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.° CSm~ES ~S TSZ e, ZSP~TOEY ~'aAcr oF RATS Z~0~m~ TO S~Om~ "~6~ 5 OR 7 naY's '" PER ~KEK FOR 6 WEEI~ REPORT I;0. RD.1519 RESTKICTED 31.8. 1977 AUTHORS : G. Smith Lynda V. Wilton R. B£nns ZSSUED BY: S.R. Evelyn I~0G. KE1r. : 11.01.06 DiSr~m~ios: Dr. S.J. Green Dr. I.W. Eusbas De. &.A. Saz~o=d K.M. Gibb, Ksq. R.S. W~., Esq. R.G. N£cholls, Esq. Herr E. KiCCershaus Dr. ¥. 5eehofer Dr. C.J.P. de Siquelra Dr. D.G. Felcou Library Copy No. 1 " " 2 " " 3, 4 || || 5 " " 6, 7, 8 " " 9, I0 " " 11 " " 12 " " 13 " " 14 " " 15, 16 .coP~ ~o. : BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

OS ILVW lP.B I CAZ,146~- 2 Group Research & Development Centre, British-American Tobacco Co. Ltd., SOUTHAMPTON. 31s= August 1977 C~UqGES IN THE RESPZRATORY TRACT OF RATS EXPOSED TO SMOKE FOR 5 or 7 DAYS PER WEEK FOK 6 WEEKS (Report No. RD.1519 Restricted) SUMMARY A comparison has been made of the effect on lunE pathology of exposing rats Co smoke for 5 and 7 days per week. for 6 weeks. Mortality rates were unaffected by the different exposure conditions. Exposure to smoke on 7 days per week caused a marginally greater reduction in growth rate than exposure on 5 days per week. Chanees ~n funk structure amsoeiacsdwlch smoke-exposure were typical of those seen in previous inhalation studies. The results of this experiment indicate that short-termcc~paratlve inhalation toxicity studies can be based on exposure of race for 5 days per week. BAT Co LTD - MINNESOTA TOBACCO LITIGATION r~

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-2- Z~DUCTZON all in_~tlscion studies done so far ec Group R. & D. Centre, exposure of animals co smoke has been carried ouc 7 days per week. We ~r~shed Co know whether race exposed for 5 days par week would show cheeses £n the resp£racoz~7 system comparable co chose observed £n au~als exposed on a 7 days per week regime. To alleviate problems associated with contLnuou8 weekend working, £c was consLdecad worchvhLXm co assess whether or not the reduced exposure schedule could be used for more routine comparative etud£es on smoke cox£c£c7. MATERIALS AND ~THODS Filter cigarettes (Code J54) used chroushouc this experiment were made from a standard £1ue-curmd bland of tobaccos and had an mvera~e del£very of 18.$4 mS/cieacetce. White albLno rats (Strain CFHB) were eupplLmd by ~a~lie Laboratory kuimals. The averaKe weisht on arrival was 160 87ns, for both males and females, and st this weisht the rats were approximately 6 weeks old. They were houlmd 6 to • cake on autoclaved wood 8hav£ngs. Food and water were ava£1abLe ad ILb£tum. All the auLmals were exposed Co two 9-m£nute session8 per day (4 hours beckman sessions) Monday Co Friday for 6 week8 on the B.A.T- N, smon 20-port /~hmlacion machine. Some an~uuale were also m=cposed once ouZy on SsCurday and Sunday (Io~nJ~gs only). All but one Kroup o£ animals were azCopsied the day (20-24 hours) after the£r ££=al exposure. & e~qle j:oup o£ rats exposed for 5 days per week, was tuCopsied 3 days (approx/~acely 65 hours) a£cer fimtl exposure. BAT Co LTD - MINNESOTA TOBACCO LITIGATION r,,o %0

