Document bBnNgDMKBB39JxZRgy79bn2xk

FILE NAME: ALCOA (ALC) DATE: 1959 Sept DOC#: ALC044 DOCUMENT DESCRIPTION: Medical Journal Article - Occupational Cancer The Ohio State Medical Journal Published under the direction of The Council for and by the members of The Ohio State Medical Association, a scientific society, non-profit organization, with a definite membership, for scientific and educational purposes. Voi. 55 September, 1959 No. 9 P erry R . A y r es, M. D ., E d ito r Ch arles S. Nelson, Managing Editor -- Bus. Mgr. R. Gordon Moore, Asst. M anaging Editor Occupational Cancer T. M. FR A SE R , M. B ,, Ch. B., B. D. DINMAN, M. D., and W. F. ASHE, M. D. H isto rical OUR K N O W LE D G E o f cancer of occupa tional origin dates from 1775. In that year, when this country was occupied with more cogent matters, Percivall Pott described in words that belonged to a more elegant genera tion a disease peculiar to chimney sweeps, which, as he put it, "always makes its first attack on, and its first appearance in, the inferior part of the scrotum, where . . . it pervades the skin, dartos, and membranes o f the scrotum, and seizes the testicle which it inlarges, hardens, and renders truly and thoroughly distempered; from whence it makes its way up the spermatic process into the abdomen, most frequently indurating, and spoiling the inguinal glands; when arrived within the abdomen, it affects some o f the viscera, and then soon becomes painfully destructive." With these words, Pott, whose name has been preserved more vividly in the orthopedic fields, described the first recorded instance o f occupational cancer, of a type which in the 1920's still produced nearly 10 per cent of the cases of scrotal cancer in England. In 1794 came the next step when Benjamin Bell observed that scrotal cancer from soot could develop in persons who were not chimney sweeps; and in 1882, a further occupation was in volved when Paris, in findings that have never been confirmed, incriminated arsenic as the cause of skin cancer in the copper smelting and tin refining industry. In 1875, scrotal carcinoma from a different Presented before the Section on Industrial Medicine at the Annual Meeting of the Ohio State Medical Association, Columbus April 21-24, 1959. for September, 1959 The Authors Dr. Fraser, Columbus, is an officer ol the Royal Canadian Air Force and presently a Resident in Aviation Medicine, Department of Preventive Medicine, The Ohio State Univer sity College of Medicine. Dr. Dinman, Columbus, is Associate Profes sor, Department of Preventive Medicine, The Ohio State University College of Medicine. Dr. Ashe, Columbus, is Professor and Chair man of the Department of Preventive Medicine, The Ohio State University College of Medicine. source was observed by Volkmann in Germany, who described three cases among workers en gaged in separating paraffin from coal distillation, and four years later a new clinical field was en tered when Hrting and Hesse reported the contro versial Schneeberg cancer of the lung, the symp toms of which had perhaps been described by Paracelsus 350 years previously (1 5 3 1 ). By the turn of the century several other oc cupational cancers had been described or speculated upon. Unna, in 1894, suggested that the hyperkeratotic and malignant skin lesions o f sailors were due to excessive exposure to the sun, and in 1895 came the first description by Rehn o f blad der cancer in the dye industry, X -ray was in criminated early in its development when Frieben described resulting skin cancer in 1906, and the effects of ionizing radiation were again recognized when Maitland found bone sarcomas in radium dial painters in 1929. 1217 Still other industries began to be involved, chromates, for examples, being suggested as a cause o f lu n g cancer by Pfeil in 1911 and con firmed by M achle years later, while in 1932 G ren fell fou n d lu n g and sinus cancer in certain nickel workers, and three years later Lynch and Smith reported a high incidence in asbestos work ers. Further, as a puzzling entity, W eil reported paranasal sinus cancer from isopropyl alcohol in 1952. These are by no means all o f the cancers whose origin has been attributed to occupation. Legal files are filled w ith allegations o f cancer produced by a single trauma. It has been suggested that exposure to carbon tetrachloride in the dry cleaning industry leads to cirrhosis with a high incidence o f hepatoma. Leukemia has been blamed on benzene and on x-ray exposure. Rub ber has been suggested as a cause o f brain tum ors, etc. H ow ever, these latter suggestions w ould appear to have been based more on a dubiously founded theory of proximate cause, than on a critical and adequate review o f the data. N evertheless it is evident that occupational cancer exists, and before we can prevent it or protect against it, it behooves us to learn how many varieties there are, to observe where they occur, and to define the etiology as precisely as possible. Eckhardt's recent book Industrial