Document 105BOJjg8JJJbknxZRO6NQgEa

FILE NAME: Celanese (CEL) DATE: 1958 DOC#: CEL053 DOCUMENT DESCRIPTION: Laubly Exhibit #6 - Medical Journal A ritish Med/cal bulletin ftS s 3 Causation o f Cancer INTRODUCTION Alexander Haddow CHEMICAL CARCINOGENS A N D THEIR MODES OF ACTION Alexander Haddow BIOLOGICAL EXAMINATION OF CARCINOGENIC SUBSTANCES E. Boyland IRREVERSIBLE CHANGES IN CHEMICAL CARCINOGENESIS J. W. O n IMMUNOLOGICAL BASIS OF CARCINOGENESIS H. N. Green ASPECTS OF ENDOCRINE CARCINOGENESIS F. Bielschowsky & E. S. Homing COCARCINOGENESIS M. H. Salomon AVIAN CARCINOGENESIS P. R. Peacock EXOGENOUS FACTORS'IN L U N G CANCER Sir Ernest Kennaway & A. J. Lindsey c a r c in o g e n ic it y OF m in e r a l OIL f r a c t io n s J. W. Cook, W. Carruthers &. D. L. Woodhouse OCCUPATIONAL CARCINOGENESIS M. W. Goldblatt AROMATIC AMINES AS CARCINOGENS IN INDUSTRY A. L. Walpole i M. H. C. Williams EXPERIMENTAL INDUCTION OF BLADDER TUMOURS Georgian/ M. Bonser, D. B. Clayson &J. W. Jtdl BIOCHEMISTRY OF BLADDER CANCER E. Boyland CHOLESTEROL CARCINOGENESIS L Hieger DYNAMIC ASPECTS OF CHEMICAL CARCINOGENESIS L. A. Ebon EXPERIMENTAL LIVER TUMOURS / . M. Bames &. R. Schoental r a d ia t io n a n d LEUKAEMIA IN MAN W. M. Court-Brown DEVELOPMENT OF LEUKAEMIA IN IRRADIATED ANIMALS R. H. Mole SKIN TUMOURS INDUCED BY RADIATION A. GUkksmann INDUCTION OF THYROID TUMOURS BY RADIATION I. Doniach DOSE-RESPONSE RELATIONSHIP IN RADIATION CARCINOGENESIS R. H. Mole b o o k R EV IEW S } L IB R A R Y VOLUME U HUMBER 2 M A Y 2953 ! JUN 16 1958 U . V^RjiTV ne re'*Q-Mi PRICE *LOO iBlishedby the-MedicalDepartment-The British Council-65 Davies Street- London-vr.i OCCUPATIONAL CARCINOGENESIS M. >V. Goldblatt OCCUPATIONAL CARCDs'OGENESIS! M. W. GOLDBLATT C.B.E. M.D. M.R.C.P. Institute of Cancer Research: Royal Cancer Hospital (at Pollards Wood Research Station Chal/onl St Giles, Bucks.) 1 Asbestos 2 Chromium 3 Nickel 4 Haematite 3 Coal and graphite Gas and coke 7 Pitch, tar, soot and mineral oil 8 Aromatic amines References Interest in this subject rests not only on the obvious implica tions for industrial hygiene and safety but also on the suspicion that there may be many more carcinogenic influences at work than are at present known or suspected, and that nonoeeupational cancer may also be related to some exogenous causes. Moreover, the recognition of occupational carcino gens must lead to fruitful experimental study not only to sustain the clinical or statistical contention but to seek some underlying unity among the diverse materials or their effects which can evoke the cellular neoplastic reaction. The agree ment that a particular material is an occupational carcinogen requires ideally that it shall be shown, by long collection and analysis of occupational and clinical data, that the incidence of the disease among those exposed to the suspected agent so far exceeds the incidence of its noo-occupational counterpart that there can be no reasonable doubt of the nature of the carcinogenic agent or its precursor, or of the process in which it resides. When, as is usually the case, it is necessary to build on retrospective data, death-certificates, befogged occupa tional histories, mobility of workers, multiple exposures, poor or no factory records and Inadequate information on past environmental conditions, the difficulties are much increased in reaching any clear conclusions. The present brief con sideration will be restricted to those materials which were more or less summarily discussed in volume 3 of Merewether's Industrial medicine and hygiene (Goldblatt & Goldblatt, 1956).1 1. Asbestos The peculiar association, ofi Carcinoma o f the itfng. with asbestosis, first presented*^ Merewether (1949) ancPiSnyne (1936, 1951) with strongly suggestive statistics, finds con firmation in the Annual Report of the Chief Inspector of Factories and Workshops for 1955. For the period 1924-55, 22% of 222 men and 12% of 143 women showed combined asbestosis and lung cancer, indicating a rising incidence of the association as compared with that reported in 1947 and in 1954. So high an association does not occur in silicosis (see Goldblatt Si Goldblatt, 1956; Gloyne, 1951; Meiklejohn, 1956). Werber (1952) states that carcinoma of the lung follows epithelial metaplasia in 7-17% of cases of asbestosis, with a latent period of 1j-20 years. Doll (1955) analysed the post mortem findings in 105 workers in a single large asbestos works, whose deaths occurred consecutively. Of these 75 had asbestosis, and of them 15 had associated lung cancer, whereas of the remaining 30 without asbestosis 3 had the tumour. All the 15 with asbestosis cancer had worked for periods of 9-23 years in the industry before 1933, when the 1931 Asbestos Industry Regulations became effective in the factory , but the association was not recorded in any person entering the industry for the first time between 1923 and 1953. In the mortality data of 113 men who had worked at least 20 years in the factory, Doll found 11 death-certificates with asbestosis and lung cancer, whereas there were none of lung cancer with out asbestosis. This incidence is some ten times that expected from the England and Wales mortality data for lung cancer. Observations published over 20 years ago in South Africa by the Miners' Phthisis Medical Bureau, cited by Doll (1953). showed that the incidence of primary lunc cancer in silicotic miners was 0.7%, for noo-silicotic miners 0.7% and for European male surface workers 0.9%. Agreement on the relation between asbestosis and lung cancer was reached at the international Symposium on the Endemiology of Lung Cancer (1953). Wyers (1949) reported the cell types to be oat cell, columnar and endothelial (pleura), the first two being the most frequgit. According to Hunter (1955) the carcinoma usually -appears many years after exposure to asbestos has ceased. This is not borne out by the data in Doll's paper, where the periods from last exposure to death in the 15 cases with the combined diseases are given as less than 1 year in 6 cases, 1 year tn 3, 3 years in 3, 8 years in 2 and 13 years in one. The induction time is probably very long, inasmuch as the tumours seem always to be of high malignancy, with only a short time between commencement of rumour process and death. As to cause and mechanism, Meiklejohn (1956) and Chiurco (1956) speak of irritant factors, whereas Bonser, Faulds &. Stewart (1955) suggest that the common factor in the exposure of the asbestos textile worker and the haematite miner (see section 4 below) is silica and that in both types of lung cancer the fibrosis precedes the malignant process. They conceive the fibrous asbestos (probably chrysotile) and the iron oxide as modifying the action of silica, or of the fibrotic process, so that silica acts more as a carcinogen and less as a fibrosing agent. No experimental evidence is available that asbestos in any form (small or large fibres) can act as a carcinogen, although peribronchiolar fibrosis has been demonstrated in rabbits by King, Clegg & Rae (1946) and others; but if the asbestos is fused and ground no fibrosis is induced even after Io d s in halation. Physical form and flexibility are evidently determin ants, since peribronchiolar fibrosis can be induced also by brucite which is a native, crystalline form of Mg(OH) and contains only some 0.9% SiO, as silicate (chrysotile contains over 40% SiO as silicate). It must be noted, also, that three of Doll's patients who had the first exposure after 1939 and total exposures of 2, 9 and 7 years, showed no asbestosis and died in 2, 12 and 11 years after the first exposure, from carcinoma of the lung. Knox &Beattie(1954a)would explain such cases as not having had sufficient time to develop asbestosis, and that the neo plastic change, induced by asbestos as such, by asbestosis 136 OCCUPATIONAL CARCINOGENESIS M . W. Goldblatt bodies or by some endogenous agents, including decomposi tion or solution products of asbcstosis bodies, may precede the changes necessary in the inhaled tt71TM"1 m inri'n-.asbestosis proper. In smother communication, Knox <t Beattie (1954b) confirmed Gloytse's view that with time the number and size of asbcstosis bodies and fibres in the lungs diminished, an opinion held previously by the pathologist M. J. Stewart of Leeds. Stewart regarded the fibres and asbestosis bodies as being gradually dissolved, the products inducing the lesions which survive the fibres. Evidence sup porting these views as to solubility was obtained with electron microscopy by Champeix & Bouteville (1950). Knox (1955) is, on the whole, of the opinion that the epithelial changes leading to carcinoma arise from: (i) chronic irritation leading to increased thickening and compression of the alveolar walls and (ii) subsequent slow disintegration of the asbestosis bodies with liberation of something which, acting on the already abnormal epithelium, induces malig nancy. The views of Chiurco (1956) apply here as elsewhere, to the effect that, in the interpretation of the occupational precancer and tumour states, it is very important to consider the soil prepared for cancer; the aetiology is multiple, syncarcinogenesis and cocarcinogenesis together with a whole constellation of factors, co-factors and co-causes; these bring about and favour a restless terrain, labile, unstable, dynamic, on which will develop cancerization by the release of factor X. 2. Chromium In the case of chromium we have an element of which particular compounds are either poisonous or induce chronic ulceration, dermatitis or caustic effects. Chrome holes, nasal septum perforation, chrome dermatitis and chrome burns are not followed by neoplastic change (cf. Legge. 1922). But from 1935 onwards. Continental and American observers presented evidence in support of a lung carcinogen in the chromate industry, in the manufacture of chrome pigments and in the use of zinc and lead chromates. Hueper (1942) thought that the true carcinogen was produced by the action of chromium on some endogenous materiaL A recent case of bronchogenic carcinoma in an Elektron1 polisher, described by Asang (1952), showed long retention of insoluble Cr compounds in the lungs (8-10 mg. Cr) even seven years after leaving the work. On the other hand. Miller (1956) states that only those exposed to the mists of water-soluble chromates (Cr4) develop lung tumours, but, of course, these must undergo reduction to be retained. In Britain, however, Sidstrup (1951) could find only one case of lung cancer (later fatal) in a radiographic survey of 724 workers in three chromate factories. In a later study of the 723 workers in the six years following the first survey, Bidstrup & Case (1955) found that, of 59 deaths, 12 had been certified as due to cancer of the lung. 9 to nrniouiSSgjpother sites and 38 as due to ^ th ^ p u s e a ; in addition l otherilungcancer death and 2 llyin|ppati6nis with lung ca n r were known but not included. Only the lung-cancer cases were found to be significant, being almost four times that expected, all statistically important factors having been allowed for. It is likely that the hazard will appear much higher than this with the passage of years as more and more workers die. * E lekvna m eul :s aa tlloy of M t tnuU u ao u flu o f AL Z x . Si xnd M a. T b * roctai o b icc u ir e diocwci in alk alin e d ic ir a tn a le ia pro d u ce coating; o f AJ chrorotic ana M t csromaie. As in aJi occupational cancers the latent or induction period is long, in this series 21 1 0 years; and the tumours may appear many years after exposure in the industry has ccascd. Nothing is known as to the active agent but it appears to the writer that it is likely to be a Privaient chromium com pound (Goldblatt & Goldblatt, 1956). 