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-3- In all there were 8 groups o£ 20 rats (10o'and I0~). Table I shays the exposure conditions used for the various experimental groups. At the t~o dilution levels used in the study (1"8 and 1:12; smoke:air, v/v) averqe T~d concentrations in the exposure chamber were 6.26 and 4.17 n~/L respectively. The larynx, tr•ch•• and lungs were removed £rmn all rats, and paraffin sections prepar•d £or exsm£nation. Quantitative microscopy was married out •s in previous studies. RESULTS Lqort•lities (Table 2) There were only 7 premature deaths in the experlment. The majority o£ these ~ere £rom groups exposed to the higher smoke concentration, and all were females. Deaths were predominantly in the early part of the week and rats exposed for both 7 and $ days per week were •qtmlly involved. Th• death of • shah-smoked rat was unexplained. There was • reduced growth rate in all smoke-exposed groups when compared with the cage controls. Sham-smokers had an intermediate Sro~ch rate. JLtl the female rats exposed to Isoke had similar growth pjt~srn~ irrespective of smoke dilution and number o£ days per week exposed. Their sham-smoked controls also had similar rates o£ growth, intermediate between that of the smoke-exposed and ease control groups. Kale rats exposed to smoke at both dilutions had similar growth curves. However, exposure £or ? days per week produced a 8rester reduction in Srow~h rate compared with S days per week. S~larly, shah-smoking on 5 days per week had less e££ect on growth rate than treatment on 7 days per week (Figure I). BAT Co LTD - MINNESOTA TOBACCO LITIGATION %0 %0

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-4- Histopatholo~y The types of les£ons observed in this study were as reported previously and their morphology need not be described in detail. For all parameters, there were no apparent differences in response be~ueen male and female rats. For this reason all tables refer to combined data from an/reals of both sexes with£n a particular group. All smoke-exposed groups had a comparatively low incidence of I)~phocytic infla~ation associated with the a/rways, b~ood vessels and parenchyma. This was particularly evident when rats with both multiple perivascular cuffs (>6 cuffs/lung sect£on) and focal pneumonicis were recorded on a group basis (Table 3), There were no significant differences between the smoke-exposed groups. The incidence and severity of alveolar metaplasia wirh the associated clusters of macrophaKes was low (Table 4). IC was observed in on/y 4 rats, • 11 exposed to the higher smoke concentration. The r•cs exposed on 7 days per week accounned for 2 examples, the remainlng cases being one in each of Groups 2 and 5. Of the an/~sals exposed •t the lower smoke concentration Chafe was only one case in which clusters of macrophaees were evident. This raC was exposed 7 days per week. Alveolar macrophages, found throughout the paranchyma, increased in numbers in all rats exposed to smoke. The control groups all had similar, comparaCively low vaEues CTmble 5). Rats exposed to the higher smoke concentration had the highest values and exposure for 7 days per weak produced • slightly greater response than exposure at the same dilution level for only 5 days per week. Molding the rats for 3 days mmmmh r~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-5- prior to autopsy produced a slight reduction Ln macrophase numbers during the post-L~posure holding period. Exposure to smoke produced a marked increase in goblet cell ~tiviCy in the left intrapulmonary bronchus (Table 6). As in the case of alveolar macrophales, the higher concentration of smoke produced the greater response. Also, at each dilution level exposure for 7 days per week produced a greater response than exposure for 5 days per week. Molding animals £or 3 days £ollo~r~ng their final exposure brought about a decrease in the number of race per group ~th goblet cell hyperplasia. The overall d£strlbutlon of goblet cells wms greater in all smoke- exposed rats with no evident d£ggerences between the varLous groups (Table 7). There yes some indication o£ £ncreased haemosideros~s (excess of iron p£gmant from the breakdown of haemoglobin) in mnokJ- exposed rats, but no group compar£sons vere ~ade. Trachea There were no marked changes in the tracheal epithelluR of smoke exposed rats except for a small but consistent increase £n epithelial thickness. Variation in e~posuze conditions did not ~fect the degree of response, except that the 3 day hold£nE prior to autopsy caused a reduction in epiChe1£al thickness (Table 8). Goblet cell activity Ln the ~d-trachea was hyparplastlc in the majority of smok~-axposed rats. The number o£ rats per Broup shoving increased activity was not clearly related to exposure conditions, although exposure for $ days a w~k at 1:12 dilut£on and also hold£ng the one Stoup £or 3 days £ollow£ng exposure save a reduced response. One control group had • comparatlvely large number o£ rats ~th incrlased goblet cell actlviCy (Table 9). BAT Co LTD - MINNESOTA TOBACCO LITIGATION O r~ r',o

