Document 6R0dmQ7G99pK33qkGkO1ego2o

FILE NAME: Celanese (CEL) DATE: 1956 DOC#: CEL049 DOCUMENT DESCRIPTION: Laubly Exhibit #2 - Book Excerpt Oo 10 99 1 6 : 3 0 FAX 1 4 10448236S 0 0 2 INDUSTRIAL MEDICINE AND HYGIENE Etliidl hy E. R. A. nMEREWETHER C B.. C B E . O.SrJ.. M.O.. F.R.C ?.. D.I.H.. FA S Et.!.. Umulti tn.*r-L tw H M Senior M edic *l K s m 'Tcm of FtcTumrs. vI inisikv m L t n i n n ini S.iHjNki. S m i n i . ChiEi Mti)irL A utist*. MinuTkv he 4i h u ; ; It k> fltl.fllt *ND Ftw11> VOLUME 3 BITTERWORTH & CO. iPUBLISHCKSl LONDON 1956 LTD. no 10 S3 1 6 . 3 0 Fa.V 14 104 4S2368 003 CHAPTER 3 INDUSTRIAL CARCINOGENESIS AND TOXICOLOGY M. W. Goldblatt and J ldith G oldblatt Part I: Occupational Carcinogenesis P art H: Sonic Aspects o f Industrial Toxicology Part 1 Occupational Carcinogenesis SOME GENERAL CONSIDERATIONS T he lack, of knowledge of causes of spontaneous cancer in man is -often held to be the most serious handicap in real advance towards cure. But. .in the case of occupational cancer the causes are in several instances known, but cure in the sense of chemotherapy is far off. On the other hand, prevention is a more attainable target, when a cause is known. ifj It may be helpful to quote from one or two statements recently made by /i. Haddo^ (951): " . . . the cancer cell is but a modification of the normal celi . . . conversion to malignancy may be due to a subtle and elusive re-orientaiion of enzyme construction quite unaccompanied by any gro`ss changes affecting protein structure or immunological specificity and that there is on this account little or no protective reaction on the part of the host such as occurs in infections": " . . . the malignant cell appears highly stable, if not indeed irreversible, as is shown by the manner in which us newly acquired genetic properties arc transmitted and maintained, quite indefinitely and with no sign of reversion In occupational carcinogenesis no less than in spontaneous carcinogenesis these statements are equally justifiable, and indeed cast a certain light on certain facts, whilst making it more difficult to understand others In occupational carcinogenesis the outstanding characters are: tha" the tumours are not distinguishable from non-occupaiiona! tumours' the causes are ct;her known or van he reasonably assumed to he known, the time ol t- * Clo 10 99 1 6 : 3 0 F.vX 141044S2365 004 A50ESTOS there was I milligram per gramme of nickel in the lung even 8 years after cessation of exposure If token's results were correct, there must have been some 1-2 grammes of nickel in the lungs--a wellnigh incredible figure-- completely out of harmony with Barnes and Denz's conception of nonretention unless there was very great difference, as seems likely, in the physical form and states of the nickel. ASBESTOS The association of what appears to be purely mechanical trauma with a later development of neoplastic change has a long history both in the ex perience of myriads of medical observers and in that of theorists who invoked it in the exposition of a theory of cancer. If such an association is looked -at askance it is not because it is denied that it can occur, but rather that it is too facile and even sterile an explanation. Of the tens of millions of mechanicaltraumas occurring daily, the number which can be later recognized as having possibly initiated a neoplastic process in situ is minute. Most pathologists would sum the matter up by saying that if trauma is followed by the develop ment of a tumour at the site of the original trauma, then that site was not normal at the outset. Co-carcinogenesis The classical experimental basis for the effect of the super-imposition of trauma on an abnormal site is the Deelman phenomenon. Deeiman showed in 1923 that if a tarred area of animal skin is injured by wounding or other physical effect, tumour formation might be hastened and its location thereby determined. This observation was later confirmed by other workers who used pure carcinogens and laid the foundation of what is now called co- . carcinogenesis. Co-carcinogenesis may be defined as the augmentation oi the action of a carcinogen by some suitable additional treatment which shows itself in increased numbers oT induced tumours and/or shortening oi the induction time. ]n general the term co-carcinogenesis is applied to an effect produced by local application of an agent to a tissue (Bcrenblum, 1947). A co-carcinogen is not itself a carcinogen although Anderson (1948) appears to think otherwise, regarding co-carcinogenesis as a synergy between sub liminal doses of two or more