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ii. Mortality - Depending on the natu: e ef the smoking aaterial ser%-inE to generate the smoke which is inhaled by the experi-r.eatal animals, as well as on the dose of smoke inhalation, n:ortality in the experisr.eztal group should at no ti:ne be greater than irn the control groups. IL neces- sary, proper adjustraents in the dose of smoke i: :alat:on should be made. iii. Blood carbor. monoxide content-= Deterrsnation of carboxyha-.oglobin in some animals at selected time intervals should demonstrate that there is no carbon mono2ride buildup in the blooc during chronic expost:re to smoke. Otherwise, sharp increases in the mortality of the experimental . s.nimals would be predictable, and a reduction in the dose of s=oY.e inha- lation would be indicated. iv. Sacri:ice of a;irr:als at selected time Intervals - L- order to allow studyi=g :istopat:zolo_:c changes in the ani-rials in progressive stages, lots of from six to 12 hamsters will be sacrificed at selected t:z-..e inter- vals, e. g. after approximately 45, 60, 75 and 90 weeks of exposure to smoke. Moribund zr-i:nals, as judged mainly from sudden bo_y weight changes (see eader i above), will be sacr'ficed without regard to t:-me schedule. v. Gross (5bseryatioI:s at a_toDsv - Co^n.1ete alltopsies will be =a:!e o.^n all anl..'71a:s upon sacr.fice, an d any abnc77`:L:iacs, 2s evident --:o-. ,,rz~ss observat:o=, will b: recorc_c. vi. Or ¢a- » e's¢=:s at a•a:v-)sv -^e K•eig-•s c° the .DL'c-•czng c: z=-.s :11 be dete:.-_4-.ea u~o= ac.opsy: '-• ^gs, aea:, li•+er, adre ='_s, aplcc=, br ain and pit-: :ary. His:ozat :o'.ocic st•:dies Co-s-plete histopataologic st•,id:es ... be made of t_e lur.es, .rachea, iary =r, nesocaaryr~, anz _: all ..ss_es cf ab nD:::•ia'_ apzearan:e. ln addition, st_dies on kidneys, sclee=, .. -r, adre-.als r-.d jituitary will be made in some izsta=ces. S~ecia_ care will :,e used in the prepar ation o: the lungs for 'r.istoiogy, by the fres ::; excisec or gar. t: ro•.:g'.^. the tra:^ea, si- :=e:l}'s Ln _er constant presst:r e to avoid damaging the tissue. PATI:OLCGY Pathological observations have been made on ha-::ster s exposez to t1-e smoking machine for up to 90 weeks. Sigr.ificant obser vations ar e as follo..•s: -8- CTR CCHTRACTS 005697 11225438 C TR HN 0422417

------------ Pulraonarv parerchv-na - No turnors have been found In the alveoli or terminal bronchioles. Hamsters exposed to smoke appear to show an increase in type II alveolar cells. Iron-positive alveo]ar macrophages tend to clump in both of the straias studied, but there Is a marked strain difference in their behavior. In strain BIO 87.20 animals (Fig. 1) the olnmps of rrmacrophages appear at an earlier age and are much larger than in strain BIO 15. 16 (Fig. 2). Trachea and bronchi - Changes attributable to smoke exposure are infrequently seen. They consist of occasional foci of squarnous meta- plasia in the traeaea (Fig. 3) and bronchi (Fig. 4) and in very rare benign papillornas of the trachea (Fig. 5). Laryruc - Most o: the pathological changes occur in this area. The upper surface of the ha: :ster larynx is nor:nally cover eZ by squamous epitie- lium, the lower portion by pseudost: atified colur:Lnar epithelium (Fig. 7). Smoke-related changes occu: in the latter tissue. They consist, first, of very slight thickening with increased pro-•iinence of nucle° (Fig. 6), then of sc,ua:^zo_s rne:aplasia (Fig. 8). Soon the larynx is liced by thick - L squa.ous tissue, s:owi•g acarthos:s, parakeratosis a--d s]i_^t n_clea: atypicality (Fig. ?). Eventually the basal layer of this eoitheliurn ~ becomes irregular and begins to g: o^: down into the u".de:1';ing st: c•.... (pseLdeep:thelic--atous hyperplasia? (F ige. 10 and 11). The rnost ad- vanced stzges c: =~is p: ocess a:e sugges::-e of a p: err.aligr.a-t ch=nge - (Fig. 12). i\o :-,::no: s of the -asccharv =.c have been four.d in o•a: cage- held cont: ols or _ s^am- s:::okei ham s:e: s. In the srnoke-eroos e-_~ a-Ii- raals there has been one large adeno°-c-cystic tu mor thougat to have c:igi- na:ed fro:n a min o: salivary gland or fron: mucus-secret!_ng n asal ep:ttie- liu.:. (Fig. 13). -here has also been one very large sarco:na:ous :_-::o: (Fig. 15) with rr.iti=le s:r.all p_l:nenz:y :ne:as:ases (Fig. 1:). - 9- s = CTR COKTRACT6 005698 11225439 L_r TR f f f w'f S.•,f'"Y' 2'""f' .i. 8

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