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~n Larynx Squamous netaplasie in the floor of the larynx was observed in all smoke-exposed rats, irrespective of exposure conditions (Table SO). Holding animals for 3 days following exposure increased the number of cases of ~ncomplete meteplasia, and also reduced the thickness of the ventral epithelium (Table ll). The deEree of squamoue hyperplasla on the medial aspect of the vocal cords was marked, and similar, for all smoke-exposed rats (Table I2). The an;m~lS held for 3 days prior to autopsy showed a reduced respoDse. A fully di£ferent£ated 8~ratum come,u- was absent £rom all control groups but was frequently observed fn exposed animals (Table 13). The number o£ rats per group 8ho~rinK this feature followed no clear pattern related to the seve=£ty o£ exposure, boa:, the i~oups of rats exposed for § days a week at a 1:12 smoke dilution and ~ose autopsied agter a holding period of 3 days had a lover incidence of keratin£sation on the vocal cords. DISCUSSION Keduci~K the exposure to S days per week from the more usual 7 days did not agfect the mortality rate o£ the animals. As in previous studies there was the tendency for deaths to occur at the beginning o£ the week. Under the c~itlon.s used for this experiment there was no appreciable d~££erence between the 8ham-mnoked and ~he cage control ra~s. Thus from a pathology point of view one or other o£ the controls could be omitted. Preferably, shmn-moked animals should be retained since they represent the t~ treamanC control in an experJJmenc. BAT Co LTD - MINNESOTA TOBACCO LITIGATION w t..r'l.

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-7- Exposlr~ animals to dilute smoke for 5 days instead of the usual 7 days per week produced similar histological lesions in the respiratory system. The extant of the lesions did vary with the different exposure conditions used in this study, the deKree of chsnKe dependinK on the level of the respiratory tract under consideranion. A al~sary o£ the histolosical £indinss is shown in Table IA. All values in smoke-exposed Kroups were greater than their corresponding controls. The chenKes in the lunK parenchyma and bronchi were all greater in those animals exposed to the hiKher concentration of smoke. For each smoke dilution level, those rats exposed to smoke 7 days per week had consistently higher values than those exposed for only 5 days per week. This general rule applied to those raCs 8utopsied the day £ollowi~ their final exposure. Of those held for 3 days. there was usually a marked regression of lesions. This pattern of regression corresponds with previous observations (1). Zn the trachea, epithelial thickness at the level of the first tracheal ring was increased in all rats exposed to dilute smoke. Of those autopsied the day following final exposure variation in dilution and the number of days per week exposed did not affect the degree of response. HoldinK animals for 3 days prior to autopsy produced a marked reduction in the tracheal epithelium thickness. Goblet cell hyperplasia in the main incrapulmonary bronchus was more frequently observed in smoke-exposed rats. Exposure at 1:8 for both 7 and 5 days per weak, together with 7 days per week at 1-12 produced 8iJnilar results when 8n/~al8 were autopsied the day following their final exposure. Rats exposed for 5 days ac 1:8 but held for 3 days and for 5 days at 1:12 smoke dilution showed a decreased response. t~ r~ r~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

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-8- The larynxes of all smoke-exposed rats shoved signs of sqzus mecaplasia and hTperplasia. The chauKes were readily identified and in the rats aueopsied within 24 hours of Che£r final exposure, variation in exposure conditions did not produce any differences in response. quanci£iable changes were sim£1ar in all rats exposed to mnoke. A possible exception was the reduced frequency of keratin on the modial aspect of the vocal cords in race exposed aC the lover smoke concentration for $ days per week. Holding anLmals for 3 days caused e resolution of all laryngeal Lesions (squsmous meCaplasi.a and hyperplasia, keraCinisacion). With regard to Che exper/mencal design it is noticeable that, with the exception of alveolar metaplssia, there was resolution of all lesions. All animals must therefore be auCopsied as soon as possible a£Car, and certainly v£Ch 24 hours o£ their ££ual exposure. Dec£ding on 5 days or 7 days per week exposure over a 6 week period will depend on the reKion of the respiratory system ,mder consideration, and the aims of the project. T£ the trachea and laz~y~x are under ~nvesCiKation there ~s no d£££erence between 5 and 7 day per week exposure reS~nms. Tn the lunK 7 days per week cons£scenCly produced greater changes than 5 days per week. But £n both cases (7 and $ days per week) the Stoups exposed at different dilution levels of smoke could he d£££eranc£aCed. Thus £f max£mun response £s not nacees&~y, only Stoup separation, 5 days per week for 6 weeks, would be suitable for the &ssesmnsnc o£ comparac£ve £nhelac£on cox£cicy. Zn this connection it is worth mention£nS thac apparently more severe exposure conditions do not necessarily produce a maximal or optimal funk patholoKy response. As far as inhalation bioassay work is concernod, differences between test Stoups are more readily observed BAT Co LTD - MINNESOTA TOBACCO LITIGATION ¢,..m

