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BATCo document for Province of British Columbia 8 November 2000 BATCO 00290337

CLTEGOHY ~ Smoking and Hea!:h - ~io-assay Results 4969 It was suggested that the U.K. representatives should emphasize at the T.S.C. "Skin-Painting Conference" their interest in the T~/~29 comparison. This appears to be a significant alteration in mouse-skin bioassay reaction brought about by an alteration in tobacco composition. T.R.C. are hampered in following this up by the practical difficulties of specifying the actual compositions of T~ and T29. The Conference agreed to invite T.S.C. to communicate their findings to Dr. Griffith of the University of Kentucky, explaining why they could not follow them up and hoping that the University of Kentuc}D" would use the wide ranse of tobaccos at their disposal, of kno~ genetic origin, to investigate how great a variation in "mouse-skin reaction" could occur within a conventional classification, e.g. Virginian flue-cured,~Burley, Oriental, etc. Followin~ a discussion of the differences in the bioassay results on T.R.C. samples T~ and T29, Dr. Huy~hes agre@d to produce a paper on the laboratory tests which could be made to investigate t~h_is. Fractionation experiments at Harrosate The Conference devoted some time to considering the value of this line of research. They took note of the T.S.C. paper E. q628,. which attempted to set out the objectives. The general opinion was that this work should be continued in the hope that it would be possible to identify specific initiators and promoters. Herr Sottorf reviewed the Lokstedt I Programme, and .mentioned that the Lokstedt II Programme would include different reconstituted tobaccos; it is not yet clear when these results would be published. ~. Wade outlined the new pro~ects which the Canadian Industry would be supporting at McGill University and the University of Montreal. Dr. Felton agreed to ensure that Montreal were kept informed of similar studies by Dr. Fletcher and others supported by T.R.C. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290338

CATEGORY ~ 2. ~969 The position in the United States, with respect to the gas phase, was discussed, and the general opinion is that this will become an important issue, and that some publication of the analytical results for certain gas phase constituents will be made within the near future - possibly within one year. It was guessed that the constituents which would be measured would be selected from the following: acrolein, carbon monoxide, formaldehyde, sulpher dioxide, nitrosamines, formic acid, oxides of nitrogen, hydrogen sulphide, hydrogen cyanide, and phenols. It is likely this will lead to great activity in the areas of charcoal ~nd water filters. Dr. Sanford undertook to produce a list of analytical methods and their costs, and methods of removal; Dr. Felton will consider toxicity aspects and nhe Droblem of estimatin5 the overall toxicity of the ~as phase. "Bridging the Gap" The Conference agreed that this was an exlperimental problem which could be specified ~nd attacked experimentally. They accepted that to make a start cn this, it was necessary to set up some hypothet±cal model of how smoke aerosol could cause cancer in the basal cells of the human lumg epithelium. They accepted that the view advanced by Sir Charles Ellis could form one such hypothesis, and could form a basis for an investigation. In broad terms, they supported an investigation into the absorption of smoke constituents by the mucus of the ituug, the identification of what was absorbed, and what changes occurred in time. They recognized the significance of studying the effects on the basal cells of such a modified mucus blanket, but realised that it constituted a major and difficult research pro~ect that lay beyond the resources currently available to members. o BATCo document for Province of British Columbia 8 November 2000 BATCO 00290339

CATEGORY Q 3. ~969 Short-term toxicit~ ~nd other tests Historically, bioassay experiments were undertaken by the Industry with the object of clarifying the role of smoke constituents in pulmonary carcinogenesis. The most widely used of these methods, mouse-skin painting, proved onerous and time-consuming, and therefore e)~ensive to carry out and attempts were made to find "short-term tests". Many such have been proposed and developed, and it is important to note that they were regarded and assumed as more speedy tests for carcinogenesis, or at the least as screening tests for which samples should go forward to long-term painting tests. however, it began to be appreciated that the physiological effects of smoke aerosol in the broad field of "bronchitis" were important in their own right, as distinct from carcinogenic effects, it became apparent that some of the short-term tests might be more directly relevant to this phenomenon. Thus the curre$ ~ position is dominated by the uncertainty of ~he role of the short-term tests, and the profound effect tha~ the resolution of this uncertainty would have on the use of mouse-skin painting. A priori, it seems unlikely that a short-term test can give relevant indications on what is essentially a long-term process, unless and until we can identify the early cellular changes leadin~ to carcinogenesis. At present, this is not in sight. On the other hand, long-term and short-term are descriptive phrases which must be interpreted in relation to .the life cycle of the organism being --~ studied, and there is a possibility that the experiments o taking place at R. ~ud D. Southampton, with the membrane ~ of the chicken embryo might be showing genuine carcinogenic ~m effects in days. -m~ BATCo document for Province of British Columbia 8 November 2000 BATCO 00290340

