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NCI SM'O'KIING AND HEALTH PROGRAM ..lul-,e 19.1969 FROM 1977 REPORT ~om 1978 status report tom 1978 status report Cig~ette Stn<Y~e a~l of I.s ~. Sa-n P. B~ll~a Effects on C__akary F~-~or'~ the re~=r=to~f eC~l~ebum of e:cDenmenl~ a~ma~s in 2) To devetop and evaluate a model system to ~etannme whe~sr c~gerette smoke has offects on c,~,cinogene~s =n the chckan trache~ as ~rdluonced by ex.penmental removaJ of the tracheal epcthol~um; 3) To determine the chronic effects in chckans of exposing lung and trachea to tobacco smoke administered along ~ w~th d~ethy~n~tro~c"~mme ~n denuded as well as nor~denuded tracheal epithelium. c~ed out at 14 day interw/s .~ven DEN. smoke or smoke p~us DEN- De~P~te these early changes, no malignant tumors were observed in a.mf of f~e ~'~cheas reflmdleas of t~eatme~t. Dunng the 3 yr beatment panod in which some chickens received smoke from 2 cig/day, the inc~de,nce of malignant chang,esin the lung in animals that died ,dunng the study up to time of final sacnfice, and those sacnficed after 1 and 2 yrs of treatment were as follows: Co.rots, 2.8% (2/71); DEN, 17.5% (14/80); smoke 10% (4140) and smoke ptus DEN 15% (?_/20). A 2rid generation of the ertginal ADL smoking system has been developed. 7 Senes III cig less toxic than SEB, based on ciliary potency bioa~say. Highest cofrelabons for bolh cytotox/city a~]d ciliary ic.hib~fions foLtnd w~th TPM. phenol, =soprene and HCN. Lowest corr found for CO2 and NOx Avian model acceptable for direct exposure of lower respiratory tract to cig smoke. Chickens exposed to NCI #2 cig for 31/2 yrs had variety of pre-necpiastic changes in lungs; 9% incidence in smoke vs 1% in controls. DEN (10 doses) g~ven intratrache_.~ inslillations not additive or synergistic w}th smoke. In dogs, doses of condensate or cond + DMBA applied directly to bronchus resulted in hyperpla,~a but not tumors after 86 wks

~CI SMOKING AND HEALTH PROGRAM ~low 1 Part ~) ~ept. t975 (Part 979 sial:us repcfl 1tom 1979 statu,~ repor~ from 1979 from 1979 s~atus report ~ w a~'~ w~o DI,~A oro N.-Me-NI " a-¢I3 Oak Ridge National Lab.oratory (YO1-CP6- 0206) Cotlection, SE~3aFaJlon, and Bucidation of the Components of Cigarette Smoke and Smoke Condensate. Part I. Chemical CharactenzatJon of Cigarette Smoke. Part II. Inhalation Bioassav Monito~inc from 1977 report from 1977repoR Dr. Michael R. Guenn Part I - Dr. W. H. Griest Part II - Dr. J. R. Sto~ety Dr. J. E. Calon Part I - Prowde maximum charactenzahen of cigarette 3mokes undergoing biological testing by o~er ;cctractors. Part II - Develop and implement procedures for ;hem~cal anaty~s whicl~ wll increase intedaboratccy .~omparability of inhalahon bioassays. Page 2 .ap~ed to bronchus for severat monlt~s to 3 ye~r,s. DrOg~ e(~t'(~$p~l~ ~ ~ :zoces~ tot Im-sto evak.,~x~. Sw~mrmng esdurance ~ected as method to detenmino ¢~e effects of CS on fuacl~o~. Prelim results show that endL~a~ce is reduced in adiuvant-treatod rats comp~ed to controls ~ reep~n~ ~o h~s~m'~e more reliable ~han methachobne~ Results w~th CS not defind]ve due to high degree of variabdity in dala; ~ thai endurance is desrea~d due to cigarette smoke. Smoke delivered by 28 varlar~ts in Senes III analyzed. Methods dev and routine applied to smokes and/or cend to detm 75 constd, - including pl~enolics, carboxytic acids, PAl-I, alkaloids, GP carbo.nyls, terpen~ds, toxic gases, trace elements & a emitters Devel. method for B(a)P and multicompenent PAH determ. Visualization of benzothiophene and dibenzothiopheno in condensate; GP limonene indicator of terpenoids in cenc. and correlates highly w=th biol activity. 