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F : t b ._" • ....... 1 ......... 28th~yp 1962. Reeea-----~.h--~-~'n!~'~' ........ ' HEALTH PROBLEM AND ..... OBJECTI~8 IN RESEAHCH : -':., 2 :~',IAY1962 L o. ~Z~AKET~ ~ESXbR. " By OHAR~_ES 5U~LIS. 1. ' I h~ve.for some time been tr~i~ to ge~,,," -- clear--in. my own mind what are our objectives, and on happening to discuss this reoentlywith I. W. Hu~hes I found that he and I were thinking alon~ similar lines except that he had experimental data which took him beyond the point I had reached. The object of the present note is not to propose emy new experiments, or ehan~es of programme, but to suggest some points of view which seem worth examining. Since Hughes had quite independently started along the same lines of thought it is possible that others have also done so. • • . • . . It is a tenable assumption that if smoke aerosol were not inhaled into the lungs there would be a marked reduction of damage to the lung, and of lung cancer. A problem that is therefore worth considering is how to provide the smoker with his customary amount of nicotine, and with his accustomed psychological satisfaction from the social gesture, without making it necessary for those who currently inhale to continue to do so to the same extent. I do not regard it as a practical solution to hope that memy people will go over to pipes or cigars, ~he cigarette has an appeal all its own, and our object must be to improve the safety of oigarette smoking. I presume ~hat inhalers do so because thereby they absorb more of the nicotine and more quickly. One partial solution would be to increase the nicotine/ tar ratio so that the inhaler can get the nicotine he craves for with less mnoke aerosol in his lungs. It is difficult to achieve much by choosing a high nicotine ~obacco and filterlngheavily since usually such ~obaecos are copious tar producers. .However, supposing an ordinary cigarette had i~s nicotine content doubled by straightforward addition of a nicotine salt to the raE, and then the filtration was also doubled, we should arrive at a ci6arette which for the same quantity of nicotine only delivered half the quantity oftar. It would obviously be safer to inhale. o

°p I ° -2- e 1 understand from l. W. Hughes that there may be a poseibility of modifying the design of the cigarette, or ,re-treating the rag, so as to increase the nicotine/tar ratio in the smoke, when again it would be possible to employ extra heavy filtration but yet give the smoker adequate nicotine to satisfy him and maintain him in his habits. This appeals to me as a very interesting llne of progress. 0 /o A smoker gradually develops the habit of inhaling because thereby he achieves a larger and quicker uptake of nicotine. Thus, if we could speed up the absorption of nicotine in the mouth the smoker would find it unnecessary %o inhale and mau7 would in due course cease to do so. Nicotine has to get into the blood stream to give its various physiological reactions, and it is plausible that this can happen more quickly from an aerosol droplet deposited in the lungs as opposed to deposition in the mouth or throat, But absorption can take place in the mouth since many smokers do not inhale but yet demonstrably absorb nicotine because the characteristic reactions occur and nicotine is found in the urine. An aerosol droplet has a watery phase on the outside and ~he nicotine will be here partly as esterst or as salts of various organic acids. The-a--~5~tion of nicotine in the mouth does depend on its state, the free base for example being taken up very quickly, and thus even a slight shift of the nicotine in the direction of physiologically more active salts might have the effect we are looking for. Yor example, if a small amount of free ammonia could be released in the puff some of it would certainly be picked up by the aerosol drop- lets, and when the droplet was caught on the wet surface of the mouth presumably the nicotine would be in a slightly more basic state than w~thout the ammonis, The attitude which emerges from all this is to regard the absorption of nicotine by the smoker as good and the basis of our industry, end to regard the smoke aerosol, which arises from an ingenious end convenient way of releasing this nicotine, as relatively harmless except when it is inhaled. Our problem is to enable the smoker to absorb the nicotine he wants without the necessity of takir~ as much smoke into his lungs, Two lines of investigation seem possible, either to increase the release of n~r.n~:In,._ 4.%n "~he TnRin s%re~Jn ~ermi%~i~ heavier

Copy for= FiLe ~'o.46D s,Ww/ $Ilt CI~RL~S ~LLZS) MILLBAN~. 2Sth ~ay) 1%2 g Dear Site haoles, Z em sorry to have taken so long to answer your questlon on cigarettes) cigars and plpes. I a= enclosing two copies of Dr. Hughes' sum~arywhtch should helpo t~hat he has found) I think) cannot be fitted neatly Into the plcture summazised tn the R.C.P° Report. Either the statistics ere wrong oz benzwrene is o£ tmpo=tance only If Inhaled. You=e sincerely, Encls ~ 2 C.co File No.46D J

s /vc/ D Ho Do ANDERSONp ESQo~ RESEARCH & DEVELOP/~ENT, ~ILLBANK~. 22rid May, 1%2 I a~ sending you my views on Smoking and Health - as requested. I am afraid the note has become rather long because I wanted to step back as it ware and have a good look at the , problem. As you know, I have discussed this at length with ,'" Felton and Hughes and although they are broadly In agreement any Indiscretions are mine. If it appears that we have not reacted sharply enough to the recent report, I think it is fair to say that at the research level this ~oduced no new tnfo~mations we have known the contents for some time and our current programme on 'smoke° has been developed accordingly. I would not like to see this work sacrificed to a crash programe ot shorter range work, nor would I like to give the impression we are not deeply concerned. Neverthelesst I think we ~ust be careful not to give the Impression that there is a cheap way out or, tndeed~ that R.& D.E. ts capable of making more than a small contributions however significant and effective, to the total effort required. I am sending you three copies of thls note In case you might wish to send Sir Charles one. $. 3. GREEN Enclss 3 .I