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-9- when patholosY end-points lie on • simple dose-response curve than at the higher end of a ranKe. For example, we have observed lover alveolar macrophaKe counts in swoke-exposed animals compared with those in groups exposed to lower TFM concentrations of smoke (2). A possibly more familiar illustration of the same kind of affect is Kiven by the "high dose anomaly" phenomenon seen in skin paintEng experimenCs (3). Tf the 5 days per week regina is employed the number of days with two exposures per day following 2 days without exposure (usually Saturday and Sunday) may be significant. In this study, before autopsy there was a mln~ number of 3 days of "full exposure" to smoke following a weekend without exposures. Until further evidence is available this must be reKarded as the minim~n period. CONCLUS ~ONS The followlnS Kuidelines, based on the results of thls study, will be used for the conduct of the next short-term bioassay study: 1. CaEe controls may be excluded provided sham-smoked controls are used. 2. Exposure of animals to smoke Wic_.____ee daily, on 5 days pc= week for 6 weeks. 3. Animals ~ast be killed within 2A hours followinK nhe final exposure to smoke. &. &t least 3 days "full" exposure must be siren follovins • smoke-free weekend. 5. One sex only, preferably female, may be used. REFERENCES 1. • •2. 3. EAT Eeport No. RD.1477 ~stricted, 23.3.77. BAT Rmport No. RD.1281 Restricted, 23.10.75. Biolog/cal leporc B26, May 1972. BAT Co LTD - MINNESOTA TOBACCO LITIGATION r,,o

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-I0- TABLE 1 OUTLZNE OF EXPER]34ENTAL DESIGN Smoke D£1uC£on (v/v) Number of Daya~eek Kxposed Co Di2uCe Sa~ke 7 5 5 7 day lweek Sbmn Smoked t ,m 5 day/reek Group Number 6 7 1:8 1 2 5* ., | ! 1:12 3 4 { *Killed 3 days afcer fimll exposure 8 TABLE 2 s .u~¥ ol, P.~-T~TXO. D~TSS i~C Number and Sex 1891 ~997 1917 2 xs93 x97s 2 2940 1970 Smoke DiluC£on Level 1=8 5hmm-smoked 1:8 1:8 1:8 1:12 1:8 Number of Dmys Exposure co Full Smoke **DOSe** L,,. 22 24 32 34 3O 2 1 N~mber o£ Days/ Week Exposed Day of Deal:h ~aursday Thursday Monday Tuesday Tuesday Sunday Honday r~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-11- TABLE 3 NUMBER OF RATS WZ~ BOTH HULTZPLE ¥F~XVASC~.AI CUFFS AHD FOCAL PHEUHONZTTS/TOTAL NUMBER IN GROUP Smoke Dilut£on (v/v) Number of Days/Week Exposed co D£luce Smoke 7 5 5 1:12 Sham Sham Smoked Sn)ked j7 day/week 5 day/week t | Incidence of Lesion .. ,,,, 1:8 1/17 4/19 2/20* i 9119 13/20 10120 I 2/19 1/20 Smoke DiluC£on (v/v) 1:8 1:12 Humber of Days/Week Exposed to Dilute Smoke 7 5 5 Sham Smoked J 7 day/week Shmn Smoked 5 day/week Incidence of Alveolar Metaplas4a 1/19 1118" O/19 0/20 (i) 2/17 (i) (2) o119 (1) 0120 *Killed 3 days after final exposure. 0/2O BAT Co LTD - MINNESOTA TOBACCO LITIGATION J~ k.J'l