3. Nickel In a paper enumerating certain substances which* cause cancer in industry, Bonser et al. (1955) suggest that nickel may induce cancer of the respiratory tract, but add that the proof that the tumours are industrial in origin is doubtful, and that no experimental proof has been adduced. This is a surprising statement inasmuch as carcinoma of the mucous membranes of the nose and air sinuses, and bronchial carcinoma, are pre scribed diseases for the purposes of the National Insurance (Industrial Injuries) Act, 1946, and the nature of the occupa tion is given as decomposition of a gaseous nickel compound. Manifestly the framers of the prescription had Ni(CO)4in the Mond process in mind (see Amor, 1939), and left no doubt that they believed the condition to be industrial even if they did not indict nickel metal or even the carbonyl as such. The indictment was of an industrial process and it may be that Bonser and her co-workers imply that nickel, as such, is doubtful as the industrial cause. The problem is presented by Goldblatt Si Goldblatt (1956), and the two common Steories --the " arsenic theory" and the " metal theory"--are dis cussed. The "arsenic theory" (metallic arsenides) is out of favour because: (i) there is no collateral evidence of arsenical affec tions (dermatitis, skin cancer); (ii) other dusty industries in which sulphuric acid with a high A s,0, content has been used for many years are not prone to cases of ethmoid or lung cancer; (iii) heavy exposure to arsenical dusts sufficient to perforate the nasal septum does not induce such cases. Nevertheless Perry (1947) found a raised As content in the lungs, hair and urine of two nickel workers in whom extirpa tion of the lung had been successfully performed. The "metal theory" rests perhaps on stronger grounds and, inasmuch as cases of Ni(CO)4poisoning still occur, we cannot ignore the likelihood of deposition of nickel at susceptible points. Indeed. Hunter (1955) does not discard either nickel or the carbonyl as possible causes. For an account of the removal of nickel after exposure to Ni(CO),, see Barries & Denz (1951). Nickel is not an inert substance; dermatitis occurs fre quently following exposure to nickel. Calnan 4 Wells (1956) patch-tested hundreds of patients and found nickel to be the commonest specific skin sensitizer, nearly always in women (ear-rings, suspenders, spectacles, brassire fastenings, brace lets, eta). Once established, the sensitivity was usually main tained, and secondary spread was a feature. Schinz & Uehlinger (1941) and Hueper f1951, 1952) in duced tumours in highly artificial conditions, and Loken (1950) found three cases (two more later) cf bronchogenic carcinoma in men working cm electrolytic refining of nickel (no carbonyl involved) in a single factory; one lung, analysed eight yean after cessation of exposure, contained 1 mg./g. nickel It is, perhaps, significant that the nickel mineral used in most countries consists of a mixture of NiF:5, CuFeS, and Fe,S,, with small amounts of Au, Ag, and P*_ Cancer of the nose and ethmoid is a rare condition in the 137 OCCUPATIONAL CARCINOGENESIS M. W. Ooldblalt genera! population. The mean induction time of the occupa tional tumour is about 23 years. V'e suggest that the carcino gen enters the ethmoid sinus and tha t the rapid decomposition of the carbonyl in the tissues leads to the deposition of very finely divided nickel in the thin mucous membrane, which is very' closely applied to the bone. Retention would be accen tuated by any decree of stenosis at the fine orifices connecting the sinuses to the nasal meatus, say from slight oedema. It is significant that Loken makes no mention of nasal or ethmoid rumours in his five cases, a carbonyl process not being involved. Barnes Sc. Denz 0951) showed that rats exposed to Ni(C0)4 frequently develop severe and extensive "fibrosis of the lungs, a reaction evidently due to a sable deposition of nickel or a nickel-protein complex in the alveolar walls. Tee significance of the mild cases of N i(C 0)t intoxication in factories may become apparent in later years. 4. Haematite Faulds Sc. Stewart (1956) have found that, in the six-year period 1948-53, 15% of 89 consecutive necropsies ofhaem atite miners showed cancer of the lung, and that the tumours usually lay in the areas of fibrosis caused by sidero-silicosis; they consider that the latter condition predisposes to carcinoma of the lung. The view of Bonser et al. (1955), that a modifica tion of the action of SiO, by asbestos and by iron oxide may turn it into a carcinogen, recalls that Kennaway &. Kennaway (1947) found no evidence of an increased cancer-rate among orkers exposed to the risk of silicosis except in the case of netal-grindcrs. Turner & Martin (1949) confirmed this by finding that 60% of deaths from cancer in grinders with silicosis are due to cancer of the lung. It may also be recalled that Kettle (1932) found that a thin layer of iron oxide over quartz particles prevents the development of silicosis in animals. But Doll (1953) attributes any increased cancer hazard in grinders to " some other, and more specific, indus trial hazard" and not to silica. 5. Coal and Graphite Kennaway Sc. Kennaway (1953) found a lower incidence of lung cancer in coal-miners than in the general population, thus going further than Gooding (1946) who found no evidence of increased primary lung cancer in pneumocooiotie anthracite-miners. Moreover, it appeared that there was an almost inverse relation between the two conditions. James (1955) casts more light on some selected findings of Stocks (1952) that the relative incidences of lung cancer in the period 1946- 49 in the South Wales towns of Merthyr Tydfil (high coal-miner population), Cardiff and Swansea (few coal miners) were as 77 : 126 : 132, the lower incidence being main tained in the mining area even after correction for the largtn population and urbanization of the latter two towns. For 1947- 52 James found primaryflunj} cancer al necropsyrin 3.3% of 1.827 South Wales coal-miners and in 5.4% of 1,531 non-miners over the age of 21. In both series the frequencies of cell types and of metastases were of the same order. Where massive fibrosis and cancer were present in the same lungs, it was relatively unusual to find the two conditions near each other, which may suggest an anagonism between the canccrizing process and the tubercular process of progressive massive fibrosis (cf. the same thing in silicosis). Graphite pneumoconiosis according to Paxmeggianni (1950) is a relatively mild condition in spite of th: 11% SiO, in Italian graphite (56% C, 11 % SiO,. 8.6% A l,0,. 3% F e,0,), but the modified action of the silica does not appear to entail an increase in cancer. 6. Gas and Coke Kennaway Sc. Kennaway (1947) found that the certified deaths from cancer in gas-workers during 1921-38 exceeded the expected by 29-184 %. Doll (1952) examined the mortality data of 840 pensioners over 60 years of age from a single large London gas-company, who died in the period 1939-48. The expected deaths from lung cancer were 10.4 calculated from data for England and Wales, and 13.8 from estimated London data, whereas 25 were found {P less than 0.001 and 0.01 respectively). This is very significant. Sixteen of the 25 men had probably worked in contact with tar, 23 having been employed in the gas-works for 30 years or more. Doll found only 4 fatal cases of skin cancer as against 2.4 expected from rates for England and Wales; these seem few when we note that Fisher (1953), at a tar distillery in South London, found that 60-100 % of his men exposed to tar for 30 years or more showed varying degrees of skin changes. The great improvement in working conditions may now have removed the twofold hazard of lung cancer found by Doll (1952) in pensioned gas-workers. In the National-Coal Board's coking-plants Reid Sc. Buck (1956) could find iSL evidence among men dying between 1949 and 1954 to indicate an increased hazard of lung cancer to all categories of workers. This may be related to the newer retort designs and the less emphasis on cracking and illuminant production in both coalgas and coke processes. 7. Pitch, Tar, Soot and Mineral Oil In some sense the problem of industrial skin cancers has been resolved, inasmuch as the clinical incidence, signs, symptoms, treatment and prognosis are understood and ex perimentally one or more carcinogens have been isolated from soot, pitch and tar. The active agents in mineral oil have not been identified. Fatal cases still occur. In 1955, 211 cases (18 fatal) were notified to the Chief Inspector of Factories: 48 due to mineral oils and 163 to pitch and tar. A classical fatal case of chimney-sweep's scrotal cancer on the left side (see Henry, 1946)* was reported in the same year. Goulden & Tipler (1949) obtained from domestic soot the fluorescence equivalent of 290 mg./kg. of 3:4-benzopyrene. The cutting-oil formulations used in machine-shops vary according to the speed of the tools. For low speeds mineral, vegetable or animal oil (with addition of phosphorus, sulphur or chlorine compounds) suffices; but, for high speeds, oilwater emulsions containing surfaoe-active agents, rust in hibitors and disinfectants are used. Much oil is thrown off the machine and contaminates the workers. Cruickshank Sc. Squire (1950) found that about one-third of 138 workers in three factories had hyperkeratoses or warts, increasing with length of service, Cruiekshanle & Goursvitch (1952) found, of 37 cancers of the band and forearm (1941-50) and 34 can cers of the scrotum (1940-48) recorded in Birmingham, 30 derived from 88,859 mem-workers and 41 from the whole) remaining population of solme 271,000. Mastroraatteo (1955 found six cases of squamous carcinoma and one of wan in a1 1Sex ilia Henry, BrU. mtd. Bull W7, 4, 359,--Exj, 138 OCCUPATIONAL CARCINOGENESIS M. W. Goldblatt machine-shop in Canada, and Gilman & Vesselinovitcb (1955) confirmed this experimentally (cf. 3 landing, King, Priestley & Refiner, 1951) on mouse skigwith the soluble oil formulations which produced so much higher a response than that obtained by Woodhouse (1951, 1952) with mineral oil fractions that they cast suspicion on the additives in the formulations. Cruickshank & Squire (1950) found that rabbit sldn was more responsive than mouse sldn; and also Hieger & Woodhouse (1952), in vety careful experiments, showed conclu sively that rabbit skin is much more responsive to certain oil fractions and stated that . . it is unsatisfactory to exclude carcinogenicity on the basis of tests on mioe only". Berenblum & Schoental (1947) had come to similar conclusions with certain constituents of coal-tar. But Woodhouse (1951, 1952) found 9 : 10-dimethyl-l:2-benzanthracene more potent on mice than on rabbits. The great need is for quantitative analysis of mineral oils, but this, as stated by Hieger and Woodhouse, is an immensely difficult matter. 