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FILE NAME: ICI (ICI) DATE: 1958 DOC#: ICI011 DOCUMENT DESCRIPTION: Book Chapter THE PRACTITIONER Edited by SIR HENEAGE OGILVIE K.B.E., D.M., M.CH., F.R.C.S. W ILLIAM A. R. THOMSON, m .d . JOSEPH GARLAND, m .d . Vol. 1 8 1 July-- December 9 5 I THE P R A CT ITIO N ER 5 BENTINCK STREET, LONDON, 195 8 A ll Rights Reserved W. x ISO THE PRACTITIONER coniosis panels who review each certified case at stated intervals--usually one or two years. If the general practitioner is to be successful he must have a working knowledge of the legal and administrative arrangements for disablement and death benefits: an excellent series of pamphlets in nonlegal language is available at offices of the Ministry of Pensions and National Insurance. I would particularly underline that, save in exceptional circum stances, a death claim is dependent upon a post-mortem examination. Hence the need immediately to advise the pneumoconiosis panel or H.M. Coroner so that the examination can be arranged with as little upset to the dependants as possible. GENERAL CARE The care of pneumoconiosis cases is very similar to that of cases of chronic bronchitis and emphysema, with, in severe cases, a tendency to congestive heart failure. In silicosis cases particularly, the general practitioner must be vigilant for possible active tuberculosis. Once a patient has been diagnosed as pneumoconiosis there is a tendency to ascribe all his ills to the dust. Pneumoconiosis does not confer immunity to other diseases and so the doctor must be alert to recognize and treat promptly any irftercurrent disease. I would plead that consultations should not be hurried; allowing time to listen will achieve the most important items of therapy: support and encouragement. Medicines should be prescribed sparingly, and then only of the simplest kind. Finally, a word about certificates: be honest and factual. And remember that the decisions of the pneumoconiosis panels are based upon the law as it is--justice within the law-- and not on what you or I think it ought to be. CONCLUSION It is improbable that in the near future we shall see any radical alteration of the existing National Insurance (Industrial Injuries) Act. This being so, there are certain matters concerning pneumoconiosis which demand urgent attention by the Ministry of Pensions and National Insurance:-- (1) Whether disabling bronchitis and emphysema is an occupational disease in certain industries and occupations. (2) The need for less formal and more informative reports by the pneumo coniosis panels to general practitioners and employers in all cases requiring their cooperation. References Jones, W. W . (19 52): ` Tuberculosis in Industry", National Association for the Prevention of Tuberculosis, London. Sutherland, C. L . (19 56 ): Trans. Ass. industr. med. Offrs} 6, 103. OCCUPATIONAL CANCER By M. W. GO LDBLATT, C.B.E., M.D., M.R.C.P. Institute of Cancer Research, Royal Cancer Hospital S in c e I last reviewed this subject in The Practitioner (Goldblatt, 1950) agreat deal of work has been carried out which has extended our knowledge not only of the industrial carcinogenic agents then known, but also of the im portance which must be attached to a constant awareness of the probability of new or even old industrial agents inducing tumours in man. MODE OF A B S O R P T I O N OF O C C U P A T I O N A L C A R C I N O G E N S Once an occupational carcinogen has been recognized as existing in an industry, its mode of entry into the organism must be considered im mediately because there is bound to be a considerable time-lag before its elimination or inactivation or before improved protective measures can be operated. The simple formula that manufacture or use must cease im mediately is seldom practicable. The recent cases of demonstrable clinical bladder carcinogenicity of a rubber anti-oxidant containing a significant proportion of unreacted (3naphthylamine led to the immediate cessation of manufacture and use of the preparation. But this will not be followed by immediate cessation of cases attributable to exposure to it; hence, follow-up and cytological examination of all men who were exposed is now going on and should continue throughout their lives. Similar action was taken in the United States in respect of an aromatic amine--4-amino diphenyl or xenylamine-- which was found to be carcinogenic, although the rubber anti-oxidant manufactured by condensing it with an aliphatic ketone has, after several years' experiment, not been found to be hazardous. It is now common knowledge that toxic substances in industry may be absorbed by all the available routes, most frequently by inhalation, very often per cutem and relatively rarely by mouth. In certain operations absorp tion can occur by the conjunctiva. Absorption from the mucous membranes of mouth and nose is an infrequent occurrence but has occurred in labora tories. In industrial conditions combinations of routes of absorption arise depending upon the physical properties of the materials involved. Inasmuch as many of these are insoluble in water and in lipoids we must envisage phagocytic action in the lung and later deposition in the affected areas; for the more soluble materials, greater mobility and effects at remoter areas may be anticipated. The relation between ultimate deposition and retention in the affected areas is by no means easy to describe: no single mode of action on the relevant cells seems possible except in terms of as yet obscure energy transferences, or potent alternative attacks on the cell structure or cell internal economy. For most of the materials it is not pos- August 1958. Vol. 1S 1 (151) J52 THE PRACTITIONER sible as yet to lay down environmental concentrations and total periods of exposure which might be held to determine the development of malignant change. PERCUTANEOUS PENETRATION Penetration of the skin may occur either through cellular layers or at the orifices of the sebaceous glands. Aromatic amines.