2.3-butanedione also cord highly w activity. ~len-protocol assays: 1 ) MS of blind assay PAH isolate 2) GC & MS smoke anaJysls - alkyl naphthalene 3)HRGC for tob smoke analysis, 4) trapping and analysis of WS from ADL 11 smoke inhalatien exposure dewce. Special Studies- 1) char of smoke from domestic and commercial cig. 2) chem eval of cond for sebaceous gland bioassay 3) detm of 210Po; 4) eva] of BaP specific ant~bedy as selective filtration agent;

NCI S,M,O,KliNG AND HEALTH PROGRAM Feb. 24, f 970 Amencan Health Foundatior~ (ECI-SHP- 74-t 06) 1978 status report [rom 1978 status report [rom 1978 status report [rom 1979 status report from 1979 status report Evaluation of Carcinogenic Agents in Cigarette Smoke. Part I. Ep~demiological Eveluation of Carcinogenic Agents in Cigarette Smoke Dr. Ernst L. Wynder Dr. Peter B. Peacock Determine endogenous and exogeno~Js carcinogenic lactors in humans; to identify major etiologic factors relating to various types of cancers; evaluate the risk associated vath different smoking habits, including type of cigarettes smoked, and to i.denfify the kinds of cigarettes that are less carcinogenic to va~ous organs. Page 3 pa-bc~e ~ze for ~ exzt CO/C02 Parl 1: Detm of NCI protcc~ c~ns~tuents fo¢ Se~es IV c~j and ccodensa~e ~ method fc~ NO, (ct3em=turnmescec~ analy~s) r~<xted. S~ ~on~ 150 for~ commerc=~l c~g analyzed for NCI spe~l~ed Part IL Estimates of smoke dose and doee vanabl,rty fa~ctors in inhal stud=es cc~:~uctecl. O,ev. method for nicoti:ne/cobr'=ne in physiological fluids. Us~ of optical sink particulate sen~0r in rat inhal exp indicates gra~est fraction of sink :~rt, retained comes from the last few p~Jff of cig. Pat I.Goed correlatier= found between 'tar"and CO deliveries for filter cig, but not for NF cig. Chemduminescent analyses 50-100% too,re Nox in fresh cig. smoke than prewo~sly reported. Pat II. Estimates of offered smoke dose and dose variability factors completed. Developed a dosimeter for quantitative characterization of smoke inhaled by dogs. Dev of anaty method for dos~metry in human underway. Study csetinue-s to demonstrate a reduced nsk of cancer of the larynx, lung, oral cavity, esophagus and bladder for persons smoking low-tar cigarettes for 10 years or more and as length of ex-smoking increases. Gig smoking, nonfilter cig, becoming habit of less educated, non-Jewish, lower socioecenomic group of indiv. Ratio of filter to nonfilter smoking higher among whites and those with college education.

NCI SM,OKI;N,G AND HEALTH PROGRAM ~rom 1978 stalus report ~om 1978 status report ~rom 1978 status report I~e~bty toOecco and toOecco smoke ~=co~e~ a ma~="~ of e~ ~ ~ reduce'~cj Iheee ~ n~k~,~ ~ ~n,~ i~ ~ ~ ~ ~e. D~a ~ ~ ~ ~e f~m~, in ~, ~ng ~e ~ng ~ t~. NNN ~ ~ ~ ~X bm~s in r~S, tr~e~ hu=m~ in ~s ~ Iu~ Sm~e ~ns ~n~ c~e (l~ciO). C~onne in ~mt m~l~ ~ce of VG n c~on ~ucts. Pot~ ~r c~cin~lG ~W~ ~um~ prom~ng ~t ~t~. for ~t~hd~, ~fi~ in w~ acidic ~c~ons: h~uinone, c~if~t-~c~s, f~ cy~henols ~ hydro~et~henones. Newly id~f. c~in~s re~de in the na~th~ene, ~thr~e ~ hi~ PAH ~s. TSNAs tested for mutagenicity and carcinogenicity in strain A mice and in rats. NNK rink highest in act and induced hepatomas in rats. ~om 1979 slatus report ~rom 1979 status report ~rom 1979 status report 9t~&£890~ The active weakly acidic fraction amounts to - 0.5% of tar. The cocarcinogenic neutral subfraction that have been freed of PAH contain tob specific terpenoids and their p~/rol~/sis products. A basic subfraction, containing flavor cpds, found to be mutagenic. Alkylated pyrazines and pyridines isolated and being assayed for biol. act. NNN and NNK induce tumors and carcinomas in resp. tracts of mice, ats and hamsters. These are also active as contact carcinogens in rats and hamsters when given in ddnking water, inducing tumors in resp tract, mouth and esophagus. _ Page 4

N,CI SMOKING AND HEALTH PROGRAM • ~uly 1971 ,~prd 1,1972 l..,b~ary (YO1 -CP4- 0"20~} Vete~ens Admlnistrat~en Hospital East Orange, NJ (YO1- CP4-0205) from 1977 report ~rom 1977 report Effects of High and Low Nicotine Cigarettes on Male Beagle Dogs ~om 1977 report from 1978 status report Jan 1974, 115 adult male beagle d~)~s sta.rt~d on testing reg~r~on. To date, 7 dogs :lied due to effects of chronic smoke exposu.re. Pathology showed pu[monan/a~yp~c, preneeplas~a, and ba~l cell hyperplasi~L Some dogs showing clinical mar~festatiens of intoxication and hypox~a while smoking, and this phenomenon becomming mo~e E~v~dent as the accumulated smoking t~me ~ncreases. esults in this report same as reported previously 18 dogs died dunng first 31 months due to effects of chronic smoke exp.; of these 12 exp to HN and 6 exp to LN cig. Animals remaining sacrificed when cig supply ran out... HN dogs after 1328 days exp and LN dogs alter 1377 days. Page 5

NCI SMOKING AND HEALTH PROGRAM 1974- June 24,1974 Hazle(cl~ Lal:x~a.lo~e~ I01} A~thur D. IJttle. Inc. (ECI-SHP-75-116} C, gareffe Smo~ from 1977 report Oevelopme~'~ of a Flav~ System for Acceptabdity to Smokers of Candidate Less Hazardous Cigarettes Mr. James L GargusI from 1977 Report from1977Report Mr. Jot~ Ange~=ne To understand & reproduce charactenst~cs of a '~garette" which make it acceptable to smokers. Cigarettes for lhe S&H Program expe~mental cigarette ~ertes are compared to the envelope of acceptal:~lily, a flavor profile model developed by A. D. Liltle. from 1978 status report from 1978 status report ~ C~ette~ rr~i3e wl htcjrl poroedy peOeL tho~e m~:~e of tct)~:~,o ~e rn~ tho~e made w~ recan from s;taz~lbrd e~D, enmenta~ ~end c~gegette~. T~af pt~3elics ~ the leeve0 H2O~garette. ~ benz(a}a~hr~, weak a~d~ tar phenols and n=c.~an e in ~e ~e were emo~j l~e factors found to be h~gi~y co~Te~ated wrth tumongen~ly. Mouse s~n bioassays for I st, 2nd, ~ 3n:l series of condensates completed - report xtbl~shed. 4th se~es completed ~n painting - his~opatholo~cal studie~ in pfog. Smokers hke a full blend ot flavor and character, tJkes wl~en the smoke produces a sense of wel~ess in the mouth. The flavors of all of lhe less hazardous cigarette tested fell be]ow mir~mum cntena for &cceptability. Higt~er acceptability assoc w full blend of flavor a~d character notes indtcative of woody and tob fragarence. Developed representative profile of acceptability. Ravors of all of the less hazardo~r cig tested fell below min cntena for acceptability Special study eval impact of flavor of ni.cotine added as free ~kalcid and bound citrate salt to a epecia] a~]ficla~ tobacco substitute. Screened organic chemicals approved for use in food and tob products to create a more acceptable flavor for less hazardous cig. Prelim results indicate possible to extrapolate formulation and flavor screening tech to eval of natural flavonng materials. Developing flavor system for NF cig red that simulate effects of added nicotine in range of .5 to 1.0 mgfcig. Nicobne "mimic" exhibits many flavor properties of rob substrate w injected nicotine citrate. Page 6

