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~OEr I;O. LD.1553 EE .S"~r_rCTED 28.12. 1977 AUTHOE: G. Sml t:h ISSlrED' BY: S.R. Evelyn PROG. REF.: 11.O1.10 DZS.TIUS~ION D~. S.J. Green Copy No. 1 Dr. Z.W. Bu4~b~s " " 2 Dr. R.&. Sanford " " 3, G E.M. G£bb, Esq. " " 5 R.S. Wade, Esq. " ' 6, 7, 8 R.G. N£choE1s, Esq. " " 9, 10 Herr E. Ritne~ahaus " " 11 Dr. F. Seehofe= " " 12 Dr. C.3.P. de S£que£ra " " 13 Dr. D.G. Pelion " " 14 LibrarT " " iS, 16 COPY NO.: m C~. M cr~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

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GS/CAL/46D Group Research & Development Centre, British-American Tobacco Co. Ltd., SOUTHAMPTON. 28cb December 1977 RESPONSE OF THE RAT LARYNX AND TRACHEA TO SMOKE DURING SMOKE ACCLINATISATZON PERIOD (Report No. ED.1553 Restricted) SUM~AEY Groups of rats were exposed to 2 dilut£ons of c£garecte smoke for a maximum of 8 days (7 days acc11macisacion plus Isc day of "full" smoke exposure). The race of development of smoke-lnduced chm:Kes, pmrnicularly in the larynx, was £nvestLKated by sacrific£ng animals at Intervals throughout this period. Early signs of squamous metaplasia were evldent after 2 days of acclimatlsaclon and the incidence of this lesion increased with continued exposure. Squsmous hyperplasia, only just notiesablm after 2 days, became siEnificanC after 5 and 8 days of exposure. Keratinisation was rarely seen but whmn found was predominantly found in the L-roup of rats exposed to the hiKher concentration of smoke. There was no definite corre~atlon bet~ean smoke concentration and the excent of the response of the larynx to smpke exposure. Possible reasons for this are given. This study has shmm that for bioassay of smoke to.city based on smoks-lnduced chanKes in the rat larynx, shore experiments of up to BAT Co LTD - MINNESOTA TOBACCO LITIGATION k.ra O", O',, m

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-2- 14 days exposure cannot be used satisfactorily. Such studies do not d£fferentlate between groups of animals exposed to smoke, within the range of smoke dilut£ons no~ally used in our studies. The use of a Ere&tar range of smoke concentrations may, in shorter studies, produce a dose-related response in the larynx. However, results to date suggests that exposure periods of an least A weeks and up to 12 weeks are required to produce consistent responses. Shorter studies tend to give more erratic laryngeal changes which are not related to the degree of smoke exposure. C~ CQ BAT Co LTD - MINNESOTA TOBACCO LITIC;ATION

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-3- I~TI~ODUCTZON All levels of the rac respiratory crate have been shown co respond Co exposure to dilute smoke. For most lesions the magnitude of the smoke- induced changes can be related to duration of exposure and the average smoke concentration to which animals ere subjected. The larynx, in particular, has been of interest due to the consistency and rapidity of the types of changes observed. Bowever, with the exposure conditions previously selecned any observed lesions were often maximal or near maximal after the shortest exposure period used (2 weeks). Tf the larynx is to be used for short-term bioaeeay of smoke it is important to know the rare of developmann of smoke-induced lesions in this region. Thus exposure conditions may be optimised to allow accurate, sensitive comparisons of materials. With this in mind, the response of the larynx over the normal accl~na~isation period was examined. MATERIALS AND ~THODS The filter cigarettes (J54) used for this study were made from e flue-cured blend of tobaccos and had a TPM delivery of 18.5 mE/cigarette. The CiSLTette but-ned to a standard butt length of 25 --- in 9 puffs. The average smoke concentration in the chamber durlng exposure of animals was 7.3 mg/litre (at 1:8 dilution) and 4.9 ms/l£tts (at i:12 d£1uclon). The basic desiKn of the study is shown in Table 1. BAT Co LTD - MINNESOTA TOBACCO LITIGATION o',, O-,,

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-4- TABLE I OUTL]~E OF EXPER.~blT Exposure Period Dilution Up to Day 2 Up Co Day 5 Accl~latisetion &cclimatismtion Up to Day 8 Group Number 1:8 1:12 Sham-smoked 1 4 7 2 5 8 3 6 9 There were 6 smoke-exposed Stoups (20 anluals/$roup) plus corresponding sha~-smoked controls (10 animals/group). The exposure schedule used was as £ollows: Day Number 1 2 3 4 5 6 7 8 Exposure Period HoruiuS &fte~oon Number of Pu~£s m 30 30 60 60 9O go 108 ~osurs Duration (-;us) n 2.5 2.5 $.0 5.0 7.5 7.5 9.0 Number of Pu££s 30 30 60 60 90 90 108 lO8 ~osure Duration (z~us) 2.5 2.5 5.0 5.0 7.5 7.5 9.0 9.0 BAT Co LTD - MINNESOTA TOBACCO LITIGATION C~

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