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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