618

were paced for frank Stokes-Adams attacks; a small

minority for heart-failure with bradycardia, continu-ing heart-block after myocardial infarction, or heartsurgery; and a further few for complex arrhythmiasassociated with bradycardia. No death from pace-maker failure or electrode movement was recordedin the 31 patients who died between 1 month and6 years after initial implantation.

Evaluation of New Smoking ProductsCIGARETTE sales continue to rise in Britain (although

the absolute weight of tobacco sold is levelling off)/and deaths from lung cancer inexorably increase yearby year, so that it is now by far the commonest causeof death from malignant disease.2 The widely acceptedcausal relation between these two,3 although stillcontested by some,4 means that any attempt to producea

" safer " cigarette must be taken seriously. But

there’s the rub. How can we be sure that such productsare safer ? The Hunter Committee, established toadvise the Secretary of State on this evaluation, facesa thorny problem. The tobacco industry-presumablyanxious to maintain both its profitability and its workforce-joins with the general public, through theTreasury (which derives from tobacco revenues a

large support for the social services), in a commoninterest in the maintenance of the smoking habit. Themoral dilemma thereby implied is put most startlinglyin the suggestion that the ultimately " safer " cigarettemay be a totally synthetic product, with addition ofnicotine alkaloids, so serving to satisfy the widespreadcraving for tobacco smoking. But even if such a new

smoking product could be produced and shown to bedevoid of risk of lung cancer, chronic bronchitis andemphysema, or ischsemic heart-disease, would we bemorally justified in producing it ?The pragmatic clinician in daily contact with the

ravages wrought by the cigarette habit, saddened bythe failure of apparently responsible and informedcitizens to abandon it, is likely to endorse attempts toproduce such a substitute cigarette, if indeed it canbe shown to be safer. The tobacco industry is col-laborating with Dr R. B. HUNTER’S committee in thecareful evaluation of the first generation of new smokingsubstances, which are intended as additives to tobacco,the resultant " new smoking product " thus being amixture of tobacco and the new substance. Thesenew substances, derived so far from cellulose, producea smoke which differs chemically, in both the natureand number of its components, from that of tobacco.Cigarette smoke is a very complex mixture, changingwith both time and temperature as water particles1. Tobacco Research Council: Statistics of Smoking in the United

Kingdom. 1972 and 1973 supplements. London, 1974.2. Registrar-General’s Annual Report, England, Wales, and Scotland.

H.M. Stationery Office, 1972. 3. Royal College of Physicians of London. Smoking and Health Now.

London, 1971.4. Burch, P. New Scientist, 1974, 61, 458.

dissolve constituents and coalesce. A point stressed at aRoyal Society of Medicine meeting last month is thatevaluation of the disease-producing potential of suchsmoke in man involves far more than mere considera-tion of the chemical composition of the smoke.

Painting mouse skin with smoke condensate, which isaccepted as a biological test for carcinogens in smoke, 5,6is obviously a far cry from the repetitive exposure of thehuman bronchial epithelium to both the condensateand the vapour phase of cigarette smoke over manyyears. Nonetheless, in skin-painting studies, the newproducts do indeed seem to be less active in inducinglocal neoplasia than tobacco condensates, and, com-plex though this problem is, few would deny that thisconfers an a-priori advantage.The next stage seems to require exposure of animals,

of at least two species-one a rodent and the otherprobably canine-to repeated inhalation of smokefrom the new substance many times a day for at leastseveral months. Careful haematological and biochemicalstudies in life must be followed by pathologicalexamination post mortem. Such investigations haveinevitably led to public concern-particularly at

the use of animals to study a human vice. Wouldthat this public concern might also be directed todiminishing the prevalence of this alleged vice in man.These animal studies raise many practical problems 7

-not least in inducing the animal to inhale smoke intoits lungs without filtering the smoke through the nose-as well as reawakening the moral questions interwoveninto this story. Squamous or oat-celled bronchogeniccarcinoma, common in man, has rarely been producedby tobacco smoking in animals. 8 Therefore it isdifficult to evaluate any such risk from these new pro-ducts by studies of this nature alone. The R.S.M.meeting agreed with Dr HUNTER that evaluation involunteers must not be much delayed, for prolongedand expensive studies in animals will not be com-mercially warrantable if " the stuff is so foul that

nobody could smoke it " or if immediate toxic hazardsemerge. Here the analogy with drug evaluation seemsreasonably close. The acute functional consequencesof smoking one conventional tobacco cigarette includebronchoconstriction, due to the particles in smoke 9

