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DOSIMETAY 4N0 OISTRIBUTION OP C1GAR8TT8 SMCKB IN MICB 187 ( F1ESU LTS The effect of total exposure time on the deposition of TPM in mlce exposed on the Walton is shown in Table 1. Female C3H/Anf Cum mice exposed to 10% 2A1 cigarette smoke for a total of 100, 200. 300. and 400 sec showed that deposition of TPM in all tiastass increaeed with increeaing espo8ure time. Such e0osure times resulted from 10-. 20-. 30-. aud 40-sec smoke-expmure intervals per miaute for 10 consecutive -minutea. Deposition was nonlinear, when exposure time was doubted, deposition increasedd more than twofold. The coefficient of variation for deposition in the luln{s from 10 anienele esposed at four different times was between 0.10 and 0.20 (interanimal variation). RRepeat8d exposures performed at separats times yielded a coefficient of vananon of 0.10 to 0.15 (intesassay TA8L8 L EfPect of Time on Aeposition and Diseribvttion of Toe®L Pareictdate Mattiar (TPM) in C3H/Aaf Cum Mice After Eapo6sae to 10% 2Al Cigsrette Smoke ' Total smcke eaposuee.6 an Tione 100 ' 200 300 400 Dopo®tion of TPM.t ItQ l Luxiqa 3210.191 8310.18 )~ 148(0.14) 226(0.17) Iaeynn 1 1 3 22 Flem! 5 8 22 56 Stomach 8 9 24 53 Total 44 101 197 357 • Pereent of Total Body Disuisntfoo3 :ue8s 73 82 75 63 Laeyos 2 1 2 8 Head 11 8 11 l8 Stomecd 14 9 12 13 ResPftsor9 txaet 99 91 88 85 °Potal smoke espnsuas of 100. 200. 300, and 400 toe eesulted dom 10. 20. 30. and 40 see of smeko roUoe.ed by 30. 40. 30. and 20 we of eu. wer,+mctivdy. each migute 'rar 10 eonenluttae minutess fCata are given in tolme of mosn TPM depeated Por 40 mice: eoeMci®no oi Qatianoa an in pnranttiumtr *Percent of TPyI deposited per given tiuue is calculated l'tom the msn total trem 40 mim. HT®012009 4

r fee N6NRY @T a1L varratlon 1. At exposure tlmes of less thm 300 set. the disttibutton of TPM in the body was -, 3 to 82% in the lungs and 89 to 919e in the entire esspuatory ctact. The effect of smoke concenustion an depasition and distribu- tion of TPM in mice exposed on the walton is presented in Table 2. Femsle C3H/Aat Cum mice were exposed to four diffeaent 2t1I cigarette smoke concentradons Ivol./vol.l. i.e.. 5.9. 10.1. 14.1. and 23.3'1e, for a total exposure time of 300 sec. The total quantity of TPM deposited in rde respiratory teact increased with increa:ing smoke concentnltion. in the lungs the increase was linear• with a correlation coefScient of 0.98. The distribution of TPM in the body was similar at all smoke concentrations except 23.3%. Some partmcalav. aggregation may occur at this concentration since TABLE 2 „ Effect of Smolie Coneantsadan on aopasltion sad Dismbution of Total Particulate Matter (TPM) in C3$/Aaf Cum Mice Aft.e:300-ser Eaposuse to 2A1 C%ttette Smoke• 1 Peieent'of smoke cooeonteath IvoL/roLl T1MM _ 3.9 10.1 14.1 23.3 Dapasiemo of TPM.t ue (.upgs 75(0.13) 127(0.14) 186(0.16) 298(0.20) Larynx 2 2 S 54 Hesd 9 1' 28 123 Stomach 12 20 25 40 'btal 98 168 214 $13 Pereenc of Total Body Dntufbaaon; Luoge, 77 "7 '.3 58 Leyna 2 1 2 10 Head 9 10 13 24 Stomach Raspir.toey 12 12 12 a traet 88 68 8B 92 •Smoke exposures of 300 we re.nlted from 30 sae of sefoke to8oved by 30 see of air eaah minuto for 10.eonaseutive mfnutosm t8ats ato given in tams of inesn''P!t deposition from 40 miae: 'coetiieiente of vaeiation are in pateniheau. +*Peeeene of '1'PM deposited per given tidue iA celculated from the m®n total dom 40 mice. HT00120092