--All occupational carcinogenic aromatic amines are lipoid-soluble solids but, according to circumstances, can penetrate through the skin when applied to it as dust, in a molten state or as hot fumes--most easily when molten. The probability is that they are absorbed mainly through skin apertures. Radiation.--For the energy of radioactive particles or electro-magnetic waves to produce pathological effect, it must be absorbed by the tissues affected. The precise way in which the energy thus absorbed leads to cellular changes is the subject of much theorizing but, so far as malignant disease is concerned, it seems probable that there occurs a physical and chemical change in the chromosome make-up (chromosome breaks; rejoining in abnormal ways; changes in nucleic acid or nucleoprotein in the nucleus; mutagenic action) which irreversibly sets the previously normal cell on the course of malignancy. Soft radiations are absorbed by skin cell layers. More penetrating radiations (harder radiation) will pass through the skin layers and affect organs and tissues according to their radiosensitivity. Some tissues are very sensitive, others are relatively insensitive. In regard to neoplastic disease, the skin is one of the sensitive tissues, by virtue of the damage and destruction produced by radiation in sufficient dose (wave-length, duration, intensity, total dose) and the subsequent ingrowth from less damaged ad jacent areas of epithelial cells which have absorbed sufficient energy to cross the line of normality to malignancy. Lymphatic tissue (anomalous in some respects), blood-forming tissue, germinal epithelium, and intestinal mucosa are in a truer sense radiation-sensitive tissues, whereas the more stable tissues, e.g. liver, pancreas, kidneys, muscle, connective and nervous tissue, are much less affected by radiations. The general view is that tissues in which much `turn-over* of cells takes place, are more radiation-sensitive than other more static tissues. `Turn-over* in this context is synonymous with `mitotic replacement*. Radiation sensitivity means greater than normal tendency to respond to a dose or doses of radiation by cellular degeneration or chemical and metabolic aberration. The modern conception is that a chemical carcinogen penetrates into the skin and is metabolized. This metabolic process entails the liberation of energy which is absorbed by the germinal layer of the skin until a critical level is reached at which the cells become malignant. This energy-trans ference view of carcinogenesis has the virtue of bringing the picture of this process into a more or less familiar background. It may also be that small OCCUPATIONAL CANCER 153 amounts of radiation or chemical energy applied appropriately to a cell may render it more susceptible to endogenous completion of the carcinogenic process. Some animal experiments give support to such a co-carcinogenic action by radiation. It is obvious that a cell change which leads to malig nancy must be one which is compatible not only with survival but also with independence, enhanced power to multiply, resistance to normal inhibitions of growth and competitive superiority over normal cells. Tumour-cell nuclei are abnormal not only in morphology and staining properties, but also in the mitotic process. An enhanced rate of multiplica tion, however, does not mean that all phases of mitosis are accelerated. Thus, in tissue culture, tumour cells show a retardation of metaphase. I N G E S T I O N OF C A R C I N O G E N S This involves absorption from the gastro-intestinal tract, including the oral mucous membrane. Radioactive paints.-- Ingestion of carcinogenic agents in industry is, on the whole, an unusual factor, the only well-authenticated case being that of luminizers, with which, following deposition of radioactive compounds in the bones, there follow blood diseases and osteosarcoma. Absorption probably occurs from the oral mucous membrane, as well as from the gut, as a result of 'pointing' the paint brushes with the lips. The use of pens instead of brushes largely eliminated the practice and in this country the stringent `luminizing order' incorporated into the Factories Acts has led to a full realization of what is involved. Aromatic amines.