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THE LANCET

Sugar in Tobacco: Theory and FactTHERE has been a surge of interest in the theory

that cigarettes made from tobacco with low sugarcontent may be less hazardous to health than the

high-sugar-content, flue-cured cigarettes which havebeen smoked in Britain for many years. 1,2 2 On theother hand, it presumably will not be long before thefirst of the Government’s tables listing the tar andnicotine deliveries of cigarettes is made public. 3 It isa good moment to look at the basis of theories con-cerned with the significance of sugar in tobacco.A characteristic of flue-cured tobacco is that, in

undergoing a relatively rapid curing process, thesugars in the leaf are fixed, whereas in the slowerair-curing process, accompanied in certain cases byinduced fermentation, the concentration of sugarsfalls as a result of an enzyme-mediated degradation.Many kinds of air-cured, low-sugar tobaccos are

smoked in different parts of the world. These include

cigar tobacco, burley tobacco, which is a constituentof American cigarettes and of certain pipe-tobaccoblends in Britain, and Maryland tobacco, whichforms part of the blend of some American cigarettesbut is little smoked in Britain. The suggestion thattobaccos with low sugar content may be less liable tocontribute to lung cancer stems from a series of

experiments carried out by the late R. D. PASSEY.4 4He and his colleagues at the Chester Beatty ResearchInstitute carried out two kinds of test. In the firstof these, rats were exposed in a chamber to smokeeither from standard flue-cured cigarettes or fromcigarettes made from air-cured cigar tobacco or air-cured burley tobacco. In each of two such experi-ments, rats exposed to the smoke from flue-curedtobacco died early with enlarged and severelydiseased lungs (tracheitis, bronchitis, and terminalbronchopneumonia), whereas most control rats andrats exposed to the smokes from the air-cured tobaccos

1. Sunday Times, Nov. 19, 1972.2. Chatelier, A., Waller, R. Ecologist, December, 1972, p. 24.3. Hansard (House of Commons), 1972, 174, col. 336.4. Passey, R. D., Blackmore, M., Warbrick-Smith, D., Jones, R

Br. med. J. 1971, iv, 198.

survived for longer periods. The second kind oftest involved the repeated application to the dorsalskin of mice of tars prepared by smoking standardflue-cured cigarettes or cigar-(air-cured)tobaccocigarettes in smoking-machines. According to

PASSEY et al. this experiment revealed a difference inthe nature of the two tars. The tumour-producingeffect of the tar derived from cigarettes made ofcigar tobacco, they said, " paralleled its greatercontent of chemically recognised carcinogens ". Thetar prepared from flue-cured cigarettes, " thoughpossibly more irritating to the skin, induced onlyone tumour ".

It is difficult to relate the results of the two kindsof experiment one with the other. The pathologicalfindings in the rats which died rather suddenlywhilst being exposed to the smoke from flue-curedcigarettes were suggestive of an inflammatory con-dition of a kind not regularly encountered in man.Chronic respiratory disease and bronchiectasis,which were said by PASSEY and his colleagues to beendemic in the strain of rats used for their smoke-inhalation studies, are recognised scourges in coloniesof laboratory rats housed under conditions where nospecial precautions are taken to exclude infectiousdiseases. It is also well known that exposure ofrats in such colonies to non-specific irritants such aschlorine 5 lights up latent lung disease, and mostexperimentalists would regard it as mandatory touse only animals with clean lungs for toxicity testing,especially when test agents are to be administered byinhalation.6 6 Within the hot and humid conditionsof a smoke chamber, respiratory disease could beexpected to spread easily. The chance inclusion of

only one seriously infected animal within a groupmight, therefore, lead to an epidemic of deaths fromlung disease in that group at any time during anexperiment. A failure to select rats for inclusion indifferent treatment groups by a random processcould explain how, even in two experiments, a

minority of carriers of the most severe kinds of lungdisease found their way only into groups to be

exposed to flue-cured tobacco smoke. In experi-ments in which clean-lunged rats of a differentstrain were exposed to smokes from air-cured orflue-cured tobacco at three different levels of

exposure, LAMB and REID ’ saw no differences in

response to the two types of tobacco smoke in termsof mucous goblet-cell count in the bronchial epi-thelium. Although even the highest level of exposurefell slightly short of that used by PASSEY et al., onewould have expected there to have been differencesin mucous goblet-cell counts if " flue-cured smokewere more bronchitogenic than " air-cured " smoke.Since the experiments of LAMB and REID were the

5. Elmes, P. C., Bell, D. J. Path. Bact. 1963, 86, 317.6. Roe, F. J. C. in Modern Trends in Toxicology (edited by E. Boyland

and R. Goulding); p. 39. London, 1968.7. Lamb, D., Reid, L. Br. med. J. 1969, i, 33.