Carcinogens states that o f the cancers proved to be o f occupa tional origin , 75 per cent involve the skin, 15 per cent occur in the bladder and 10 per cent occur in lung, bone, paranasal sinuses and larynx. Skin O f the 75 per cent of occupational cancer in vo lv in g th e skin Eckhardt states that 60 per cent comes from exposure to coal tars and 3d per cent fro m exposure to shale oil. H y d ro c a rb o n s: T h e early studies in England presented a confusing picture because scrotal can cer occurred in apparently unrelated occupational grou p s: Chimney-sweeps, mule spinners in cotton m ills, the coal gas industry and Scottish shale pits. . T o com plicate the problem of correlation ot these apparently unconnected occurrences numer ous other factors were found to enter the picture, such as: rt. T h e susceptibility to the development of skin cancer appeared to vary from individual to individual; b. T h e ' time o f exposure required for its de velopm ent appeared to vary from as little as four m onths in the case o f bituminous shales to as m uch as 50 years in the case o f British lubricating oils; 1,2 1 c. In some individuals the appearance of skin cancer w ould not manifest itself until long after exposure ceased. ' A s a further complication it was discovered that the carcinogenicity of these substances ap peared to vary with their geographical source, the European, M iddle and Far Eastern oils and tars being more carcinogenic than the American, and the Scottish shale oils being more carcinogenic than the other European. Consequently inquiries carried out in the earlier days in Europe and the U. S. A. on the basis of the English reports showed a relatively low in cidence o f skin cancer from these substances. Thus, because of the interplay o f many different factors it took some little time before the common factors were observed in soot, pitch, tar, mineral oil, and various petroleum tar distillates. W ith the discovery by Yam agiwa and Ichikawa in Jap an in 1915 that cancer could be produced in anim als by prolonged inunction with coal tat, a great step forward was made; and in 1928, Twort and In g published the results of their investiga tion into the carcinogenicity of various lubricating oils, showing that while sperm oils were harmless, petroleum oils possessed some carcinogenicity and Scottish shale oil was twelve times as dangerous as the petroleum oils. They also observed that the hazard of the petroleum oils varied with the boiling point o f the fraction, the higher boiling series being greater than the low. T h e greatest advance, however, came in the 1930's when Shear and Andervont,18 while in vestigating the polycyclic hydrocarbons, discovered that the synthetic substance 1, 2, 5, 6-dibenzan thracene was carcinogenic, while Cook, Hewett, and Hieger went on to isolate from carcinogenic coal tar the related substances 3, 4-benzpyrene, and methylcholanthracene which they also showed to be carcinogenic, the former being considerably m ore potent than the dibenzanthracene. Kenn- away, in England, went on to demonstrate that carcinogenic activity was not restricted to the polynuclear aromatic hydrocarbons but was shared by other substances such as the benzacridines, benzocarbazoles, the aminostilbenes, the amino- phenyls and numerous other compounds. T h e carcinogenic subclasses o f polynuclear hy drocarbons can, however, be clearly related to their parent substance phenanthrene. The evidence in dicates that the carcinogens so developed may com bin e with cellular substrates in the body and lead either directly or indirectly to the elimination of certain key proteins or enzyme-proteins essential in the regulation of normal growth. H ow then do we fare today in the occurrence . o f occupational skin cancer from oil or tars? It The Ohio State Medical Journal is, o f course, relatively more common in England and Europe than in the United States, Heller10 showing in a study he carried out for the Rocke feller Foundation that the incidence here is rare. Cases, however, continue to occur throughout the world, the highest incidence arising in workers with cutting oils whose constituents, namely ani mal, vegetable, and mineral oil with added agents, vary widely accordingly to use. The active agents in cutting oils of mineral origin, nevertheless, have been shown to be the now fam iliar 3, 4-benzypyrene, and 9, 10-dimethyl-l, 2-benzanthracene, and consequently a degree of hazard continues to exist that warrants a continuing drive to have such oils replaced by inert materials.8 In the coal gas industry, which fortunately is uncommon in this country, and in the shale oil industry, nearly 4,000 cases had been reported in England by the middle of this century, and of those cases o f occupational skin cancer that have occurred in this country approximately 70 per cent have been associated with the handling of gas works tar and pitch. In the petroleum industry, however, a greater danger arises-- that from the ''so-called" "slack