8. Aromatic Amines Goldblatt (1947, 1949) reviewed the problem of cases of occupational cancer of the bladder induced by aromatic amines and analysed 100 cases collected in two factories in the period 1934-47. Case and his co-workers (Case, 1953; Case, Hosker, McDonald & Pearson, 1954) made a statistical analysis of all death-certificates in England and Wales for 1921-50, in which tumour of the bladder was mentioned. From the data thus obtained the fallowing results emerged: Nominal roll of workers engaged in (i) manufacture, (ii) use or (iii) purification of one or more of aniline, 1-naphthylamine, 2-naphthyIamine and benzidine Expected number of death-certificates (cause: cancer of the bladder) in the three groups allowing for age and date of entry into the in d u s t r y ....................................... Number of eases of bladder tumour in the three g r o u p s ....................................... Number of these 341 cases which had con tact with one or more of 1-naphthylamine, 2-naphthylamine and benzidine Including aniline (4) and magenta (9) Number of these 311 who appeared in nominal roil, i.e,, worked in the industry for more than six months Number of death-certificates (cause: cancer of the bladder) among the 262 4,622 3-5 at least 341 298 311 262 127 Thus, the over-all risk of dying from bladder cancer in the manufacture of synthetic dyestuffs was about 30 times that in the general population. It was also concluded titat there was a definite, hazard 6'f bladder cancer in the maiiufacrare of auramine (a dipbenyimethane dyestuff) and of magenta (a triphenylmethane dyestuff). It may be recalled that the earliest cases of occupational bladder cancer described by Rehn (1895) were among workers in magenta manufacture. Case & Pearson (1954) found no evidence to suggest that the use or manufacture of aniline during 1910-52 has been a cause of bladder cancer. From Cast's analysis the number of fatal tumours already found among the manufacturing workers was 243 out of 2,466 during 1915-50, and the calculated forecast is that a further 243 fatal tumours will be found, even if no further exposure takes place. Scott & Williams (1957) have presented a valuable guide to practice in industries making or using bladder carcinogens. The substitution of Tobias acid (by amination of sulphonated 2-uaphthol) for the old method of first aminating the naphthol and then sulphonating the 2-naphthylamine, obviates the need for separation of the free amine, thus eliminating the cancer hazard, provided that conditions are such as to minimize the instability of the acid as well as the incomplete sulphonation of the naphthoL Benzidine; an undoubted carcinogen in men and animals, is closely related to the important intermediates o-tolidice, dianisidine and dichJorobenzidine, but these compounds are not carcinogenic. l-Naphthylamine, however made, contains 2-naphthylamine which probably constitutes its hazard. The jV-alkyl and N-aryl derivatives of the naphthyiamir.es axe not carcinogenic. Sulphonation of the bases eliminates carcino genicity. The making of naphthionic acid and its salts (l-naphthylamine-4-sulphooie acid) entails hazard because the amine is the starting material; the sulphonation is cot complete, thus leaving free l-naphtbylamiae and 2-naphthyl amine in the wash-waters and in the tar residues. Case & Hosker (1954) traced statistically that during 1936-- 1950 there appeared a marked increase in a large ntsfcof the rubber industry and associated it with the use in~thaf-period of a condensation product of the naphthylamines with metaldehyde, which, however, contained 2-5 % of unreacted bases. The material was at once withdrawn frem manufacture and use; but the potential of bladder tumours in exposed workers will require many years to discharge. Walpole, Williams & Roberts (1952, 1954) having shown that 4-aminodiphenyl was a potent bladder carcinogen in dogs, there followed the report of Melick, Escue, Naryka. Mezera & Wheeler (1955) that in an American factory where this compound was manufactured from 1935 till 1955, 11.1 % of 171 workers developed bladder tumours, the induction time varying from 5 to 19 years and the exposure times from 1-i ta 19 years. The rubber antioxidant made from this com pound by condensation with an aliphatic ketone does not appear to be a bladder carcinogen when fed for long periods to Jogs (personal communication from Dr E. R. Wheeler). For the control of amino compounds in the clothing and urme of workers, analytical methods have been given by Butt & Strafford (1956) and Glassman & Meigs (1951). For the early diagnosis of bladder tumours Crabbe (1952) and Cribbe, Cresdee, Scott & Williams (1956) have described the application, in the field, of the Papanicolaou technique and the results of the examination Sf 1,800 workers. O 63 men examined both by the cytological technique and by cystoscopy, the cytological procedure failed to anticipate the later cystoscopic findings in only 6; but of 23 men later found to be cystoscopically negative, 10 were reported positive by cytology. The detection of abnormal cells in the urine is greatly facilitated by the concentration method of Rofe (1955, 1957). Bonser, Clayson Sc lull (1951)3, using the method of Clayson (1950) for estimating 2-amino-l-naphthol conjugates, showed that the susceptibility of various species to the carcanogeaic action of naphthylamine {per on was direotiv * Sec --ED. Bonier. uil, p- 1*6 o r tiui suirrarr of ciui Builcua. 139 OCCUPATIONAL CARCINOGENESIS M. H'. Goldblatt ' I related to the fraction of the dose thus eliminated and in prepared solutions were much less effective in this respect. i f the following order:' rSbbit:r a t:mouse: dog as 1:2:4:5. Using lull's technique (1951) for implantation of paraffin Moreover, in the dog the urine-plasma concentration was pellets containing the base into the bladder of truce, Bonser, about 200. This difference is evidently a real characteristic, Bradshaw, Clayson 4 Jull (1956) induced carcinoma, benign for Henson, Somerville, Farquharson & Goldblatt (1954); tumours and squamous metaplasia, but to a much less extent Somerville, Henson, Cooke, Farquharson 4 Goldblatt (1956) than with the metabolite 2-amino-1-napbtbol. Similar results and Somerville, Henson Cooke and Goldblatt have injected were obtained with 4-aminodipbenyl. Tae authors conclude 2-[8-14C]oaphthylamine intraperitoneally in dog, rabbit, that both these bases possess slight carcinogenic activity; but guinea-pig, mouse and rat and found 87%. 86%, 114%. 80% see also Bonser, Crabbe, Jull 4 Pyrah (1954). With l-amino- and 65% respectively of the dose excreted in the mine but at 2-napbthoL a very high yield of tumours was obtained; different rates (paper in preparation). similarly with 3-hydroxy-4-aminodiphcnyl and its 4'-njtra Bonser, Clayson Jull Sc Pyrah (1956) showed that all their derivative. These findings strongly sustain the ortho-hydroxy- dogs that had been fed 2-naphthylamine (purified or very amine theory. However, some nitrogenous compounds in highly purified4 by Case's method of gradient sublimation) jected directly into the bladder may act as carcinogens, as for two years or more (max. cumulative dose, 310 g.) de was shown by Bonser, Clayson 4 Jull (1954) with 3 : 4-5 : 6- veloped bladder tumours. Arachis oil solution of 2-naph dibenzocarba2ole (.025% weekly for 12 months--transitional thylamine allowed to stand for four weeks and injected sub cell papillomatosis 2\ years later), and was first observed by cutaneously induced local sarcomata and hepaiomata; freshly skin-painting by Boyland 4 Brues (1937) and Boyland 4 Mawson (1938); sarcomata were produced by subcutaneous * Im purities commoJj' found in 2aat>bihylimiiie include l-tutphlfeylxmifie, pyTene, 3 : : `dtbeoxoetu'tjuale, 2 : 2*dHUp0ifcjrUmioes 1 ; .3 : &*lit>eixopbun o e (C u-e i P a r w a , 1922). injection, and sarcomata and cbolangiomata by intraperitoneal injection. Rjettrencts Amor, A. J. (1939) Bericht ber den VIII. intemasionaien Kongress fr Unfallmedirin und Berufskrankheiten. Frankfurt aM . 26. bis JO. September 1938. voL 2, p. 941. Thieme, Leipzig Annual Report of the Chief Inspector of Factories and Work shops for 1955 (1956) HMSO. London Asang, E. (1952) Zbl. Arbeitsmed. Arbeitsschutz, 2, 181 Barnes, J. M. 4, Dear, F. A. (1951) Brit. J. industr. Med. 8, 117 Berenblum. I. 8c Schoental, R. (1947) Brit. J. Cancer, 1, 157 Bidsirup, F. L. (1951) Brit. J. industr. Med, 8, 302 Bidstrup, P. L. 8c Case. R_ A. M. (1955) Brit.'J. industr. Med. 13, 260 Blanding, M. S., King, W. H., Priestley, W., jr 8c Rehner, J. (1951) Arch, industr. Hyg. 4, 335 Bonser, G. M,, Bradshaw, L., Clayson, D. B. 8cJull, J. W. (1956) Brit. J. Cancer, 10, 539 Bonser, G. M., Clayson, D. B. !c Jull, J. W. (1951) Lancet, 2, 286 Bonser, G. M., Clayson, D. B. 4 Jull, J. W. (1954) Nature, Land. 174, 879 Bonser, G. M.. Clayson, D. B,, Jull, J. W. & Pyrah, L. N. (1956) Brit. J. Cancer, 10, 533 Bonser, G. M,, Crabbe, J. G. S., Jull, J. W. & Pyrah, L. N. (1954) J. Path. Bact. 68, 561 Bonser, G. M., Faulds, J. S. 8c Stewart, M. J. (1955) Amer. J. din. Path. 2S, 126 Boylind, E 4 Brno, A. M. (1937) Proc. roy. Soc. B, 122, 429 Boyland, E 4 Mawson, E. H. (1938) Biachem. J. 32, 1460 Butt, 1_ T. & Strafford, N. (1956) J. appl. Chem. 6, 525 Calnan, C. D. it. Wells, G. C (1956) Bril. med. J. 1, 1265 Case, R. A. M. (1953) Bril. J. industr. Med. 10. 114 Case. R. A M. 4 Hosker, M. E. (1954) Brit. J. prey. sac. Med. 8, 39 Case. R. A. M.. Hosker, M. E., McDonald, D. B. &Pearson, J.T. (1954) Brit. J. industr. Med. 11, 75 Case, R. A. M. 4 Pearson. J. T. (1952) II' Congrs.International de Biochimie, Paris, 21-27 Juillet J9S2: ConferencesJet Rapports, p. 464 f : 'S Case, R. A. M. & Pearson. J. T. (1954) Brit. J. industr. Med. 11,213 Champeix, J. 4: Boutcvle, J. (1950) Arch. Mai. prof. 11, 607 Cniurco, G. A (1956) Prccanccrogenesi e turner! professional!, voL 2, p. 282. LN.AI.I_. Milan Clayson, D. B. (1950) Biochem. J. 47, 46 Crabbe, J. G. S. (1952) Brit. med. J. 2, 1072 Crabbe. J, G. S., Cresdec; W. C . Scott, T. S. 4 Williams, M. H. C. (1956) Brit. J. industr. Med. 13, 270 Cruickshank, C. N. D. 4 Gcurevuch, A (1952) Brit. S. industr. Med. 9, 74 Cruickshank, C. N. D. Sc Squire, J. R_ (1950) Brit. J. industr. Med. 7, 1 Doll, R. (1952) Brit. J. industr. Med. 9, 180 - Doll. R. (1953) Brit. med. J. 2, 521 - =L_ Doll, R. (1955) Brit. J. industr. Med. 12, 81 Faulds, J. S. 4 Stewart, M. J. (1956) J. Path. Bad. 72, 353 Fisher, R. E- W. (1953) AJrfui. Arch. Industr. Hyg. 7, 12 Gilman, J. P. W, 4 Vesselinovitch, S. D. (1955) Brit. J. industr. Med. 12, 244 Glassman. J. M. 4 Meigs, J. W. (1951) AM.A. Arch, industr. Hyg.4, 519 Gloyne, S. R. (1936) Tubercle, Land. 18, 100 Gloyne, S. R. (1951) Lancet, 1, 810 Goldblatt, M. W. (1947) Brit. med. Bull. 4, 405 Goldblatt, M. W. (1949) Brit. J. industr. Med. 6, 65 Goldblatt, M. W. & Goldblatt, J. (1956) In; Merewcther, E. R. A . cd. Industrial medicine and hygiene, voL 3. Butterwor-h, London Gooding, C. G. (1946) Lancet, 2, 891 Goulden, F. 4Tipler, M. M. (1949) Brit.J. Cancer, 3, 157 Henry, S. A (1946) Cancer of the scrotum in relation to occupa tion. Oxford University press, London Henson, A F., Somerville, A. R,, Farquharson, M. E. & Goid- blatt, M. W. (1954) Biochem. J. 58, 383 Hieger, I. 4 Woodhouse, D. L. (1952) Brit. J. Cancer. 6, 293 Hueper, W. C. (1942) Occupational tumours and allied diseases, Thomas, Springfield, IU. Hueper, W. C. (1951) Cancer Res. 11, 257 Hueper, W. C. (1952) Tex. Rep. Biol. Med. 10, 167 Hunter, D. (1955) The diseases of occupations. English Univer sities Press, London James, W. R. L. (1955) Brit. J. industr. Med. 12, 87 Jull, J. W. (1951) Brit. J. Cancer. 