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better controlled, one must attach more credence totheir findings. The deductions of PASSEY and his

colleagues from their mouse-skin work, althoughtheir results were not at variance with those of certainother groups,8 probably oversimplify the situation.HOMBURGER et awl. found little difference in the

tumour-producing activities of tars derived from

cigarettes made of various tobaccos including cigartobacco and pipe tobacco, but in a small experimentWYNDER and HOFFMANN 10 found that tars preparedfrom two types of air-cured-tobacco cigarettes wereless carcinogenic for mouse skin than a tar preparedfrom a flue-cured-tobacco cigarette. In perhapsthe most carefully planned study of this kind,DAVIES and DAY 11 found that, while cigar-smoketar was significantly more carcinogenic for mouseskin than tars from flue-cured-tobacco cigarettes orcigar-tobacco cigarettes, the two types of cigarettetar were of approximately equal potency in this

respect.In general, the application of the results of

investigations on laboratory animals to the humansituation is fraught with difficulties and pitfalls. It isconceivable that the results of the inhalation studies

reported by PASSEY and his colleagues may be ofsome relevance to chronic inflammatory lung disease(e.g., purulent bronchitis) in man, but there are nogrounds for regarding them as relevant to lungcancer. Nevertheless, in the course of the publicitythat has been given to research in this area, theresults of PASSEY’s experiments have somehowcome to be taken as relevant to lung cancer.

They have also become linked with a theory of themechanism of lung-cancer induction advanced byBRAVEN and FENNER and their colleagues. 12,13These workers found that smoke from flue-curedtobacco inactivates cysteine to a greater extent thansmoke from air-cured cigarettes. They suggestedthat this was because there was more acetaldehyde influe-cured smoke and that the extra acetaldehydewas derived from sugar. Acetaldehyde inactivatescysteine in bronchial cells, and this may renderthem more susceptible to cancerous change becausefree cysteine has been found to protect cells againstthe mutagenic effects of radiation. There is, however,no evidence at present that cysteine does in fact

protect epithelial tissues from cancer-inducing effectsof chemical agents.

It is tempting to think that it should be possibleto settle the question of the relative carcinogenicity ofsmokes derived from low-sugar (air-cured) and

8. Croninger. A. B. Graham, E. A., Wynder, E. L. Cancer Res.1958, 18, 1263.

9. Hamburger. F, Treger. A., Baker. J. R. J. natr. Cancer Inst.1963. 31, 1445.

10 Wynder, E L . Hoffmann D. J. An. med. Ass. 1965. 192, 88.11 Davies. R F., Day, T. D. Br. J. Cancer, 1969, 23, 363.12. Braven, J. Benker, G. J., Fenner, M. L., Tonge, B. L. ibid.

1967, 21, 623.

13. Fenner. M L. Braven. J. ibid. 1968, 22, 474.

high-sugar (flue-cured) tobaccos by comparingcancer death-rates for countries where differenttypes of cigarettes are smoked. In practice there arenumerous obstacles. For the purpose of makinginternational comparisons it is necessary to haveinformation about tobacco consumption for eachsex separately, but such information is available foronly very few countries. Lung-cancer death-ratespresumably reflect exposure to tobacco smoke andother environmental agents over periods of 20 to30 or more years. It is necessary, therefore, alsoto have information about the changing patterns oftobacco consumption by males and females ofdifferent ages during the past three decades. Detailedinformation of this kind is available only in respectof the United Kingdom.14 Disease risk may also beinfluenced by factors such as inhaling habits andbutt length. Only about 50% of Frenchmen who-smoke cigarettes inhale,15 whereas about 80% of

cigarette-smoking males in England and Walesinhale a lot or a fair amount.14 Americans leave, onaverage, longer butts than do British cigarettesmokers,16 and this has a disproportionately largeeffect, since the amount of tar per puff increasesexponentially as a cigarette burns down. Perhapsthe greatest obstacle of all, however, relates to

variation between countries in standards of medicalcare and diagnosis. In spite of these difficulties inmaking valid international comparisons, much atten-tion has been focused on the lower lung-cancerdeath-rate in France than in England and Wales.But even at this rather superficial level of considera-tion, there are other figures which merit at least

equal attention. Between 20 and 30 years ago the

average consumption of cigarettes per head of

population in France was only between a third andhalf that in the United Kingdom,1’ and in contrastto the difference in death-rates from lung cancer, the1968 death-rates for cancers of the larynx and oralcavity in males in France were 6 and 3 times, respec-tively, those for males in England and Wales."On the basis of common sense, and on the advice

of experts, Governments in Britain and othercountries have taken steps to encourage smokers toreduce their exposure to tar. In view of the lack ofa clear indication, either from mouse-skin paintingstudies or from inhalation studies on animals, and inview of the difficulties of making accurate deductionsfrom human death-rate data, there is no basis forthe United Kingdom Government to recommendthose who must smoke to choose cigarettes made

14. Todd, G. F. Statistics of Smoking in the United Kingdom. TobaccoResearch Council, Research Paper 1. London, 1972.

15. Schwartz, D., Flamant, R., Lellouch, J., Denoix, P. F. J. natnCancer Inst. 1961, 26, 1085.

16. Doll, R., Hill, A. B., Gray, P. G., Parr, E. A. Br. med. J. 1959,i, 322; Hammond, E. C. ibid. 1958, ii, 649.

17. Beese, D. H. Tobacco Consumption in Various Countries. TobaccoResearch Council, Research Paper 6. London, 1972.

18. W.H.O. Annual Epidemiological and Vital Statistics 1956-61 andWorld Health Statistics Annual; vol. I, 1962-68.

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from air-cured tobacco with low-sugar content inpreference to cigarettes made from flue-curedtobacco.