CATEGORY d a. q969 6.cont. The conclusion of the Conference was that at the present time the Industry had to recognize the possibility of distinct adverse health reactions to smoke aerosol : (a) Lung Cmucer (b) Emphysema and bronchitis a~.d present and future bioassay tests could usefully be classified according to their applicability to one or other or to both. The hyperplasia test hss been developed into a dependable empirical tec~ique that can be used to grade smoke condens~tes. It shows a high but not complete correlation with mouse-skin bioassay. it is probably closely related to "bronchitic effects" but the nature of this relation is not understood. The sebaceous gland tecfanique has been studied intensively and there is a body of expert opinion which considers that it is possible that it may correlate closely with longer-term carcinogenic effects. The majority of the other many biological reactions that have been studied seem more related to immediate toxic effects than anything else. The Conference took note with interest of B.A.T. (Hamburg) experiments and also of collaboration with Professor Lather' on s~udying the relative amo~_nt of Lactic Acid Dehydrogenase isoenzymes. In an attempt to take a broad view of this complicated situation, the Conference reached the following conclusions: In the foreseeable future, say five years, mouse-skin painting would remain as the ultimate~::D court of appeal on carcinogenic effects. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290341

7. cont. (b) (c) There was a possibility that short-term cellular phenomena such as hyperplasia, sebaceous gland suppression, alteration in cell metabolism, reaction of chicken embryo membrane, might develop sufficient credibility to lighten the burden of mouse-skin work by screening. However, the preceeding decision developed. it was already clear that techniques such as hyperplasia, observation of ~oblet cell activity, and ~uything that could be directly related to chan6es in cell behaviourism merited intensive study in their own right. The immediate action agreed was: (i) To accept ~zd use hyperplasia as an empirical grading system of tobacco smoke under the proviso that this interpretation of the results was the responsibility of the user. (ii) To support research into the meaning and interpretation at the cellular level of the various short-term tests. Dr. Green stated that hyperplasia tests could be made available to members for about ~ ~,000 per test. Dr. Griffith and Herr Sottorf felt that greater sensitivity might be required before adopting this test rountinely but Dr. Fordyce was of the opinion that attempts at further refinement would be a waste of time. It was agreed~ however, that, with a test of this nature, it would be wise to take samples with maximum differences in order to establish the trend likely to be found with commercial samples rather than submit proposed aud current brands. o o BATCo document for Province of British Columbia 8 November 2000 BATCO 00290342

CATEGORY ~ 6. 9969 Dr. Seehofer suggested that it was desirable ~o discover in all short-term tests the dose level which gave a constant and optimal response rather th~n to assume that all dose response relationships were linear. It was agreed to consider this in relation to all our short-term tests. The Conference reviewed the progress made in reducing the amount of carbon monoxide in smoke and aEreed that it was very unlikely that a substantial reduction would be achieved by filtration~ and therefore attention is being ~iven to alteration in the factors controlling combustion conditions or overall reduction of the gas phase by ventilation. Following a discussion on the possible relevance of free radicals~ Dr. Fordyce undertook to formulate a research programme which might resolve the matter~ ~ud which could be undertaken by one of the bi~er laboratories. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290343

CATEGORY 2 Pharmacolo~Ey - ~icotine q969 The Conference reviewed Dr. A.K. Armitage's paper on nicotine, which confirms the intuitive approach which has ~uided Group research on nicotine in the past. The Conference a~reed that all the evidence conZinues to demonstrate the importance of nicotine to the smoker, and a~ain emphasizes the importance of keeping separate TPM and nicotine £i~ures. It was suggested that all analytical data should be reported in relation to Zhe nicotine values. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290344