-- In former times--say, 25 years and more ago--it is certain that many of these solid compounds were taken in orally as dust and fume. It is impossible to say what proportion of the carcinogenic action was attributable to absorption by this route. In modern conditions of manufac ture and use (Scott and Williams, 1957) it is reasonably certain that this route of absorption is not significant, but testing of the mouth and saliva for free amines of workers would be of interest, especially at those locations where the final solid product emerges and is weighed into drums. This would, of course, only be relevant where the processes of manufacture of carcinogenic bases are still in operation. I now propose to consider a few occupational carcinogens in greater detail. ASBESTOS In his report for 1955 the chief inspector of factories has extended his data on the association of asbestosis and cancer of the lung by pointing out that between 1924 and 1956, 22 per cent, of 222 men and 12 per cent, of 143 women had the combined disease, thus demonstrating an increasing in cidence of association. Such an association does not occur in silicosis (Goldblatt and Goldblatt, 1956; Gloyne, 19 5 1; Meiklejohn, 1956). Werber (1952) found that carcinoma of the lung occurs in up to 17 per cent, of cases of asbestosis, with an induction time of to 20 years. *54 THE PRACTITIONER D oll (19 5 5 ) studied the post-mortem and occupational data of 105 consecutive deceased workers in a single large asbestos works, of whom 75 had asbestosis; of the latter, 15 had associated cancer of the lung, of the remaining 30 without asbes tosis three had also cancer of the lung. In 19 3 1, the asbestos industry regulations were issued and in this particular factory it could be reckoned that it was not until 19 3 3 that they became effective. In all 15 cases of asbestosis cancer there was a history o f the individual having worked in the industry for from 9 to 23 years prior to 19 3 3 , but there was no case among those who had entered it between 19 23 and 19 5 3 . T h e mortality data of 1 1 3 men with 20 years in the factory yielded n cases of the combined disease and none with lung cancer without asbestosis. Doll (1953) points out that such an incidence is about 10 times that expected in England and Wales and far exceeds that of silicotic miners published over 30 years ago by the South African Miners Phthisis Medical Bureau-- 0.7 per cent, for silicotic miners; 0.7 per cent, for non-silicotic miners and 0.9 per cent, for European male surface men. Agreement as to the association between asbestosis and lung cancer was reached at the international symposium on the endemiology of lung cancer (1953), Wyers (1949), having already stated that the oat cell and columnar cell types were the most frequent. Hunter's (1955) belief that the malignant tumour appears many years after exposure to asbestos has terminated, is not borne out by Doll's data on the 15 cases referred to: six in less than one year, three in one year, three in three years, two in eight years, and one in thirteen years after cessation o f exposure. These tumours are very malignant and soon become fatal; so we must suppose that, whatever the mechanism of cellular change, it requires a very long induction time to reach the tumour state. The interesting suggestion is made by Bonser et al. (1955) that silica is the common factor in the en vironmental exposure of the asbestos worker and the haematite miner and that, in both, the fibrosis precedes the malignant change in the lung. They conceive the asbestos and the haematite (iron oxide) as somehow converting the fibrogenic action of silica into a carcinogenic action. K ing et ah (1946) were able to induce peribronchiolar fibrosis in rabbits exposed to asbestos fibre dust; but when the fibre was reduced to dust by fusion and grinding, no fibrosis followed long exposure to it. Lung cancer in animals, however, has not hitherto followed exposure to asbestos or to brucite (crystalline) which also induces peribronchiolar fibrosis although it contains only 0.9 per cent. S i02 as silicate, whereas chrysotile (the most used of the fibrous sili cates) contains over 40 per cent. S i02 as silicate when mined. The clinical problem is difficult since Doll found three cases of lung cancer without asbestosis, after such short periods of exposure as two, nine and seven years. Knox and Beattie (1954), who have had much direct experience of the asbestos industry and its hazards, regard the malignant changes in such cases as due to asbestos as such or to asbestos bodies and their decomposition products; in their view the fibrosis would require a much longer time. The observations of Gloyne and of M . J. Stewart, of Leeds, that there is a gradual dissolution of asbestosis bodies and fibres in the lung is confirmed by Knox and Beattie and the view upheld that the OCCUPATIONAL CANCER *55 lesions induced by the decomposition products survive the fibres. Champeix and Bouteville (1950) applied electron microscopy (magnification 25,000) to asbestosis bodies and, using micromanipulation, obtained appearances which seemed to indicate the gradual solution of the fibre located in the asbestosis body. Knox (1955) regards the1slowly disintegrating asbestosis bodies as yielding a product which acts upon the already chronically irritated and, probably, abnormal epithelium. This is, of course, based upon the location of the asbestosis body in the alveoli and the