c ODSIMBTRY AND DISTRteUTION OF CIGAAE7Y8 SMOKE IN MICW 10 relatively higher deposition was observed in the larynx and head. For HT001200a3 the four concentrations. 58 to 77 0 of the TPM was found in the lungs and 88 to 92% in the respiratory tract. The conditions of 23.3% (vol.lvol.) smoke concentration and 300-sec exposure time was the memmum tolerated nontosdc dose of smoke. Approsiatately 40% of the mice died when exposed to 26.6% (vol.lvol.) smoke concentration for 300 sec (data not shown). Data for deposition and distribution of TPM in three inbred and two hybrid ateains of mice after exposure on the Waltoat are presented in Table 3. Twenty female and 20 male mice of each strain were exposed to 10% 2A1 a8arette smoke for a total of 300 sec. Deposition was similar in all strains, as was the peicent of TPM found in the hmp and respiratory tract. Some differences were observed between male and female mice: male mice appear to have higher TPM deposition. The differences, however, may be related to the higher body wagh in msJea TABLB 3 Pnimomry Deposition of Total Particulate MIatter (TPM) in Five Sttaios of Mice After 300-9ec Exposure to 10% 2A1 Cigarette Smotse• Body Pulmonaey Peieent of total body dlaCribtaton areiptt. depodtioq Bo~emy 14oao® , g of TPM.T 9g Lasg teeet [ C3!!lwnr Ctem Paa110s 20.6 88(O.Z9)e 72 84 9Sa1. 23.2 129(0.16) 67- 87 CS:BLIe Cma E'emale 18.6 108(0.18) 84 79 Maie 19.4 12940.22) 68 80 DSA/2J 7opniv 19.3 94(0.22) 69 79 N1nH ZR.9 L28(0.14) 66 34 9C3Fi/Cam rea.le 1'..1 113(0a2) so 85 AAsN 11.9 133(0.17) 32 88GLP1/Caw Female 19.8 80(0.1i) e1 90 DWa zs.4 89(0.11) 80 8ii •Bspoaura eondit(ona ar In Table 2. @'o:ty mico hom en¢h strain weee .utposed to rmoke oa the Walton nem¢kine. tDe{roaition hae twen normalised to 1096 etooke coneentration bas.d upon the aotemi amok. eaneeutistion menwed during these e:t+asure eonditiona rCoeftlelents of vaeiation are in paeentheefs. ~

1 1410 MeNpV Er AL. H T® 012 0 0~` 4 I The deposition and the distribution of TPM in BC3F1/Cum mice after 300sec exposure to 10% 2,A1 cigarette smoke generated on the Walton (40 mice) or the SEM U (120 mice) ase found in Table 4. The deposition is similsr, particularly in the luags and respirstory tract. The distribution of TPM is also similar•. 70 to 801% of the TPM wae found in the lensp and 86 to 88% in the respiratory cmt after exposure on either machine. The only dtffetenee between animals eaposed on the Walton and on the SEM Q was observed in the larynx. EIowever, the high unrepraducibility aasociated with meeatue- ments of radioactivity in the ieryna makes this ditferencedifficult to assess. 1Qote-detailed resatts of dosimetry studies pedotmed witb the SEM II are pramted elsewhere (Henry et el., in press). TABLE a Depoeition and Distobution of T'ocal Partiaulate Matter (TPM) in EC3F1 /Cum IvCoa After 300-sec Egpogm t®10% 2A1 C'*tette Smoke Generated in the Walton or 9EM it :Vlacttinea' TtIMIo 34aehine LueO Layna Hmd Stottt.eh Ranpieatoty t,act DaPotitlciLot TPHL ue Walton 123(0.20)t 2 ' 22 188 SFM Q 134(0.09)t 29 il t8 174 Percant of Totat PJody Dtatdbutlan aveiton eo 1 5 14 ee SEM Q r0 is 8 12 . 88 •Fsposue conditions ae in Table 2. Data are given itti terma of mean 'PFYM depoaited per given tieaue for a total of 40 mice (20 m91es. 20 females) expcued on the Walton machine and ot ' 20 mice (30 molea, 90 femal®1 expwad on the S®9 II machine. tCooKiaiaat of aeriation. OISCUM1O(6 Although the Walton and the SEM II generate and deliver cigetette smoke in different avays, the amount of smoke taken up and Its dista5ution within the mouse ate remarkably similar. Standaed smok3ng conditions were used for exFoeure, and the resultant deposition and tissue distribution of smoke particulates. were determined. Table 5 summ.eeiaee the factors esaanined for