Allocation c.:' divi.~i:n :.f 7,. ]] .:..:bo:.s acreeO thst the z'r..~uit.- of all work done c~ sa::::~!es from individual co::D=:ies could be circu!atcd to all mcmberm of the Biological Testing C.:~:~v:~itt~e, preferably identified by code numbers. Dr. Green said that Zhe intention was that the results of tests specifically paid for by a sponsor ,,,~uid not be circulated without the permission of the sponsor. It ',:a:: ;:rLreed that it would be helpful if bodies m_~r'h as T.P,.G. could bc uz'g~¢ to investigate the smoke from cigarettes made f':o::: tobacco claimed to be free from pesticides an@ !o:.:.~r than normal in funEal spores, There wan a ~eneral discu.~.sion on the role played ~,-" t}~o new Research Fla:n]in< ~ection~ establiched ]'o!louin~ the last Confez',~nc~. Great e,m~'eciation...._. was e:.:pressed all ro~d for the service beinC provided zn, o~.n~ion, ~d p~rticularly cn L:: ]:in~ ~nd Htelth " ' " for the critical co:neural2.- Rrovided. The pl~nin~ nro~_~Gee far enou5h ~,cZivit$-, however, for its usefulness to be a::c<.csed. Sir Charles Ellis .u,,g~stcd that the various- prec,'atones, includinc ll~,~z'oLate, LohsteCt, J~]UL, ~u-~O ]luntincdon, mi5ht be usr.fully ~alzsed under the following headings: (a) i.]odified (b) Health H<'s~arch (c) Consumer r, reference and psychological and phyri~!oLical fsctors (d) ~roccss Im~rovement, etc. 0 BATCo document for Province of British Columbia 8 November 2000 BATCO 00290345

• T;~, Conference nt:'~.~,d ~) :~:.~'i:'L in this t~.~]: ~y i~:l'orminG Dr. i~c!~on of the project objectives !i~tcd in the procra..nmc,q. The aim is ror each laboratory to control itc own ~ork in such a ~ay that it integrates into a total effort, so that th~ laboratory cets ~he mo::ir.um advantage. There was a discuccion on information retrieval .'.,~',.C ~b.e pro~rc~ of kc~u:o:.d codinC at Louisville, ~[ nt~'oal, ][ambur5 ~n6 SZ.-Cn~V. Dr. $anford a~z'eed ',..~ ai.'-culate hi:' ]~:,y'..o~~] t~.o:aurus, and to send to L]ul.hempton the he~-<:ords ro far abstracted from ~,. "u~] D.E. re~or, t[.. Th,- other ;nomber'n nlno n~eed t~ circulate th~ir kej~:or£ indices. 0 BATCo document for Province of British Columbia 8 November 2000 BATCO 00290346

CATEGORY a S~fe Cigarette q969 A discussion followed on the criteria which might be adopted in considering new smoking materials, modified cigarettes with health orientation, and changes in commercial cigarettes. It was agreed that the criteria included: (i) (ii) (iii) (iv) (v±) House-skin painting Hyperplasia tests Chemical analyses for carbon monoxide and other gas phase components, as well as other chemical substances, e.g.,~ benzpyrene. Goblet cell test Cytotcxicity tests Ciliastasis and parameci'am tests. It is foreseen tha~ the use of reconstituted tobaccos will increase both for economic reasons and on health grounds, despite the possibility of increased carbon monoxide production. It also appears likely that some of the non-tobacco binding materials are becoming more attractive. Dr. Seehofer agreed to supply samples of cigarettes, made by a variety of reconstruction processes from a single blend of tobacco, for submission to the hyperplasia and other short-term bio tests. Dr. Fordyce also offered to send,some cigarettes containing non-tobacco binders. Dr. Hughes suggested that R. ~nd D. might examine the combustion characteristics by thermo gravimetric analysis and other techniques. The proposal that ethanol-extracted tobacco might be combined with one of the non-tobacco binders was accepted and Dr. Seehofer undertook to arrange a supply of such a product at the optimal sheet thickness. This mea~s in the long run that the basic technology of the cigarette industry will move more into the realm of chemical engineering, and this could have important effects on many other Company activities. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290347

CATEGORY 4 2. q969 The Conference considered what the characteristics of the "safest" cigarette might be, in terms of the criteria established earlier. It would contain some or all of the £ollowing features: (a) Reconstituted mr.d/or non tobacco smoking materials (b) CRS treated by the St. Pauli or si~ilar process (c) tobacco bearing additives to modify combustion (d) a ~riple filter containing carbon and possibly water, sodium carbonate, manganese dioxide (e) possible construction as an axial and/or ventilated cigarette It was decided to accept as a research objective that such a prototype cigarette should be developed. When it is judged to have sufficient acceptibility of taste as a prototype product, it should be manufactured on a scale sufficient to permit complete bioassay. Dr. Hughes agreed that R. and D.E., Southampton, would undertake this, and Dr. Seehofer offered to supply stems treated by the St. Pauli process. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290348

