CII,`1MICS TO 2R1 CIGARETTE SMOiCL ........................... L01 A. Introduction/Objectives ....................... 3. Data Collection/*ianage.aent .................... C. Daily Observations ............................ D. Cocumentation of Smoke Generation ............. E. Cocumentation of Inhalation of Smoke by 101 103 103 10S BC3F1/Cum Mice ............................... 1.06 F. Oocumentation of8ody Weights ................. 107 C. Survival ...................................... 108 H. Microscopic Evaluation and Analysis ........... 108 I. Effect of 2R1 Cigarette Smoke on Mice Pretreated with 3ap ........................... 114 CTR coh{Tf2acT5 029171 11248921 CTR HN 043915-6

*lnal ReQor: Con::aet: CTR-0030 TABLE 0F CONT=:ITS (con:ld) ?AGE `70. V. CTR-1013: EXPOSGRS OF 3C3F1/CC`i MIC3 TO 2Z1 and 3A1 CIGaRETTE S::ORE .................. 203 a. :ntroduction .................................. 203 3. Smoke Exposure Reqimen, '"oxiciny and e{lstopatholoqy ........................... 204 C. Dosiaecry .................................... 205 0. Shor:-Te:a Marke:s to Monitor tse Effects of Smoke ............................. 206 S. DisPOSition of AQiaall ........................ 207 ?. Summary of Results ............................ 207 VI. COROLL.IRY ST?DIES: ?HaR.KACOICINETICS 0F IvFiALE7 :!ATERIaLS .................................. 271 A. Vicotine, 3aP, and DTC ....................... 271 3. Catschol in Ciqarette Smoke ................... 272 C. Cateclol As a Chemical Aerosol ................ 273 0. TPA as a C::emical aerosol ..................... 276 VtI. REPERENCES ...................................... 291 VIII. ??9 LICaTIOVS ............... ...... 296 CTf2 CONTRRCTS 029172 11248922 C TR NN 04.%39..ffl=%_5q

CTR coHTRacTS 029173 11248923 CTR HN 043960

?inal Regort Con:rac:: C':R-0030 ?.BBR.'. VI.1TIONS ABBREVIATIOYS AAC aCN AH AHH A:JCv ASC AO 36 CCM, 36N 3 A P 3AP-7,3-DIOL C0Ft3 C.V. D2J,D2N DNA DP!i DTC, 14C-DTC Ha HB HE?A H0 HYP I? IT YIC 4-D1Q0 0DC ALVEOLaR ADEVOCaRCIVCNA aLVrOLaR COMPRESSING NODULES • ALVEOLaR HYPERPLASIA ARYL HYDROCaR90N HYDROXYLaSE ALVEOLAR :10N-COHPRESSI:IG YODULES ADENOSQUa.K00S CARCINOMA CyCLaSSIFIED .1DEJIOCARCINOMA C579L/6 C".M, C57BL/6N INBRED wOCSZ 9E;IZ0(A) PYRE;lE 7,8-DIHYDRO-7,8-DIFiYDROXY- BE:]ZO (A) ?YRENE CaRBOXYH_MOGLOB IJJ COEFFICIE:JT OF VARIATION DBa/2J AND DBA/2Y, INBRED MOOSe: DEOXYRI30NOCLEIC ACID DISI.4TEGRATIOyS PER MINUTE DOTRIACONTANE, CARBON-I4-DOTR:ACONTANE HElSACCLUTIaATING ANTIBODY HE.`SOGLOB IN HIGH EPFICIEHCY ?ARTICULATE AIR FIL:ERS HYDROXYCREA HYDROXYPROLINE I:lTRAPERITONEAL, INTRAPERI':0`7EaLLY IvTRATRACHEAL, I!ITRATRaC;{EALLY LITER LaBELLI:IG INDEX MICROBIOLOGICaL aSSCCIATES 3-METHYLCaOLAN'rHRE;IE ;iILG:GRA.K (10-s grams) METHYL METHANE SULFONATE !1ANOGRA.'t (10-9 grams) NICOTINE 4-NITR0Q0INOGI:lE-N-1-OXIDE ORNIT'{INE DECARBOXYLaSE i CTR coNTRACT5 029174 11248924 L.J' )) 1 l~/ 7 7 0413C.36 1

?Saal Repor: Cont:act: CTR-0030 138Rl.'VIATZCNS ABBREVIATIOYS (cont'd) ?A-`Ll PIGMENTED ALV:,'OLAR MACRO?HAGE ACCQHULATION PDC POORL'i DI?FERENTIATED CARCINOMA PEC PLAQOE FORMING CELL PSI POQNDS PER SQQARE INCH PRESSURE RCS RETICOLOM CE;LL SARCOMA RDS REPLICATIVE DNA SYNTHESIS SCC SQUAM00S CELL CARCINOMA SCE SISTER CHROMATID EXCHANGE SD STANDARD DEVIATION SE:! II3, C SMOKE EXPOSORE MACHINE SN SQQA.KOUS :SETAPLAS IA SN SQOA.lSOOS NEOPLASN SRSC SHEEP RED SL00D CELL 3H-TDR TRITIATED THY*lIDINE TPA 12-0-TETRADECONYLPHORSOL-13-ACETA:E TPM TOTaL PARTICOLATE MATTER ODS ONSCHEDOLED DNA SYNTHESIS OR "DYA REPA:R" OG MICROGRAM (10-6 qrams) GM MICRON (10-6 aeters) ti cTR coHTRacTS 029175 11248925 CTR NN 0439.wu-2

CTR COHTE2ACTS 029176 11248926 CTR HN 043963

8ina1 7epo:c Con::ac=: C':R-0030 S:. Kl4AAY Su'uF-k ZY . ZI... I. *VTROCCCT.CY Tsis :s the Final Report for Calt:act 0030 entitled, "Cigarette Snoka Znhalation Studies in yice." This report descrizes: 1) the facilities and equipaent, 2) the :esults f:cm three major smoke inhalation studies, and 3) the :eaul:s from corollary studies that supported tae three major programs. The five chapters that -make up the Final Report are sus.zarized here. II. ?AC:L:T:?S AND SQO*.?y*NT The cigarette smoke generation and animal holding equir:ent were designed to provide high exposure to fresh aainscrean cigarette saoke on a daily basis for a major portion of t::e 11=et:me of the animals. ':::e =acilities provided the following: o Tao Smoke Exposure machir.es (SEM LI 3 and C), one stiam exposure machine, three animal contai::ment units, twenty-four exposure modules, and 400 animal restraint trays. o Capacity to expose 480 mice simultaneously, and up to 2000 mice per day, to cigarette smoke under conditions where greater than 90% of the smoke partfculates were deposited in the respiratory tract of the :nices o Doc~.Laentation of the quantity of smoke presented to the mice during each exposure session. o Safety systems t::at assured exposure of -tice to saoke only under preset exposure conditions. o Generation of cigarette smoke under conditions controlled for cigarette type, smoke aerosol concentration and smoke partic:e size. o Capacity to 'louse up to 10,000 mice at a tiae under conditions that insured a clean and controlled environment. 1 CTR CONTRRCTS 029177 11248927 CTR HN 043964