(reversed by isoprenaline 9 or atropine 10), which isprobably more pronounced in smokers," tachycardia,12and a rise in both cardiac output 13 and blood-pres-sure,12 these cardiovascular effects being mainly dueto the nicotine content of smoke. Immediate interest

5. Homburger, F., Treger, A., Baker, J. R. J. natn. Cancer Inst. 1963,31, 1445.

6. Davies, R. F., Day, T. D. Br. J. Cancer, 1969, 23, 363.7. Lancet, 1974, ii, 506.8. Auerbach, O., Hammond, E. C., Kirman, D., Garsinkel, L. Archs

envir. Hlth, 1970, 21, 754.9. Nadel, J. A., Comroe, J. H. J. appl. Physiol. 1961, 16, 713.

10. Sterling, G. M. Br. med. J. 1967, iii, 275.11. Guyatt, A. R., Berry, G., Alpers, J. H., Bramley, A. C., Fletcher,

C. M. Am. Rev. resp. Dis. 1970, 101, 44.12. Herxheimer, A., Griffiths, R. L., Hamilton, B., Wakefield, M.

Lancet, 1967, ii, 754.13. Pentecost, B., Shillingford, J. Br. Heart J. 1964, 26, 422.

619

lies in the acute effect of these new smoking productson human airways-both on those of large diameterwhere effects can be measured by changes in airwaysresistance, 11,14 and also on small airways, the lung’ssilent zone, which may possibly be reflected by changesin the frequency dependence of dynamic com-

pliance 1-1, 16 or in the shape of the flow volume curveduring forced expiration.1? It is possible that such smallairways may harbour the earliest lesions of future

emphysema.If no undue hazard is revealed by this short-term

experience in man, longer-term work in animals willthen be required, preceding long-term studies involunteer smokers. Careful recording of symptoms,such as cough, sputum production, incidence of

respiratory illness, and chest pain, will be needed,along with repeated estimates of respiratory function,and, of course, the subjects’ cigarette preference.Several thousand volunteers may have to be recruitedif statistically valid conclusions are to be drawn at theend of a 5-year period-no mean organisational effort.Despite even such extended studies, the final answer tothe question " Is it a safer cigarette ? " must awaitthe Registrar General’s pronouncements on the causeof death in 10-20 years’ time, but man’s apparentlyirrational urge to smoke will not wait so long. Thus,Dr HUNTER and his colleagues will bear the responsi-bility for a considered and skilful judgment. In

addition, though, they will profoundly influence re-search in this area, for their judgment, which may yetinvolve legislative powers, will have to be based onevidence. What evidence, and how to collect andassess it, will involve many agencies apart from thetobacco industry. Independent established researchbodies, such as universities and the Research Councils,cannot sit idly by in this important development,affecting as it does one of the largest epidemics ofmodern Western man. The Hunter Committee mustnot discourage such bodies from taking part.

THEORY AND PRACTICE IN ENDEMIC GOITRE

ENDEMIC goitre is one of the world’s more commonhealth problems, with probably over 200 millionpeople affected. Although the central role of dietaryiodine deficiency in the production of endemic goitrehas been recognised for over half a century z19 andvarious investigators have more or less establishedthe somewhat complex pathophysiological basis ofthe disease,2o-24 endemic goitre and cretinism are still

14. Dubois, A. B., Botelho, S. Y., Comroe, J. H. J. clin. Invest. 1956,35, 327.

15. Woolcock, A. J., Vincent, N. J., Macklem, P. T. ibid. 1969, 48,1097.

16. McFadden, E. R., Kiker, R., Holmes, B. deGroot, W. J. Am. J.Med. 1974, 57, 171.

17. McFadden, E. R., Jr., Luiden, D. A. ibid. 1972, 52, 725.18. Marine, D., Williams, W. W. Archs intern. Med. 1908, 1, 349.19. Kimball, O. P., Marine, D. ibid. 1918, 22, 41.20. Ramalingaswami, V. Ann. intern. Med. 1973, 78, 277.21. Kochupillai, N., Deo, M. G., Karmarkar, M. G., McKendrick, M.,