carcinogens. Such mechanical irritation as strongly brushing the skin, and foreign body fibrosis, have been shown to be effective as co-carcinogens. Heal, cold, radioactive radiations, croton oiland resin, all possess co-carcinogcnic power. The precise naiurc of co-carcinogenesis is difficult to understand except as an expression or certain experimental facts, The significant matter from our present viewpoint is that for a co-carcinogen to produce its ciTccts n must be applied after a preparnlior. or the tissue has taken place by a carci nogen, or even after an overt carcinogenic response has regressed Although the whole concepiio.n of co-carcir.ogenesis has arisen from l i 11 e INDUSTRIAL C a RCINOGENEIS a n d t o x ic o l o g y evpermer.'.a! work on mouse and rabbit skin, some such idea roust be evoked by a problem such as that of asbesiosis and cancer, until some more expcrimeiv.al evidence oT direct carcinogenesis by asbestos or a decomposition pro&ucunf it can be obtained, If such an idea is feasible, then we must also assume a pro-neoplastic preparedness in the organ in which the co-carcinogen iasbestos or the fibrous tissue in ihc peribronchiolar reaction 1later induces a funner development into true neoplastic growth. The preparedness of the .!.->ue if it i.i to be tegarded as more than a form of words is brought about h> something independent of the asbesiosis. and this must be regarded as an endogenous factor. Bui some special property must also attach to the asbesiosis lor the alleged cancer induction in this condition is not apparently found in the long-standing cases of silicosis. We will first consider the evidence that asbesiosis leads in a proportion of cases to cancer of the lung. As long ago as 1938 the suspicion arose that asbestos workers might be more than normally prone to lung cancer^ Mordmann (1938) analysed six cases of lung cancer and showed that the rang; of exposure periods was 7-21 years, and the range of intervals between entering the industry and death was 15 to 21 years. The malignant disease in. some cases occurred years after leaving the industry. Half of these cases were comparatively young. 35--41 years of age at death. In one remarkable case a 7]-year old woman had worked in asbestos for only 19 months Laier in the same year he referred to a further seven cases of associated asbesiosis ar.d lung cancer, including Gloyne's (1936) finding of six cases of carcinoma of the lung in 50 necropsy cases of asbesiosis. In the 1947 Annual Report of the Chief Inspector of Factories, Merewether tabulated the age incidence among 235 deaths caused by asbesiosis: in 13 2 per cent of these cancer of the lung was present, and it is especially important to note that 4-8 per cent of the age-group 25-34 years and 5-6 per cent of the age-group 35-44 years had this condition. It will be seen that the over-all figure is closely in agreement with Gloyne's findings In a further report* carrying this analysis up to the end oT 1954, he found that amongst 344 deaths, in 55, or 16-0 per cent, cancer of the lung was present. In their series of papers on asbesiosis Lynch and Cannon (1948) give an analysis of the post-mortem examination of 40 cases of asbesiosis among which 3 cases of carcinoma of the lung were found associated with medium or advanced grades of asbesiosis, which, according to these authors, is seven limes the general incidence in the United States. In a more recent study of the clinical picture and paihology of asbesiosis. Behrens (1952) estimated that of 309 cases of asbesiosis reported In the literature there were 44 cases of carcinoma of the lung (14 2 per cent) whereas in a series of 2,204 cases of silicosis only 32 such tumours were found (I 4 per cent). A n n u a l R ep o rt C h * r Inspector of Factor for 1934. pp. 19 0 - 19 i The order Stales Sua dissali at ina series which to am Dei cover: wcari couel the tx oval prim; scatti logici piasti io be the a to thi led le respc A goric of ait est!: case yean radii lowe midi Li kera was turn 1viti; exp; A 37 ) indi tare aul! 0 5 10 3 9 1 6 : 3 0 FAX U 1 0 - US 2 3 6 S 2; oo6 )ksd ocrition also seen :es a ' the DOUl s an the :ntly n of that the >een e' *e iths. a ted a of ries, : by it is ears 3 be ngs. , he lung : an ong ium wen It r.m 3sis% .the ent) vere ? I The discrepancy between the two incidences in Switzerland is of the same order as that found in the smaller series by Lynch and Cannon in the United Slates, Suggestiie as these and other data are, Stoll. Bass and Angrist (1951) were dissatisfied with the statistical weight one could put noon