Document LoyJpBzLDxNGXXdGveYQXqen7

FILE NAME: Kent (KNT) DATE: 1951 Feb DOC#: KNT121 DOCUMENT DESCRIPTION: Journal Article - Environmental Lung Cancer Industrial Medicine and Surgery  Feb %$/ ,. \0b L INDUSTRIAL MEDICINE a n d SURGERY %" The Jou rnal o f bledicine in I-ndustri/ itk k ic k r cooluL *t*4 *Tk lu 4u **ri*i D octor* 4 * In l ro lio n a I Jou rn al o i M die And 5 u f^ * r r ' >:'> ............... -- ' Yoimm* 20 FEBRUARY 1951 Number 2 tv>u \ Environmental Lung Cancer 1^^'. ?r r*." W . C ^H U EP ER , M.D. Cancerigenic Studies Section National Cancer' Institute aic- Bethesda, Maryland V>"T;' -J' ' M; /"'ANCKR of the respiratory tra c t had a relaV--' tively m inor role in the cancer problem before the turn of the century but has become of major importance because of the rapid rise in the frequency of these tumors during the lung cancer occurs most often. Since approxi mately 77 % of all lung cancers occur during the ages of 40 to 69 years (M atz), the rise of this age fraction of the population from 18.9% in 1375, to 21.6% in 1900 a n d - 29.9% in 1940 * U" last three to four decades (Simons: Schinz; (Sixteenth Census, U.S., 1940), was bound to jL v . Mason; Kennaway; Heady and Kennaway; be reflected in a corresponding increase in the ;jl'- Gemmesen and Busk; Dorn; Herbut and Clerf; Steiner;.1 In fact, in a few areas death from number of lung cancers during the last four decades. However, Dorn as well as Potter, I., cancer of the lung threatens to displace cancer found in their recent statistical analysis of can of the stomach as the most frequent cause of cer deaths in the United States th a t there had ^Vath from cancer in males. Many investigators occurred a consistent rise in the frequency of { Insider the recent increase in the frequency of lung cancer deaths after eliminating the effect ding cancer as purely apparent, attributable to of changes in the age composition. Potter stated fi the marked s h ift in age distribution of the popu th a t this annual increase amounted to 5.8% for lation. to improvements in diagnostic methods, males and to 2.1 % fo r females d u rin g the years to greater interest of the medical profession in 1933 to 1944. According to D orn's calculations cancers of the lung, and to a change in the ratio on this point, the annual percentage increase y of lung cancers to all cancers because of a re was 10.5% for males and 8% fo r females be duction of deaths from cancers of other organs. tween 1914 and 1931, and 8.5% for males and However, this concept is not shared by some 2.5% fo r females between 1931 and 1940. Since investigators, who feel th a t a t least a p art of almost all lung cancers are fatal, mortality rates the increased frequency of lung cancers is due and m orbidity rates are practically identical. to an alteration in the environmental canceri- In view of the observation of this increase in genic spectrum, sta rtin g some 75 years ago. the autopsy m aterial of many large European related to new occupational hazards and newly hospitals which had for many decades an econo acquired habits (H alperti. Although critical mically rather stable patient population, a con review of the available evidence does not permit sistently high autopsy rate and a competent a definite conclusion concerning the general pathological sendee, there is little reason to a t question as to the real or apparent nature of tribute an appreciable portion of this develop the rise in lung cancers, it provides much c ir ment to improvement in medical sendee and cumstantial and conclusive evidence regarding recording. The consistency and increment of the the role which environmental cancerigenic trend, moreover, would not support such an ex j agents apparently play in the causation of these planation. tumors. It was noted, on the other hand, that the time Circumstantial Evidence of onset and degree of the lung cancer rise varied considerably in different countries (Ca- Merical Increase of L ung Cancers: With- solo), and in different p arts of the same coun T . out doubt the rapid prolongation of the try (F isch er >. This observation seems to ex average life span ha3 brought in recent decades clude the possibility that racial and hereditary S.