CATEGORY ~ Smoking Characteristics ~969 The Conference reviewed the progress of studies of smoking behaviour in the U.K., U.S.A., and Germany, carried out since the last meeting and concluded that these were important not only from the aspect of smoking and health~ but also because of the light shed on market requirements. For example, it has been indicated that smoking consumption tends to vary with the bodyweight, which might lead to the suggestion of lighter, thinner cigarettes for women; there is also some evidence that hearD" smokers tend to maintain their intai~e of smoke constant, even when the size of the cigarette or its delivery of TPM is changed. If thi~ finding were to be con£i2med,.it would be a matter of great significance, particularly in relation to the social objectives in publishing TP~I figures. In view of the likelihood that smokers may modify their smoking habits when presented with impingement filters, ventilated and other unconventional filters, it was suggested that these products should be evaluated using a "slave" smoking machine and a number of humau subjects. A general discussion on the problems of product design ~nd sensory assessment concluded that professional psychology could play an important part in this field, particularly if integrated into research pro~ramme~ along with other disci ~lines. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290349

CATSGOEY 5 2. q969 Owing to the trend towards reduced TPM and nicotine, it was agreed that more attention must be ~iven to flavour. It was, however, pointed out that in some situations the maintenance of nicotine delivery at the normal level may overcome taste and flavour deficiencies due to low TPM. The use of non-tobacco materials would accentuate this problem. The use of finely-cut tobacco and tobacco extracts in the filter in order to enhance the flavour are worthy of further consideration. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290350

P:'. Gr'iffith ez~rez.~ed the vie;.: that I{.E.W. ncc~pt that a mou[c.-skin za_~c~• cigarette is a ;..'or'th:;hile objective and th~ Conference reaffir~Jed their opinion thaZ this '~'?.~ ~ ;.:orth~.:hile objective 0 0 0 BATCo document for Province of British Columbia 8 November 2000 BATCO 00290351

Production ~969 The work on the microbiological flora of ~obacco has been started at R. and D.E., Southampton. So far, there would appear to be no danger from bacteria, but work was continuing on moulds where there might be a hazard associated with mycotoxins. Dr. Sanford said that Louisville was in agreement with this view. There followed a full discussion on the application of Research and Development techniques for Product Development. It appears likely that Philip ~]orris, in particular, are more successful in this than B.A.T. Dr. Griffith adversely compared the general position of Research in the B.A.T. Group with that in Philip Morris. He reported that Philip Morris are currently doubling their expenditure and stated, for example, that they are using low resolution mass spectrometry techniques to determine how to utilize Venezuelan tobaccos. Following an account of the similarity between the changes which can be brought about by processing conditions, and those attributable to ageing, the meeting felt that considerable caution should be exercised in reducing holding times in the tobacco process, and in terms of tobacco durations, merely to gain short-term economic advantages in terms of inventories etc. Nevertheless, there may be present an opportunity for the development of methods of accelerated ageing. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290352

~' ~ .... q969 Freeze-drying of tobacco was discussed, particularly in the light of the recent publicity from the University of North Carolina. The process is in a very early stage of development, and is unlikely to become of any importance for the next few years at least. It concluded, however, that such a process might affect the combustion characteristics of tobacco~ and it was agreed that R. and D.E., Southampton, should ez~lore the effect of this and of other processes in this respect. Consideration was given to the interestin5 proposal :,dvanced by Dr. Smith of lq,ntreal for the ozone treatment of tobacco and the conclusion was that R. and D.E., should consider this as pars of their 5eneral programme of investi~atin~ the effects of various tobacco treatments. N~. Wade reported on the progress made at Bristol on the irridation of tobacco for mould inhibition. This work is continuing. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290353

Marketing [he Meeting agreed that, in general, a substantial reduction in TPM (e.g. from 75 mg to 40 mg) will lead to considerable differences in taste and that these differences will be observed particularly when the observers are aware that changes have been made; however, as far as the reaction of the smoking public is concerned, it may be possible to make such changes without significant reaction, especially if these are made slowly. In discussin~ the possible taste deficiencies associated with low TPM cigarettes, Dr. Fordyce suggested that attempts might be made to express sensory responses in terms of intensity per unit weight of TPM. General opinion was that further filter development should be aimed largely at changing the composition of the smoke in a desirable sense, instead, of merely reducing the total quantity of smoke. The Conference agreed that I'iontreal should be encouraged to pursue their suggestion on the treatment of tobacco with sodium silicate in order to alter smoke characteristics. Dr. Fordyce described the treatment of Australiam tobacco with ~% citric acid in an autoclave for short periods of about 2 minutes, and the benefits conferred on the smoking qualities. The irritation of the smoke was reduced, and there was a marked increase in the filling power of the tobacco. Dr. Fordyce will send details of this process to members so that the effect on a wide variety of tobaccos can be investigated on BATCo document for Province of British Columbia 8 November 2000 BATCO 00290354