June 28. 1974 June 30, 1974 June30,1974 l*~r~:joon Reseerc~ ,Center (N,O1 -CP4- 5622) Microbiological Associates, ~nc. (N,O1- CP4-3309) Battelle Pacific No~qhwest Laboratones (NO1 -C P4-3315) Battelle Pacific Northwest Laboratories (EC/-SHP-75-121 ) NCI S,M'OIKIN'G AND HEALTH PROGRAM ~rom 19/9 ~atu~ ~ep~t M~ax~ of TObaCCO Smoko Cons~Is Standardization of Aryl Hydrocarbon Hydroxylase Assay as a Screening Method to Determine Smoking Haza.q3~ in Man Inhalation Bioassay of Cigarette Smoke in Dogs: High and Low Nicotine Co~tent |nhalation Bioassay of Cigarette Smoke in Rats from 1977 Report from 1978 status report Dr, R. E. Koun Dr. Gary M. Zwlcker Dr. Alfred P. Weaner 6~ I~176c;c90~ 1) renew ec~er~ htera~u¢o On effects of smo~'~j dose8 of r~.o~ he. NOx. CO and I-ty~ogen cya~:le on metatx~sm of mamm~i~n ~ems ~ the rela~onsr=p of these dala to smo~ng and hl.m~an 2) perform metabolic sk~ies on the ~. ~creti~, metric, ~ h~o di~on of CO. ~dr~ ~e, ~ ~ a~ar ~m~ni~i~ ~ ~ ~ oo~ commie to th~ ~mi~ar~ to rats in ~e ~NL sm~ mac~ne. Standardize the coed~tians for obtaining reproducible quantitation of aryl hydrocarbon hydroxylase (AHH) activity in humal tissue. Develop techmque~ nesessa~/for the use of a beagle dog bioassay model. Use of high- and low-nicotine cigarettes are tested. Pulmonary and cardiovagcular function tests are performed. Evaluate the rat, as an thhaJat~on bioassay model. Physiological and histopathelog~cal data are analyzed fo determine whether changes related to different cigarettes smokes can be detected. Page 7 Dev~cOf, g a flavanng system tar a ftle~eo suc~=e og ~ e~L~a~ maenads. Mettx~oevk:)rpcepe~ng H CN. arK:tl~'appc~gsy'stemsfar "=C(~ar~H~'CN de,J~c~ed fer ~ dat a or= phacmacofon, s~cs arv3 ~an of CO ar=:t HCN ar~ ~e=r melal~htes. Prir, c=pel organs ware found to contai,n readdy mea.onred a~oants of radioact]v=ty 15 mlr~Jte~ after adminisl~on of a dog~ of hydrogen cyanide. AHH act. can be roaQriy detected in control and 3MC treated cfuturod penpfteral lymphesytes. Activity linear w respect to brae of assay and cell conc and optimal at pH 8.5. Lymphocytes are still operational for bioaesay up to 24 h~ after cellectio~. Indiwdual results using tech not reprodu,cib~e. Signif. differences between indiv when aasayed an same day. Relahve differences between individuals remains. Unable to reproduc~bly detect low noelnduced or control AHH activity. Groups of dogs smoking as few as ~x cigarettes per day, ~ days/week had apparent lung damage atler 1 year of exposure. All data eva] to determine extent of pulmonary changes, including emphysema and cardiovascualr system eval. ProcEElures~lechnmlues develop to evaluate rat inhalaE~n model. Phys~ol~;g[cal lests/histopatholog=cel methods standardized. Smoke exposure procedures/cigarette smoke characterization determined. Long term exp of rats to cig smoke began. Prelim analy~es indicate signif, differences between cig smoke exposed animals and ~entrel animals for a variety of phy~o~ogicaJ measurements. Prelim analyeis indicate high incidence of smoke granulomas and lower incidence of related changes, -- vesicular empt~ysema & squamous metaplas~a in smoke-exposed animals. No signif, incidence of prtmary maltgant tumors of resp trot observed.