Weightman, D., Evered, D. C., Hall, R., Ramalingaswami, V.Lancet, 1973, i, 1021.

as prevalent today in many parts of the world as theywere in the past. Some reasons for the failure totranslate this theoretical knowledge into action havebeen discussed by Stanbury and others. 25Endemic goitre is generally said to exist in a com-

munity when more than 5% of adolescent childrenhave a grade-i goitre (i.e., a thyroid that is easilypalpable, and also visible with the head raised), thoughother definitions are also used. 25, 26 The cause of thisthyroid enlargement has been extensively investigated,in South America by Stanbury and his colleagues ’27in the Himalayas by Ramalingaswami ’20-23 in Africaby Delange and his colleagues, 24,28 and in many otherparts of the world. Iodine deficiency seems to be theprimary cause in all endemic areas, though otherfactors (e.g., dietary goitrogens) may in some casesaugment the effects of iodine deficiency. The goitreprobably results from the effects of thyroid-stimulatinghormone (T.S.H.), which is secreted by the pituitaryin increased amounts because of the decreased thy-roidal output of thyroxine secondary to iodine defici-ency. 21,28-32 The size of the goitre shows a relationwith the serum-T.s.H. level and is inversely related tothe level of serum-thyroxine.21 1 The functional re-

sponse of the thyroid gland to iodine deficiencyconsists mainly of an acceleration in the rate of iodinemetabolism, which is particularly striking in childhoodand adolescence, and slows down gradually with

growth. 24 In addition, the thyroid makes more econo-mical use of the iodine available by preferential secre-tion of triiodothyronine, which is metabolically moreactive than thyroxine but contains less iodine (threeatoms per molecule, compared with four for thy-roxine). 21e 23, 24, 33When endemic goitre is identified in a population,

what can be done ? There is no doubt that an increasein iodine intake by those living in endemic-goitre areasis invariably followed by a dramatic fall in the incidenceof goitre and cretinism. The two main questions are,Is the incidence of goitre or cretinism high enoughto justify a prophylactic programme ? and if so, Whatis the simplest and most economical means to get theiodine to the population at risk ? The first question isusually easier to answer than the second, and variouscriteria for preventive action have been generallyagreed, under the auspices of the World Health

Organisation.25 Only iodisation of salt or administra-

22. International Symposium on Endemic Goiter. Acta endocr., Copenh.1973, 74, suppl. 179.

23. Karmarkar, M. G., Deo, M. G., Kochupillai, N., Ramalingaswami,V. Am. J. clin. Nutr. 1974, 27, 96.

24. Delange, F. Endemic Goitre and Thyroid Function in CentralAfrica (Monographs in Pædiatrics, vol. II). Basle, 1974.

25. Stanbury, J. B., Ermans, A. M., Hetzel, B. S., Pretell, E. A.,Querido, A. W.H.O. Chron. 1974, 28, 220.

26. Pérez, C., Scrimshaw, N. S., Muñoz, J. A. in Endemic Goitre(Wld Hlth Org. Monogr. 44); p. 369. Geneva, 1960.

27. Stanbury, J. B., Brownell, G. L., Riggs, D. S., Perinetti, H., Itoiz,J., del Castillo, E. B. Endemic Goitre: the Adaptation of Man toIodine Deficiency. Harvard, 1954.

28. Delange, F. M., Hershman, J. M., Ermans, A. M. J. clin. Endocr.1971, 33, 261.

29. Adams, D. D., Kennedy, T. H., Choufoer, J. C., Querido, A.ibid. 1968, 28, 685.

30. Buttfield, I. H., Hetzel, B. S., Odell, W. D. ibid. p. 1664.31. Pisarev, M. A., Utiger, R. D., Salvaneschi, J. P., Altschuler, N.,

DeGroot, L. J. ibid. 1970, 30, 680.32. Karmarkar, M. G., Kochupillai, N., Deo, M. G., Ramalingaswami,

V. Life Sci. 1969, 8, 1135.33. Lancet, 1971, i, 898.