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-12- TABLE 5 GROUP MEAN NUMBER OF ALVEOLAR MACROPHAGES IN FIXED SU~'I.EUEkL STRIP (0.54 sq..n altO) Smoke Dilution Cvlv) 1-8 1:12 Number of Days/Week Exposed Co Dilute Smoke 29 25 7 5 5 7 day/week 27 23* 23 Sham Smoked Case Control s 5 d~ylweek NacrophaKe Count 6 8 6 IIII TABLE 6 GOBLET CELL IYPERYLAS~ AT FLIED SITE OF MAIN LEFT ZNTEEPULMONAEY BRONCHUS Smoke DiluC£on (v/v> 1:8 I" 12 Number of Days/Week Exposed to Dilute Smoke 7 5 5 7 day/week Sham Smoked 5 day/week 2.75 2.28 2.35 2.17 Goblet Cell Zndez 2.06", 0.17 0.3 *E/11ed 3 days after final exposure. CaKe Control O. 42 BAT Co LTD - MINNESOTA TOBACCO LITIGATION r,o %0 t..,,a "-.,.t

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-13- TABLE 7 i|., GOBLET CELL DISTRIBUTION IN LEFT LOBE OF TEE LUNG Smoke Dilution <v/v) 1-8 1-12 N,mber of Days/Week Exposed Co Dilute Smoke 7 5 , ,,, lJ, Sham Sham Smoked Smoked 5 7 day/week 5 daylmk ,i Goblet Cell Index 2.2 2.1 2.2 2.1" 1.3 0.8 2.1 Cage Control Smoke Diluc£on (v/v) 1:12 N~bar of Days~sek Exposed to Dilute Smoke 7 5 $ 23.2 22.8 23.3 23.2 Slum ~ked 7 day/week Sham Smoked 5 day/reek Cage Control Epithelial Thickness 20.1" 19.7 18.1 19.1 *Killed 3 days after final exposua. BAT Co LTD - MINNESOTA TOBACCO LITIGATION ",O ",,¢D

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-14- TABLE 9 COBLET CELL HYPERPLASIA IN UPPER-HID TRACHEA ~>5 GOnT.~':T C~:Y.T-~ PEE T~qSVRRSE SECTIONt ,.RATS ~ZGTF..I)/TOTJ~ EATS ZN GROUP) Smoke Dilution (v/v) N,e~ber of Days/Week Exposed Co D~luCe Smoke Sham Smoked 7 5 5 7 day/week 5 ctay/veek 1:8 1:12 1~/18 12119 Incidence of Hyperplm~ia 1&/19 7/15" 1119 ! 6120 2120 m 9/20 TABLE 10 SQUJaOUS t~T~..xs~ I, n.oo~ oF ~,~ LAan~ ~T *FFEC~D/TO~. ~S XX CROUP ~.CO~LrrE ~._~sz.)) Smoke Dilution (v/v) 1:8 1,12 Number of Days/Week Sham Facposad Co DiLute Smoked Smoke 7 5 5 7 day/week Sbmn Smoked 5 dayl1.~ek , ,.,. , 18/18 18/18 (I) (I) 19/19 20120 (i) (0) $nc£donc@ of Metaplasls 17117* 0/18 0/20 (6) ii *Killed 3 days after final exposure. 0119 BAT Co LTD - MINNESOTA TOBACCO LITIGATION ¢,,.m tNa %o

INDEX HAS INDICATED GAP IN BATES RANGE HERE

TABLE i I EPITWA'LEAL THICKNESS ON VENTRAL SURFACE OF THE LAR~q~X Smoke Dilution (v/v) 1:8 1:12 tbmber of Days/Week Exposed to Dilute Smoke 7 5 5 |, Sham Sham Smoked Smoked 7 day/week 5 day/week Cage Control 23.6 23.7 26.2 Ep£thelial Th£ckness (tun) 16.2* 9. O 9.2 9.3 | 25.2 TABLE 12 D~-E OF sQu~0us m?~~ oN T~ MZDL~, ASrECr OF ~ VOCAL CORDS Smoke D~luClon (v/v) Number of Days/~eek Exposed to Dilute Smoke 7 5 5 1:8 35.4 | , 1:12 7 day/week 5 day/week 36.0 EpiCheliaE Thickness (.m) 29.4* 23.1 I 25.3 i 22.2 e| 36.6 *Killed 3 days after f£nal exposure. BAT Co LTD - MINNESOTA TOBACCO LITIGATION