available figures at that time which included, in addition to those of Lynch and Cannon, a series of 2.15 cases of asbestosis v, ith 31 carcinomas of the lung (13 - per ceil!) which is again almost identical with the finding of Behrens. They refer also to another series of 115 cases with 1*4-8 per cent lung tumours. Describing the case of a worker who had been engaged for only 6 years covering pipes with asbestos and who had refused to take precautions by wearing a respirator, they point out that except for weakness and persistent cough nothing noteworthy was found until malignant cells were found in the bone marrow. Radiographs of the chest showed numerous large discrete oval shadows which were interpreted rather as metastatic deposits than primary tumours. Post-mortem examination showed asbestosis with scattered large nodules and metastases in kidneys, brain and liver. Histo logical examination confirmed the presence of asbestosis bodies and ana plastic carcinoma of the lung, with numerous metastases. There appeared to be sorpe doubt about the primary focus of malignancy in this case, and the authors inclined toward a multiple origin. Whether this case is relevant to the problem of asbestosis cancer is open to question, but the authors were led to suggest that asbestos must itself be regarded as a direct carcinogen in respect of its composition as a silicate. A less compromising attitude is taken by Werbcr (1952) who states cate gorically that in 7-17 per cent of cases of asbestosis after a latent period of about U-20 years, as a result of epithelial metaplasia, carcinoma becomes established in the lung. Werber then reports what appears to be a clear-cut case successfully operated on. The patient was a man of 58 years who, after years of work in asbestos with complaint of irritant cough, showed, in a mass radiographic investigation, a well-marked dense round shadow in the right lower lung field associated with bilateral finely granular shadows in-the middle and lower fields, more marked on the right side. Lobectomy of the right lower lobe confirmed the presence of a non keratinizing squamous cell carcinoma. Nearly the whole of the lower lobe was occupied by an almost certainly bronchogenic (postero-lateral segment) tumour. Asbestosis bodies were Found in the lung and in an excised hilus lymph node. Recovery was uneventful and x-ray examination showed later expansion of the upper and middle lobes. A suggestive case is also described by Cureton (1948) of a young woman of 37 years who 15 years before had left asbestos work after 7 years in the industry. Necropsy showed a predominantly squamous-celied bronchial carcinoma accompanied by asbestos bodies and fibrosis in both lungs. This author 5 cautious about the relation between the neoplasm and the asbestosis u 3 i o y 'j 0 - 3 0 KVV 14 1044623158 :iS INDUSTRIAL CARCINOGENESIS AND TOXICOLOGV hut poi.'HS out that the woman was very young for a squamous growth. As in the case of most other occupational tumours, it is commoner to nod workers without the ncopiastic reaction than, with it. even after all the apparently necessary and sufficient conditions for its development have been found to exist. Many such cases have been amply described. We give one or two from the Continental literature.- Having worked for 22 years consecutively applying insulating (asbestos) material to articles, a man aged 40 years was killed in a street accident, never having complained of respiratory troubles. Franchinl and (aar.epn (1949) performed the post-mortem and found a fracture of the base of the skull as the immediate cause of death. The lungs were massively and exten sively fibrosed mainly in the middle and lower lobes, with lymphocytic infiltrations and thickened elastic tissue; many asbestosis bodies were.found occupying the lungs and lymph nodes. No mention of neoplastic change is made. It is specially interesting that, as in so many other cases, the mnss'vc pulmonary changes should have been unaccompanied by complaint. This is of importance because if after a period of exposure to asbestos dust a certain measure of fibrosis is developed and thereafter the industry is left, we may picture a static non-symptomuuc. non-progressive librosis. but a continuing process of caneerization in a certain number of case. Whether the preceding fibrosis is necessary for the subsequent neoplastic process or whether the latter is conceivable without the former, it is not as yet possible to say. Tne entry of any particles or fibres into the lung, even when they are soluble in water, produces a phagocytic