5, 328 Kennaway, E L. 4 Kcnnaway. N. M. (1947) Brit. J. Cancer. 1, 260 Kennaway, L L 1 Kennaway, N. M. (1953) Brit. J. Cancer, ", 10 Kettle, E. H. (932) J. Path. Bact. 35, 395 King. E. J., Clegg, J. W. & Rae, V. M, (1946) Thorax, 1, IS3 Knox, J. F. (1955) Lancet. I, 1275 [Letter] Knox, J. F, 4 Beattie, J. (1954a) AM xi. Arch, industr. Hyg. 10, 23 Knox, J. F. 4 Beattie, J. (1954b) AMui. Arch, industr. Hyg- 10, 30 Legge, T. (1922) Brit. med. J. 2, 1110 Laken, A C. (1950) Tidsskr. norske Laegeforen. 70, 3"$ Mastromaneo, E (1955) Brit. J. industr. Med. 12, 240 Meiklejohn, A (1956) In: Merewether, E. R. A., ed. Industrial medicine and hygiene, vol. 3. Butterworth, London Melick. W. F,, Escue, H. M., Naryka, J. J., Mearra, R_ A 4 Wheeler, E P. (1955) J. Urol. 74, 760 Continued e! foot of pege 14! ttauaittXW imniwiBi 140 AROMATIC AMINES AS CARCINOGENS IN INDUSTRY A. L. Walpole & M. H. C. Williams AROMATIC AMINES AS CARCINOGENS IN INDUSTRY A. L. WALPOLE Ph.D. B.Sc. Imperial Chemical Industries Limited (Pharmaceuticals Division) Alderley fork, Macclesfield, Cheshire M. H. C WILLIAMS B.M. M.R.C.P. Imperial Chemical Industries Limited ( Dyestuffs Division) Manchester 1 Dyestuffs industry 2 Other industries 3 Examination of new aromatic amines a Aminodiphenyl derivatives b AminostUbene derivatives 4 Conclusions References 1. Dyestuffs Industry The history of cancer as an occupational disease is closely linked with that of the manufacture of synthetic dyestuffs from coal-tar. This industry dates from Perkin's exploitation o f his discovery of mauve, accidentally made, in 1856, when he was trying to synthesize quinine (Perkin, 1856). The manu facture of triphenylmcthane dyes, which rapidly developed from this beginning, required for the first time the produc tion on a large scale of aromatic amines--aniline and the toluidines and xyUdines--from coal-tar. For a long time these amines were used for the manufacture of dyes as crude mixtures of variable composition, characterized only by the ranges of temperature over which they distilled. Their acute toxic effects on man were quickly appreciated as a result of unfortunate experiences, but chronic toxic effects were not expected. Nearly 40 years later, however, Rehn (1895) drew attention to the fact that four men whom he was treating for tumours of the urinary bladder all worked, in the same dyestuffs factory, and further inquiry revealed that they were ail employed in making the same dye, fuchsin (magenta). Rehn's suggestion that the tumours in these men were due to their environment was received with scepticism which increased as a further 60 years passed and no further tumours were attributed to the manufacture of this dyestuff in any country. But in 1954 Case <Sc Pearson published statistical evidence showing that there had been a significant excess of bladder tumours in Great Britain, during the previous 35 years, amongst men who made magenta. Tne facts established by these observations. 60 years apart, have not yet been ade quately explained, despite an abundance of theories. The suspicion has been entertained at one time or another that aniline can cause cancer of the bladder, which far many years was known in the industry as " aniline cancer ", and Hergt (personal communication) believed that some of the early cases in Germany could be attributed to toluidines; but there is no satisfactory evidence that any of the simpler aromatic amines already mentioned are, in fact, carcinogenic. Walpole, Williams & Roberts (1952) suggested that the early tumours in the German industry were due to contamination of these amines by naphthylamines and xenylamines, but such an explanation is scarcely applicable to tumours occurring in British workmen as late as 1920-53. It has also been suggested that Rehn's cases were exposed to other aromatic amines such as 2-naphthylamine and benzidine, which are nowjtngwn to be bladder carcinogens in man, but in the British factories in question these amines were not made or used. The possibility that magenta itself, a triphenylmetbane dyestuff, is carcino genic, has not been neglected. Yoshida, Schimauchi &. Kin (1941) claim to have obtained papilloma of the bladder in rats following intravesical implantation of the dyestuff in collodion, but WiUheim & Ivy (1953) saw no tumoun of any kind in rats to which it was given in the diet in high concentration, and in the experiments of Bonser, Clayson <5t Jull (1956) no sig nificant yield of tumours resulted in mice from repeated oral dosing. The sulphonated tripheoylmethane dye. Light Green SF Yellowish (Schiller, 1937; Hams, 1947), produces sarcoma at the site of its repeated subcutaneous injection in aqueous solution in rats. No distant tumours are produced, however, and when given by mouth the dye appears inactive (Aiimark. 1956). There is no evidence whatever that its manufacture is associated with any hazard to the workers involved. Two cases of bladder tumour were attributed by Mtiller tia 1933 to the manufacture of the dyestuffauramine, a derivativ c OCCUPATIONAL CARCINOGENESIS Continued from page 140 Merewether. E. R. A- (1949) Rep. Insp. Fact. Wksh., Land., 947. HMSO. London Miller, S. E. (1956) Proc. Amer. Cancer Sac., pp. 77--! 18 National Insurance (Industrial Injuries) Act, 1946. HMSO*London Faimeggnnni, L- (1950) Brit. J. industr. Med. 7, 42 Perry, K. M. A. (1947) Tnoras. 2, 91 Rehn, l_ H39J) Arch. klin. Chir. 50, 588 Reid, D. D. & Buck, C. (1956) Brit. J. industr. Med. 13, 265 Rofe, P. (9551 J. din. Path. 8, 25 Rofe. P. (1957) Brit. J. industr. Med. 14. 164 5chinz. H. R. & Uelingcr, E- (1941) Z. Krebsforsch. 52, 425 Scat!, T. S. & Williams, M. H. C. (1957) Brit. J. industr. Med. 14, 50 SomcrviUe. A. R_, Henson. A. F,, Cooke. E.. Farquharson. M. . & Goldblart, M. W. (1956) Biochtm. J. 63, 290 Stocks. P. (1952) Brit. J. Cancer, 6. 99 Symposium on the Endemiology of Lung Cancer (1953) Acta In . int. Cancr. 9, 443 Turner. H. M. Sc Martin, W. J. (1949) Brit. med. J. 2, 1148 Walpole, A. L., Williams. M. H. C c Roberts, D. C. (1952) Brit. J. industr. Med. 9, 255 Walpole, A. L-, Williams, M. H. C. & Roberts, D. C. (195--) Brit. J. industr. Med. 11, 105 Werber, M. (1952) Zbl. Acbeitsmed. Arbeitsschutz. 2. 1-9 Woodhouse, D. L. (1951) 29th Rep. Brit. Emp. Cancer Campr% p. 170 Woodhouse, D. I- (1952) 30th Rep. Brit. Emp. Career Ca.-r.pp-., p. 223 Wycrs, H. 1949) Post Grad. med. J. 25, 631 141 AROMATIC AMINES AS CARCINOGENS IN INDUSTRY A. L. Walpole & M. H. C. Williams liphenylmethane. Tnis manufacture as incriminated on statistical grounds by Case & Pearson in 1954. They described eight more cases, in Great Bntala^Attnbutable to this cause. Bonser et al. (1956) produced a few hepatomata in mice with a commercial sample of the dyestuff given in the diet, but all the chemicals involved in its manufacture have not been fully investigated and a conclusive explanation for the bladder tumours in workmen making this dyestuff has not yet been reached. Tbe discovery by Griess of diazotization in 1858 and of the coupling of diazonium salts in 1864 led to the development of a new class of coal-tar dyestuffs, the azo dyes, for which new aromatic bases, including the naphthylamines and benzidine, were required as intermediates. Occupational cancer of the bladder was first attributed to naphthylamine at the turn of the century (Leichtenstern, 1898). 2-Napbthylamine was accepted as a cause, on epidemiological evidence, shortly after the First World War (International Labour Office, 1921) and 16 years before bladder tumours were in duced with it in dogs (Hueper & Wolfe, 1937; Hueper, Wiley & Wolfe, 1938). Although no experimental evidence is available to mcriminate 1-naphthylamine, Case, Hosker, McDonald & Pearson (1954) presented evidence of a signifi cant excess of bladder rumours amongst both users and makers of the commercial product, which contains 4 of 2-naphthylamine, 23 years after cases were first attributed to it by WignaU (1929). Benzidine, which bas been under suspicion since the I920's, as not accepted as a cause by the Americans Gehrmann, tiger &. Fleming as late as 1949, despite the attribution to j f numerous cases by workers in different countries. For many years, Maguigan in the USA maintained that benzidine was a cause of bladder cancer in industrial workers, and in 1950 Spitz, Maguigan &. Do brine: demonstrated its carcino genicity in rats and dogs. Case et al. (1954), in their survey of the British chemical industry already referred to, obtained statistical evidence that a high incidence of bladder tumours had developed in men exposed to benzidine, and so replaced suspicion by statistical proof. Suspicion that azo dyes themselves might be carcinogenic was aroused by early work by Fischer (1906) on scarlet red. Intensive study of the subject was initiated by Japanese workers in the early 1930 s and taken up later by others, including Orr, Kirby and Peacock in Great Britain, and Shear and more recently the Millers in the USA, o-Aminoazololuer.e was found to be a potent liver carcinogen in rats and mice, and to produce bladder tumours in rats. 4-Dimethylaminoazobenzene (butter yellow) was found to be even more active in inducing liver tumours. Numerous related azo compounds have since been examined and many of these produce neoplasms, particularly of the liver, in rats and mice. Work in this connexion has often been reviewed (Miller & Miller, 1953, 1955; see also Miller, Miller & Finger. 1957), and will not be discussed further here. Bladder rumours have been produced in dogs with o-amincazoioluene and butter yellow (Nelson L Woodard, 1953) but there is as yet do pub lished evidence that any azo compound has caused cancer in man. 2. Other Industries A'Lisoc, De Eds &. Cox in 1941 made a toxicological study of 2-acetamidofiuorene, which was of interest on account of its insecticidal properties. They found that on continued oral administration to rats it produced tumours of several organs, notably the bladder, liver and lungs. As a result the compound has never been manufactured on a scale sufficient for its carcinogenic action to become an industrial hazard. Its versatility as a carcinogen was confirmed by later work, reviewed by Bielschowsky in 1947. More recently Morris & Eyestone (1953) have obtained bladder tumours with it in dogs. Its action and that of numerous related substances have been widely studied, especially during recent years by the Millers and their associates in Madison, Wisconsin, and by Morris and his co-workers in Bethesda, Maryland (Miller, Sandin, Miller & Rusch, 1955; Miller Si Miller, 1955; Morris, 1955). Interest in 4-aminodiphenyl (xenylamine) as a potential carcinogen was first stimulated by learning from the literature that it bad been isolated by Hofmann in 1862 from the crude mixture of bases derived from coal-tar which was an inter mediate stage in the manufacture of triphenylmethane dyes (Walpole el al. 1952), and also by the demonstration of carcinogenic activity in the related substances ATv'-dimethyl- 4-aminodiphenyl (Miller, Miller, Sandin &. Brown, 1949) and benzidine (Spitz et al. 1950). As 4-aminodipheny! pro-, ducsd a variety of tumours in rats (1952) and bladder tumours in dogs (1954), Walpole, Williams i Roberts fore cast that bladder tumours would develop in men exposed to it. Melick, Escue, Naryka, Mezera & Wheeler (1955; f a u n f bladder tumours in 19 men