2
31 of early emphysema. They estimated the M.B.C. in 328 patients with pulmonary disease (tuberculosis in most cases) for which pulmonary resection was later carried out. Suitable specimens for study were obtained at operation in all but 3 of these cases, and emphysema was demonstrated in 150. The M.B.c. was considered abnormal when the volume was 95% or less of the predicted value and when, in addition, elevation of the spirogram indicated trapping of air. On these criteria, the M.B.c. was abnormal in 92 (61%) of the 150 cases of proved emphysema, but it was also abnormal in 22 (12%) of the cases in which emphysema was not demonstrated. In some patients with emphysema, the spirogram was raised, although there was no apparent reduction in the volume of the M.B.C.; and this evidence of air trapping came to be considered the more significant factor. The ratio of residual volume to total lung capacity was determined in 48 patients with proved emphysema, but in only 17 severely affected patients did it amount to more than 35% of the total lung capacity, and this test therefore failed as a useful indication of early emphy- sema. The timed vital capacity (T.v.c.), a test in which prolongation of expiration is indicated by measuring the proportion of the vital capacity which can be expired in a given time, was performed in 113 patients, 79 of whom had proved emphysema. A two-second T.v.c. of 90% or less was considered abnormal, and this was found in 71 (90%) of the 79 patients with emphysema and in 18 (53%) of the others. A test devised by CoMROE and FOWLER 15 to detect uneven alveolar ventilation during a single breath of oxygen was used in 114 patients, of whom 70 had proved emphysema. A rise of nitrogen in the expired breath to more than 2% was regarded as abnormal. This test was abnormal in 59 (84%) of the patients with proved emphysema and in 20 (46%) of the others. The most sensitive indication of emphysema was a combination of prolonged T.v.c., elevation of the spirogram to hyperinflation level during the M.B.c. test (whether or not the M.B.c. was apparently reduced), and a rising curve of alveolar nitrogen after a single breath of oxygen. These tests are, of course, by no means specific and their practical value will have to be further assessed; but they are all easy to perform, and the first two do not require expensive apparatus. Any work which may help the clinician to gather some fruit from the physiologist’s tree of knowledge is certainly welcome. 15. Comroe, J. H. jun., Fowler, W. S. Amer. J. Med. 1951, 10, 408. 16. Stocks, P. Regional and Local Differences in Cancer Death-rates London, 1947. General Register Office, Studies on Medical and Population Subjects, no. 1. Soil, Water, and Cancer IN 1947, STOCKS 16 noticed a peculiar-distribution of deaths from cancer in Greater London which he could not explain by differences in age-groups, social con- ditions, or number of hours of sunshine. This led him to observe that the four London boroughs supplied largely by well water had lower cancer mortalities than most of the boroughs supplied by river water. STOCKS and his colleagues are continuing their inquiry, into the possible relation between what might be called the geological conditions of habitation and cancer mortality, in the North Wales area. They have demonstrated an association between an increased mortality from cancer of the stomach in Anglesey and residence on a particular soil group,1718 though this association was less definite for agricultural workers. The soil in question, because of the equable distribu- tion of moisture at all levels and at all seasons, has a continuous period of plant growth and biological activity, whereas soils not associated with an excessive cancer mortality are subject to late spring or summer drought due to shallowness or rapid drainage, or they have a long wet season because of poor drainage. Earlier work 19 in North Wales and elsewhere suggested that the high organic content of cultivated soils was associated with increased cancer mortality. To overcome the great shortage of drinking-water in the Netherlands, schemes have been suggested for the introduction of river water as the main source of supply. TROMP,20 aware of STOCKS’s ideas, took note of these plans and decided to study the relation between the physicochemical properties of drinking- water and cancer mortality. In Holland, the highest total cancer death-rate for all sites had been found amongst municipalities supplied by river water,21 and where the water had a high SiO2 and low manganese and natron content. Further studies suggested that a high manganese content of the drinking-water is associated with lower cancer frequencies. Recently, TROMP and DIEHL 22 have extended their work to a more detailed study of the relation between soil and cancer mortality and especially cancer of the stomach. The period studied was 1900-40. The average cancer mortality (all sites together) per decade for persons over 50 years of age was ascertained for the seven principal soil types in the Netherlands. These soils range from the acid reclaimed and poorly drained peat soils, through sandy soils, to the more alkaline river- clay type. The highest cancer death-rate was found in municipalities situated on peat and reclaimed peat soils and the lowest on river-clay soils. Thereafter, for the period 1946-52, they studied the total numbers of deaths from cancer of the stomach in men over the age of 50 living in municipalities on the various soil types. As in the case of cancer in all sites, it was found that there was a lower mortality from cancer of the stomach, at all ages, among people living on river- clay soils and a higher mortality among those on peat soils. Moreover, the order of frequency in relation to soil was, with one exception, similar to that of cancers of all types. TROMP and DIEHL conclude that the association between soil type and cancer mortality is a real one. They feel that they have eliminated differences in sex and age grouping which might influence such a relation- ship. They also considered the question of differences in type and character of the municipalities (for instance, rural, semi-rural, and urban) which might have affected the figures. Regarding genetic and racial factors, they say that no obvious correlations have been found in the department of anthropogenetics of the Netherlands Institute of Preventive Medicine between soil units and racial groups. Nevertheless, in 17. Davies, R. I., Wynne Griffith, G. Brit. J. Cancer, 1954, 8, 56 18. Wynne Griffith, G., Davies, R. I. Ibid, p. 594. 19. Legon, C. D. Ibid, 1951, 5, 175; Brit. med. J. 1952, ii, 700. 20. Tromp, S. W. Brit. J. Cancer, 1954, 8, 584. 21. Diehl, J. C., Tromp, S. W. Foundation for the Study of Psycho- physics. First Report on the Geographical and Geological Distribution of Carcinoma in the Netherlands. Oegstgeest, Holland, 1954. 22. Tromp, S. W., Diehl, J. C. Brit. J. Cancer, 1955, 9, 349.