response from the septal cells in the alveolar walls and giant cells with many nuclei soon develop. In the case of a soluble compound the ultimate degeneration of the dust cell permits the second stage of the absorption of the compound. This is readily shown ex perimentally with any of the common laboratory animals. The lune presents a temporary barrier to soluble particles; in the case of insoluble "particles the barrier is more permanent, depending on the size of the particles. The smaller particles may be taken up by phagocytic cells arising from various sources and disposed of in lymph glands, in the interstitial tissue of the lung and even to some extent in organs from which they can be excreted. Every thing depends upon the size. Phagocytic cells may, however, be completely frustrated both "by the nature and size of particles. In such cases they surround the foreign material and a process of local fibrosis sets in, the foreign unaiiackablc materia! remaining more or less iit siw. A small particle (2-3 micrograms) will ultimately enter the alveoli and ihc fibrous reaction will start from the alveolar walls and lymphatics, if it cannot otherwise be disposed of. If the particle is bie (ICM5 micrograms) and cannot therefore proceed into the ultimate air passages, it is held tin and the reaction occurs more proximally in the bronchiolar tree. -6J 00 7 In then ticui phys diffc T! of Ct whit DOS' is b< the astn wor T ind ( the (= of H, H, c H n a o (J l 99 Iti : 30 F U 14 104 4 s:'3bS ills growth. Dner io find Tier all the t have been give one : (asbestos) :t accident, nd Canepa base of the / and extenymphocytic were found c change is :he massive aint. ' asbestos lustry \ . orosis. r of cases, neoplastic it is not as r. they are cells in the In the case permits the "shown ciing presents le particles rides. The j'm various of the lung ed. Every th by the i t material lc material K <jiii and the if it cannot ;.rams) and 'ip and ASBESTOS 211 In respect of the basic features of the body's reaction to asbestos fibres there is nothing to choose between them and particles of silica. The par ticular differences, which are undoubtedly observed, arise from different physical form; difference in solubility; difference in size, and the possible difference in carcinogenic properties. The term asbestos is vague and industrially may refer to any df a scries of complex silicates. It belongs to a group of crystalline magnesium silicates, which include talc (steatite) MgiHjtSiOj),. Meerschaum Mg,H; (SiOs)J.H10. possessing varying degrees of resistance to heat and to chemical agents. H is best as recommended by Spencer (1937) to preface the word asbestos with the particular mineral from which it is derived, lot example serpentine asbestos and amphibote asbestos (hornblende). Unfortunately, more words than one arc used in this industry for the same natural product. The common forms, with country of main origin, used in the various industries with which our present theme is concerned are: (1) Serpentine asbestos (Canadian) (chrysotile*: amiar.t). 'Chrysotile is the most used of the fibrous silicates. Empirical formula : H3MgjSi,0, (= 3MgO H,(SiO,).,). As mined the following is the analytical composition of an average sample of thc naturally found mineral (serpentine: hydrous magnesium silicate): per cent SiO. 43 AI., FeO.Fe.Oj MgO 0-52 10 41-36 H,0 13-79 (2) Amphiboles. Empirica! formulae: H.CajMgj(5iOj), Tremolile (Ualian) H,c,(MgFe),(SiO,), Asbeslos (amphibole asbestos) CiMg,(Si03)4 Actinolite H;N1Fe'Te;'"(Si03)< Crocidolite (Blue asbestos--South Africa, Australia) (3) Amosite asbestos (South Africa) (ferro-anthophyllite). Empirical formula: H,(MgFe),(Sl03),. Their commercial value is due to the long fine, infusible, non-conducting fibres in which these silicates exist and can be worked and it is this char acter which motivates the characteristic changes in the lungs when inhaled over considerable periods. In the mining of serpentine and of the asbeslos from it as a mass of fine, silky crystals in Canada. Cartier (1949J found that he could divide the 3.242 workers of whom 40 per cent had been in the mines for tO-40 years into two groups, one exposed to the dust of serpentine, which remained free from asbestosis and the other, exposed in grinding. " N o t lJ be cOtiluAcU su b Ik a.** ntu'ffctM r m i w r e vt N j l C , u*.-'*!