July 15, 1974 Sept. 1, 1974 NCI SMOKING AND HEALTH PROGRAM North TeX~L~ State Univer~ty (NO1-CPS- 5626) Univers~P/of Maryland NO1 -(3 P4-3312) Ir(~n 1978 Irorn 1979 s~at~sreD~rt ~rom 1979 status report Star~da~d~zatzorl of Aryl Hydrocarbon Hyd~oxylase essay asa Screening Mebhod ! '.o Determine Smoking H~azds in Man Metabolic Studies on Tobacco Dr. Elroy Cantreti Dr~ Joseph Adir l) to optimize and Standa~hze methods for measu~lr'~ ~arcinogen metabol:iem I human tissue w/ "eproduc=bilily and accuracy; 2) im~eve & ;haractenze techniques for measunng induction & nducibflity of the a~Jl hydrocarbon hydrexylase (AHH) ~nzyme ;omplex =n I~umans; 3) examine altemste enzyme inducers & substrates for use in the above test systems, and 4) suggest procedures for potential screening tests of AHH levels in humans as they may re~ate to the risk of cancer. Determine the rate and extent of nicotine metabolism Smoke Constituents and Pharmacokinetice of Nicotine n Animals and to characterize =ts pharmacokinetics in rats after ;igarette smoking 0~6~90~ 12.18 ~ 24 rnon~ teeing i~:~c~e I:x:~3y wl= acid ~ r~e~ ~ower m smoke- ex~o~d rats, ~ood pre~=t~e ~ncree=ed. E~dy wt ar~ suntrval d=ffere~ces ~ enough to re~lect two dee~ gro~p~ ~n~l~.,at~d by in v~vo do~ melry mea~urerne~ Smoke induced ~tope~o~og~c le~.ons corm=steEl pn man~y of pLdmo~ary smoke ~ra~ulomas. D~fferec, ces in seventy o1' gran~omas make poe~ble to d~ffere~tJ~te rat~ =nnal=ng smoke trom LTa'~I HTctgaretteso AHH levels in PAMs compared w=th the charactenstlcs of AHH induction in alutured human lymphocytes. In hesJthy smokers and NS, po~bve con (s=~rlificant) between AHH in PAMs and inductron ratios in clatured tymphocytes. Inverse con- in confirmed lung c&ncer patients. Heathy smks variation in AHH levels in PAMS and induction in lymp~ocytes - 70% low in both charaotonstiss. Only 15% low in both in smoking CA patients. A simplified assay proc. developed for AHH in cultured lymphccytes. A ~rter/anaiyzed used to quantitate arnt of OH-B(a)P in )ndiwdual cells. 1 ) nicotine'distr~buted into 2 klneticaliy'iJistinct compartments - a rapid deposition phase having an aver half-life of approx. 15 min. and a siow disposition phase having a mean hail-life of - 1 hour. 2) it possesses alarge volume of distribotion & total body clearance which are indicative of its extensive tissue penetration & biotranstormation; 3) formation of cotinine is rapid - elimination is slow (av. 1/2 life of 6.4 hrs); 4) Nicotine-N-oxide & other metabolitss reach a max. plasma value very rapidly, whereas the decline of their levels is very slow; 5) the rate and extent of ~listnbution and elimination of nicotine, cotinine, nicotine-N-oxide, and other metabolites are dose-dependent. Page 8

NCI S,M,OKtNG AND HEALTH PROGRAM J~n. 1.19Z5 lan. 1, 1975 June 30, 1975 - Sept. 1, 1975 New Y~ Un~ve~mty M,ed~cal Center (NO1- CP3-3241 ) Battefle Pacific Norlhwe~ Laboratories (NO1-CP3-3374) Johns Hopkins Univeralty (ECI-SHP-74- 103) Cocarctnogentc and Tumor- Promoting Principles of Tobacco a~d Tobacco Smoke Research on Standarctizmg the tung pellet Implantation Technique in the Rat Pulmonary Screening Tests for the Effect of Cigarette Smoke on Small Airways in the Human Lung Dr. Gerald E. Dag~e Dr. Harold A. Menkes De~ermine the nature of the carcinogenic, cocarcinogemc, and tumor-promoting agents that are known or suspected components of tobacco leaf extracts and of cigarette smoke condensate using one and two stage mouse dermal as~qys. T~ standardize the beeswax-tncaprylin-c~garette smoke condensate lung pellet implantation technique for the bieassay of ~elect cigarette smoke condensates and to determine if such standardizatien would allow a shorter )eriod for the bioassay of these condensates than other presently used techniques. Determine which of the presently avatlable s~mp~e tests of pulmonary function including a newly developed test - moments anaJyms is most useful in evaluating the effects of cigarette smoking. M(~e tr~ 11 cx3ntracts r~ve been e~a~aneo, ~ s~r~ co~ ~ =nformabon In 1979 a tO~' ~demiolo<~3 ~+e~ were monitored; 8 9ut~conf renew,sis and a number of SLgCenl='aat m(;d.