waxes" that remain after the processing of para ffin wax, in wax or paraffin presses. These have been shown to contain some unsaturated aromatic hydrocarbons which can be highly carcinogenic, and on occasion have given rise to a clinical lesion. In addition, some of the aromatic components of high-boiling fractions o f petroleum have been shown to be carcinogenic, as have some of the tars prepared from petroleum by catalytic crack ing processes. Fortunately, the degree of carcino genicity o f the latter is by no means as great as that of a high temperature coal tar. Eckhardt20 states that 60 per cent of occupa tional skin cancer comes from exposure to coal tars, and 36 per cent from exposure to shale oil. Today, knowing much about the where, when and why o f these occupational skin cancers, preven tion is now possible, A rsen ic: We know far less about the other 4 per cent o f occupational skin cancer. Arsenic was incriminated as a carcinogen in 1887 by Jonathan Hutchison whose opinion has been confirmed to a limited extent by others. Arsenic is now re garded as a cancer-auxetic, i. e. a substance which provokes changes in epithelial cells predisposing towards cancerous change. The occurrence of car cinoma associated with exposure to arsenic has been observed particularly in the manufacture and use o f sheep dip, where a squamous cell car cinoma may be produced after many years of exposure. It has in addition been noted after prolonged medicinal treatment and has been for September, 1959 shown in Europe to occur from the constant presence of arsenical dust on the skin. Fortunately, as with other occupational skin cancers, prompt excision is usually effective, and can be prevented by scrupulous attention to the personal hygiene of workers so exposed. N itrates: As far as other inorganic compounds are concerned the nitrates have been reported in Chile as a source of occupational skin cancer by Prunes18 who describes a hyperkeratosis which after 10 to 30 years may undergo carcinomatous change. However, since only 17 cases have oc curred among 30,000 workers over a 9 to 10 year period in Chile, further evaluation of this agent as a carcinogenic material is indicated. Physical A gents: T h e best known physical agent implicated in carcinogenicity is ionizing radiation. The effects and dangers of radiant energy from x-ray and radioactive compounds are well known. It should be remembered that in addition to the therapeutic use o f such agents, with consequent exposure o f both patient and ther apist, there is an increasing use of powerful radio active sources in industry fo r such purposes as inspection of manufactured parts, tagging of com pounds with radioactive isotopes, manufacture of luminous paints, oil surveys, etc. Thus there is an increasing risk of exposure which, if prolonged, might give rise in some cases to malignant change. In the early days of investigation into the ef fects of radiation numerous instances of malig nant change developed in the skin following dermatitis or ulceration, with occasionally the de velopment o f osteogenic sarcoma following expos ure to ingested internal emitters in addition to the more common effects o f excessive exposure. But as the hazards were slowly recognized the subsequent precautions which were devised slowly reduced the incidence of malignancy to a negligible amount. However, the danger still exists, and in the per haps less rigidly controlled industrial situation the potential danger becomes all the greater. Both heat and ultraviolet light have been blamed for skin cancer, but in neither instance has there ever been proof that the incidence of skin malignancy among employees with such exposure exceeds that in the general population relatively free of such exposures. Local trauma of a con tinuing nature, such as the rubbing of a basket or hod on a particular part certainly predisposes to or causes cancer at the site in a very limited segment of the w orld's population. Bladder The history of occupational carcinoma of the bladder dates back to the origin o f the German synthetic dye industry in the latter part of the 1219 last century, when the accidental discovery o f the dye, m agenta, led to the development of the vast com plex that constitutes the present-day chemical industry. T h e condition was first observed by Rehn in 1895, who dem onstrated to his skeptical colleagues the occurrence o f bladder carcinoma in a series of dye workers. The causal agent he con sidered to be aniline, a view that was held for many years, although more recently it has been conclusively shown that pure aniline in itse lf is noncarcinogenic, although it may in an apparently pure state be contaminated with carcinogenic m aterials. I'or som e time afte r the initial discovery the re ports o f these tum ors were confined to Germany, but with the expansion of the British synthetic dye industry during W orld W ar I cases began to ap pear in Englan d in the 1 9 2 0 's, and by 1931 what would ap p ear