°- .:° S~KING AI~I} HEALTH The object here is to consider B-A.T. policy on research into health aspects of cigarette smoking. The observations made are intended as a basis for discussion around a central them e of research policy. I understand that the present policy for the United Kingdom is that all research work concerned with health and smoking is done on an Industry basis as far as possible and that all immediately relevant information is conlnunicated to the Industry no matter how., ,/ it is obtained. For example, I understand ttwould be contrary to this policy for btoIogtcal research to be carried out on a Company basis. If this statement and interpretation of current poItcy is not correct this serves to underline the first need - that the policy shall be clearly formulated and con~nuntcated. Ig there has been a change in policy, or if it is more fluid than has been indicated, it underlines the need for some provision for continuous interpretation and the flexible development of our research policy. I suggest that research policy should, in fact, be reviewed once or twice each year in some representative manner which relates tt to a practical programmer- a research policy committee? The accumulating evidence for the influence of smoking on health now clearly threatens the future o~ the Industry. The evidence for the causal influence of smoking on lung cancer zests largely on statistical eptdemtological studies and by more general consideration against the whole background of medical science. This evidence is supported to a minor extent by mouse-painting experiments. For the effect of smoking on circulatory disease the evidence is more directly experimental, but as far as lung cancer is concerned I think it would be wise to plan our future policy on the assumption that the statistical evidence will become stronger year byyear.

" 2 " Paced with this problem the Industry can react in several ways. For examplez 1. The companies'involved can attempt to elucidate and to solve the problem of producing a completely safe cigarette by scientific research. 2. The situation itself can be utilised to promote short term speciality sales or to reorient smoking habits. 3. The companies can increase, redirect or widen their advertising and public zelations activities. 4, Individual companies can diversify financially, connercially-and technically. , /" Apart from the last of these, I understand the present policy is aimed to contribute along all these lines on an Industry basis andp particularly, for example, to eliminate exploitation of the situation. by companies promoting short term objectives with health claims. B-A.To, however, is operating outside the U.K. and it is legitimate in any case to consider whether there are alternatives to the present policy. Research work can be used and is being used in connection with the pursuit of all these lines, and clearly the same experimental work can be used in certain circumstances to pursue different commercial . objectives. For convenience these approaches are considered separately. 1. The question to be answered here is whether B-A.T. could or should do more on direct research into the health problem, or whether we should stLmulate addttional work or an expansion of current work being carried out by T.M.S.C. As mentioned above, it is considered that the mouse-painting experJJuents play only a minor part in the case against smoking, and I think that this evidence is likely to become less Important rather than more. At present it looks likely that Harrogate can refine the mouse-painting technique and, in the absence of anything more promising, our support for the current work planned there is fully

I, 3 e Justified. It is likely that they will be successful in refining this technique and tn this event there will be Immediately a big demand for their animal test services. It would be very easy to plan a useful progra~e of tests based even on our present knowledge of the components of cigarette smoke. It it is considered essential to contain all mouse-painting experiments at Harrogate, then I think we could make a case Mediately for pianntng this extension considerably. There are some things, however, we would like to see done as quickly as poasible - for example, the examimtion of the phenols as possible co-carcinogenic agents, or the immediate pcoduction of low B.P. cigarettes. If it were agreed to do these, should this I extension o£ ectlvlty be carried out elsewhere than H arrogate? .Th~ answer need not necessarily affect the general policy but would mean that we could speed up the work, For example, If resources in Canada were used we could fatrly quickly obtain some information on some specific fraction of tobacco smoke. By the time then that Harrogate had refined their technique we would have some answers that stood a 50~chance of being acceptable to us in the light of the Harrogate refinement. All this assumes, however, that mouse-painting is important. ~ own view is that it might be worthwhile as a short teem project which can be pursued quite quickly, but that if funds are limited it would not get the highest priority. AII experiments based on n~use-painting in the absence of a good deal of further biological work are bound to be a long way removed from the central problem of producing a cigarette safe for man. There is a great gap involved in the interpretation of evidence related to animal skin tumouzs and cancer of the Iung in man. Meanwhilej the~e is still a considerable amount that can be done. Ideally~ we would like to establish further biological tests before considering a programme based on smoke. For example, tests for carcinogenicity in other animals, co-caroinogenictty and tests for irritation, for examples could be investigat~ by techniques other than animal experiments and that these techniques (possibly tissue culture for example) might best be utilised away from Harrogate. In this event 0 0