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Page 1: Soil, Water, and Cancer

31

of early emphysema. They estimated the M.B.C. in328 patients with pulmonary disease (tuberculosis inmost cases) for which pulmonary resection was latercarried out. Suitable specimens for study were

obtained at operation in all but 3 of these cases, andemphysema was demonstrated in 150. The M.B.c.was considered abnormal when the volume was 95%or less of the predicted value and when, in addition,elevation of the spirogram indicated trapping of air.On these criteria, the M.B.c. was abnormal in 92

(61%) of the 150 cases of proved emphysema, but itwas also abnormal in 22 (12%) of the cases in whichemphysema was not demonstrated. In some patientswith emphysema, the spirogram was raised, althoughthere was no apparent reduction in the volume of theM.B.C.; and this evidence of air trapping came to beconsidered the more significant factor. The ratio ofresidual volume to total lung capacity was determinedin 48 patients with proved emphysema, but in only17 severely affected patients did it amount to morethan 35% of the total lung capacity, and this testtherefore failed as a useful indication of early emphy-sema. The timed vital capacity (T.v.c.), a test inwhich prolongation of expiration is indicated bymeasuring the proportion of the vital capacity whichcan be expired in a given time, was performed in113 patients, 79 of whom had proved emphysema.A two-second T.v.c. of 90% or less was consideredabnormal, and this was found in 71 (90%) of the 79patients with emphysema and in 18 (53%) of theothers. A test devised by CoMROE and FOWLER 15 todetect uneven alveolar ventilation during a singlebreath of oxygen was used in 114 patients, of whom70 had proved emphysema. A rise of nitrogen in theexpired breath to more than 2% was regarded asabnormal. This test was abnormal in 59 (84%) ofthe patients with proved emphysema and in 20 (46%)of the others. The most sensitive indication of

emphysema was a combination of prolonged T.v.c.,elevation of the spirogram to hyperinflation level

during the M.B.c. test (whether or not the M.B.c. wasapparently reduced), and a rising curve of alveolarnitrogen after a single breath of oxygen.

These tests are, of course, by no means specific andtheir practical value will have to be further assessed;but they are all easy to perform, and the first two donot require expensive apparatus. Any work whichmay help the clinician to gather some fruit from thephysiologist’s tree of knowledge is certainly welcome.

15. Comroe, J. H. jun., Fowler, W. S. Amer. J. Med. 1951, 10, 408.16. Stocks, P. Regional and Local Differences in Cancer Death-rates

London, 1947. General Register Office, Studies on Medical andPopulation Subjects, no. 1.

Soil, Water, and CancerIN 1947, STOCKS 16 noticed a peculiar-distribution of

deaths from cancer in Greater London which he couldnot explain by differences in age-groups, social con-ditions, or number of hours of sunshine. This led himto observe that the four London boroughs suppliedlargely by well water had lower cancer mortalitiesthan most of the boroughs supplied by river water.STOCKS and his colleagues are continuing their inquiry,into the possible relation between what might becalled the geological conditions of habitation and

cancer mortality, in the North Wales area. They havedemonstrated an association between an increased

mortality from cancer of the stomach in Anglesey andresidence on a particular soil group,1718 though thisassociation was less definite for agricultural workers.The soil in question, because of the equable distribu-tion of moisture at all levels and at all seasons, hasa continuous period of plant growth and biologicalactivity, whereas soils not associated with an excessivecancer mortality are subject to late spring or summerdrought due to shallowness or rapid drainage, or