connective tissue in the asbes tosis lung and upon the evidence of irritation given by the thickened, com pressed alveolar walls. Although British authorities are probably inclined to accept asbestos or asbestosis as strongly influencing the tendency to malig nancy, it must be kept in mind that until quite recently Lynch (1956) con sidered the evidence as inconclusive but worthy of extension and further investigation. In this field, as elsewhere, the great need is for a reliable experimental method for the induction and study of pulmonary carcino genesis. HEMATITE Haematite mining is associated in varying degree with the presence of free silica and in the last twenty-five years it has become increasingly clear that silicosis is a hazard in this industry, especially since the introduction of mechanical drilling and blasting methods produced a lot of dust. Some 20 years ago in the Cumberland mines there was a certain amount of con fusion on the silicosis hazard because a good many miners had formerly worked on the Rand and because of the use of the term `siderosis' . In the period 1930-35, 48 haematite miners were certified as having died from silicosis and silico-tuberculosis. As regards etiology such cases fit in with foundry workers and grinders who have been exposed to both iron and silica. The old experimental finding of Kettle (1932) that a thin layer of iron oxide over quartz particles prevents the development of silicosis in animals is not relevant to the haematite problem because here the silica particles are free and associated with, but not coated by, iron oxide and do induce silicosis but perhaps in some modified way which seems to predispose to the later development of carcinoma of the lung. Thus, Faulds and Stewart (1956) report that in the six-year period, 1948-53, 15 per cent, of 89 consecutive necropsies of hematite miners showed cancer of the lung and the tumours were usually located in the areas of fibrosis--due to sidero-silicosis, socalled by Stewart because of the amount of silica present in the lungs of these workers, and to distinguish the condition from the benign pulmonary siderosis seen, for example, amongst iron and steel welders after years of work in confined ill-ventilated spaces. Investigation of the health of arc-welders, even those who used welding rods (electrodes) containing silicates, carbonates, fluorides and other com pounds, has not revealed any effect on health and this applies to those ! i 56 THE PRACTITIONER workers who showed x-ray evidence of siderosis, reticulation or nodulation but no fibrosis. The condition is slowly reversible when welding is left, the iron oxide lying inert for years (Doig and Duguid, 1951). It may be recalled that Kennaway and Kennaway (1947) found no in crease in cancer rate among workers exposed to a silicosis risk, except in the case of metal-grinders; this was confirmed by Turner and Martin (1949) who found that 60 per cent, of cancer deaths among silicotic grinders were due to cancer of the lung. Doll (1953), however, does not accept silica as the significant factor in the development of the lung cancers and leaves it to `some other specific industrial hazard' but without any suggestion as to what this might be. Policard and Collet (1952) found deposits of silica in the lungs of the desert inhabitants of North Africa (in the peri-bronchial and peri-arterial sheaths: i.e. the same locations as characterize coal particles in anthracosis and ferric oxide in siderosis), but no evidence of silicosis. Desert fine sand is innocuous both clinically and experimentally. Policard and Collet point out that desert sand always contains ferric oxide and it may be that this is the reason for its innocuousness, as would have been held by Kettle. The alternative explanation of `old1 sand as opposed to freshly fractured silica must also be kept in mind. It would be of great interest to know the in cidence of pulmonary cancer among desert people. Clinical and experimental evidence all points to the inertness of iron oxide. In reference to both asbestos and haematite the position is summed up as follows by Bonser et al. (1955):-- ` It seems possible, therefore, that the fibrous nature of asbestos or the presence of haematite dust may exert a modifying effect on the chemical action or on the fibrotic process itself. . . . it is suggested that this (silica) may be the carcinogenic agent. The presence of silica (as silicic acid) causes pulmonary fibrosis which precedes the malignant process. The fibrosis is usually of lesser degree, however, in those lungs in which cancer supervenes. On published evidence the case for an etiologic relationship between nodular silicosis per se and lung cancer is much less strong than in silicosis associated with siderosis and in asbestosis'. NICKEL The problem of the cause of the remarkable tumours of the ethmoids and of the lung among workers engaged in the carbonyl process for the refining of nickel was briefly dealt with by Goldblatt (1950) and in greater detail by Goldblatt and Goldblatt (1956). The condition is a `prescribed disease* under the National Insurance (Industrial Injuries) enactment and is defined as: (1) Carcinoma of the mucous membrane of the nose and associated air sinuses and (2) primary carcinoma of a bronchus or of a lung; the carcinogen being defined as `nickel produced by the decomposition of a gaseous nickel compound'. In the period 1923-50, 52 cases with 49 deaths from cancer of the nose and 93 cases with 90 deaths from cancer of the lung were reported in the 1950 Report of the chief inspector of factories. The mean induction times OCCUPATIONAL CANCER l 57 were 23 and 25 years respectively and all the cases arose in the same nickel refining works. In spite of the rarity of cancer of the ethmoids and of this high incidence in a single works operating a single refining process, Bonser et al. (1955), with all the weight of their authority, are doubtful of its indus trial origin and state that there is no experimental support. The indictment in the official definition is really of a process rather than of a substance and it may be that Bonser and her colleagues are implying that nickel is doubtful as a carcinogen. Certainly, nickel in its ordinary applications is not to be regarded as a carcinogen or as offering a hazard of this kind to the very many people who are skin-sensitive to nickel-plated articles. Finely divided nickel, however, such as would be deposited from the decomposition of inhaled small volumes of nickel carbonyl, would have properties different from those associated with the bulk metal. Further, finely divided nickel absorbs gases, catalyses hydrogenations and is easily oxidized in the air and may, perhaps, form significant compounds with tissue proteins and enzymes. The ethmoid sinuses are under slight negative pres sure; nickel carbonyl is quickly decomposed in the tissues and finely divided nickel could thus be deposited and immobilized in the very thin mucous membrane, extremely closely applied to the bone. A measure of cedematous stenosis at the fine orifices which connect the sinuses to the nasal meatuses could accentuate the process of retention. Barnes and Denz (1951) found that severe and extensive fibrosis often followed exposure of rats to nickel carbonyl, an observation which must be considered of great significance in the elucidation of the cancer hazard. In the industrial electrolytic refinement of nickel, in which no carbonyl is formed, no cases of ethmoid or nasal tumours occur in this process but five cases of bronchogenic carcinoma were discovered by Loken (1950) in a single factory operating this process in Norway. The lung of one of these cases analysed eight years after cessation of exposure still contained some 1 mg./g. nickel. The whole question is very complicated and cannot be pursued further here, except to say that continued observation of workers, past and present, in the carbonyl process is proceeding. The occasional case of nickel car bonyl poisoning still reported may perhaps yield new cases of the old disease. The older arsenic theory of causation is not acceptable and the officially accepted nickel and nickel carbonyl theory is not finally decided. ` isopropyl oil* In 1950, in a chemical factory in the United States, seven cases of tumour of parts of the respiratory tract-- lungs, paranasal sinuses, vocal cords-- were discovered. The ages at death in three cases were 31, 36 and 41 years, and the periods of exposure to a particular process were from 6 to 16 years. The process was theoretically a relatively simple one for the manufacture of isopropyl alcohol. i 58 THE PRACTITIONER Th e process was a catalytic hydration of the gas, propylene, as follows:-- C H 3-CH = C H 2 + H 2S 0 4 CH 3.CH .CH3 Hydrolysis (C H 3)2.CH(OH) Propylene 1 O SO ,O H Intermediate compound ---------------- > + H 2SO< Isopropyl alcohol T h is is the basal reaction sought, but the technical impurities of the propylene led to many other undesired products; e.g. isopropyl ether, sulphur dioxide, and an oily product called `isopropyl oil' for want of more specific information about it. A high- boiling petroleum residue was used as a heat transfer agent and also as an anti foaming additive. Leaks of the isopropyl oil on concentrating produced a brown ta r; in addition, a black tar of carbonaceous matter formed on the isopropanol-sulphuric acid solution, which had to be removed before recycling to increase the concentra tion of the alcohol. No arsenic or nickel or iron oxide was present at any stage of the process and the acid fume was not under suspicion. From a consideration of all the products available, both from the occupa tional and experimental points of view, Weil et al. (1952) concluded that the isopropyl oil was the most likely carcinogen. This would seem to imply a potent volatile hydrocarbon, but its nature is not known. T h e conditions might promote some epoxide formation, but one hesitates to suggest more without greater information about the process. It may be recalled that the di-epoxides are among the more suspicious cytotoxic agents. T h e process is now discarded. But it would be most instructive to trace so subtle a car cinogen as must have been present somewhere in the reaction. I CHROMIUM Although the association of carcinoma of the lung with the manufacture of chromates is widely recognized, the nature of the carcinogen is not known. In 1952, Brinton et al. published an analysis of the morbidity