564 MARCH 29, THE CANCER-PRODUCING FACTOR IN TAR. rTRBTETISU 19241 IMDICAIJOURNAr. I wlhiel eacll fraction is produced; the figures are onlv very ON THE CANCER-PRODUCING FACTOR rouglh, for the practice varies considerably in different tar- IN TAR. works, and also in the same works in accordance with fluctuiations in the BY miiarket for different products. Tlhus the proportion of creosote oil produced may vary from 9 per E. L. KENNAWAY, M.D., D.Sc. cent. to 25 per cent. of the crude tar. (From the Cancer Hospital Research Institute, London.) TABLE I.-Fi'ractions of Gasworks Tar. TH.AT tar can produce cancer has been known for nearly fifty years, but no systematic attemipt to tlle par- Limit of idenitify Fraction. PrCn.UppDer ticular comiipounds responsible for this effect was possible Pof TCar. Temperature until tlleexperimental productionof cancer in lower animals a became practical method. In thle absence of such experi- 1. Ammoniacal liquor ... ... 2 nmenltal evidence from the laboratory, th'e capacity of any 2. Crude naphtha ... ... ... 2 material to produce cancer must be learned from those accidental experiments on man which are the cause of 3. Light oil ... ... ... ... 9 2250 "industrial diseases." When a new cancer-producing 4. Middle or carbolic oil ... ... 5 2550 substance comes into industrial use on a large scale no danger will be detected during the long latent period, 5. Creosote oil ... ... ... ... 14 2750 whieh in man is probably of many years' duration; the 6. Anthracene oil ... ... 3 320P* effect of the will then become apparent, as we substaneo 7. Pitch ... ... ... ... ... ...63 have seen recently in the case of mule-spinners. The object of this paper is to bring together the evidence, * Steam distillation. from both the industrial and experimental sources, which The anthracene oil is the only one of these fractions of whicli the inidicates the presence *r absence of carcinogenic power further treatmient by the tar-distiller must be described here. in the different fractions obtained from coal-tar and in the Anthracene oil contains a quantity of crystalline material in suspen- pure substances isolated from it. sion. These solids, which amount to about 5 per cent. by weight of the oil, are separated from the oil by centrifuging or filtration, and constitute " 40 per cent. anthracene." The oil is now known as SECTION I.-THE DIFFERENT FORMS OF TAR. green, strained, or dead oil; this is used for the manufacture of Tlhe fo-ms of tar which are of most importance in the " grease " (see below) and for other purposes. The green oil is a study of cancer are: (1) lignite tar, (2) gasworks tar, (3) pro- saturated solution of the crystalline substances removed. The 40 per cent. anthracene is washed with solvents in which anthracene ducer-gas tar, (4) coke-oven tar, (5) blast-furnace tar. Of is not very soluble, and by this means is converted into " 85 per tllese, (1), (2), some forms of (3), and in all probability (4) cent. anthracene "; the material removed in this way, which col- produce cancer, while (5) does not. What, then, is the sists chiefly of carbazole and phenanithrene, with acridine and of course many otlher substances, will be spoken of here as factor which determines whether a tar shall or shall not have "anthracene residue." cancer-producing properties? The composition and mode of formation of the various tars, and the occurrence of cancer The relationsllips of the derivatives of tar which must be in the workers handling them, cannot be dealt with in the dealt witlh in this section may be represented by the follow- present paper; but the lack of cancer-producing power in ing scheme (Table II); those which are known to produce blast-furnace tar provides such important evidence that it cancer are inidicated by italics. is necessary to state the chemical characteristics of this tar. TABLE II. Crude naphtha. Blast-Furnace Tar. Blast-furnace tar does not produce cancer either in men JLight oil. (Legge') or in mice (Leitch2). Unfortunately the composi- Carbolic oil. tion of this tar has been little studied; almost all the cur- rent statements about it can be traced to the analyses of Tar Creosote oil. {85 % Anthracene. Watson Smith3 published about forty years ago. f40 % Anthracenze. Ant hracene oil. residue. The chief differences between blast-furnace tar and the Green oil. Anthracene ordinary cancer-producing gasworks tar are as follows: (a) The total quantity of phenols in blast-furnace tar is more than (Pitch distillate. twice that in gasworks tar. Blast-furnace tar contains much less Pitch ... carbolic acid, but much more of the phenols other than carbolic Pitch coke. acid (that is, cresols, xylenols, pseudo-eumenol and alpha and beta naphthol). Thus the phenols other than carbolie acid make up over Distribution of the Cancer-producing Substance among the 98 per cent. of the mixed phenols of the carbolic-oil fraction of Fractions Tar. blast-furnace tar, and 35 per cent. of the