they have a long wet season because of poor drainage.Earlier work 19 in North Wales and elsewhere suggestedthat the high organic content of cultivated soils wasassociated with increased cancer mortality.To overcome the great shortage of drinking-water

in the Netherlands, schemes have been suggested forthe introduction of river water as the main source of

supply. TROMP,20 aware of STOCKS’s ideas, took noteof these plans and decided to study the relationbetween the physicochemical properties of drinking-water and cancer mortality. In Holland, the highesttotal cancer death-rate for all sites had been foundamongst municipalities supplied by river water,21 andwhere the water had a high SiO2 and low manganeseand natron content. Further studies suggested thata high manganese content of the drinking-water isassociated with lower cancer frequencies. Recently,TROMP and DIEHL 22 have extended their work to amore detailed study of the relation between soil andcancer mortality and especially cancer of the stomach.The period studied was 1900-40. The average cancer

mortality (all sites together) per decade for personsover 50 years of age was ascertained for the seven

principal soil types in the Netherlands. These soils

range from the acid reclaimed and poorly drained peatsoils, through sandy soils, to the more alkaline river-clay type. The highest cancer death-rate was foundin municipalities situated on peat and reclaimed peatsoils and the lowest on river-clay soils. Thereafter,for the period 1946-52, they studied the total numbersof deaths from cancer of the stomach in men overthe age of 50 living in municipalities on the varioussoil types. As in the case of cancer in all sites, it wasfound that there was a lower mortality from cancer ofthe stomach, at all ages, among people living on river-clay soils and a higher mortality among those on peatsoils. Moreover, the order of frequency in relationto soil was, with one exception, similar to that ofcancers of all types.TROMP and DIEHL conclude that the association

between soil type and cancer mortality is a real one.They feel that they have eliminated differences in sexand age grouping which might influence such a relation-ship. They also considered the question of differencesin type and character of the municipalities (for instance,rural, semi-rural, and urban) which might haveaffected the figures. Regarding genetic and racialfactors, they say that no obvious correlations havebeen found in the department of anthropogenetics ofthe Netherlands Institute of Preventive Medicinebetween soil units and racial groups. Nevertheless, in17. Davies, R. I., Wynne Griffith, G. Brit. J. Cancer, 1954, 8, 5618. Wynne Griffith, G., Davies, R. I. Ibid, p. 594.19. Legon, C. D. Ibid, 1951, 5, 175; Brit. med. J. 1952,

ii, 700.20. Tromp, S. W. Brit. J. Cancer, 1954, 8, 584.21. Diehl, J. C., Tromp, S. W. Foundation for the Study of Psycho-

physics. First Report on the Geographical and GeologicalDistribution of Carcinoma in the Netherlands. Oegstgeest,Holland, 1954.

22. Tromp, S. W., Diehl, J. C. Brit. J. Cancer, 1955, 9, 349.

Page 2: Soil, Water, and Cancer

32

view of the work 23 24 which has shown that cancerof the stomach is commoner among people of blood-group A and is particularly rare in those of group 0,they suggest that a study of the blood-groups in theNetherlands municipalities would be relevant to thisquestion. They are not prepared to speculate aboutthe causes of the observed correlation between soil andcancer, except to point out that traces of metals insoil, drinking-water, and food (which in the smallermunicipalities is mostly locally grown) would besufficient to disturb enzyme balance ; and they seemto have made a start in searching for such traceelements. The labour involved in the search wil]be prodigious.

All these considerations bring us back to the oldquestion of how firm can be the conclusions drawr

23. Aird, I., Bentall, H. H. Brit. med. J. 1953, i, 799.24. Køster, K. H., Sindrup, E., Seele, V. Lancet, 1955, ii, 52.

from death-certificates. The Dutch workers believethat registration of deaths in Holland is accurate,partly because the secrecy of death-certificates isassured and partly because the mortality data arecollected by a very competent organisation, theNetherlands Central Bureau of Statistics. They assertthat, except in the largest cities, the population doesnot migrate much and that doctors and hospitals donot vary in competence or facilities in different partsof the country. We can agree with all these arguments,but there still must be many inaccuracies in deathcertification without post-mortem examination (andeven with it). Despite the evidence of a fairly stablepopulation, changes in habitation must be considerableduring a long life and with easy means of transport.Perhaps the strongest argument in favour of a soil-cancer relationship is its demonstration in two com-munities as widely separated as Anglesey and Holland.

