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cyclical response changes, including those underlyingcyclical depressions, before the whole picture becomes clear.

Center for the Study of DemocraticInstitutions,

Box 4068, Santa Barbara,California 93103, U.S.A. ALEX COMFORT.

SMOKING AND LUNG CANCER

SIR,-Mr Manning (Sept. 14, p. 666) puts forward aningenious hypothesis to account for an association at thegenetic level between smoking and lung cancer. He alsoassumes that a cigarette-associated increase in the incidenceof lung cancer has occurred during the course of thiscentury. However, his genetic theory does not requiresuch an increase and the most reliable evidence fails toendorse it.The recorded age-specific and sex-specific death-rates

from lung cancer in England and Wales, 1901 to 1970,have been analysed previously. 1,2 My analysis showedthat the enormous secular increases,l and changes in therates of increase2 were almost entirely synchronous in thetwo sexes. On the other hand, the secular increase in therate of cigarette smoking by women lagged some 30 yearsbehind that of men. In other words, the recorded increasesin lung cancer, considered for men and women separately,are not associated in time with the increases in cigarettesmoking.This analysis of secular trends leaves open the possibility

that at least some of the recorded increases in lung cancerare genuine although they are not associated with cigarettesmoking: they might, for example, be attributed to en-vironmental factors-such as atmospheric pollution-whose impact on men and women was synchronous. How-ever, certain details of the secular changes in the age-dependence of the death-rates indicate that diagnostic errorhas made a large contribution to the apparent increase inlung cancer.1,2

Despite their many limitations,2 findings from necropsyseries provide the best test we have of the genuineness, orotherwise, of the apparent secular increase in lung cancer.Doubting the genuineness of this increase and bearing inmind the frequent misdiagnosis of lung cancer, Willis 3

argued that only fully proved necropsy records are of valuein such contexts. From reviews of necropsy series, Passeyand Holmes, and Rosenblatt and co-workers,5-’ were

unable to confirm the reality of the supposed secularincreases. The latter authors concluded that changes inclinical diagnosis-from drastic underdiagnosis at the be-ginning of the century 5 to net overdiagnosis during thelast decade or so 6-have been largely responsible for theapparent increase in the incidence of lung cancer. Mr

Manning’s assertion that " there has been a secular changein lung-cancer incidence, as the recorded rate of increasediffers between the sexes " assumes that proportionateerrors in diagnosis must have been the same in the twosexes. This is improbable as the diseases with which lungcancer has been confused (mainly other respiratory dis-orders) are more frequent in men than in women.To return to Mr Manning’s hypothesis, the existence of

a genetic association between a predisposition to smoke anda predisposition to lung cancer-as first proposed byFisher 8-can scarcely be doubted. Thus, in Tokuhata

1. Burch, P. R. J. Lancet, 1972, ii, 132.2. Burch, P. R. J. ibid. 1973, ii, 102.3. Willis, R. A. Pathology of Tumours. London, 1960.4. Passey, R. D., Holmes, J. McD. Q. Jl Med. 1935, 4, 321.5. Rosenblatt, M. B. Med. Counterpoint, 1969, 1, 29.6. Rosenblatt, M. B., Teng, P. K., Kerpe, S., Beck, I. N.Y. St. J. Med.

1971, 71, 2189.7. Rosenblatt, M. B., Teng, P. K., Kerpe, S. Prog. Clin. Cancer, 1973,

5, 71.8. Fisher, R. A. Smoking: The Cancer Controversy. Edinburgh, 1959.

and Lilienfeld’s 9 study, the frequency of smokers amongthe first-degree relatives of non-smoking lung-cancer pro-bands was significantly higher (p ≃ 0.03) than among corre-sponding first-degree relatives of non-smoking and race,sex, age, and residence matched controls. This complica-tion, coupled with the many anomalies 1-8 in the evidence,undermine the popular view that the association betweencigarette smoking and lung cancer has a straightforwardcausal basis.

General Infirmary,Leeds LSI 3EX. P. R. J. BURCH.

SMOKING AND THE HEART

SIR,-A remark in the survey by Dr Ball and Dr Turner(Oct. 5, p. 822) about the need for methods to help manrid himself of the smoking habit reminded me of a curiousincidental finding when I was engaged in exposing animalsto methyl mercury compounds.1O I did indeed include it ina footnote in the original version of the small piece which Iwrote about these experiments, but this was subsequentlycut out.