to b e the first American case w as reported. D espite stringent precautions in the in ' dustry, tum ors continued to occur, and in 1954, Case and his colleagues in a remarkable statistical study o f mortality in England and W ales during the period 1921-1950 showed that the overall risk of death from bladder carcinoma in workers en gaged in the m anufacture o f dyestuffs was 30 times that o f the general p opulation .5-6 However, along with the development of the dye industry, research into the causal agent w as proceeding in G erm any, England and the U . S. A , and befo re long it w as etsablished that the aro matic com pounds w ere those responsible. N um erous com pounds were incriminated, including aniline, toluidine, xylidine, benzidine, the naphthylam ines, etc., but o f recent years it has become accepted that although other carcinogenic agents exist in the dye industry the naphthylamines, particularly the beta isomer, are the prim ary culprits. Occupational carcinom a was first attributed to the naphthylamines in 1898, but after W orld W ar I beta-naphthylamine became accepted as the cause cm epidem iological grounds, some 10 years before bladder tum ors were produced by it in d ogs by H ueper an d W o lfe. Both the alpha and beta isom ers are common dye intermediates, de veloped during synthesis o f the various dyes, and beta-naphthylam ine, at least, has been shown to be carcinogenic to anim als. Some controversy ex ists over the carcinogenic properties of the alpha isom er which can be separated in its pure state from the beta only with considerable d if ficulty, but it is generally believed that any re su ltin g carcinogenicity arises from associated betanaphthylam ine which may contaminate it up to 5 per tent. T h e discovery o f diazotization by G riess in 1858 led to the development o f the azo dyes fo r which new aromatic bases, including the naphthylamines were required. Benzidine, chemi cally related to the azo dyes, and incriminated as a cause for many years by M aguigan, is known to be carcinogenic to rats and dogs, and has been conclusively shown in the statistical study o f Case and his colleagues in England to produce a high incidence o f bladder tumor in man. The azo dyes themselves, although evincing no evidence o f carcinogenicity in man, have been shown experimentally to be carcinogenic to animals-- o- aminoazotoluene, and 4-dimethylaminoazobenzene (butter yellow) producing liver neoplasms in rats and mice, and bladder tumors in dogs. The aniline dyestuffs, auramine and magenta do not appear to be carcinogenic per se.18 The tumor which develops from the aromatic compounds in man is of relatively low grade, and its development is influenced to some extent by the age at which exposure begins, there being a slightly increased susceptibility in older men. It generally develops in those susceptible some 4 to 18 years (average-- 16 years) after initial ex posure, the required duration o f the latter being approximately one year. As far as the mode of action on the genito urinary system is concerned, the compounds dis cussed above, although established carcinogens, do not appear to make their attack in the form in which they are absorbed. T h e action occurs within the bladder, renal pelvis, or ureter, and not via the blood stream, and appears to be af fected by metabolites of the substances concerned. The effective carcinogens are probably hydroxy derivatives o f the amines, to which man is highly susceptible. Since this susceptibility is not shared with the common experimental animals there is considerable difficulty in producing the tumor in the laboratory. There is some evidence that th urinary precursors of the orthy-hydroxy-amines are the glucuronic acid conjugates.7 ' Boyland8 has linked this ortho-hydroxy theory with the metabolism of tryptophan, and has shown that one o f the metabolites o f tryptophan, 3-hy- droxy-anthranilic acid, which is greatly increased in bladder carcinoma, is itself highly carcinogenic, and suggests that this is the active causal agent in the occupational carcinoma o f the bladder. The dye industry, however, is not the only source o f carcinogenic aromatic amines. In 1954, W alpole and others10 in England showed that the compound 4-aminodiphenyl, used in the manu facture o f a rubber antioxidant, was a highly potent carcinogen, and shortly thereafter Melick14 and his colleagues in the United States showed that a high incidence of workers where this com- The Ohio State Medical Journal W5KSR pound was made from 1935 to 1955 developed bladder carcinoma, although the rubber antioxi dant produced from it does not appear to be car cinogenic. In addition, another compound, 2acetoaminofluoride, used as a commercial insec ticide has been shown to be carcinogenic. responsible for carcinogenesis. On the other hand, Koven et al., suggest that acid-soluble, waterinsoluble compounds in chromate ore ate the etioiogic agents. At this time one may conclude that the specific etioiogic agent is