* and *5-0 o') 10 93 1 6 : 3 0 FAX 14104 4 8 2 3 6 8 220 INDUSTRIAL CARCINOGENESIS AND TOXICOLOGY screening. suction and bagging lo the dust of the dried separated fibrous siiicaie. i p which all the cases of asbestosis developed. Among the 22 cases of asbestosis found by radiography and confirmed post-mortem, there was :to mention of any cases of cancer of the lungs More clinical and occupa tional data On these cases would have been desirable. On the basis of (he findings elsewhere.'"]~or 2 cases oT lung cancer would have been expected Or. the experimental side Cartier implies that his clinical data are confirmed by exposure of animals to the two kinds of dust. Cartier makes two statements of consldera'ble Interest as to the severity of asbestosts among his miners. (1) During his 3 years of clinical observation (more than 10.000 complete medical examinations) no worker has died of uncomplicated asbestosis under the age of 60 years, even after 20-30 years' severe exposure to asbestos dust: nor has he seen among asbestosis cases as severe cyanosis or dyspnoea as that seen in asthmatics, lung cancer or advanced tuberculous cases. From this he concludes that pure asbestosis is not as severe a disease as it is considered in Great Britain and elsewhere where manufacturing processes arc earned out with the separated asbestos. (2) Pure asbestosis. often even radiologically very advanced, is found among workers vvho show no clinical signs, no diminution of respiratory function and can without discomfort carry out their habitual tasks. The claim by Cartier amounts to this, that asbestosis as usually described is really a mixed disease, complicated by cardiopathies and even tuberculosis, and that 11pure " asbestosis as seen by him is by no means a severe condition. Having been in close association with such notable authorities as Gardner and Vorwald, these statements cannot be ignored because of relatively short experience of the industry It may be that Cartier considers a life of 60 years amply sufficient for the relatively few cases who develop the disease severely enough lo die from it. He does not, however, in this paper give the popula tions at risk so that we cannot calculate essential data. It may he relevant to his thesis that the population around the Thetford mines is almost entirely pependent upon them for their " gagne-pain " , Cartier's second statement is, however, borne out by the case of Franchtnt and Canepa. It will be recalled that whereas the general view in Great Britain is (hat the symptomatic picture is more severe in asbestosis than in silicosis, the reverse view is held in America. The long period of absence of symptoms has been known for many years, but the diminution in vita! capacity is demonstrable even when the worker is perhaps unwilling to admit nny respiratory abnormality. As was pointed out over 20 years ago by Merev.cihcr and Priee (1930) and Mcrewether (1930). the vvoiker is inclined o attribute his ctscomforts tv) causes other than his work. A more normal case history is that given by Luton, Champeix and Faure (!95i) who describe what is stated to be the First case of asbestosis reported m France This was a man aged 62 years who, having worked for 11 years 009 in an asbestos cl air) complained Radiographically lobes until He dii kind, diffuse fibt bodies with mam Dust pnri.cles v No mention is n discour,; the post pulmonary tissue: W; have been a evidence in the ii than a verbal attr the fibroitc effect: sharp " insoluble King. Ciegg and theory of Gardne lungs of rabbits fibres. Gardner mentioned, with innocuous, big p. from those of silk Nevertheless. Kir of small (2-5 y) f fibrousmissue tet waffs Qlh hypei of giant-cell rcac easy enough to larger fibres (ii overlapped by a , fixed the asbesto: King, Clegg a somewhat acellu comparable to. i that the lung dot 1 In respect of : were insufflated, i wall and fail to case of Luton an | discharged into t I his co-w.orkers. : of the l.ver. kid: Summing up on the etTecis t 05 10.-99 1 6 : 3 0 FAX 1 4 1 0 4 4 8 2 3 6 8 Oil 333 _ INDUSTRIAL CARCINOGENESIS AND TOXICOLOGY inhalation, intratracheal insufflation, intravenously or intraperitoneally. Vorwald, Durkan and Pratt (1951) recall that ordinary industrial (asbestos) dust and, especially, long fibre asbestos dust from which the small fibres had been separated, produced characteristic peribronchiolar fibrosis which remained static on discontinuance of exposure, whereas to particles of .3 ;i and less there was no issue reaction (King. Clegg and Rae. 1946). --On substituting Bruciie (native magnesium hydroxide containing only 0-9 per cent silica as silicate--Brucite is a crystalline compound easily split irrfo thin sheets and has a flexibility comparable to ihtt of asbestos fibre), for the asbestos peribronchiolar