engaged in its manufacture in the USA since 1938. Thus it had taken 17 years for this amine to manifest its carcinogenic potential and during that time 171 men bad been exposed to risk. It will be many years before tbe full extent of the damage caused by this manufacture, now abandoned, will be known. In Great Britain manufacture of 4-ami nodiphenyl was never started, because of the experi mental evidence quoted. One of the uses of 4-aminodiphenyl in the USA was in the manufacture of an antioxidant for rubber (Case, 1954). A similar condensate, prepared from naphthylamine and an aldehyde, was marketed in Great Britain as a rubber anti oxidant as early as 1927. Its manufacture was abandoned in 1949 when the danger from free naphthylamines in the final product became apparent. Case & Hosker (1954) demon strated an excess of cases of bladder tumours in rubber workers in a county borough where this naphthylamine alde hyde condensate had been used for many years. The fate of American rubber workers exposed from 1938 to 1955 to the xenylamine condensate is no doubt being followed with concern. While considering rubber workers it is well to remember that the use of benzidine as a hardening agent is still advocated in text-books of rubber technology, Such a use must be regarded as hazardous. Both benzidine and 1-naphthylamine have also been extensively used in textile printing. Although no tumours have been attributed to their use in this industry it would seem advisable to handle them there with precautions similar to those in the chemical industry.' Benzidine has been used for many yean in the manufacture o f " security paper " to produce a stain in the presence of bleach and thus to expose attempts to delete and alter writing (Simons. 1951). It is expected that this use of the compound will produce its quota of tumours. The suggested use for this purpose of other carcinogens, including naphthylamines and aminodiphenyls (Simons. 1937) and 4 : 4 '-diamiDOsiilbcne (Smith, 193*), 1 See Use C o ta b u it. p. 136 o r lim ouraber of U\c Buileun.--*d. 142 AROMATIC AMINES AS CARCINOGENS IN INDUSTRY A. L. Walpole & M. H. C. Williams which produces a high incidence of liver tumours in rats (Walpole &. Williams, unpublished), must also be regarded as hazardous. __ The human exposure involved in using benzidine in clinical and forensic laboratories as a test agent for occult blood is probably insignificant, but its use for spraying chromatograms in biochemical laboratories must be regarded as potentially hazardous. Many other carcinogenic aromatic amines already exist, and it is inevitable that technologists will look for new amines to produce improved products and unique technical effects. 3. Examination of New Aromatic Amines With the object of learning more about the effects of ring substitution on the carcinogenic properties of amines known to be active in this respect, we have examined a number of substituted aminodiphenyls, diaminodiphenyls, aminostilbenes and diaminostilbenes. The results will be published in detail elsewhere, and we give only a summary of the more significant of the findings. a. Aminodiphenyl Derivatives Table I relates to derivatives of the 4-aminodiphenyl series. In the first instance these compounds were given by repeated subcutaneous injection in arachis oil. at doses near the maximum tolerated, to groups of 34 male albino Wlstar rats. For each are shown in Table I the total dose in g..kg. and the main sices of tumour incidence in descending order of frequency. Sarcomata at the injection site, which developed late in the experiments with several of these substances, are probably to be attributed to the oily vehicle and are not included. Consideration of the detailed results of these experiments in rats leads to the conclusion that the introduction of a methyl group into the 3-position in 4-aminodiphenyl, with or without methyl groups in other positions, enhances carcinogenic efficacy, especially for the intestine. Methyl substitution in the 2-position, on the other hand, results in a compound which produces liver tumours only, and these in relatively low yield, while 4'-methyI-4-aminodiphenyl, in very large doses, causes tumours of the acoustic sebaceous gland, intestine and liver in descending order of frequency. The results obtained with 4'-fluoro-t-aminodipheny], which produces tumours of the liver and kidney in high yield (Hendry, Matthews, Walpole & Williams, 1955V, and with its chloro- and bromo-analogues, are in line with the observa tions of other workers who have fed to rats derivatives of 2-acetamidofiuorene halogeaated in the 7-position. Thus 7-fiuoro-2-aceomidofiuorene is more active as a carcinogen than acetamidofluorene itself (Miller el al. 1955), while the corresponding chloro-compound is less active and the iododerivative appears inactive at any site (Morris, 1955). Even in the butter-yellow series of liver carcinogens, substitution of fluorine, chlorine and bromine in the 4'-position has similar over-all effects upon carcinogenic potency (Miller. Miller 3c Finger, 1953; Miller, Sapp & Miller, 1949; Kuhn <5:Quadbeck, 1949). The activity of 3-methoxy-4-aminodipheoyl in producing bladder tumours recalls a similar result obtained by Hackraann (1956) on feeding 2-arruno-3-mcthoxydipbenylene oxide to rats. *See Mtrtiacwr W*lpou(1953) B ril. J . Cancer, 12(la prtaa) TABLE t. TUMOURS PRODUCED IN RATS BY THE REPEATED SUBCUTANEOUS INJECTION OF 4-AMINODIPHENYL AND SOME DERIVATIVES THEREOF Compound ToiaJ aoe 'j/nt'j Qrjins mwhicn umoun vote m sifnmcut yiid O O *- CH, CK> CH, O ^ C / NH' s.o Intestines, liver 1.2 Intestines, acoust-c sebaceous gianc 2.4 Liver ch '0 ~ 0 n h * CH, CH, O O **- CH, CH, OO CH, CH, CH, CH, CH, ch, < ^ V ^ 2 > nh: 10.1 Acoustic sebaceous gland. mtesune,. liver 2.8 Intestines, acoustic, seoacecus -yar.jjT^ 14 Intestines, acoustic sebaceous gland 1.4 Intestines, liver 1.4 Intestines, liver 0 - 0 "*O O ** O O "' 10 Kidney, liver, intestines 3.3 No significant yield at 700 days 4.1 No significant yield at 800 days O O h* 7.0 Intestines OCH, OO' 4.4 Bladder The derivatives of 2-aminodipheay!ene oxide (aminodibenzofuran), and those of 2-aminofluoreae, constitute two series cf compounds which may be regarded as derived from the corre sponding substitution products of 4-aminodipheayl by the 143 AROMATIC A M IKES AS CARCINOGENS IN INDUSTRY A. L. Walpole M. H. C. Williams 'ABLE II. TUMOURS PRODUCED IN RATS BY THE REPEATED SUBCUTANEOUS INJECTION OF 4-AMINOSTILBENE A+W--SOME DERIVATIVES THEREOF CombouAd i oxii dote i|.Aj ) tOurmg ionui lmarwtwneicmn <itnif>c*m yieid 0.2 Acoustic sebace ous gland (vari able yield of load sarcomata) 0.2 Local sarcomata only (less than 190 days) CH, < ^ ^ - C H = :C r ! --- ^ J J iN K , OCH, 0 -o ta C H - 0 NM' / \ --CH- CM-- H. 0.2 Local sarcomata only (less snan 2C0 days) 0.2-1 Local sarcomata only (less than 230 days) 0.23 Local sarcomata only (3C2-423 days) 0.2 Acoustic sebace ous gland, liver, intestines insertion of an --O-- or --CH:-- bridge in the 2 :2 '-position. Carcinogenic activity in these series, and in others with differ ent bridging atoms or groups, has been investigated and kept under review, on a comparative basis, by the Millers and thesr associates (set their publications from 955 onwards). b. Aminostilbene Derivatives In view of their possible future use in industry, we have carried out similar tests with analogous substitution products in the 4-aminostilbene series. Haddow, Harris, Kon &. Roe (1948) obtained local sarcomata at the site of subcutaneous injection, carcinomata of the "acoustic duct " and mammary adenomata in rats with 4-aminostilbene, A-JVA'-dimethylaminostilbene, 4-A'A'-dimethylamino-2'-methylstilbene and l-(4'.AW-dimethy|aminophenyl)-2-(r-naphthyl)-ethylene. In our experiments 4-aminostilbene and its substitution products were given to male rats by repeated subcutaneous injection in arachis oil (daily or twice weekly) up to a total in aU cases of about 0.2 g./kg. The results shown in Table II may be sum marized as follows. 4-Aminostiibene itself produced a high yield of carcinomata of the acoustic sebaceous gland (after 175-643 days), with local sarcomata in a yield which appears to depend in some way on the precise schedule of dosing. Vith 3-methyl-, 3-chioro- and 2-methyl-4-aminostilbene, local sarcomata only were observed. These tumours appeared in almost every animal treated and all arose between 150 and 250 days after injection. These rumours must be attributed to the specific action of the respective compound and no: to the oily vehicle used for its injection. In one feeding experi ment with 3-methyl-4-amioostilbene (average total dose 0.35 gwTtg.), two of four animals surviving for 190 days or more developed tumours of the acoustic sebaceous gland. The injection of 3-methoxy-4-aminostilbene produced local sarco mata in 18 of 24 animals, but these tumours appeared much later (302-625 days). 4-Amino-4'-fluorostilbcne gave the same high yield of tumours of the acoustic sebaceous gland as 4-aminostilbene itself and produced rumours of the liver and intestine in significant yield but no local sarcomata. Fewer compounds in the 4 : 4'-diaminostilbene series were tested. We have shown that the parent diamine, in a total dose of 0.2 g./kg., produces tumours of the liver, with some late local sarcomata. On the other hand 4:4'-diamino-3:3'dichlorostilbene, in comparable dose, produced only local sarcomata. These occurred in all but ddc of 24 animals in 200-400 days. 4 :4 '-Diamino-2.'2'-dichlorostilbene was less toxic and, given in a total dose of 1.4 g./kg., yielded liver tumours in 18 of 24 animals, a few tumours of the intestine and local sarcomata. The interpretation of these results, and in particular the explanation of the differences in the site of action of these related chemicals, must await further experiment. In the meantime they show that carcinogenic activity in somcfopsi is a property common to many derivatives of 4-aminodipheiyt and - : 4'*diaminodiphenyl and of 4-aminostilbene and 4 : 4'diaminostilbene. 4. Conclusions The history of occupational cancer of the bladder shows that many years may elapse before the danger from an in dustrial carcinogen is recognized or even suspected. Sixty years of scepticism passed before Rehn's original indictment of fuchsin manufacture in Germany was confirmed in Great Britain; 23 years elapsed between the attribution of the first case to naphlhylamine and the general recognition of the hazard from 2-naphthylamine; for over 30 years benzidine was under suspicion before it was universally accepied as a bladder carcinogen in man; 25 years passed before bladder tumours were discovered in rubber workers exposed io naphthylamine-aldehyde condensates in Great Britain and, as a more recent example. 