=fica~ons and extans~ons negotiated and executed. 4 new ~ontracts p~epared & put into Not all tumor promoto~ng agents were touncl to nave cacarmnoganic act. Mayo( in the wealdy acidic fraction of tobacco smoke does not show tumor-promoting in two stage carcinogenesis.Phenol inhibits B(a)P carcinonger~s on mouse in l-stage cocarcinogensis exp. Catechol, pyrene fluoranthene, B(e)P, B(g,h,i)pe~/lene, decane and undecane carcinogens vath Bla)P. SquaJene, quercetin, esculin, and o~eic acid completely inhibited carcinogenic act of B(a)P on mouse skin. Phenol, eugenol, resercinol, hy~oxyquinone, hexadecane and limonene all partially inhib B(a)P carcinogenicity. Desane, tetredecane, anthralin, and phorbol mynstate acetate found to be cocarcinogans v, qth tumor promoting ability+ Squamous metaplasia (SM) assoc, w/tl~e lung pellets was more severe w/the larger size pellets & the higher concenlration of condensates. The SM was not appreciably. different between the two cigarette smoke condensates and did not markedly #rogress. ~rel~m work indicates that moments analys=s may be a useful tool in differentiating the ~cute reversible changes asses vath broncheprovocatJon from chronic irreversible ~,hanges. Technfque utitizes "all of into obatined with forced expiration vath helium. Page 9

NCI SMOKING AND HEALTH PROGRAM 1975 to smo~ W~lt~rawal from 1978 s~atus repeal Fea~billty of Ir~atian Teshng of Cigarette Smoke in Found~cn |ECI-SHP- 744 Southwest FoLv~datIon ~r Research ~ Education (ECI-SHP-74. t02) Dr. Henry C~ McGHI 1) demons~Jrate that the babo(~ can sere a~ a surrogate ciga'elte smoke ~milar to the human: 2) Baboons collect betlaviora/and chemical abgorption d~ta as the er]im~Js smoke severa/different types of cigarettes; 3) conduct experiments to detect poss=bte nlcobne from 1977 Report dependence in smoking animals; 4) develop an automated cigarette dispenser; and 5) ma~e recommendations as to the fea.°~b~lity of using the baboon as a model to study the effects of cigarette smoking, especially on the cardiovescuiar system. "i~O~t.l'OlTieiltS Of O-~CO (x~5.1 ± 3+1 v$116+5± ~I~ I - Attempt made to Oeterrrirle v#~ei~'-aer r~J~S tar~e anl3 c~alrs ne tallza/~ m~d este~r ttm systemic cl~culas~on ~a kJr~;~s. A a~cjr~r~cant ~crea~ ~n he~l rate wa~ ~ ~ r~.olne w~ adrr~'~J~ed u~'~g a Bamn~on ne~:x~ze~. ,Cotsrl~e ~ placet~ adrnir~b'a~on did ~ have t~ ~e r~H, ~e ~ts ~n ~. ~ ~ De ~n~ w/o ~ i~ f~ up to ~v~ m~ ~ tn~s ~m~. i~ I~ ~ eff~. ~m c~nine ~ Co~ m~ts ~ i~,~ of ~tber ~ng ~ n~l~z~ Tr~ 11 ~tm~s ~o sm~e ~eHes tn a ~m~hke f~1~. ~m~s ~11 sm~e ~ le~ 5 d¢~r~t ~ ~ ~es. B~s ~ewl~ c~x~em~obn leves ;omp~le to tho~ ~ ~m~ cl~e~e smok~ Smoke ~ profil~ ~ ~e b~n~ ~milar to those of human smokers. Studied relationships between variables in blood and unne (CO, Cotinine, thiocyanite, ~nd nicotine); Performed pulmonary function test and lavage procedures for detm of 14C-DTC tracer meth(xJ; performed pdot effort on AHH act of alveolar macrophages from 1978 status report Demonstrated depos~bon of s~gnif amts of part matter in alvecii using 14 C DTC. :3t)served marphological, physio~og~caJ, and biochemical changes, including AHH act, #hich are co~alated with duration of smoking and degree of inhal. from 1978 status report Pulmonary function char. of smoking animals not different from normal smoking ~imals had greater bronchoconstdction in response to methacholine aerosol ;hallenge. Decrease in platelet fact. IV & increaee in fact VIII levels. Page 10