fibrosis is similarly established, but dust of glass fibre which is not flexible and, of course, cannot be split does not, on long inhalation, lead to fibrosis. The dependence of the fibrosis on physical form was. however, settled by the failure to induce fibrosis by long inhalation of asbestos which, having been fused and ground, no longer retained its original structure. The Gardner school held that the combination of size, physical form and immobilization in a rhythmically moving organ is the determinant of the pathogenic effect. Effects somewhat similar to this pulmonary fibrosis can be obtained by injection of asbestos fibres into the peritoneum. * But at no stage in all these impressive researches was any clue obtained which might have offered any support to the possibility that asbestos could act as a carcinogen. There is no reliable criterion by which one can anticipate carcinogenicity and, as is well known, relatively minute changes in the structure of a chemical carcinogen are sufficient to diminish or eliminate carcinogenic action. If asbestos is indeed to be regarded as a carcinogen, the need is felt to demonstrate some property which can be regarded as something more than inertness. The simplest such property is solubility. Solubility confers some activity on a compound as, for example, in the case of silica, the solub'ffity of which in aqueous conditions is sufficient to found a chemical theory of silicosis. Asbestos has, however, not given much evidence of a solubility which might be significant. In analysing the working environment for asbestos dust Sundius and Bygden (1938) made the curious remark that only amphibole asbestos could be recognized in their analyses, in spite of the fact that the asbestos commonly used in industry contains mainly chrysolite and to a considerably lesser extent amphibole asbestos. This statement, if confirmed, might mean that chrysotilc is dissolved in the analytical process. In fact, chrysotilc is the least resistant of asbestos types to chemical and physical agcnls: it is decomposed by hydrochloric and sulphuric acids, it loses water at red heal and i fibres can be fused in the bunsen flame. (Crocidolile--blue asbestos--is also fusible to a. black magnetic glass but is resistant to chemical agents). Assuming that chrysotilc might be capable of exerting some chemical i effect by. to the asl have sorit structure experime bodies di Cooke made tht spicules.i soluble f salt, hav alveoli In rece in the el' that Cha the aetio' i .4 Electron The p i t the elect *-- the phot Cham Aik: 10 min Hon cautioi Dec. To t To < microof the fnciu! As re mlcrosc with th always I envelop I i impress fust forn Two no non the col mar.ipu it were Thcs .. D .J V r -.a n W T i i . O O ) r.................. ............................................ ' asuestos 2:3 lly. effect by virtue of these and perhaps other related properties, the mind turns os) to the asbestos body which, lying in the lung tissues Tor long periods, might res have some significance other than that usually attributed to them of being a ich structure in which the enclosed asbestos fibre can lie innocuous, In the 3 u experiments of Gardner and nis school the injection of isolated asbestos On bodies did not produce fibrotic reactions. But this need not deter us. Der Cooke (1930). who. with MacDonald, discovered the asbestosis body, 'to made the following comment: **they consist of central nuclei of asbestos the spicules upon which colloidal aggregates of blood proteins, plus, possiblj. ass soluble fractions of asbestos, and, in the case of chrysotile workers, iron mg salt, have been absorbed and moulded by currents in the bronchi and ' alveoli ", by In recent work Champeix and Bouieviile (1950) examined asbestosis bodies me in the electron microscope at magnifications of 25.000. It may be recalled that Champeix was associated with the view opposing a chemical factor in nd the aetiology of asbestosis (Luton and his colleagues). .he Electron microscopy The procedure io examine an object as delicate as an asbestosis body in ea the clearon ..microscope presents much difficulty, and the interpretation of lid ihe photographs obtained should be correspondingly cautious. He Champeix nr.d BouteviUe treated expectorated material as follows: he Alkaline digestion of the diluted sputum with NaOH (equal volumes). Afier He 10 minutes' warming in a porcelain dish, allowed to cool. Homogenized fluid divided among several centrifuge tubes and centrifuged cautiously to avoid disintegration of the asbestos bodies. to Decanted and residues