not known. In Britain also, the incidence appeared to be Respiratory Tract When considering occupational cancer of the respiratory system, which in this context includes the tract from the nose and paranasal sinuses to negligible until 1955, when Bidstrap and Case1 showed in a statistical study that the incidence of lung carcinoma in chromate workers in the pre vious six years was four times greater than expected. the alveoli, it is pertinent to observe that there has been a considerable overall increase in the incidence o f lung cancer during the past 25 years. How much of this is due to improved As with other occupational cancers, the latent or induction period may be very prolonged, often as much as 20 to 30 years, and in some instances the tumor has appeared long after exposure ceased. diagnosis and greater frequency of autopsy and N ickel: Nickel, which is known for its ten how much to atmospheric pollution, increased dency to produce a sensitization dermatitis, has exposure to occupational carcinogens, and other also been incriminated as a potent carcinogen. as yet unknown factors can only be a matter of A significantly higher incidence of respiratory opinion. And, because of a paucity of experi- carcinoma has been shown to occur in workers in f | mental evidence that points conclusively to any the nickel industry, the carcinoma chiefly affect specific compound, it has become more and more ing the mucous membranes o f the nose and air necessary in analy2ing the occupational factor to sinuses, although sometimes found as a bronchial rely on the results of the long-term controlled carcinoma. Several theories have been propounded statistical study. However, much can be gained to explain the occurrence o f these tumors, all of in this type o f study and several compounds will them handicapped until recently by lack of ex be discussed that have been shown to be asso perimental confirmation.' The original theory that ciated with a significantly increased incidence in the responsible agent was a metallic arsenide cancer among those exposed to their hazards. formed from associated compounds has been dis Chrom ium : Chromium compounds have long carded largely because o f a total absence of any been known to produce chronic ulceration, der other evidence Of arsenical poisoning. matitis, and caustic effects, giving rise to the well The favored theory relates the occurrence to known "chrome holes" (perforation of the nasal the Mond process of nickel preparation in septum ), chrome dermatitis, and chrome burns. which nickel carbonyl is heated to drive off the These, however, are not followed by neoplastic carbon monoxide and allow the deposit of finely change and it was originally thought that chrom divided nickel. It is suggested that thereafter ium had no carcinogenic properties. In 1936, the nickel carbonyl, which hydrolizes in water to however, some 25 cases of pulmonary carcinoma nickel and carbon monoxide, or finely divided were recognized in Germany in men who produced elemental nickel, is inhaled and deposited at sites chromates from chrome ores and residues, and suitable for the production of the tumors. A l in those who used chromates in tanning, plating though previously it has not been found possible and similar procedures. to produce tumors in animals from nickel except Until 10 or 15 years ago there were few reports by parenteral administration, this theory in 1958 of cases outside Germany, but in 1948 Machle and found support from H ueper11 who managed to his colleagues14 published a study of incidence in produce adenocarcinoma in animals exposed to the five chromate-producing companies of the fine nickel dust. United States showing that the death rate from A sbestos: There is no experimental evidence respiratory cancer in the chromate industry was 16 times higher than expected. They further at this time to suggest that asbestos is carcinogenic in any form. It has been shown statistically in showed that the incidence o f nasal irritation did England, however, that there is a high incidence not parallel the incidence of lung carcinoma and of lung cancer in asbestos workers known to be that the incidence of lung carcinoma varied from suffering from concurrent asbestosis, D o ll in 1955 : plant to plant in populations that were otherwise noting in a study o f men who had worked 20 l similar. Investigating further they concluded that years or more in the asbestos industry that the the difference in incidence lay in the nature of the incidence of lung carcinoma was 10 times that ; compounds handled and consequently suggested expected, while in the official statistics of the that the monochromates may be the compounds Chief Inspector of Factories and Workshops in for September, 1959 1221 1955, 22 per cent of 222 men and 12 per cent of 143 women showed combined asbestosis and car cinoma.8 T he induction period appears to be very long and the tumor is highly malignant. Although claimed by some that any tumor from asbestos is the