( -many more persons into the age group in which factors played an im portant role. The available 'i. I D e. H v i ^ f i j rvfervnr a n in a datailad aziS statistica l'evidenc e suggests, therefore, th at any btbltot-rauhy of w hich a corry m ay bw o b tain ed by real in crease in the frequency of lung cancel's w rttin r him at C a n c e n y y fu c StL*ii*a S e c tio n . C a n c e r C o n tro l S c in c h . U .S . TS1111 H e a lth S e r v ic e . N a tio n a l I n i t it u t e <r( Health. Bethew U H . M aryland. if such has occurred, may most likely be ascribed to the action of exogenous factors which en- " ,.,g * \ : ~ < ; T'i'i: W -c 1 ' <*,-T*-* -! \nri v.-~ 'v T & Page 50 IN D U S T R IA L M E D IC IN E AND SURGERY F ebruary, 051 tered the human environment during the last half century. This conclusion receives some support from the fact th a t the m ajority of more recently discovered environmental cancerigens cause cancers of the respiratory tract, while those previously established mainly af fected the skin. DlSTKtBUTiON: There is general agreement that lung cancers are more frequently pres ent in males than females. Since the consider able rise in the occurrence of lung cancers dur ing the past four decades has been accompanied by a definite shift in the sex distribution of the lung cancer in favor of the male sex, the in crease in lung cancer incidence seems to depend on agents to which males become exposed more often or more intensely than females and which are essentially unrelated to endogenous, sex con ditioned factors. This conclusion is supported by the fact that the male-female sex ratio of lung cancer ex hibits remarkable local differences varying be tween 2:1 in Sweden (Henschen) to 20:1 in p arts of the United States (O 'Keefe), while averaging most often 5:1 to 10:1 (Fulton: 7.3:1 in 1610 cases). Clemmesen reported from Den mark that a shift in the male-female sex ratio has occurred there during recent years, after having stood at 5:4 in 1931, it changed to 3:1 in 1945 and is expected to become stabilized at a ratio of 8:1 in the near future. An exogenous origin of the sex differential of lung cancer is suggested Ynoreover by ob servations made in connection with occupational cancers of the respiratory tract. Merewether found that the male-female ratio of asbestosis cancer stands a t 2.4 to 1. This ratio illustrates the trend toward an equalization of incidence rates of cancer for the two sexes whenever the conditions of exposure to an environmental cancerigen tend to become identical. Highly ex cessive incidence rates of lung or nasal sinus cancers among males, on the other hand, exist whenever for occupational reasons contact with exogenous cancerigens is restricted to members of the male sex. such as workers in chromate factories, in radioactive mines, and in coppernickel ore refineries. TLTlSTOLOGrCAL Types: Sex and Age DistribuA tion: Probst stated that, in recent years, there has been a shift toward a more frequent occurrence of epidermoid cancers in pulmonary malignancies of unknown etiology. This ob servation may be related to the proportionally greater increase of lung cancers among males than females, because squamous cell cancers and round cell cancers predominate in males, while adenocarcinomas are more frequent in females <Proe. F irst N at. Cancer C o n fJ . The sex dis tribution of the various histologic types of lung cancers according to this source, is as follows: Males: 44 G epidermoid type. :i8r r undifferenti- ated type, and 18f:c adenocarcinomatous type; females: 11 rc, 37!c, and 52 % respectively. While Hollingsworth recorded a similar sex dis tribution of adenocarcinomas. Mason noted that adenocarcinomas were present in this series in 6.7 % of the male cases and in 13-7r of the fe male cases. Lingskog, on the other hand, re ported th at adenocarcinomas occurred with equal frequency in both sexes, and th a t all adeno carcinomas observed were present in individuals below the age of 40. A sim ilar dependence of adenocarcinoma on the age of the individual was noted in the pro ceedings of the First National Cancer Confer ence. The proportion of adenocarcinoma dropped from 3 0 c,'c in the age group 0-49 years, to less than 20% in the age group 60 years and over. There was a corresponding rise in the propor tion of epidermoid carcinomas, while the un differentiated type of cancer seemed to be un affected by the age factor. Gebauer reported th a t adenocarcinomas originate in DO'A from the secondary and small bronchial branches, while the majority of the undifferentiated and epider moid cancers develop from the main bronchial branches. The proportion of the various histologic types of bronchiogenic carcinomas thus appears to dif fe r according