spread on several slides. an 1 To examine in the optical microscope, mount in Canada balsam ne j To examine in the electron microscope the smear allowed to dry and with a ity i micro-manipulator a Single asbestosis body is lifted o n to the collodion membrane bf i of the object carrier. This operation is difficult and delicate anc the hazard of j fracture of the asbestos body is great.. cr, ! As regards the general morphology of the asbestosis body, the electron V j microscope confirms in greater detail and without deformation the findings nd j with the optical method--the central, needled fibre ( i-l ;i thick, length ild | always > 10 ;jl) surrounded by an amorphous, somewhat opaque rounded ily I envelope (2-3 a thick I in parts appearing as if burst and giving a general impression of a colloidal, proteinous gel: the extremities ovoid, ellipsoid, iat fusiform or sometimes angular. is-: Two observations suggested solution of the asbestos fibre: (1) there were ad no fibres less than 10 ^ in length in any asbestosis body; (2) removal of its the colloidal envelope of the asbestosis body by means of the micro- so manipulator shows the central fibre with one edge semi-transparent as if it were being dissolved away. , These facts lead the authors to some dubiety on whether the fibrosis is OS IO 99 1 6 : 3 0 FAX 1410- HS2368 224 INT>L'STRUL CARCINOGENESIS AND TOXICOLOGY due to a maintained mechanical irritation produced by the insoluble amphi- boie, o r to a chemical effect brought about by the dissolving silicate. It mas be recalled that Alden and Howell (1944) stated that.amosite needles are capable, here embedded in epithelial tissue in the skin, of eliciting.a non inflammatory epithelial proliferation. This statement was made from obser vations on amosite workers who developed hyperkeratotic epithelial thicken ing after penetration by a small splinter-like fibre X-ray examination and biopsy show no evidence of a foreign body in these " corns ". Solubility of asbestosis bodies More work is required on this problem especially quantitative studies of Ihe solubility of asbestos types in a variety of conditions, together vtith an identification of the products after solution. The question is not one of explaining fibrosis of the lung by a chemical process, for this is almost decisively negatived by the undoubted Tact that the smallest particles of asbestos have not in fact produced a fibrosis in the experience of most investigators. The question is rather one of finding a product of solution which, by entering the modified squamous epithelium of the lung, or by changing its environment, can lead to de-differemiation or to tumour for mation, The majority of pulmonary tumours in men arc anaplastic or undifferentiated or (epidermoid) squamous epitheliomata and they con stitute a type of new growth in the lung which has hitherto eluded the experimentalist. Probably the only claim to have induced a true cancer in the lungs of mice was that made by Nordmann and Sorgc (19*1) who exposed ICO mice to undefined asbestos dust and stated that 20 per cent of the animals developed cancer. There is considerable doubt, however, whether the evidence presented is really acceptable In fuel, cancer oT the lung Uruiy so called--not adenomas ns found and induced ir. rnicei has not hitherto been produced by inhalation of any material. W. E. Smith 11952) in a very forceful consideration of the exparimcma! aspects of cancer of the lung concludes " that we arc singularly illequipped for the experimental study of one of the chief problems of human cancer ", Until this charge is successfully answered we may lor practical purposes regard asbestos or a derivative of asbestos as a probable co-c;trcni<5gun in that proportion of cases of dill'use fibrosis of the lung in which the necessary preparedness of the lung has been brought about, probably endogenously Such a view has. at least, the merit of less sterility than the common panacea lor carcinogenic dilemmas, irritation. AROMATIC AMINES Ofthe lew identifiable chemical agents which may without doubt be accepted as standing in the line of causality of particular types of human neoplastic disease, certain aromatic ammo intermediates in the dyesuuVs industry occupy the most interesting and, from the point of view ofthe experimentalist, the most fruitful position. Not only have they been repeatedly reported in S O 13 every their work non puIrTi,f and . vital appa be el the v Th foun coos the l It stati a sir mar poss post befc Wfa, only exp; T the amt in t C doyre : the dye In fro 3ri me ren off bel ye; tui . M