Annotations

MYXOMATOSIS

SINCE October, 1953, man and the rabbit-flea (Spilo-psyllus cuniculi) have contrived to spread myxomatosisthrough the length and breadth of the land. Pockets of

countryside have escaped entirely ; in other areas the

pestilence has passed and the few survivors are beginningto re-stock the warrens ; but in most farming countiesfoxes make do with rats, field-voles, and even vegetablematter, while buzzards lack the rabbit-meat they needto produce the normal 2-3 eggs. Some of these changeswere discussed not long ago at a meeting of the MammalSociety of the British Isles 1 ; but we must recognisethat the entry of myxoma virus has redrafted the

ecological play, and we are watching only the openingscene.

Fleas feed on the head and ears of rabbits, and in thiscountry the rabbit-flea is the most important vector ofthe virus. Its range is short and it probably cannotspread the disease more than a few miles each month :in Kincardineshire, for example, there were manyinfected rabbits only a few hundred yards-but on thefar side of a stream--from a single focus deliberatelyintroduced some months earlier. In Australia myxoma-tosis takes wing on mosquitoes, but here only Anophelesmaculopennis atrovarus, which may carry virus for sixmonths, is a possible vector. Nor can infection be readilyinduced by mechanical contact, or by contaminatedgrass or vegetables ; and this, no doubt, largely accountsfor the absence of the disease in backyard and animal-house. The virus still maintains its extraordinary host-specificity, and, apart from a few brown hares, rabbitsare the only mammals known to have been naturallyinfected.Our wild rabbit has qualities that will almost certainly

ensure its survival ; but a virus-resistant strain has notyet emerged, and, though immune rabbits have beenbred, their progeny are normally susceptible. On theother hand, attenuated field strains of virus are wellknown, particularly in Australia but also in France, andrecently recovered immune rabbits have been picked upover an area of 50,000 acres in the Dukeries in Notting-hamshire. This attenuated strain is said to kill only abouthalf its victims, compared with the 99% mortality bythe strain prevalent elsewhere. So far this seems to bean isolated instance ; but, should the attenuated strainspread or appear in other areas, both myxomatosis andhordes of rabbits may be permanently with us. Toavoid this and to increase food-supplies, the Minister ofAgriculture is pressing on with the designation of rabbit-

1. See Nature, Lond. 1955, 176, 1155.

clearance areas in which occupiers of the land must

destroy the rabbits or, if this is impossible, prevent theircausing damage. There is strong financial inducement tofarmers to carry out the provisions of the 1954 PestsAct, for conservative estimates for England and Walesshow that last year the grain yield in rabbit-free areaswas raised by about two hundredweight an acre-equivalent to something over SIC million sterling. Theseare immediate returns, but the eventual gains could bemuch more striking. For those with only an eye for thecountryside, ash and oak saplings are beginning to appearwhere they were scarcely seen before, gorse is shootingprodigiously, grasses are higher, and wild flowers such ascowslip and rock-rose, and even the rarer orchids, havebloomed unexpectedly.

1. Regna, P. P. Amer. J. Med. 1955, 18, 686.2. Umbreit, W. W. Ibid, p. 717.3. Crowfoot, D., Bunn, C. W., Rogers-Low, B. W., Turner-Jones,

A. In The Chemistry of Penicillin (edited by Clarke, H. T.,Johnson, J. R., Robinson, R.). Princeton, 1949; p. 310.

4. Behrens, O. K. Ibid, p. 657.5. Few, A. V., Cooper, P. D., Rowley, D. Nature, Lond. 1952,

169, 283.6. Gale, E. F. Symposium on Mode of Action of Antibiotics,

2nd Int. Cong. Biochem. Paris, 1952.

CHEMISTRY AND ACTION OF ANTIBIOTICS

THE structure of antibiotics and the way in which theywork have lately been reviewed by Regna and Umbreit.2The term " antibiotic " has come to refer to any chemicalsubstance produced by a micro-organism which can

inhibit the growth of, or otherwise destroy, other bacteriaor micro-organisms. By this definition, the firstantibiotic was penicillin. In the molecule of penicillinthe side-chain R can have various configurationssuch as benzyl, pentenyl,amyl, and so on. Theelucidation of the chem-ical structure of thismolecule was finallyachieved by a brilliantand painstakingcrystallographicanalysis of the molecule,3 after organic chemists, both inGreat Britain and in the United States, had been unableto decide between two possibilities. Biosynthetic path-ways 4 have been used to vary the group R, and otherclinically useful preparations have been devised by saltformation with the free-acid group of penicillin (theprocaine, chloroprocaine, and ephenamine salts, for

example). Penicillin seems to be adsorbed to and therebydeactivates a specific component of the cell wall of thebacterium.5 This inactivation appears to lead to a

disturbance in the synthesis and metabolism of thenucleic acids,6 and this causes, in turn, disturbances in