4-aminadipheny! had been manufac tured in the USA for over 17 years before the danger involved was pointed out. Every year that inadequate precautionary measures are taken, the final yield of bladder tumours increases. Tr.e chemical Industry has taken active measures to combat this danger. The manufacture of 2-naphthylamine has been abandoned in Germany, Switzerland and Great Britain, and rubber antioxidants from 1- and 2-naphthylamine are no longer made in Britain. The publication by the Association of British Chemical Manufacturers of a code of practice for the handling or known bladder carcinogens (Scott & Williams, 1957) has laid down a standard to be aimed at in achieving safe working conditions. If all these measures are successful, the future yield of tumours due to known carcinogens in the dyestuffs industry should fall rapidly in the next 20 years, bu: the casual use of these dangerous substances in other industries must be a matter for concern. We present the summarized results of our tests cf amices and diamioes as a guide to chemists and technologists who may contemplate using them in the future. In this way we 144 AROMATIC AMINES AS CARCINOGENS IN IN D USTR Y A. L. Walpole '.W. H. C. Williams hope to anticipate seme of the dangers from compounds of this nature and thus prevent a recurrence of the unfortunate experiences of the past. ACKNOW1XDG EMENT We wish to thar.k Mrs P. A. Braid for her considerable lechr.ical assistance in the laboratory. RSFSSNCES AJIrr.ark, M. G. (1956) I. Pharm.. Land. 8, 417 Bicischowsky. F. (1947) Bril. med. Bull. 4. 382 Bonser. G. M.. C.ayson, D. B. iJu ll, J. W. (1956) Brit.J. Cancer, 10,653 Case, R. A. M. (1954) Brit. med. J. 2, 50 Case. R. A. M. Kosker, M. E- (195a) Brit. /, arev. soc. Med. 8. 39 Case. R. A. M., Hosker. M. E,, McDonald, D. B. <5t Pearson. 3. T. (1954) Brit. J. indiare. Med. 11, 75 Case. R. A. M. it Pearson, 1. T. (1954) Brit.J. industr. Med. 11, 213 Fischer. B. (1906) Mnch, med. Wschr. S3, 2041 Gehrmann, G. H.. Foulgcr, J. H. St Fleming. A. J. (1949) The Proceedings o f the Sinih International Congress on Industrial Medicine, London, ldth-17th September, 1948, p. 473. Wright. Bristol Gricss, P. (1853) Liebigs Ann. J06, 123 Griess, P. (18641 Phil. Trans. 153, 679 Hackmann, C. (19561 Z. Krebsforsch. 61, 45 Haddow. A.. Harris. R. J., Kon. G. A. R. it Roe, E. M. F. (1948) Phil. Trans. 241. 147 Harris, P. N. (1947) Cancer Res. 7. 35 Hendrv. J. A.. Matthews. J. J.. Walpole, A. L. St Williams, M. H. C. (1955) Nature. Load. 175. 1131 Hofmann. A. W. 1lgAZl C. R. Acad. Sci., Paris, 55. 901 Hueper, W. C., Wiley, F. H. it Wolfe, H. D. (1938) J. industr. H v g . 20.46 Hueper. W. C. it Wolfe. H. D. (1937) Amer. J. Path. 13. 656 International Labour Office (1921) Cancer of the bladder among workers in aniline factories (Studies and Reports, Series F, No. 1) International Labour Office, Geneva Kuhn. R. it Quadbeck. G. (1949) Z. Krebsforsch. 56, 242 Leichtenstem. O. (1898) Dtsch. med. Wschr. 24. 709 Melick. W. F.. Escue. H. M.. Naryka. J. J., Meaera, R. A. & Wheeler. E. P. (1955) J. Urol. 74. 760 Miller. E. C. St Miller. 3. A. (1955) J. net. Cancer Inst. 15. 1571 Miller. E. C . Miller. J. A.. Sandin. R. B. it Brown. R. K. (1949) Cancer Res. 9, 504 Miller, J. A. S t Miller, E. C. (1953) Advane. Cancer Res. 1, 339 Miller. J. A., Miller. E. C. it Finger, G. C. (1953) Cancer Re;. 13. 93 Miller. }. A.. Mler, E. C. it Finger, G. C. (1957) Cancer Res. 17. 387 Miller, J. A.. Sandin. R. B.. Miller. E. C. St Rusch. H. P. (955) Cancer Res. 15, 188 Miller, J. A.. Sapp, W. R. it Miller, E. C. (1949) Cancer Res. 9. 652 Moms, H. P. (1955) J. net. Cancer Inst. 15, 1535 Morris. H. P. it Eyestone, W. H. (1953) J. not. Cancer Inst. 13, 1139 Muller, A. (1933) Z. urol. Chir. 36. 202 Nelson. A. A. it Woodard, G. (1953) J. nat. Cancer Inst. 13, 1497 Perkin. W. H. (1856) British Patent No. 1984 Rehn. L. (1895) Arch. klin. Chir. 30, 588 Schiller. W. (1937) Amer.J. Cancer. 31. 486 Scott, T. 5. it Williams. M. H. C. (1957) Brit. J. industr. Med. 14. 150 Simons. F. L. (1937) U.S. Patent 2.085,675 Simons. F. L. (1951) TAPPI. vol. 34. No. 10, p. 113A* Smith. B. W. (1937) U.S. Patent 1073.764 Spitz. S., Maguigan. W. H. & Dobriner, K. (1950) Cancer, if. Y. 3. 789 r F Walpole. A. L.. Williams. M. H. C. it Roberts. D. C. (19) Brit. J. industr. Med. 9, 255 Walpole, A. L.. Williams. M. H. C. it Roberts, D. C. (954) Bril. J. industr. Med. 11, 105 Wignail. T. H. (1929) Brit. med. J. 1 258 Wiltheim. R. St Ivy. A. C. (1953) Gastroenterology, 23. I Wilson, R. H.. De Eds, F. <5t Cox, A. J., jr (1941) Cancer Res. 1. 595 Yoshida, T., Schimauchi. M. it Kin, C. (1941) Gann, 35, 272 Publication o f: Technical A uociatioa o f lbs Pulp and Piper Industry. S12 East 4Znd Street, New York 145 Notes on Contributors Da J. M. BaanXj hat beeo D irector o f the Medical Research Council'i Toxicology Research Unit since iu inccpuon in 194?. The w oi4 irf ibe U nit is devoted to a detailed study of the mode of action of c*rujjt toxic tu h s u n c a tuch find * use tn wduxtry or agriculture. Much of Dr Barnes'i expenmeataJ work hat been cancerar with the toxic action of insect!odes and he u author of s World H ealth Organizanoo monograph on \hu ubjtxi entitled "T oxic ha zards o f certain pesticides to man. to gether with a select bibliography on the toxicology of pesticides io man and mammals'* {1953. M onofr. Ser. N o. 16). H u other interests relate to the design o f suitable tests for as.'cssing the toxic properties of new material!. D r Barnes has previously contri bultd to Brttijh Medical Bulletin a paper entitled "H ealth hazards from in*ecuddea*' (Brit. med. Bull. 1930. 7 , 2J). D a F. BituCHQtvsxY ras Privatdoxent at the Uni versity of Freiburg and lecturer on metabolic diseases in M adrid before coming to Bn tain. He worked from 1935 until 1948 in the Departm ent o f Pathology o f the University of Sheffield. After colla berating wuh Professor H. N. Green m an investigation o f the mode of action o f sulpbaniiana'd*, he began in 1942 to work on problems o f canter, studying the action and the metabolism of arom atic amines. His earlier work dealt with problems o f the metabolism of nucleic adds and o f lipids. D r BicUchowiky has since 194J been D irector o f the Cancer Research Department o f the Medical School. University of Otago, Dunedin, New Zealand, and o r the New Zealand branch o f the British Empire Cancer Cam paign. During the Iasi ten yean he has studied the endocrinological aspects o f cancer (see Brit. J. Cancer, ]95*. 9, BO). D r Bielschowaky has pre viously contributed to (he Bulletin a paper on the cxreinogetuc acod o f S-acetyUminofluorcnc and related compounds <Bru. med. Bull. 1947, 4. 382). D a C . M. Bo.vst* is Reader in Cancer Research in the University o f Lcedi and Consultant in M orbid A natom }. St James's Hospital. Leeds. She has bean engaged in cancer research for thirty years, wofksng first on intra-thoracie cancer and later on the hor monal and genetic aspects of mammary and testicular cancer. During the last twcnty.five years, she and her colleagues have undertaken a combined bio* logic! and chemical im estigation of the metabolism asid carcinogenic properties c f aromatic amines, especially of those reted to the dye intermediates. Her publications include: " A microscopical study of the evolution of mouse mammary cxnerr: the effect of the milk factor and a comparison with the human dis ease" (.'. Path. Bar:. 1945. ST, 4 |J ) ; with E. C. Armstrong. "T he carcinogenic action of 2-acetylammo-ftuorene on vinous strains of mice" (/. Path. Baet. 194?. 59, 19): and. with L. Bradshaw, D. B. Clayson L. J. W. Jull. "A further study o f the carcinogenic properties of ortho hydros}.amines and related compound! b> bladder implantation in Ibe mouse" (Bnt. J. Cancer. 1936. 10. 339). D r Bonier contributed a paper to an earlier Dumber o f the Bulletin, on experimental eancer of the bladder [Bril. med. Bull. 1947. 4. 279). P x o rm a a E. Boylavd is Professor of Biochemistry ir. the University o f L oados at the Chester Bcatry Research Institute. Royal Cancer Hospital, where be has worked (except for the war yean) since 1931. He bas earned out work on ihe mtcabolisra o f aro mane compounds, the chemotherapy o f cancer, the metabolism of tumours, and in (he field of carcino genesis. In work on metabolism of aromatic compounds he discovered tbc metabolic proems of perbydroxyliuoa (e.g.. "The conversion o f anthracene to l . 2*dibydroj:y.: : I-dihydroaathrxcene" (Boyiand L Levi. Bttxhem. J. 1935. 29. 2679): "The nature of the acid-labile mereapmric acid precursor ex a cted whea arucuis are treated with Biphihlene"(BcylaQd &. Sims. Btochem. J. 193$. 61. 440)1. Professor BoyUod has also idratified 15 meCaboUtcs o f the CArcusogemc 2-napbkbyUisunefef. Boyland it M anson. B lockem .J. 1957, 67, 273). Id the field o f caraoogtocaji be demoncstTBLed the eam nogttue activity o f dibeaxcarbxxohss (Boyland L Braes, Proc. ray. S a c . B, 1937, 121, 429), abrogea mustards fBoyland it H orning. Brit. J. Cancer, 1949. 3, 1II), aad o f the tryptophan m etabolite 3-bydroxyxmhraaic ad d (Allen. Boyland. Dukes, Homing Watson, B r .J. Cancer. 1957, H , 212). During the war Professor Boylaod worked for the Ministry f Supply on problems o f Chemical warfare and for the Ministry o f Agriculture oa atumal diseases. He nsceivrd the Judd Award for Cancer R esearch in New York in 1941 and the tntdaJ o f the Socit de Chimie Biologique in 1956. Before s ta rt ing paacer research be srudied in the D epartm ent o f Physiology o f the University o f M anchester, the Lister Institute for Preventive Medicine ta London, and the Kaiser WObelm Institut fur m tdm aiscbe Forschung in Heidelberg. At present he is working o s the causes o f cancer o f the bladder, in u s line, Jong and cervix, on the treatment of o n c e r of the bladder and breast, and on the metabolism o f arom atic com pounds. and be is interested tn carcinogenic hazards, particularly in foods, contraceptives, tobacco and cosmetics. Professor Borland contributed a paper, together wuh Dr F. Wejgen. to an earlier number of the Bulletin, entitled " Metabolism o f carcinogenic com pounds" (Brit. med. Bull. 1947, 4, 354). D W, CAXAITKras graduated as Ph.D. in chemistry at the U nivenity or Glasgow in 1949. then took up an ppomtnrcnl with the Medical Research Council at Glasgow to investigate ihe chetaiitry o f high-bo Bins carcinogenic fractions o f mineral oils, under the direction o f Dr J. tv . Cook. In 1966, he moved to Exeter, and took charge o f the laboratory o f the Council's new Carcinogenic Substances Research G roup. The present work of the Group includes a study o f the chemistry of tobacco smoke, as well as a continuation o f the investigation o f mineral oil fracu css. A number of papers h a s t been published incorporating the results so far obtaioed in the mineral oil work. D a D . H. Clayson is Elizabeth and Louisa W ard Fellow m the Department o f Experimental Pathology and Cancer Research in the University o f Leeds. After training as an organic chemist at O xford he cam to Ld.t in l?4g to work with D r G . M. Bonier on the relation between the m cuboc fate of the aromatic amines and their carcinogenic actioa. His published work includes: with G . M. Borner L J. W. JuiL " An experimental inquiry into the cause o f industrial bladder cancer" (Lancer. 1951. 2, 2$6V, "A working hypothesis for the mode of carcinogenesis of aromatic am ines" (Brit. J. Cancer, J93. T. 460): and, with G. M. Sonser. L. Bradshaw it J. \V. JuU. " A further study of ihe carcinogenic properties o f ortho hydroxy-artunes and related compounds by bladder implantation in the m ouse" (Brtt. J. Cancer. 1936. 10. 