At that time I was an addicted cigarette smoker, butfound quite consistently that for an hour or so after tendingthe animals, smoking was so distasteful that, if I inad-

vertently lit a cigarette, I forthwith stubbed it out. I havenever experienced anything like this under any othercircumstances and can only attribute it to a slight exposureto the vapours of methyl mercury compounds. These

unfortunately are dangerously toxic substances. I amneither chemist nor pharmacologist, but I have wonderedwhether there is any chance that similar substances mightbe found with the same ability to produce aversion tosmoking but without the toxic properties.

Woodways,Little Baddow,

Chelmsford CM3 4SZ. R. R. BOMFORD.

PEAK-FLOW METER VERSUS PEAK-FLOW

GAUGE

SiR,—The findings of Dr Campbell and his collaborators(July 27, p. 199) coincide with our experience of the peak-flow gauge. In October, 1973, we carried out a field

survey in a random population living in a rural area ofthe Netherlands. Besides other lung-function measure-ments, we measured the peak-flow rate with a Wrightpeak-flow meter. During this study of about 500 subjectsa day, we learned of the release of the new peak-flowgauge and decided to include measurements with the

gauge for a short trial, provided that the measurementswith the gauge were always carried out after the measure-ments with the meter, in order not to disturb our ownsurvey protocol.We compared the highest value of 3 measurements with

the Wright peak-flow meter with the highest value of2 measurements with the gauge in a random sample of475 men and women. On average the readings of themeter were higher than those of the gauge. With themeter the mean peak-flow rate of the total group was 5118litres per min. (s.D. 1015); with the gauge the mean ofthe same group was 489-0 litres per min. (s.D. 99-4). Themean of the individual differences between the reading ofthe meter and the reading of the gauge was 22 78 litres permin. (s.E. 2-05 litres per min.). The mean percentagedifference was — 4 12 (s.E. 0-42), using the meter as referencemeasurement. In 342 subjects the difference between theinstruments was smaller than 10% ; in 111 the difference fellbetween 10% and 20%; in 17 it was between 20% and

9. Tokuhata, G. K., Lilienfeld, A. M. J. natn. Cancer Inst. 1963, 30, 289.10. Hunter, D., Bomford, R. R., Russell, D.Q. Jl Med. 1940, 35, 193.

951

300,,; in 5 the difference was larger than 30% (in 3 of thembetween 30% and 35%). We consider these results to bevery satisfactory.The gauge showed itself to be more " robust " than the

meter (when in continuous use as in our survey (about onemeasurement every 2 minutes)), which, considered in

conjunction with the fact that it is much cheaper than itsparent instrument, is a distinct advantage. We agree withDr Campbell and his colleagues that the peak-flow gaugecould well prove to be a useful addition to the instrumentsavailable for measuring airways obstruction, both in

epidemiological work and in the clinic.

TNO Research Unit for

Epidemiology of CNSLD,Lung Function Laboratory,

Division for Pulmonary DiseasesUniversity Hospital,

Groningen, The Netherlands.

R. VAN DER LENDEE. J. JANSEN-KOSTERS. KNIJPSTRAR. PESET REIGP. BARKMEYER-DEGENHART.

ÆTIOLOGY OF CROHN’S DISEASE

SIR,-Although the incidence of Crohn’s diseaseseems to be increasing,l its xtiology remains unknown.In 1970, evidence for a transmissible agent was providedby Mitchell and Rees.2 They inoculated mouse footpadswith tissue homogenates of Crohn’s disease and foundfocal granulomas in 5 out of 24 non-immunosuppressedmice. Biopsies were performed between 169 and 500 days.Granulomatous changes were also seen in the ileum in2 out of 10 mice at necropsy. Subsequently, the same groupof workers described similar changes following inoculationof Crohn’s homogenates into the ileum of rabbits.3 3 Ourown work 4 using homogenates from 7 patients with Crohn’sdisease and 295 laboratory animals (mice, rats, and guinea-pigs) did not reveal any sarcoid-like granulomas.

RESULTS OF INOCULATION

+ = Positive. E =- Equivocal. — =- Negative.* 14 footpads showed non-specific post-inflammatory changes.t 5 ileums showed amyloid deposits.