- 4 - the question whether tests are best done on an Industry basis or on a Company basis should be resolved on the grounds of expediency. In either case, even the broad current policy need not be violated. It might be suggested that our cuzzent Company £aciltttes should be Immediately redirected towards the central problem. I think that this suggestion has some merit but it should be clearly understood that most of the research work being carried out at Southampton is as much directed towards health as towards any other problem. ~Jch o~ our present pzogramne of work is aimed to understand the factors involved in the combustion characteristics of cigarettes and their relatton ±o the chemistry of smoke. The present programs ¢ can be bent a little in some directions with advantage to cover phenols, polycyclics, aldehydes, etc., but generally I think there is no part of the present research programme which should be neglected. If it were decided that the heaith question has become more urgent then I would recommend extending our present work rather than replacing it with anything else. We could,.foz example, with advantage double our benzpyzene assay facilities and also Increase our general facilities on gas chromatography. I think that we could usefully increase the effort by 3 or 4 graduates which would increase our revenue expenditure by about ~30,000 per annum. Coupled with this we should require to utilise further modules in the building and, if we were not to af£ect our other prograa~ne~ this would mean an increased capital expenditure of around £IC,000 in the first year. If it were decided to make animal testing immediately available on an independent basis, this could be used within our programme to an extent, I would guess, of around £I0,000 in the first year. There is one relevant b~ological test which might be developed quite qutcklys t~e Dalhamn technique for measuring ciliary inhibition. The chances of success here appear to me to be fairly high and I think this should certainly be developed somewhere and cigarette smoke investigated in this connection. If we were to break with the present policy concerning animal tests I would recommend that serious 0 0

- 5 - Consideration should be given to undertaking this work at Southampton. This would involve recruiting a physiologist and support staff. Assuming this were agreed and there were no Iocal obstacles, I think it would represent quite a big step physiologist among us and a viable, progzamme would enable us better to problem and thus play a better part forward. The presence of a however small, physiological formulate the cen~alised research in the dtzectton of the work, whether carried out by the Industry or the "Co.,~any. This suggestion would increase revenue expenditure by around a further £15,000 per annump and would require capital expenditure around g30,O00. Although I certainly have very little knowledge of T.M.S.C. and the H arrogate experiment, I have the impression (which could,be." quite wrong) that something much more creative should be organlsed. This appears to me to require twoorgantsationaI changes! first the direction should be on a pe=manent basis and second there should be a suitab1e budget with some fzeedom to operate inside it. Underlying our whole approach to this question is the tacit assumption that there wii1 be discovered a technical situationwhich can be remedied within the fzamewo=k og the present business. For this reason, of course, work on PCL and solvent extraction is directly relevant. However, it may be found ultimately that there is in fact no small fraction or individual component of cigarette smoke which can be indicted but that the ~hole smoke or perhaps nicotine itself is hammful. In these circumstances quite clearly some thought should be given to the ~roadez aspects of the smoking habit end what is likely to replace it. It is certainly insufficient, in my opinion, for any tobacco company at the present time to +ely for its future on scientific research into smoking and health. 2. In present circumstances there is bound to be considerable short term activity with respect to modified cigarettes. This need not be considered as entirely on a gimmick level. A low benzwrene cigarette could be produced quite qutckl¥t the work we are doing on filters and on filter-tow in particular will give us somecontrol over

6 the smoke~ ~he work on ftlltng power is also relevant. We could then, without making health claims and with commercial advantage, move qutte zeadtly Into thts field. We are currently Investigating the differences in the chemts%~/ of the smoke from pipes, cigars and cigarettes, and the present tntentfon ts to continue ±his line and to investigate the effdct of the shape of pipes, etc. I think It would be wrong to redirect much of the effort we are ~cing tn this direction at present. Al%houghv~ could~ for example, speed up our ~ozk on extracted stem or expand t¢ into a general consideration of "irritation" at thts level, I do not think irritation by smoke constituents can be tackled on a long term research basis until a suitable biological test has been developed, but we could probably. /• do somethfng empirical using "taste and flavouz" techniqueSo This tacit acceptance of the essential concIustons from the statistical evidence seems to me to be a sensible and useful approach and %o be complementary/ to our main research and development theme. 3. Whatever use is made of the facts by the Company or the Industry, it is ou~ Job to state the position as objectively as we can. I think there is little point in reproducing experimental work if we consider it creditable. There is still a possibility, howevezp that physiological benefits may be demonstrably associated with smoking. Any newsworthy ~echnical achievement in any field can also be used in ~his connection. When Lucozade came under pressure Beechams most successfully countered proposed legislation by announcing their penicillin discovery (for the second time!). 4. The direct contribution of research to diversification is generally outside the scope of this note but the emphasis end urgency can best be understood by clearly appreciating the size of the central problem. It ts also relevant to point out that a significant increase in research ef£o~c in any field ts likely %o result in a bonus~ unpredictable though it may be, which could be commercially exploited. For example, in recent years perhas the major commercial advance in