result of simple irritation, it has been observed by Bonser, Faulds and Stewart2 that in the exposure of both the asbestos worker and the iron ore miner, in each of which a high incidence o f pulmonary carcinoma is noted, there is a common factor of silica-induced fibrosis which in each case precedes tumor formation. They 1 suggest that in the one situation fibrous asbestos, and in the other iron oxide, modify the action of silica such that the silica acts more as a ; carcinogen and less as a fibrosing agent. ' Dissenting voices however still refuse to ac cept asbestos as a carcinogen, and in a recent article Braun and Truan4 report an epideminologi- cal study o f asbestos workers in Canada, showing that the incidence compares favorably with that in other workers. It should be noted, however, that the asbestos exposed to these particular min t ers was obtained from chrysolite, while that asso : dated with lung cancer is usually derived from hornblende. Iro n : A s mentioned in connection with as bestos, an association has been shown between siderosis and pulmonary carcinoma, statistics from Germany and England indicating that the in cidence o f carcinoma in hematite or iron ore workers is approximately two and one-half times as frequent as in the general population. How ever, in view of the frequency of the siderosis of welders one wonders why more cases of pulmonary carcinomata are not seen in this group of workers if the foregoing reports are true. B eryllium : Of perhaps more immediate local interest is the metal beryllium, noted for its wide complexity o f toxic effect in extremely minute P dosage. Although it has been known for some time that osteogenic sarcoma could be produced by injection of beryllium it has not been possible until recently to demonstrate any carcinogenic ef fect by experimental exposure analogous with that of normal occupational use. However, recently Vorwald17 has shown that, under certain circum stances of prolonged inhalation, experimental ani m als could develop pulmonary carcinoma, and thus another hazard has been added to an al ready highly toxic material. A sph alt, Coal Gas, Coke: In other fields, dust from asphalt paved roads has been incrimi nated as carcinogenic, and there was a suggestion 10 years or so ago from British investigators who examined the mortality statistics of pensioned gas- workers, that prolonged exposure to coal gas and coke predisposed to respiratory cancer; further studies, however, in 1956 could not confirm this, although it was suggested at the time that a change in processing of the coal gas could have altered the incidence. An interesting situation arises, too, among workers in coal and graphite. Investigators12 in the Welsh coal fields have shown that there is a significantly lower incidence in lung cancer in coal miners than in the general population, and that where massive fibrosis and cancer are found in the same lungs it is relatively unusual to find the two conditions in apposition to each other. This suggests that there is an antagonism be tween the carcinogenic process and the tuberculous process of progressive massive fibrosis. Atmospheric Pollution: Occupational expos ure to potential carcinogens is, however, only one factor in the etiology of lung cancer, and there are other fields requiring, and receiving, urgent exploration, notably that of general atmospheric pollution, and in particular, the smog pollution of Los Angeles, London, Pittsburgh, and the like. How much of the hazard so discovered will eventually be laid at the door of industry is as yet a matter of speculation. Conclusion Cancer of the skin, bladder, and respiratory tract under some circumstances are of occupational origin. In many instances the specific etiologic agent is known. When such is the case complete prevention is possible and must be applied. There are many areas of confusion concern ing the occupational origin of certain cancers. Litigation in the courts of law has muddied rather than clarified the waters. We are of the opinion that there are a number of cancers of occupational origin as yet unrecog nized and with advancing technology there will be others. To recognize these, it is necessary to have excellent epidemiological data on the incidence of cancers of all types, in all organs, by age and sex in the general population and not just per 1,000 hospital admission. Against these data the critical industrial physician must plot the incidence in specific employee groups. These data will provide the clues necessary to initiate defini tive research. Scientific proof of cause should be the only basis for the approval of occupational claims and can be the only effective basis for prevention. The hiding of evidence that can justify this proof is to be condemned and perhaps should be countered with strong legal measures. References 1. Bidsttup, P. L ., and Case, R. A, M .: Carcinoma of Rang in Workmen in Bichromate Producing Industry m Great Britain. 1222 The Ohio State Medical Journal