and mortality data of sick benefit associations in the United States. They found the cancer mortality among chromate workers to be 4.5 times the expected rate, whilst that for respiratory cancer was 29 times the expected rate. A radiological and clinical examination of 897 chromate workers in six factories (Public Health Reports, 1952) revealed 10 cases (7 white; 3 coloured) of bronchogenic carcinoma. The induction time varied from eight to 39 years, whilst the ages ranged from 40 to 50 (whites) and from 53 to 62 (coloured). Seven of the ten patients had perforated septa. In 1944, Bidstrup (1951) carried out a radiological survey of 724 workers in the chromate industry in Britain. She found only one case of lung cancer, as opposed to an expected incidence of 0.4. Some six years later, Bidstrup and Case (1955) found that 59 of these 724 workers had died and that in 12 cases the cause of death had been given as lung cancer. In addition, two of the workers still alive were known to have cancer of the lung. Using the method of comparative composite cohort analysis, the expected number of deaths from lung cancer was found to be 3.3, as opposed to the discovered 12 cases. The calculated probability against this difference being due to chance was 200 to 1. There was no evidence that factors such as social class, place of residence, or smoking habits had any effect, and it was therefore concluded that a real risk of lung cancer exists in the chromate industry, the interim figure being 3.6 times the mean corrected risk in the general population. There is still no agreement as to the carcinogenic form of chromium. Some hold that it is the hexavalent form-- chromate or dichromate. Others contend that it is the trivalent form as it is found in the ore. T h e great lack so far has been the inability to demonstrate carcinogenicity in the experi mental animal. OCCUPATIONAL CANCER 159 PITCH, TAR, SOOT AND MI NERAL OILS The presence of identifiable skin carcinogens in pitch, tar and soot is now well established, although there may be more present than have as yet been identified. With the widespread and increasing use of mineral oils not only as lubricants but also as `cutting oils' for high-speed tooling, the possible carcinogenicity of the latter has been extensively investigated, having regard to the unavoidable spraying and splashing that contaminate the operatives. Since `cutting oil' formulations contain surface-active agents (emulsifiers), rust-inhibitors, disinfectants and other materials designed to meet special requirements, these also have to be considered. The extensive work of Twort and his colleagues between 1928 and 1939 showed that the most car cinogenic of the mineral oils was shale oil, but none was as potent as tar. Since shale oil is a manufactured oil, however, its potency is more properly compared with cracked petroleum oils than with the naturally occurring petroleum oils which generally are of low potency. In three factories using high speed coolants Cruickshank and Squire (1950) found that one-third of 138 workers had hyperkeratoses and warts, liability to these affec tions increasing with length of service-- another example of the proposition that it is length of exposure rather than intensity which determines the mean induction time of the tumour. Cruickshank and Gourevitch (1952) found from the hospital records in Birmingham that of 37 cases of cancer of the hand and forearm (19 41-50 ) and 34 cases of cancer of the scrotum (1940-48), 30 derived from a population of 88,859 metal workers and 41 from the remaining population of 271,000 (population figures of 19 31). Experimental evidence of skin carcinogenicity led Cruickshank and his colleagues to regard cutting oils as significant hazards and to foretell that as the years pass more and more cases will come to light. In Canada, Mastromatteo (1955) found six cases of squamous carcinoma of the skin and one of a wart in a single machine shop; Gilman and Vesselinovitch (1955) painted used, unused, diluted and undiluted cutting oil formulations on two strains of mouse and induced high proportions of malignant tumours-- so high, indeed, that they are inclined to cast suspicion on the unrevealed additives in the soluble cutting oils. T h ey also found that tumours of very long induction time were induced even with high dilutions, if a strain of mice was used which is hardy, long lived and toxicity resistant. In connexion with the testing of any oil formulation, it is clear from the work of Hieger and Woodhouse (1952) that `it is unsatisfactory to exclude carcinogenicity on the basis of tests on mice only*, since they found that rabbit skin reacts to oil fraction carcinogens better than does mouse skin. Unfortunately, specific determinations of the carcinogens in mineral oils is not yet possible, and biological testing .for carcinogenicity is likely to con tinue for a long time yet. Certain compounds have been isolated in small amounts from mineral oils and found to be carcinogenic to mouse skin. The following two compounds have been known as carcinogens for a long time: (a) 6-isopropyl-1.2-benzanthracene, which produces epitheliomas and warts on mouse skin; (b) 4-, 5-, 6-, methyl chrysenes, which produce local sar