539). Da J. W. Cook is the ftrrt Vice-Chancellor o f the University o f Exeter and is also H o aoriry D irector o f the Medic*! Research Council's Carcinogenic Substances Research Group. Ln 1939 he v u appointed R epus Profeasor o f Chemistry in the University of Glasgow, post which be held fo r 13 years. Before that be was a professor of chemistry La the University of London and raeareb chemist to the Royal Cancer Hospital. He was responsible, with l.H scgcr and C-L. H ew eu.for the isoiauon from coal-ur pitch o f a potent carcmogeaje pure hyproscirbon and for demonitrating by ynvruc preparition that this was the hitherto unknown J ; a- benzopyrene. He also prepared tymheucaUy many other ca/mnogeaic polycyclic hydrocarbons and was associated with IL C. Dodds and C. L_ Hewett ia ta t discover/ o f the synthetic oestrogen*. Dr Cook wgj swarded the Davy Medal of the Royal Soaety in 193-4 and waa the Chemical Society's Podlc? Locurcr in 1950. He has been President o f (he Royal Institute of Chemistry and was President o f the Oscnuttry Secuan at the 1937 osocung o f the Brmsn Association for the Advancement o f Science. Da W. M. Couxt-Bxow* u on th Scieauhc Staff of the Medical Research Council and is Director of the Group for Research into the General Effects of Radiation. He Studied medicine at St Andrew's University where he graduated in 1942. After same years o f woik in radiotherapy, be commenced in 1950 the study o f the harmful effects o f ifln rn c; radiations. He spent some time in (be investigation o f the acute effects, u a result o f which a number of papers were published dealing with the factors governing the length o f the Litem period between exposure to radiation and the onset o f gnstrointestinal symptoms, and he has now become mainly interested in the study o f the long-term carm ooieajc effects- He has published several p a o c n ^ tn this subject, and particularly, in co-opera+ron gnih Dr Richard Doll, a study o f the leukaeaogemc effects of radiations (Spec. Rep. Ser. med. R et. Coun.. Land. 1957. No. 295). D* I. Don u ch . Senior Lecturer in Morbid Anatomy. Postgraduate Medical School o f London, w y formerly cancer research m istan t to Dr J. C. Moitram at M ount Vernon Hospital, London. His experi ments have been mottly concerned with the carcino genic action o f radioactive iodine on the rat's thyroid and with ebanges in thyroid function resulting from radiation. Publication! include: "A com panion of the photodynamic activity o f some carcinogenic with on-carcinogenic com pounds" (Jh-ii. J. exp. Path. 1939. 20, 227); and "T he effect of radioactive iodine alone aad in combination methyl- thiouracil upon tumour production in the rat'i thyroid gland*' (Bril. J. Cancer, 1953. 7, IS!). Da L. A. ELMS is Reader in Biochemistry in the University o f London. His first research worx was on chemotherapy at Guy's Hospital Medical School, London. He was later Jeruter Memorial Scholar at ibe LisKf Institute o f Preventive Medicine. London. After some yean with Imperial Chemical Industries Limited in Manchester, he carse to work at the Chester Beatty Research Institute. Royal Cancer Hospital. London, where he held a Brittih Empire Cancer Campaign Fellowship and was appointed Reader in Biochemistry in 1936. Among his publications, one desenbea the well-known Elion and Morgan method for the determination of glucosamine u d ehandroiamiae (Biochem. J. 1933 27. 1824). H e has contributed a tertes of papert to the British Journal o f Cancer on the in/iueoex e f the protein content o f ihe diet oo the grawth-iabibiiory action of ca/cinogcnie and tumour-inhibitory com pounds. At present be is mainly enraged on work on the cataparauve biological effects of rid iiL o a u i radio cairn cu< tu m our-iahibitory aad anti-Seukam sic cbermnais. D * A . G lL'CKSXakn is Senior Histologist to the Siraogcw*yi Research Laboratory, Gaih&r.Cge. which be jotned a 1933. He has worked mamiy on ! 90 NOTES ON CONTRIBUTORS l i e effect* of irradiation in producing malignant disea* ho effect o f irradiation m the tjy u n e a t o f malignant disease ia n u n . He has Uevetoped quxntitaavt: hisiclojical methods to i e is thee effects, and built up probably the argot collection of biopsy and operation material obtained from irradi ated hum an oncer*. He received the Rfintgea Award o f Use British Institute of Radiology in 19*2. and was Douglas Lea Memorial Lecturer to the H ospital Physicists' Association n 1953. Among his publications are: "T h e inffuence o f systemic factors on Use differentiation and radiocurability of cervical cancers'' {Brit. J. Radial. 1956. 29. -si3)* ''Relationships between hormonal changes in pregnancy and the development o f' mixed carcinoma' o f the uterine cervix" (CdJtrtr. tf.Y . 1957. 10. 831); "L o c al factors in the histogenesis o f hypertrophic s c a n " {.Brit. J. plaxt. Surg. 1951 ,4. S8). D r Cldcka- mann also cootributed a paper. " Quantitative histological analysis o f radiation-effects in human carcinom ata", to an earlier cum ber of the Bulletin {B nt. med. Bull. 1946. 4. 26). D a M- w . GoLDiLArr, formerly D irector o f Indus trial Hvgiene Research Laboratories o f Imperial Chemical Industries Limited, is now engaged at Pollards Wood Research Station {Institute of Cancer R esearch. Royal Cancer Hospital}. He is a member o f the Permanent International Commission on Indus trial Medicine. Examiner in Industrial Health for the Diplom a in Industrial Health. Member o f the Edi torial Committee o f the British Journal o f Industrial Medicine and Member of Executive o f the British O ccupational Hygiene Society. H e has published papers on physiology, biochemistry, industrial toxicology and carcinogen!*, including one in an earlier number o f the Bulletin entitled "O ccupational cancer o f the bladder" (Brit. med. Butt. 1947,4, 405). Dr G oldblatt was created C.B_E. to 1955. P a o rtiso a H. N. G ar in is Profeiaor o f Experimental Pathology at Leeds University and Director o f Cancer Research at Leeds and Sheffield Universities. He is a Sheffield graduate and. after a period as Lecturer in Pathology at Cambridge, he was for a long tim e Professor o f Pathology at Sheffield. H has published numerous papers an many aspects of experimental pathology, including particularly the subjects of nutrition, traumatic shock and cancer. He commanded a British Traumatic Shock Team. Royal Army Medical Corps, in the Second World W ar. w jih H. B, Stoner, be wrote the book flioOfteal actions o f the adenine nucleotides (1950). which was largely as outcome o f the shock nvcsugauou. These authors cootributed previously to this Bulletin an article entitled " Effects o f iajilry on carbohydrate metabolism and energy transformation'* iBrtt. med. Bull. 1954, 10. 33) in a symposium on "Reactions to In ju ry ", His immunological theory o f cancer {Self. med. J. 1934. 2, 1374) baa stimulated work in this field o 'e r a *tde from. Paorcrsoa Alxxandcx HaDdow, F.JLS., grsduatod in medicine m 1929, at Edinburgh, where ha becacaa lecturer in bacteriology (1931-36). He joined tho n a ff o f the Research Isstiruta o f tha Royal Cancer H ospital in 1936 and * u appointed, in succession to Professor E. L. Kennaway, to the Ch>Mr of E *po> mcn-ai Pathology in tha University o f London and lb directorship o f She Chester Beatty Research Inim uxa of 'die Royal Cancer Hospital in 19*6. He has pubiiihed a number o f pspers on sporial u p c o o f growto, such as the comparative pathology of tum ours, viruses in relation to the aetiology of cancer, and problems o f immunity affecting the iraaspiintaUoo o f tissues. One of his Slain interests has been in bacterial mutation, and its importance in elucidating what be considers to be analogous problems of variation in the origin o f cancer. In 1935. Professor Haddow described she growth-inhibitory property of carcinogenic com pounds, and he has developed this subject and related it to the mechanism o f *cuon o f tum our-producing and growth-inhibiting agents. He has been closely concerned with developments in chemotherapy. W ith his advice, the general plan o f the Bulletin symposium published in 1947. "Chem ical Carcinogenesis". was devised. He con tributed to th at symposium three papers, one in collaboration with G . A. R . K on, on carcinogenesis and chemotherapy o f cancer {3rit. med. Bull. 1947. 4. 314, 331, 417). H e is at present engaged (with Professor F. Bergel, D r W. C. J. Ross and M r G . M. Tunrois) in a study o f the gTowih-inhibitory alkylating agents derived from nitrogen mustard. Dm I. H irer* is a biochemist at the Chester Beatty Research Institute o f the Royal Cancer Hospital, London. He was a member o f the team of workers which under the inspired leadership o f Sir Ernest Kennawgy discovered the carcinogenic hydrocarbons and isolated 3 : -benzopyrene Tram pitch (Cook. 3. W .. Hicger, L, Kennaway, E. L. 4 Mayneord, W. v .. Prae. Roy. Soc. B. 1932. t i l . 455). He is now engaged on the investigation o f carcinogenic agents o f biological origin (Proc, Roy. Sac. B, 1957.147. I*>. D r Hieger has published a popular book on cancer (One in six: on outline o f the cancer problem, 1935). He has previously published in the Bulletin a paper em it led " Carcinogenic substances in human tissues" (Brit. med. Bull. t94?. 4, 360). Pmomsom E. S. H orning is Professor o f Experi mental Pathology (Histopathology) in the University o f London at the Chester Beatty Research Insti tute. Previous to this, ha was Reader in Experi mental Pathology and, before joining the tu ff o f the Chester Beatty Research Institute, was a scientific member o f the Imperial Cancer Research Fund. Whilst holding a Rockefeller Research Fellowship, be worked at the Kaiser Wilhelm laslirut, BerUn-Dahlem. and later at Washington University, St Louis, as well as at other research centres ia the USA. Professor H om ing was also a Beit Memorial Fellow. When at the University o f Melbourne, his earlier researches were on the enzymic function o f mitochondria in Protozoa. Since then he has published numerous papers in the field o f cellular pathology and is now working on the re lationship o f hormones to carciaogenesis. Together with D r H . Burrows, Professor Hom ing contributed to an earlier num ber o f the Bulletin a paper entitled " Oestrogen* and neoplasia" (Brit. med. Bull. 1947. 4, 367). Dm 3. W. J u u . is a Saitwell Fellow o f the Royal College o f Pbysidaas of London, working in the Departm ent o f Experimental Pathology and Cancer Research in lh# University o f Leeds. He started working with D r G . M. Bonscr in 1949. and since has been interested both in the carcinogenic action o f the aromatic amines and tha role o f ovarian and pituitary hormones in the aetiology o f cancer o f the breast in the human and th experimental animal. His publications include: " Th* induction o f tumours of the bladder epithelium in mice by lb* direct applica tion o f a caxtnnofta'* (Brit. /, Cancer, 1951, 5, 323); " The effects o f nestrogens and progesterone on th* chemical induction o f mammary cancer in mice o f the IF strata" (J. Pash. B ad. 1954. 64, 5*7); and "H o rm o n es as promoting agents in sum m ary carcinogenesis'* (Acta Vn, ins. Conor. 1956. 12. 653). Sir Ejlnwt K iwn*w*y was D emonstrator of Physiology * Guy's Hospital, London, 1908-14, and w u elected a Rad cliff Travelling Fellow in 1909. From 1931 lo 19*6 he beidth* post o f Director of the Research Institute of the Royal Cancer H etp .u l. London, now the Chester Beatty R e c ir r h Lum yie! Sinco 1921, he had been engaged on research on cancer, especially as regards cholmtcrc n a carcino gen, and cancer o f the human lung am. cervu. H u published papers include: with N . M. Kenr!aw*7l The relation between the incidence and incuhaim s period o f cancer m m an" (Yale 1. Biol. Med. 1944. 17. 