Tobacco Documents Online

COPY REQUEST FORM BRITISH AMERICAN TOBACCO REQUEST No 2210 IOrganisation I DEPARTMENT OF JUSTICE - CANADA REQUEST DETAILS File Number~j. ,~ 5.. IDATE: ~:~--/- ~ J BOX Number: ~ ~ / 'T- FIRST PAGE =1 } o!o~3, 8 (. PAGE RANGE I LAST q9 - PAGE 9 D ~[-'~ Requested By Name): OFFICE USE Copy Oeta|l~/ / Date : Z " Time: 0 5 MAR ~1, / Copy Check ,d.BY: ,(/f.~//~f///(~ Date: ~?~ ,Z# y 7{~ / v i T,me: iS.Zo. .. Delivery Details Checked By: Date: Sent By: Date: BATCo document for Legal Services • Health Canada 1 March 2001

(1) F" (2) .q- C,,) TSc. t~ 2..,~ i N 488/i :Q-mrlerly l'rogrcss RCl)orts on the Harrogate Research Prqgramm9 for the period e,,cli__l~1 30th Ap1:i[ 1975 Authors : J.K. Whitehead, D.R. Emery Date : General Although routine progress reports have been presented on the scientific aspects of the T.R.C. IIarrogate research programme sitme the transfer of the laboratories to H.L.E., no comparison of actual project costs have been possible until recently, as payment was made to H.L.E. aL a fixed monthly rate for the first 6 months of the contract. The work b'as been on a cost plus basis since February and Hazleton now present monthly statements giving actual hours spent on each project together with costs calculated using the same hourly labour and overhead rates as for the budget :. estimate and direct material costs. These figures are now used for comparison with estimated budget costs in the routine monitoring of progress in the programme. It is now proposed that joint progress reports should be prepared quarterly by the Accountant and thc Research Co-ordinator on all aspects of the Iiarrogatc contract programme. Protocols for all the current research projects in the ttarrogate programme, together with schedules of estimated price build-up and prefaces giving summaries of previous work and the planned research work for the curre,R year, were completed at the end of February. Copies of these papers have been supplied to members of the T.I:I.C. committees. IIowever, furtbcr consideration has led to the conclusion that the present arrangement of the documents will provide difficulties in updating the prog~-amme, and Glenllouse staff are now re-arranging the information to facilitate reference. It is proposed to divide the material into two parts: (a) A general section for the benefit of all T.R.C. members giving brief descriptions of the main aims of each research area,.summaries of experiments in each proiecl, price build-up sheets for each project and facilities for inclusion of progress reports in each area. CD CxD O',, ",,C) BATCo document for Legal Services • Health Canada 1 March 2001

(b) A detailed information section containing the working papers for each project including coding systems for animal experiments, detailed objectives, references, treatments, experimental details, statistical analysis of the results, and final reports. This section would be used largely by the scientists invoh, ed in the work but would be available to all T.R.C. members for reference purposes. (3) The grouping of the proiects iu the cardiovascular research programme has been modified to fit a unified system for the whole programme. The projects under the old designate are,~s CP.1, CP.3, CP.4, CP.5 have been grouped together in a single area of research into various aspects of the development of atheroselerosis, and the CP. 6 projects constitute the work carried out into aspects of nicotine metabolism. A new 3-letter code has been adopted for each of the research areas and the individual projects wiLhin these areas. Both new and old codes are gi~:en in this report. (4) Discussions have taken place between the T.1R.C. statistici?,ns (P.N.L. and his assistants at Bristol), the Hazieton scientists and Mrs. Gradwell of ComShareto agree ou a suitable system for placing the data from animal experiments carried out at Harrogate on file and on arrangements for carrying out the necessary statisticai analyses. Details of the final scheme together with costs will be considered by the S,S.C. at its next meeting so that recommendations can be forwarded to the T.S.C. at its July meeting. (5) (6) Considerable progress has been made in the discussions on the items to be included in the T.R.C. IIarrogate research programme for the second llazleton fiscal year. The research programme will cover the 11 month period from 1st Au~xtst, 1975, to 30th June, 1976. T.S.C. wilt formulate firm proposals for the programme at their May meeting for consideration by the E.C. later in the month. Final cost estimates wilt be provided by ilazleton also in May which will enable T.S.C. to finalise their recommendations at the June. meeting. Document N 494 gives details of the variations between the costs incurred and the estimated costs calculated on the budgeted hourly iabotu" ,~.nd overhead rates over the period February toApril. An analysis of the figures emphasJses the underlying problem for the II.L.E. scientific staff in forecasting the total effort and the monthly phasing which will be required ou a specific proiect. In some areas the forecasting has O O r',,o oo ON BATCo document for Legal Services • Health Canada 1 March 2001

over-estimated at~d in others under-estimated the effort and, where possih[e, the specific reasons for these variations are given in this report• An overall a~atysis of the figures for the 3 months to 30th Apri[ woutd seem to indicate that the total cost for the 6 months to 31St July. ~voutd fall beto~v the estimated costs for the period of £340,140, tha~ is the minimum contract of £355,000 less the contingency reserve of £14,860. However, a consideration of the actua...__.~l expenditure incurred for the . 3 months to 30th April show that the hour|y labour and overhead rates will have to be adjusted upxvards and that if tl~e revised rates are applied for this quarter the sales im, oices wilt be approximately £4,000 higher than origiaaUy estimated for the period with presumably an increase of roughly the same size for the months .May-July. This will, of course eat into the contingency reserve but it would seem that the total cost of the projects for the 6 months to 31s~ July shoutd not exceed the ma.ximum of £355,000. rx..) oo cr~ Ly~ BATCo document for Legal Services • Health Canada 1 March 2001 .........