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-16- TABLE 13 I~"HZF.~ OF Ek.T5 ZN GROUP v'r-'L~ A FULLY DEPP~~TED STILATUM COLqEUM ON THE HEDIAL ASPV.CT OF THE VOCAL COEDS t i i .t Smoke Di luClon (v/v) Nmuber of Days/Week Exposed co Dilute Smoke 7 5 Sham Sham Smoked Smoked 7 day/reek 5 dmylveek HmJ of Rerac£u£saC£on 1:8 10118 10118 7117- 0/18 0/20 1-12 12119 7/20 *E/11ed 3 days a~cer flnal exposure. Cage Control 0119 r,,o BAT Co LTD - MINNESOTA TOBACCO LITIGATION

N o C" I Z Z 'O (] O ,-I 0 2 ( -17- T, UlLIt 14 SUIIJMRT O1' RISTOLOGICAL FINDINGSI, 5-DAY VS. 7-DAY PElt HEEK EXFOSIMES • ,e, Ju... ~. Oroup Cosparieon Smoked vs. Controls 7-day vs. 5-day exposures L:eve. lt12 dilution 5-day aud 3-day recovery vs. S-day exposure ~ummou| 14etopLssLe + 0 o Larva Sqummus hrstinLution |yperpLesi, 0 0 Trachea Epftholisl tablet Thickness Cell 0 0 0 0 ii Bronchi Coblet Cell f Parench)ms IHecropbeae Humber Comment 8 Alveolar Hetsplssis * All lesions as described in prevLous studios + Possible reduction in frequency S-day 1:12 ÷ S-day 1812 leas thou 5-day ItS O tqreasion of sluoat all lesions over 3. days + 8reater response, 0 similar response, - reduced respouee.

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> ,.-] (.-} o I Z Z > ,-t 0 > C~ 0 .-] m 0 Z .GROWTH CURVE5 FOR f FIG I CONTROL AND .~MOKE EX,POSED RATS ('G WEEK5 IID.I.519 RE3TRIC'rED E~...RDSURE 1:8 HALF,,5) MEAN ~, RX~HT ~E - 115 IIO m ioo 90 io lo so 55 5o 45 CAGE CONTROL 5 DAY ~ ,~MOKED 7 DAY ~ SMOKED DAY EXPOBURE 5 DAY EXPO~REI 7 DAY EXF'O~RE 4O 35 11 HILLED 3 DAYS AFTER FINAL EXPOSURE 25 ~O 15 I0 5 0 5 D iS LP0 Z5 30 45 40 45 50 DAYS IN EXPERIMENT

INDEX HAS INDICATED GAP IN BATES RANGE HERE

-3- 1n all there were 8 Stoups of 20 rats (lOo~and 10~). Table 1 sho~s P the exposure conditions used for the various experimental groups. Ac the two diluclon 1~vels used in the study (is8 and 1:12; smoke:air, t v/v) average TPM concentrations in the exposure chamber were 6.26 and 4.17 m8/£ respectively. The larynx, trachea and lungs were removed from all rats, and paraffin sectLons prepared for examination. Quantitative microscopy was carried out as in previous studies. RESULTS Mortalities (Table 2) l There were ~nly 7 premagure deaths in the experiment. The majority of these were from groups exposed to the higher smoke concentratLon, and all were femaI, ;. Deaths ware predominantly in the early part of the week and rats ,omed for both 7 and 5 days per week were equally £nvolved. The death of L sham-smoked rac was unexplained. There compared s a reduced growth rate in all smoke-exposed groups when the cage controls. Sham-smokers had an Intermediate growth rat All female rats exposed co smoke had slmilar growth p&ttems irres :ive of smoke dilution and number of days per week exposed. Their controls also had sLmilar races of growth, intermediate thac of the smoke-exposed and case control Stoups. Male rats exposed to smoke at both dilutions had similar growth curves. Bowever, exposure for 7 days per week produced a greater reduction in growth rate compared with 5 days per week. Similarly, ~a~.~k~shanr- .........--~ ..... _=:~5 day.had__ less effect on growth rate than tree,natl._ on 7 days per week (Figure 1). .~, r~ %0 <~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

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