139): "T h e racial and octal incidence o f cancer o f the u teru s" (Brit, J. Cancer. I94g, 2. l??); "T h e identification o f a carcinogenic compound m ;olta r" (8r,t. med. / . 1935. 2. 749). He was an H onorary Fellow o f New College, Oxford, and w u elected a Fellow o f the Royal Society ia 1934. Sir Ernest died on the 1 January 1953. while this number o f the Bulletin as in preparation: a tnbute to him. and further inform ation about h>s life and work, are Included m the Introduction to this Bulletin. D r a . J. LtNDirr is Head o f the Department of Chenusiry at Sir John Cass College, London. He had a num ber o f yean in the fine chemical and scientific instrum ent industries before taking up his academic career in 1936. From i9*0 * i9-*6 he served in the Royal Air Force Volunteer Reserve. His research interests are electrochemistry, radiochemistry and combustion chemistry. In this latter field, h* and his research students have developed methods for the analysis o f smokes and other com bustion products, and they ere the first to dem on ra te the presence o f poljcyclic aromaCC h i? ra csrbans is tobacco smoke. The ubiquity of tfiu c hydrocarbons in combustion products, and the carcinogenic nature o f some of them, have made these researches o f considerable inter cat; they have been supponed by the Department o f Scientific and Indus trial Research and by the Medical Research Canned. This work, which has been reported in about forty original papers, has boco co-ordinated with similar projects in other centres, especially with that under the late Sir Ernest Ketuuwzy at 5l Bartholomew's Hospital. London. Published work includes; with R. L. C o o p er," 3 : 4-Benzpyrene and other polycyclic hydrocarbons is cigarette smoke" (2 m . J. Cancer, 1955, 9, 30*); with J. A. S. Gilbert, ' ` Polycyclic hydrocarbons in tobacco smoke: pipe smoieng experiments" (Brit. J. Cancer, 1956, 10. 646); and. with J. M , Campbell, " Polycyclic hydrocarbons in cigar sm oke" (Brit. J. Cancer, 1937, 11, 192). D r R . H , M q u has been working at Harwell since th* beginning o f radiobiological research work mere in 1944. His special interest has been in recovery from irradiation and its delayed effects (see " Quanti tative observations on recovery from wnoie body irradiation ia m ica", Brit. J, Radiol. 1956. 29, 16] and Brit. J. Radiol. 1957. 3Q. 40; "Shortening o r life by chronic irradiation: the experimental facts'*. Nature. 1957, 1M, 456- and. in collaboration wuh G . L N eary St R . J. Munson, Chrome raniotton hazards. An experimental study with fast neutrons. 1957). Before this, as graduate assistant in tne Nuffield Departments of Clixucal M edicne and Pathology, Raddiffe Infirmary, Oxford. D r Mo>* had an orthodox training in medicine. From to 19*6 he was a pathologist in the Royal Air Force, and in 1947 C in iczl Pathologist, Royal Infirmary. Liverpool. PunrasOR J. W. OJUt is Professor o f Pathology and D irector o f Cancer Research in the U rw ersuy oC Birmingham, and Honorary Consultant P uholeg^t to the United Birmingham Hospitals. He is a graduate o f the Queen' University of Belfast, and has held the posts o f F in t Assistant Pathologist at St M ary's Hospital. Paddicgtoo, London, and Reader us Experimental Pathology in the Umvcrury 191 J NOTES ON CONTRIBUTORS of Leeds. H il rexearch work has been mainly caneerned wsth p ro b le m of -T p-nn-nfaj, in the skin. breast. b'vci, a*try and connective u u u c, U i j w ? U i U se p a t h o l o g y O f b u m i n n t i f r f in rnm fl H a publications include: " The production of liver tum ours by u o com pounds" (Br'u. med. Bull. l47. 4, 385): "T h e cbem caJ induction of mammary end ovarian m a o u n " (Acta Un. Uu. Qancr. 1936, 12, 682); and, with D r J. G. Jackson, "T he ducts of eartinom aim u breasts, with particular re/crroce 10 connect! vw-tissue changes" (J. Bath. Sact. 1957, 74, 253- D u P. R. PtACoex it Director of the Cancer Research Departm ent of the Royal Bcatson Memorial Hospital, G U sgo. He was trained at Middlesex Hospital, London. here, after qualifying us 1924, he held resident appointments and afterwards research sokolanhips in the Baraato Joel Laboratories until 1928. H u early work was mainly concerned with fat-Mlubx vitamins and with eapcruaenuJ radiology. He was appointed to his present post us 1928, and is 1933 became the A dministrative Medical Officer ax the same hospital. He wax appointed Honorary Lecturer in Pathology to the University of Glasgow in 1943, and elected a Fellow of the Royal Faculty of P hytioara and Surgeons of Glasgow in 1944. He was appointed H onorary Treasurer, International Union against Cancer, in 1952* D r Peacock's published work includes com parative studies of fowl sarcomata induced by chemical carcinogens and of those spontaneous tumours that can be propagated by call-free extracts (Amer. J. Cancer, 1933, 2i, J; ru. J. exp. Pam. 1945. 26. 357; Cancer Res. 19*6. 6, 311). H e has made a study o f the metabolism of chemical carcinogens and described their natural routes of excretion fBrit. J. exp. Path. 1938. 19, 313, 434; Brit.J. exp. Path. 19*0. 21.227; Biochem. J. 1941.31, 1276). a paper by D r P u c o c k . on the carcinogenic action of healed fa u and lipids, was published in British Mrdical Bulletin. 194?. 4, 364. He is particu larly interested in dietary factors related to cancer of the alimentary tract. He holds the view that much human cancer could be avoided, and that closer co-ordination of clinical, statistical and experimental research may lead to identification of some avoidable forms of cancer. D a M. H. SaLamas was trained at Cambridge and the London Hospital. After qualification be studied the antigenic structure o f vaccinia under Professor S. P. Beeson and later Sir John Leduighaxa. in 1939 he entered the Cancer Research Departm ent of St Bartholomew's Hospital, and except for three yean as a paiboiogu: in the Royal Army Medical Corps, during wturn be studied serum hepatitis end was able to recommend measures for ;u prevention, he has continued to -work oo cancer. He came to the London Hospital in 1946, and u appointed Director o f the Cancer Research Department there in 1948. a post which he Itill hold*. He has been mainly interested in the mochanism o f camnogcmeais and particularly in the action o f " incomplete carono- ftu u " , i.c,, agents which can bring about p an but not the whole o f the proems o f tum our production. Three repmesiasr.vc publications arc: " The com bining properties o f vaccinia rtrtu with the anti bodies demons trip le in anti-vieetmaJ serum " (Brit. J. exp.Path. 1937. It. 243); with D . E. Lea. "E x p e n - m enu on the uuiruvauon bacteriophage by radix Lion, and their bearing on the nature of bacterio phage" {Proc. Bay. Joe. B, 1946. 133, 434); with F . J. C. Roe. "Incom plete carcinogens: eihyl carba mate (urethane) u an initiator o f akin tumour formation in the mouse" (Brit. J. Cancer, 1953, 7, 472L D* Rigina ScuotKtAL is a member o f the Scientific Staff o f the Medical Research Council's Toxicology Research Unit at CarxhaJicts, Surrey. England. Before this she had worked oo behalf o f the British Em pire Cancer Campaign at the Sir William Dunn School o f Pathology, O xford; as the Chemistry D epartm ent, University o f Glasgow; and at the Cancer Research D epartm ent. Royal Beatson Memorial Hospital, Glasgow---with the exception o f a year spent in the USA (1932-33). She has studied, among other problems, the carcinogenic constituents o f coal-tar and shale-oil, and the metabolic and chemical oxidation o f polycyclic arom atic hydro carbons. and she has sytuhexhted some o f their phenolic metabolites. Since the discovery o f the carcinogenic icuvity o f pyrroliaadinc alkaloids for the rat liver, Dr Scbocntal has been mainly interested in the mechanism o f their action, and in the role medicinal plants containing these alkaloids may play In the causation o f liver disorders in some parts o f the world. Her published work includes: " The oxida tion o f aromatic rings by purely chemical means " (Sy/np. biachem. Joe. 1950, S. 3); " Kwashiorkor-like syndrome and other pathological changes in rau as a result o f feeding v.sth Stnecio alkaloids (isstidine)" (Fording, 1935, 16. 268); and, with J. W. Cook k E. Duffy. '` Primary liver tumours in r a n following feeding with alkaloids o f Stnecio Jacobaee" (Bnt. J. Cancer, 1930. 4, 41)3). D* A. L. WaLPOLE is a traduate o f London Uruvrrsity and a member o f the research staff of Imperial Chemical Industries Limited (Pharmaceuticals Divi* sion). Since 1942 bn chief work with that Arm has been concerned with cancer chemotherapy and chemical carcinogenesis. With other members o f a research team he discovered tumour-inhibitor)' properties in alkylating agents containing nv-Jaylolasudc, rpoxiCe aqd tidylesxrmune groups and later tnvtfug au d the carcinogenic potentialities o f compounds of th a type. These researches are described in a senes of papers wniteo in collaboration with J. a * Hendry, R. F. Homer. D. C. Roberts k F. L. Rose: "Cytotoxic a*cqix: I, Methylolauudcs with tttao u r inhibitory acuviry, and related inactive compounds; H. Bu~ tpaxixtes and relatnd compounds; III, Denvaavcs of eibykm am iae: TV, The careinogmuc actions o f aoxne moDofiuieuo&aJ nhylcncuaine dcrivgiivts" {Bru, J. Pharmacol. 1931. 6, 201, 233. 337; 1954. 9. 306) With M . H . C. W iliams 4c D. C. Roberts. Dr Walpole first described the carcinogenic activity of 4-aminodipbcayl (Bril. J. indunr. Med. 1932. 9. 233). He is currently engaged in a systematic ih>eaugauec of the ca/cifldtem c properties of aromatic i c m a derived from diphenyl and sulbeac respect i*eiy. D a M. H . C- Wn.UAies is the Division Modicai Officer to the Dyestuffs and Pharma ceuucaii D ivujoq o f Imperial Chemical Industries Limited, which be joined in 1948. Before taking up this post he was working with the Medical Research Council'sPneumo coniosis Research U ait in South Wales. For eight yean, wnb his colleague D r A L Walpole, he has been carrying o ut a systematic study o f the cardnogeme effects o f substituted aromatic amines, HU publica tions include: a paper on the discovctS, wggj D r Walpole, o f the carmnogcnic effect of^*-a/isodiphenyi (aenyiaaine) (" Tumours o f the unnary bladder in dogs after isiestion o f a-uniaodin'oenyl" , with A. L. Walpole k D. C. Roberts, B n t. J. uutustr. Med. 1954, 11. 103); with T- S. Scott, " The control of industrial bladder tum ours" (Brit. J. vui'uiir. Med. 1937, 14, 150); and a chapter on occupational tumours o f the bladder in (he forthcoming volume 1H of Canetr. edited by R. W. Raven. D a D xkxu LnTOS Woodkousi graduated in chemistry at the University o f Birmingham us 1922; be obtained bis M.Sc. in 1923. From 1924 to 1930 be held the appointment as Sir Charles Hyde Research Fellow to the Joint Board for Research in Mental Diseases, City and University o f Birmingham. He took his Ph.D . in 1930. Dr Woodbouse secured the post o f Re&eareh Officer to the Birmingham Branco o f the British Empire Cancer Camnatgs in 1931. He was elected a Fellow o f the Royal Institute of Chemistry ut 194?, and has been Reader m Che=ie-ai Pathology (Cancer Research) in tbc Department of Pathology, Medical School, Birmingham, since I9M He has published papers, us the Biochemical Journal. Cancer Research. Brutsh Journal of Cancer. Journal o f fa th a lo ry and Borirr/olof)*. an chemotherapy of cancer and ajpeeu o f carctnogcomu.