One possible explanation for this disagreement is thatour mouse biopsies were performed between 200 and 258days after inoculation, which was shorter than the longestfollow-up reported by Mitchell and Rees 2 of 500 days.We have since killed the remainder of the mice from

our previous experiment to examine the terminal ileum.We have also inoculated the footpads of a further group ofmice with homogenates of bowel from three patients withCrohn’s disease. Homogenates were prepared 4 and controlhomogenates were derived from both the normal marginsof the resected Crohn’s intestine and from the normalileal margins of a right hemicolectomy specimen. Animalswere killed near the end of their expected lifespan.At necropsy, specimens were taken from the sites of inocula-tion and terminal ileum for histological examination.The results and times after inoculation are shown in the

accompanying table. No focal granulomas were seen inany specimen. It is apparent therefore that the differencein biopsy time is not responsible for the different results.

1. Miller, D. S., Keighley, A. C., Langman, M. J. S. Lancet, Sept. 21,1974, p. 691.

2. Mitchell, D. N., Rees, R. J. W. ibid. 1970, ii, 168.3. Cave, D. R., Mitchell, D. N., Kane, S. P., Brooke, B. N. ibid. 1973,

ii, 1120.4. Bolton, P. M., Owen, E., Heatley, R. V., Williams, W. J., Hughes,

L. E. ibid. 1973, ii, 1122.

An interesting incidental finding was that 5 ileum specimensshowed mucosal deposits of amyloid. All 5 occurred inmice inoculated with control, not Crohn’s, homogenate.

We are thus unable to confirm the existence of a trans-missible agent in Crohn’s disease.

University Departments of Surgerand Pathology,

Heath Park, Cardiff CF4 4XN.

P. M. BOLTONR. V. HEATLEYE. OWENW. JONES WILLIAMSL. E. HUGHES.

ENVIRONMENTAL STRESS AND

THYROTOXICOSIS

SIR,—Dr Hadden and Dr McDevitt (Sept. 7, p. 577), Ifear, draw unjustified conclusions from their interestingdata on the treatment of thyrotoxicosis in NorthernIreland. While I have no investment in one conclusionrather than another about " stress " as a precipitatingfactor in thyrotoxicosis and no special knowledge of thesubject, I feel obliged to point out that their data do notshow that environmental stress is unimportant in the

pathogenesis of the disease.One weakness is the assumption that a period of civil

disturbance in Northern Ireland serves as an indicator ofundifferentiated " stress ". Stresses are of many kinds andindividual responses are mediated by circumstances,including the ambience of group situations. Rates ofsuicide (and also rates of entry into psychiatric care)provide analogies. At times of economic depression, as inthe 1930s, age and sex specific rates tend to rise; in times ofwar and national dangers, as in the 1939-45 war, rates tendto decline.A second weakness of their survey is the absence of com-

parative information on the time-trend of the prevalence andincidence of treated thyrotoxicosis. There are no com-

parisons to assure the reader that the trend of the rates isnot downward. If it was downward, the absence of adownward gradient in the period studied might reflect anincrease in incidence. Perhaps the authors might delveinto this question of controlled comparisons.

Columbia UniversitySchool of Public Health,600 West 168th Street,

New York,New York 10032, U.S.A. MERVYN SUSSER.

YERSINIA ENTEROCOLITICA INFECTION AND

THYROID DISORDERS

SIR,-Dr Hadden and Dr McDevitt (Sept. 7, p. 577)support the view that environmental stress is not importantin the pathogenesis of thyrotoxicosis. However, theobservation that the concordance of Graves’ disease in

pairs of identical twins is 30-60% points to the influenceof environmental factors in this condition. 1 As infectionshave been postulated as a precipitating cause of thyro-toxicosis, we should like to report the frequency of Yersiniaenterocolitica infections in patients with thyroid diseases.Y. enterocolitica is one of the commonest enteric infectionsin Scandinavia, but it is not a resident in the normalintestinal flora.2 2 In nearly all infected patients antibodiesto it are demonstrable.3 The antibody to the 0 antigen ofserotype 3 is specific. 4

1. Volpé, R., Edmonds, E., Lamki, L., Clarke, P. V., Row, V. V.Mayo Clin. Proc. 1972, 47, 824.

2. Winblad, S. Med. Årbog, 1970, 13, 244.3. Nilehn, B. Acta path. microbiol. scand. 1969, suppl. 206, 1.4. Larsen Hannover, J. in Infection and Immunology in Rheumatic

Diseases (edited by D. C. Dumonde). W.H.O./A.R.C. InternationalSymposium. London (in the press).