Medical Research in EuropeMEDICAL research has two main objectives-

advancement of knowledge for improvement of thehealth of mankind, and maintenance of high standardsof medical teaching and practice. Limiting factorsare the availability of people with originality andquality and opportunities for them to develop theirtalents; the time -allowed for teaching staff to do

research; and money and Government policy.In Europe, each country has developed its own

medical research system, and these operate andfoster medical research in very different ways. In

some, independent research organisations are para-mount ; in others, the role of independent bodies is

largely to supplement the university function. In

some, applied and operational problems are empha-sised ; in others, the balance leans more towardsbasic research. In every case the policy is influencedby political objectives.The debate about which is the best system will be

hotter in the enlarged European Community, andthe chief executives of the Government medicalresearch councils already meet regularly. The E.E.C.itself, however, has done very little. One studygroup 1 raised some interesting philosophical ques-tions but unfortunately did not deal with the practicalproblem of creating better understanding, whichmust be the first step if the European Community isto have any meaning for medical research.There is much information to suggest that quality

in medical education depends on the activity inresearch of university staff, yet methods to ensurethat it can take place have not been universallyadopted. The U.K. pattern-with full-time staffin universities, clinical professorial units, andlimited entry of medical students-clearly givesmore time and opportunity for research than that incountries where student entry is less controlled,where there is less time for research, and whereuniversity staff must make their income from privatepractice. But the efficacy of the British system,formerly taken for granted, will now have to be

proved if it is to be adopted by other countries. Onthe level of Government expenditure on medicalresearch, the decisions are essentially political. In

part they will be determined by the country’s wealth,but, since the actual sum will be relatively small,it will depend much more on the attitude of theGovernment. The balance, too, between self-determined basic and clinical research and Govern-

1. Commission of the European Communities, Report of StudyGroup on " Medical research and research related to publichealth ". Brussels, Feb. 22, 1972.

ment-contracted research is a crucial subject fordebate. The increased research contacts in the

enlarged European Community will be the con-

tinuation of a process that has already started. Aswell as the cooperative groups working on treatmentof cancer, thrombosis, transplantation, and so on,and the numerous European specialist societies,there are already several schemes to improve inter-change. The Wellcome Trust has been notablyactive, having longstanding arrangements withSweden and Denmark and providing Fellowshipsfor Europeans to visit Britain. Now the Trust hasregular interchange arrangements with counterpartorganisations in France, Germany, Italy, Hungary,Poland, and Finland. The Ciba Foundation, too,has always had a strong European element at itsinternational symposia and runs a system of Frenchexchange Fellowships. The British Council en-

courages senior research-workers to make lecturetours in Europe and has helped scientists to spendtime in Britain. And the Medical Research Councilhas French Fellowships.The aim of European unity in medical research

should be the provision of the opportunity for all theCommunity’s talented people to carry their ideas tofruition and for universities to derive full benefit from

integration of research into medical education andpractice. To provide background information theWellcome Trust and the Ciba Foundation are havinga symposium on March 14-16 followed by a meetingat the Royal Society of Medicine (see p. 214). Thebook of the symposium will describe and contrast thearrangements for medical care, education, and re-search in twenty-four countries of Europe.

ACHILLES TENDON RUPTURE

THE Achilles tendon is subjected to very largetension forces during athletic activity such as sprintingor jumping. Fortunately, in young athletes the healthytendon has reserves of strength which are equal to itstask. With increasing age, however, degenerativechanges occur which render the tendon more vulner-able to rupture when exposed to an unaccustomedload. The typical patient is a middle-aged man who,while playing badminton, competing in a father’srace, or participating in the strenuous dances enjoyedby the Celtic fringe, feels a sudden pain " like a

kick " in the calf, after which he develops a limp andnotices difficulty in stepping off on the affected foot.Achilles tendon rupture is commonly overlooked ormisdiagnosed as a plantaris rupture-an entity as

mythical as Achilles’ heel itself. There are severalreasons for this diagnostic difficulty. The condition isuncommon and therefore unfamiliar to many doctors,who may never have seen a case. The patient maypresent late, because once the initial pain has settled

1. Arner, O., Lindholm, A., Lindvall, N. Acta chir. scand. 1959,116, 496.