! :i I PSC - PATHOLOGICAL EFFECTS OF SMOKE AND SMOKE CONDENSATE .. I PSC1 PSC2 PSC3 PSC4 PSC5 PSC6 - IntratracheaI Instittation - Chronic Smoke Exposure and Electron Microscopy - Acute Smoke Exposure and Electron Microscopy - UtLrastructure and Bound PAtH - Cell Kinetics and Ultrastructure - Intercellular JuacLions O CIO O',, P,O BATCo document for Legal Services • Health Canada 1 March 2001

~PSCI (p. i/i Intratrachcal Instillation Investigation of Ihe effects of int.ratracheaI administration of smoke condensate fraction,s in rats.) The maLn experiment A 2.6.9 in which fractions (R + P)G and N(QG) are bei,lg admini- stered to rats by it~tratr.acheal intubation was started on 17Lh March with the following objectives: (1) to confir,n the dose respo,lse of Experiment A 2.6.3 of the production of squamous neoplasms, squamous metapiasms and cuboidal columnar metaplasia following administration of (R + P)G by the intratracheal route; (2) to determil~e any synergic effect of hffusine by using a simpler vehicle (gelati,m) ; (3) to determine if interim kills cal~ provide useful bionss~y information; (4) to determine the effects of repeated in:ratracheal instillation of a moderately irritant but non-carcinogenic condensate fraction [fraction N(QG)] . Fraction N(QG) is proving more toxic than was e|~visaged before the experiment started, with oidy half the animals on the 2 top dose levels remai~fing, and it may be wise not to sacrifice any of this group as planned after 10 weeks treatment. SLx aud seveu animals respectively have died out of the original 2 groups of 36 rats trealedat the highest dose level of (R +P)G dispersed inlnfusine and gelatine. These deaths are largely due to toxicity of the smoke material, but the fcw deaths which have occurred at lower dose |evels are due to lack of experience in administering the mmcsthetic by new operators. This latter problem has been overcome. A few animals rcmain from the earlier experiments and these rats will continue to be examiaed by monthly X-ray to monitor the possible development of carcinoma and wit[ be examined for metastases after death. Tim numbers of animals survivillg ia the various experiments are as follows: o 0 P,o oo 0",, BATCo document for Legal Services • Health Canada 1 March 2001 , , ,i, t

Experiment A 2.6.9 No. Animals No. Animals No. Animals Started Died l~emaini ng (R + P)G 24 mg 36 6 30 12 mg 24 24 6 mg 12 2 10 3 mg 12 2 10 Infusine 0.2 ml 30 2 28 N (QG) 24 mg 24 12 12 12 mg 24 16 8 G mg 12 2 10 3 mg 12 1 Ii (R + P)G Gel Bu/f/Get Anaes Control 24 mg 36 7 29 12 mg 24 1 23 6 mg 12 12 3 mg 12 1 11 0.2 ml 30 1 29 24 1 23 ExperimentA 2.6.1 - No. Animals ~emaining 12 mg= i 24 mg = 2 Anaes Control Untreated = 6 = 4 Experiment A 2, 6.3 - No. Animals /lemaiaing 12rag = 5 24 mg= 4 Anaes Control = 5 Untreated = 5 lnfusine Control = 1 ]afusine Control = 4 Experiment A 2,6.4 - No. Animals l~emaining B + :P ia lafusine = 4 The overall cost of Pro]ect P 1/1 is above the estimate, largely due to the fact that H.L.E. had Lo carry out extra toxicity tests during February before deciding on the final protocol forA 2.6.9, and in March ~hcz'c was a greater level ofactivit.y in order O O BATCo document for Legal Services • Health Canada 1 March 2001 .......... ............

to get Lhc experiment going. During February and March the treatments were spread over 4 days per week whereas in Aprit it was possibte to organise atl treatments on 2 d.~ys. Post mortem a~d histology were slightly up but Chemical Sere, ices were below estimate. The planned kill of animals in mid-May does not appear Lo have been taken iato consideration in tim monthly estimates of labour phasing. However, it seems likely that the toLalnumber of hours over the 6 months ~o 31st July wit! n*ot greatly exceed tim estimate. O Cr,, BATCo document for Legal Services • Health Canada 1 March 2001 l

.PSCI ~. i/2 Intratra('hcal Instillation Ultrastruetural changes foUowiag intratracheal administration of smoke condensate fractions.) The work i,~ this project, which involves the examinatiou by transmission electron microscopy of lung ~issues t~tken from rats treated with benz(a)pyrene (A 2.6.'2) and with fraction (R + P)G (A 2.6.1 and A 2.6.3), has suffered during the quarter from problems arising from sickness of personet. The electron microscopist and technician were away for most of March and therefore no work was done on this project. The backlog is now bci,~g made up and it is expected that the work will be completed as scheduled by the end of July. ,T o Co Cr-, BATCo document for Legal Services • Health Canada 1 March 2001

PSC2 (P.2 Chronic Smoke Exposure al~d Electron h,Ucroseop,r The effects of chrol~ic cigarette smoke exposure on the roder~t respiratory tract.) Although no animal experiments are being carried out in this area in the programme year 1974/75, some ezpeuditure is involved ia this period to complete the Lransmission electron microscope study of alveolar macrophages in the bronchioLar arid alveolar regions of the rat respiratory system foUowing exposure to cigarette smoke using animals exposed i,~ the originaL Harrogate Smoker, and to prepare a report of this work in a form suitable for publication. Some work was carried out in February but the work scheduled for April has been postponed to May and June to enable the EhI staff ~o concentra[e on Project P. 1/2. BATCo document for Legal Services • Health Canada 1 March 2001 o 0 oo 1