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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