corresponding portion of Different of Gasworks gasworks tar. The question then arises: Into which of these fractions (b) Paraffins, liquid and solid, are present in much larger amount does the cancer-producing substance present in the original in blast-furnace tar. The solid paraffins make up about 1 per cent. tar pass? Cancer similar to tar cancer has been recorded of the whereas they are absent, or present traces only, in tar, in 40 cent. anthra- gasworks tar. The presenee of paraffins is very undesirable if a in workers hanidling creosote, green oil, per tar is to be used as a source of benzene, toluol, or anthracene, and cene, and pitch, and experimentally has been produced also hence the amount of paraffin in gasworks tar. is purposely kept as by a high-boiling distillate from pitch which is not prepared as by a low possible maintaining suitably high temperature during We now consider in detail the industrial carbonization; in a blast furnace the-temperature is, of course, not commercially. may regulated by any such considerations. and experimental evidence in the case of each fraction; (c) Of the aromatic compounds other than phenols: toluene, when no other source is stated the experimental evidence is xylene, trimethyl benzene, aniline, and a small amount of naph- derived from investigations carried out in this institute. thalene are present in blast-furnace tar, but Watson Smith could niot detect either benzene or anthracene, which are, of course, very important commercial constituents of gasworks tar. 1. The Fractions of Low Boiling Point (Naphtha, Light Oil, CarUolic Oil). Thus a comparison of the composition of a cancer- Industrial evidence appears to be almost wholly negative. Many producing and a non-cancer-producing tar shows that the of the substances contained in these fractions are present also in blast-furnace tar (toluene, xylene, trimethyl benzenes, cresols, latter contains the greater quantities of paraffins and of that workers in a carbolic acid phenols other than carbolic acid, but is deficient in soime xylenols). Ball4 in 1885 reported factory showed numerous warts; "one man whose duty it was to aioimiatic compounds. fill the bottles with pure carbolic acid, had his hands covered with them." It is not clear whether these people came into contact also SECTION II.-THE FRACTIONS OF GASWORKs TAR. with the crude carbolic oil fraction or other tar products; no cases of cancer among them were reported. Story 5 m the same year, The seven fractions which are produced by the ordinary described the case of a workman who receiveA a splash of " crude commercial distillation of coal-tar, are stated -in Table I, carbolicacid " on the eyelid; at the spot a wart of tie type familiar to carbolic acid workers which in the course of a few where an attempt is made to indicate the relative amounts developed, months became an epithelioma; this was excised and examined of lthe different fractionsL and the temperatures between microscopically. This seems to be the only case of cancer recorded MArtC 29, THE CANCER-PRODUCING FACTOR IN TAR. I (.TDR,aBLBJn..2.mA.- 565 I19241 565~~~~~~~~~ in the literature which could be attributed to the fractions of coal- 5. Pitch. tar preceding the creosote oil. Possibly the cancer in this instance Industrial Evidence.-Of the 95 cases of epithelioma notified to was of the type which occurs sometimes in scars, and was the Home Office from England anid Wales between January, 1920, independent of the chemical nature of the injury. and June, 1922, 66 were in pitch workers (Legge16). Many writers Experimental evidence with regard to this and the next fraction have described the conditions under which the pitch-breakers and (creosote) may be taken together. Bloch and Dreifuss6 refer to the briquette-makers work, and the affectiois of the skin which they experiments in which mice were painted with " the fraction of low- show (Legge,12 Warnes,17 Ehrmann,18 and others), so that it is boiling hydrocarbons "; they do not state any limits of temperature, unnecessary to give any account of the matter here. Probably pitch but it is evident that some fraction boiling below 3000 is meant. qancer could be almost wholly eliminated if one of the systems now Whether this indefinite term is intended to include the creosote in use in some works in Holland and Germanyl5 19 could be adopted. must be left uncertain; this fraction of tar would include many Thus in the Fohr-Kleinschmidt system the liquid pitch can be run substances which are not hydrocarbons at all. This fraction pro- off from the tar-stills into tank wagons and conveyed to a duced tumours which ulcerated late and were as a rule non-malignant briquetting plant, where it is converted in a closed apparatus, in character; there was a considerable development of the stroma which is patented, into a fine dry powder; this is mixed with the and blood vessels, so that such tumours might be given the name coal-dust in a closed drum.