to sex and age as well as to their topography in the bronchial system. Their rela tive sex distribution moreover seems to vary' with different investigators and thus with dif ferent areas studied. Again, it is not conceivable th at such variations in the biologic and anatomic manifestations of lung cancers are due to endo genous causes, while they would find a ra th e r ready explanation in differences of exposure to exogenous agents of various types i Lindskogl. R acial D istribution: Although neither Jaff nor Steiner observed any significant differ ences in the distribution of lung cancers be tween whites and Negroes in the Chicago area, other investigators noted that pulmonary can cers are more frequent in whites than in Ne groes (Arkin and Wagner; Quick and Brindley. H a lp e rt). Likewise, Khanolkar, reporting on the organ distribution of 3,263 cancers of a Bombay hospital, does not mention lung cancer among the eight types of cancers listed that account for 2,652 cancers evaluated. However, until proper standardization as to age and sex has been made, these observations convey no valid information as to differences in racial suscepti bility or special types of exposure to exogenous cancerigenic agents, coinciding with regions populated by different races. The various kinds of circumstantial evidence evaluated support the concept that environmen tal factors are involved in the production of cancers of the respiratory' tract, especially the lung ('Boycott). While the actual extent to which exogenous agents seem to be active in. the production of these tumors among the gen- YOU 20, No. 2 INDUSTRIAL MEDICINE and SURGERY Page 51 nd population, and the nature of such agents cannot be deduced from the inform ation a v a il- " able, observations made in the field of occupa tional cancerigenesis permit a more definite and specific, although also more limited view of these aspects of environmental cancers of the respiratory organs. Conclusive Evidence I) elation of Lung Cancer to Large Oecupationai Groups and Non-specific Irritative Chemical Agents: The remarkable increase in the number of lung cancers observed during recent decades induced many investigators to search for possible environmental causes for this development. In considering the various possi bilities Kennaway and Kennaway argued that the higher mortality from cancer of the lungs in towns noted by Stocks, the low m ortality in agricultural occupations and the absence of a social gradient recorded by Stevenson were com patible with an etiological factor in the a ir such as coal smoke. Stephens claimed some years previously that the pollution of the air by carbon monoxide from incomplete combustion of coal and gasoline represented a m ajor cancerigenic factor. Oldofredi recently revived this conten tion and pointed to the high incidence of lung cancer among former members of submarine crews of World W ar I, when it was exceedingly difficult to control adequately the carbon mon oxide content of the air. Campbell's experiments on mice exposed to carbon monoxide, however, failed to show any increased incidence of pul monary malignancies. Green was inclined to at tach a similar significance to the pollution of the air with sulfur dioxide from the b urning of sulfur-containing coal and the sm eiting of vari ous ores. Other investigators felt that members of out door occupations carry in g the hazards of dust and fume inhalation, especially dust from tarred roads and exhaust fumes from gasoline engines, were especially likely to develop cancer of the respiratory'tract (McCrae, Funk and Jackson: Matz: Schachter; Duguid; Ferenczy and Matolczy; Hutchison). This concept, however, was disputed by others, who pointed out th at in some regions (R iga) an increase in lung cancer was observed before any tarred roads were used iKonrad and Franke; Kennaway and Kenna way; G ugiielm inettia). Knox and Probst pointed out that not the quantity but the quality of dust was important in lung canceri genesis. A few investigators stated that lung cancer was more frequent among the laboring class than among professions (Brockbank: Weller). There is some evidence indicating that lung cancer is more frequent among the population of indus trial areas than among that of rural districts i Fulton : Gerbe t. Several large statistical analy ses tended to show th a t some occupations f en gineers, mechanics, painters, decorators (Brit. Emp. Canc*r C am paign1 ) ; painters and fur- Ae rp ici ckroruc