comas on subcutaneous injection. They have also been shown to be present in a high-boiling catalytically cracked petroleum. Fisher (1957) has recently reopened the question of the relation between age at entry into a `carcinogenic occupation' and the development of tar- F l6o THE PRACTITIONER warts. From his records in the gas industry, he tends to the view that the higher the starting age the sooner will the warts appear and the greater will be the susceptibility, as measured by the numbers which develop. He ap pears to hold that carcinogenic tars have an ageing effect on the skin, with the resulting greater tendency to develop squamous epithelioma possessed by the skin of old people. Animal experiments do not support such a view and to establish it in man requires an analysis of a very large series of cases. Old skin is thinner, less elastic, more or less atrophic, with less subcutaneous fat, fewer sweat glands, less sebaceous secretion and more liability to lose protective mechanisms against exogenous irritants. In regard to the latter point, it is common experience in the chemical industries to find that after many years of skin resistance to particular irritants, there is a sudden breakdown in the barrier with the development of marked sensitization. This, however, may occur many years before any manifestation of senility of the skin is apparent. It is perhaps permissible to suppose that with in creasing years there is a diminishing ability of the epidermis to metabolize both exogenous carcinogens and external irritants, or there may be a loss of some compound which can combine with such substances and inactivate them. AROMATIC AMINES The carcinogenic aromatic amines which induce occupational cancer of the bladder, renal pelvis and ureter are beta-naphthylamine, benzidine, 4amino-diphenyl and alpha-naphthylamine (probably because of its un avoidable content of the beta isomer). There has been so much clinical and experimental study of this subject in the last ten years, that only the out standing results can be given. For fuller information the reader is referred to the review by Goldblatt and Goldblatt (1956). Just under sixty years after the first cases were described in Germany in 1895, the disease was prescribed in this country under the National In surance (Industrial Injuries) (Prescribed Diseases) (No. 2) Regulations, 1953. The official definition is:-- Primary neoplasm of the epithelial lining of the urinary bladder (papilloma of the bladder) occurring in any occupation involving:-- (a) Work in a building in which any of the following substances is produced for commercial purposes: (i) alpha-naphthylamine, beta-naphthylamine or benzidine or any of their salts; (ii) auramine or magenta. (b) the use or handling of any of the substances mentioned in sub-paragraph (i) of paragraph (a), or work in a process in which any such substance is used or handled or is liberated. (c) the maintenance or cleaning of any plant or machinery used in any such process as is mentioned in paragraph (b), or the cleaning of clothing used in any such build ing as is mentioned in paragraph (a) if such clothing is cleaned within the works of which the building forms a part or in a laundry maintained and used solely in connexion with such works. Although the disease is described as of the bladder epithelium, it is t recognized by the Ministry or its advisers that the tumours may be located in the renal pelvis or in the ureters. This is important because if there is any congenital malformation or other condition which tends to hinder the free OCCUPATIONAL CAfICER 161 passage of urine from the calyces and pelvis into the ureters or from the ureter freely into the bladder, the carcinogen may attack the epithelium in those locations. Further, fulguration of the bladder tumour or tumours or partial cystectomy may later be followed by a pelvic or ureteric tumour at a time when the bladder is clear. Moreover, a unilateral renal tumour and nephrectomy can be followed years later, and after cessation of all contact with the prescribed processes, by a renal pelvic tumour in the remaining kidney, without any neoplasms in the bladder. The occurrence of a non-occupational tumour in a worker who has been exposed to the prescribed processes can rarely be asserted except, perhaps, on the following grounds: extremely short period of exposure; history of non-occupational disease of the same kind; superlatively good conditions in the factory; location of a primary tumour not in the urinary tract; bladder or renal tumour from other identifiable causes. Auramine is a diphenylmethane dyestuff; magenta is a triphenylmethane dyestuff. The inclusion of these materials is based upon a statistical analysis of death certificates and other data of the workers in a nominal roll from the principal dyestuff makers in Britain since 1910, who had made auramine or magenta but had had no contact with any of the other substances men tioned in the prescription. It was found that the number of deaths was significantly in excess and the ages at onset and death were markedly less than was to be expected among the general population. Nevertheless, it is not as yet clear what the effective carcinogens are, although there is slight