CATEGORY 8 2. ~o~ the laboratory scale. The Conference agreed that this could represent an opporttnuity for co-ordinated action by the Group, which could obtain results more quickly and over a wider rauge than those which could be achieved by any one Company. It was agreed that, if the process continued to look promising R. and D.E.,Southampton,, would make a more detailed study of the effects on smoke quality; Dr. Sanford also offered, subject to B. and W. Management approval, to carry out a theoretical study of the scale-up of the process. It was agreed further that Australia, Southampton and Louisville should consider the patentability of this process in various countries. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290355

CATEGORY 9 Filters ~969 There was a full discussion on the use of PEG as ~ additive to filters to e~_hance The removal of phenol(s) mnd the Conference agreed that it would be generally desirable to continue its use, although it was recognized that cost savings could clearly be achieved if it were eliminated. The substitution of extra triacetin for PEG is not as effective in phenol removal over a long period. It was interesting to learn from Dr. Fordyce that consumer tests showed a preference for filter tip cigarettes containing PEG; results from Canada and Louisville tended to confirm this. Because of the German Food Regulations, PEG is not used on filters in Germany. There was a discussion on the use of DEG, and, while the Conference appreciated the special position in Germany, it endorsed the AGP recommendation. Dr. Seehofer pointed out that the DEG used was subject to a rigidly specified limit of O.O~% monoglycol. ~%ile it was recognized that the AGP Minutes should not include the secientific detailed reasons for the recommendations, Dr. Felton agreed to supply the background scientific references to the decisions for the use of research staff. The Conference considered the bioassay results of PEI-treated filters, and although these are somewhat inconclusive, suggested an upper limit of 3% weight of the filter. The Conference confirmed its belief that the trend towards multiple filters, including carbon filters, would continue. This should achieve lower gas phase deliveries. In this connection, the idea put forward by Dr. Smith of Montreal on mixed-bed.filters with coincident specificity was considered well worth pursuing. ~r. Wade agreed to follow this up and to e~lore the patent situation. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290356

CATEC©RY qO Synthetic Smoking Haterials ~969 Dr. Green drew attention to the proposed non-tobacco "cigarette" which, it is said, will be marketed by Courtauld's Ltd., at the end of q969. This is believed to contain oxidised viscose staple fibre and iron oxide, to be free from nicotine aud to be tmdergoing a superficial bioassay test programme. It was the view of the Conference that such smoking materials should be the subject of serious biological study before being offered to the public but the difficulties of achieving this in all cases were recognized. It was agreed that T.R.C. should be urged to apply all available methods of bioassay to effect a comparison of non-tobacco smoking materials, e.g., lettuce etc.,~ with conventional tobaccos. There was a general discussion on non-tobacco materials ~_nd, largely due to the difficulties foreseen with the addition of nicotine, the Conference did not envisage at present the likely success of a totally non-tobacco cigarette. However~ it now seems quite likely that non-tobacco materials will be successfully incorporated into cigarettes as blend constituents, particularly in health orientated products. A large usage of non- tobacco materials would be likely to increase the demand for high-nicotine tobaccos. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290357

Tobacco as a Plant 196~9 The Conference recognized that problems associated with pesticides and insecticides were matters of world-wide concern co the whole Industry, and were outside the competitive field. The special position in Germany was appreciated by the members, and it was a~reed that any specific information requested by Dr. Seehofer should be sent to him as quickly as possible. The Conference was informed of the current investigation into Black Fat tobacco~ and a~reed that, prima facie, further investigation of this product would be desirable on health ~rounds. BATCo document for Province of British Columbia 8 November 2000 BATCO 00290358

CATE~0RY (2. Additives J969 Herr Sottorf informed the Conference that, although the threatened ban of the use of coumarin on tobacco products had not yet occurred, the German Industry had voluntarily discontinued the use of coumarin on cigarettes, while continuing its use on pipe tobaccos. Dr. Seehofer agreed to send the relevant scientific paper by B[r and Griepentrog to Dr. Felton, so that the matter might be taken up with BIBRA. Meanwhile, the Conference agreed that the Additives Guidance Panel's advised limits should stand. There was some discussion on coumarin substitutes, and Dr. Sap_ford agreed to supply samples of octahydroco~marin either directly or through Dr. HuF~hes. o BATCo document for Province of British Columbia 8 November 2000 BATCO 00290359