Rg. I. ppillomtou* pitKvliai grow+k pneumonia uich as taan after irritativa ekamical. in lung vritk avposur* to nacemen (Fulton); machinists, foundry work ers, metal grinders (Turner and Grace) ; metal workers, spinners, cigar makers (Borst) ex hibit an excessive liability to cancer of the lung. F rcm inform ation to be given later in con nection with the discussion of recognized cancerigenic agents it is apparent that an apprecia ble part of the membership of the various occu pational groups mentioned, may become exposed to one of thq. known specific environmental cancerigens i mist of lubricating oils, soot, dust from or pigments of various cancerigenic metals (chromium, nickel, arsenic). It is thu3 possible or probable that in these instances statistical epidemiologic data reflect real causal relations. There are, finally, many students of this sub ject who could not find any relation between special occupations and lung cancer formation (Brockbank; Kennaway and Kennaway; Simmrosa: Shennan; Rogers; Rice; Husted and Billman; Jaff; Bonser; Haintz; and others). How ever, the occupational data on which such state ments are based are, as a rule, too inadequate as to specific type and duration of employment and occupational period, which are important be cause of the long preparatory' and latent period of lung cancer to be of any definite value. A similar conclusion applies to the claims made concerning the tiologie connection be tween the inhalation of various irritative gases, fumes, mists and dusts of various acids and alkalis (sulfuric acid, hydrochloric acid, nitric acid, ammonia, war gases, formaldehyde) and cancers of the respiratory tract (Fig. 1). While isolated cases of respiratory cancer are bound to occur in occupational groups coming in con tact with such agents, the existing epidemit>logic evidence does not lend any valid support to a generalization from the observation of a tew cases >Koelseh 1. However, it is worth noting that at least one of the acids m en tioned. sulfuric acid, is often contaminated with appreciable amounts of arsenic. This impurity in commercial sulfuric acid has been blamed by aeawKtfciaaiitii; Page S i Xi if** Km* IN D U S T R IA L M E D IC IN E AND SURGERY February, . A typ io i Fig*. 2 ihJ 3. proliferation* in fibrome brhuninoirt lung, inoLiivg lining of gLn d -Jil* formation*. Amor for the occurrence of lung and nasal can (a) Soot, T arry Material Produced by tl cers among nickel, refinery workers. In view of Incomplete Combustion of Carbonaceous Matt< the absence of reliable epidemiologic studies it (Coal, M ineral Oil, N atural Gas, Gasoline, Dii is desirable t h a t thorough surveys of operations sel Fuel) (Domestic, Industrial and Commerci; showing re sp irato ry hazards of the above type Soots) : While the cancengenic action of soc be made so as to obtain adequate inform ation resulting' from the incomplete combustion of eo. on the incidence rate of respiratory cancer upon the skin is well recognized and best demon among workers exposed to the inhalation of strated by the chimney sweep's cancer of th finely dispersed acids, alkalies, and other irri scrotum, the causal relation between the inhala tative inorganic and organic chemicals, such tion of atmospheric soot from domestic and in r as, especially, beryllium and its various com d u strial sources and lung cancer among the gen pounds, formaldehyde, glycols, isopropyl com era! and industrially employed population i pounds, carbamate derivatives, organic solvents, much less definite (Dorn). In fact, cancer o phosphors, alloys, paints, insecticide sprays, the lung is not unusually frequent among chim weed killers, rubber accelerators, and polishes. ney sweeps (Kennaway and Kennaway). Ai There can be little doubt from the evidence though S chnure r reported that the incidence 01 presented th a t data obtained by an evaluation lung cancer in a sen e s of 342 necropsies of th< of large occupational groups with varying types Pittsburgh district increased directly with thi and degrees of exposure to irritative agents of degree of bituminosis (Figs. 2 and 3) Dorr non-specific n atu re yield little definite infor found in his statistical studies th at the lung mation concerning a causal relation between cancer rate was low in P ittsb u rg h when com occupational activity and cancer of the re sp ira pared with th a t of five other large cities. Ex tory tract. G reat progress, however, has been perimental studies conducted by Schnurer