DOSiMfsTilY ANO OISTRi8uT1ON OP CiGAFETT6 SMOKH IN MICE TaaLS 5 Factom Fsamined for Pos®bie F.geet on Deposition and Dittribution of Totat Patticulate Nateer (TP'.4l) in vlice after Expoeure to Smoke 191 Factor Fsporimeetd .Yec®m uead Dago,iuoa dep®od.nt Senote aoneeatesdon Waltoa; S8d! fI Yea Sqaoka.aposure tima Walton; S$62 [I Yeg Cigoratte typo S8M II No Sttain of enolma Walton No Se= of mouw Walton: SE6S II No Ago of motiee 9EM Q No Pnor espmto of ineqma to.moko SSM B No l possible efiecta on deposition and distribution of TPM in inbred mice. The deposition of these smoke particulates in inbred strains of mice Wae dependent on the time of smoke eaposure (Table 1) and the concentration of smoke aerosols (Table 2) bl:t was unaffected by the strain of mouse (Table 3). sex of mouse. age of mouae, or prior exposure to smoke (Henry et al.' in pres9). Moreover, under similar esposure regimens. deposition of 'I'PM was shown to occur prEmarilp in the respiratory Irat:t of the mouse (80 to 9096). with the deposition in the lungs representing 70 and 80% or 134 and 123 ug TPM per mouse (Table 4), respectivefq. for the SEM II and the Walton. An apparent difference in deposition between the two smoldng machines seemed to be higher levels of TP:V: observed in the larynpal tissues from animals esposed to smoke generated on the SLM 11. However. the high backgroumd radioa:tivity and the laege interanimal variation make this difference difflcult to assess. It may be that this difference in laryngeal deposition is related to the apparent differ6 ence in particle size observed on the Walton as complued with the SEM 11. Deposition data for mice expoaed to cigarette smoke in these studies can be compared with data for other species. including man. Data for humans are frequently given as cumulative TP:VI deposition after the smoking of 20 cigarettes. In making auoh a comparison iBitma. 1977), the amount of TPIYI deposition in mice in these studies was approximately the samd as the TPM deposition in a human who has smoked 20 cigarettes (1 pack). That is. approai- matelq 6.8 mg '1R:VI/kg body weight has been astimated to be Nr®012o095 1

( c \ 192 w6NRY ET 4L deposited for a human smoldng 20 cigarettes. The studies presented hero for three inbnpd and two hybrid mouse sttaias exposed on the Walton estimate that between 5 and 8 mg TPM/kg body weight is deposited after exposure to one cigacette (Table 4). Recent data flvm our laboratones suggest that at least 3000 sec of exposure to 2Al cigarette smoke per day (104'0. voL; vol. ) can be presented to BC3F1/Cum mice with little resulting toxicity. This exposure would fepresent a deposition of approximately 1.0 mg TPM lung- ' day- °. Long.tum toidwy studies with this regimen of smoke exposure are cusreatly in progress. ACKNOWLEDGMENT The authors gmtefiJlly acknowledge the support of The Council for Tobacco Reseasch-4J.S.:1., Inc. REFERENCES Rinos, R., 1977. fnhalatioa Toaieology Studies on C'igarette Smoke. IV. Bzpne- eion of the Doeo of Smoke Pertit;ulate yletaeial applied w the Lange of Esperimeata] amareb, Tox+e.ology. 7. 1P9-195. Caton. J. S. 1979. A Yleehod for the Detarminanon of Tobacco Smoke Lohelation Doatmetry Using 'j~C•Labaled Dotnarontane, in Ta6arco Smoire lnhalation 8ioamy Ghento" , M. R. Guann. J. R. Stokeiy. and C. E. IiEegi® ( Eds.), DUE Report ORNL•842a. Oak Ridge 4atioeal Lsboratorv. IVT1S. Guotin, 5if. R. J. R. Stakely, C. E. Hlegne. J. I{. yfoneyhun, and R. W. Holmberg. 1979, Inhalation Siosrmy Chemietry--Walton Horisomal Smok- iag Mnchiae for fuhaletjon Expoatuo of Rodeets to CqatVtto Smoke,l. Yarl. Cancer Inet.. 63(2): i•11-i•i8. Hoaly, C. J., et ai., 1980. Deposition and Diutibuoan of the Total Perticulate Ylattor of Cigecatte Smoke in Vlice Geuerated by a High Capaatty Smore Fsposure System. Twncology and AppUed Pharrnaeology. in pr.es. Hlgoas. C. E.. T. X. Geyle. etAd J. R. Stokely. 1978. Sensor for Detection of Toboaco Smoke Perticulatee in inhalation Exposure Sytteme. Benr. Ta6akforeN. fntern.. 9( 4): 188.2 81. Hbimber4, R. W.. 1979, Detemmnatioa of Particle Size in Tobacco Smoke Iahalatioo De.iees Using Methylcyanoacrylate F(oitlae and SeanninQ Mioevs. copy, in Tobaceo Smoke inha/anon 8batwy Cneettstry. A7. R. Guerin, J. R. Stokely, tmd C. B. )tigoim (FAa.). DOE Report ORNL-6d24, Dok Ridge National Laboracory. YTffi. Monoyhnm, J. H., J. R. Stokaly. and L PYotent. l9'9. Peofte and Inetrumente Corporation Antomatic Smoke Fspotare MaciJne-SEbi II, in Tofwceo Smoke ln/Fa<otion Bi'aaetor CAanttetry. bl. R. Guet+n. J. R Stokely. and C. E. Higgies (Sd..). DOE Report OttNL.•IW2a. Oak Ridpe *tetioaal Iabotstory, Wyoder, E. L., and 0. Hof&mn, 1967. Tobacco and To6aeao Smoke. pp. 94-130, Academic P+as, Nocr York HT1012009G