experimental evidence against auramine. The substances in (a) (i) are bases and it is as base that they constitute the hazard; in the case of benzidine the base character is retained even in the most modern and costly plant; in the case of alpha-naphthylamine an almost automatic conversion to an innocuous compound is effected, but some base may still be necessary; for beta-naphthylamine a process is available which eliminates all carcinogenic hazard. The word `liberated' arose from the use in the rubber industry of an anti oxidant which contained a small proportion of free beta-naphthylamine, the latter being liberated during the process of vulcanization of the rubber articles. The result, over a period of years, was a considerable number of bladder cancer cases among the rubber workers. In the United States a compound similar to benzidine, 4-amino-diphenyl, was manufactured for a number of years and used for the preparation of a rubber anti-oxidant. This compound has since been found to be a powerful carcinogen and has led to a high proportion of bladder cancers. Since the amine was not free in the anti-oxidant, no cases of bladder cancer arose among the rubber workers or among dogs to which the material was fed. In former times laundrymen were in hazard when they dealt with the heavily contaminated working clothes of process men, and developed bladder tumours. Nowadays very high-grade laundries are installed in the factories and the small amount of contamination, if any, of the suits of working ! I &2 THE PRACTITIONER clothes issued to the process men should offer no danger to the laundrymen. C A R C I N O M A OF T H E B L A D D E R The attack on the bladder is made by metabolic products of the prescribed substances; this occurs within the bladder, renal pelvis or ureter and not via the blood stream. The effective carcinogens are probably ortho-hydroxy derivatives of the amines. These are excreted by the dog in the form of sulphate ester and other metabolites are present only in minor amounts. On the other hand in man, mouse, rat and rabbit, the patterns of excre tion are similar and quite different from that of the dog. The dog is highly susceptible to these amines. Man is also highly susceptible, but the rabbit, mouse and rat are not. There is some possibility that the urinary precursor of the ortho-hydroxy amine is the glucuronic acid conjugate. In much of the most modem work the long-drawn-out feeding experiments with presumed bladder carcinogens has been, in part, replaced by direct implantation into the bladder, the material being incorporated in pellets of suitable non-carcinogenic vehicles, e.g. paraffin or cholesterol, from which slow diffusion takes place into the bladder wall. Using mice, it has been possible to distinguish the relative potencies of a great many compounds as bladder carcinogens and to test the possible precursors of the effective agents. One result of this kind of experiment has been to show that, on the whole, the primary amines as such are not effective carcinogens; but not all are completely inactive. Methods for detecting carcinogenic properties (e.g. oral, implantation, skin-painting, subcutaneous injection) all rest on the belief that a positive result in animals should be interpreted as indicating actual or potential carcinogenicity in man. There are many dilemmas in this, not the least of which are the vastly varying susceptibilities of different species and tissues. Had there been no dogs in the world, there would still be much argument about the bladder carcinogenicity of these amines, until a significantly responsive animal had been found, to which man then would have been equated. This point is mentioned here because of the apprehensions felt nowadays about food additives of very different kinds. If, for example, a food colour produces a local tumour on subcutaneous injection, or if it can be metabolized by animals to yield a carcinogenic amine, or if it induces metaplasia or neoplastic change on implantation in the bladder of mice or the vagina of rats it is at once condemned and expunged from the proposed permitted list of food colours. We cannot but subscribe to such a decision but what it means in terms of man is not a question one should expect to be answered. Arising out of the ortho-hydroxy amine theory of occupational bladder cancer, a suggestive hypothesis has been proposed for the etiology of nonoccupational bladder tumours. Fishman and Anylan (1947) found that human cancer tissue possesses greater glucuronidase activity than normal tissue adjacent to it. Boyland et al. (1955) found that the urine of patients iwith cancer of the bladder possesses notably increased sulphatase and glucuronidase activity and anticipated the later finding by Boyland and Williams (1956) that such urine contains much more of certain metabolites OCCUPATIONAL CANCER 163 of the essential amino-acid, tryptophane, than normal urine. Thus* whereas the normal daily excretion o f"3-hydroxy anthranilic acid is about 30 mg., the bladder cases excrete up to about 15 0 mg. This, and some other meta bolites of tryptophane, were found by Boyland and Watson (19 56 ) to induce carcinoma of the bladder. 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