and made in elucidating such connections whenever Haythome, and Seelig and Benignus, with the epidemiologic investigations were limited to inhalation of smoke from an eggstove or of soot circumscribed groups of workers and popula from a hospital flue used as bedding for mice, tions either exposed to chemical agents of more respectively, were equally inconclusive or un or less well defined kind or to identical or sim i convincing. On the other hand, there can be lar occupational or environmental conditions. little doubt that the soot contained in the air of P ittsburgh and other cities is carcinogenic to fYsGANic chemicals: The inhalation of coal mice, since Leiter, Shimkin and Shear and Let dust is in general not credited with being ter and Shear could elicit skin cancers in those inducive to cancer of the lung, since statistical animals with an extract of soot collected at studies conducted in coal miners were negative various localities in the United States. Passey in this respect (Feil: Jordan: Kennaway and and Carter-Braine found the fraction of house Kennaway; Gerbe; Schulte), and mice and hold soot boiling over above 250'C most active guinea pigs exposed to coal dust did not de in this respect. velop lung cancers (Campbell; Vorwald and The question of the possible eancerigenic ac K arr). This innocuousness, however, does not extend tion from the inhalation of various types of commercial soots prepared from natural gas or to the distillation and fractionation products oil residues and merchandised as lamp black, of coal, oil shale, and petroleum (ta r, asphalt, oil black, furnace black, gas black, or channel pitch, oil) and their incomplete combustion black, has become important in recent years be products, such as domestic, industrial and com cause of the huge production and consumption of mercial soots (lamp blacks, carbon blacks, oil these blacks in the rubber in dustry and for blacks, etc.). paint and ink manufacture, in the making of You 20, No. 2 INDUSTRIAL MEDICINE and SURGERY Page 53 ? records and because of their use as coloring - matter. Some of these blacks have been prepared r in late re a rs by the incomplete combustion of oil ^residues that are obtained from the catalytic ^y-crackinf process and that possess distinct can(?.-> cerigeruc properties to mice. In addition to the v possible lung cancer hazard involving the producer, loaders, shippers, and industrial conjunoers of such carbon blacks, there may exist a similar hazard for the general population liv ing in the neighborhood of carbon black plants, because d uring the production of these m aterials large amounts of soot may be released into the t air. A similar environmental cancer hazard may ;? perhaps result from the b urning of oil dumps cear refineries giving rise to considerable '.amounts of soot. Little experimental work 1.40 far has been done in stu d y in g the potential acerigenic properties of the various commercial soots which, depending upon the production 'process and raw m aterial used, differ appre- strciabl)' In chemical and physical respects and t;especially in t a r content (M unteli). * Steinbrueck reported the experimental pro1-(faction of skin cancers in mice painted with ?-black of printing ink. Seeiig and Benignus, on ig jj the other hand, failed to see any lung cancers in mice exposed to the inhalation of lamp black. Experiments of Miescher and Schwarz, using an ^ ointment containing a benzene extract of oil burner soot applied to the skins of mice, were isiTequally negative. Since the carbon black indusSi'.try is supporting experimental investigations on % the potential pulmonary cancer hazard connected irith the inhalation of various carbon blacks, hi more definite inform ation may soon become ^'available. .(b) Diesel and Gasoline Engine Exhaust: A similar degree of uncertainty exists in regard to the potential cancerigenic properties of the & normal and abnormal exhaust products of low ' compression Internal combustion gasoline enjinei and of high compression- Diesel engines il m connection w ith the development o f occupa tional and environmental re sp irato ry cancers j i ' (Lorentz: Heilmann; Duguid; Ferenszy and . ilfttolcsyi. The contention th at the inhalation exhaust fumes from gasoline and Diesel en: gines and thus the increased automobile traffic, f ,.ia causally related to the rise in the incidence ri'oi iung cancers in recent decades has been at tacked on various grounds. ,,r It was pointed out that the exhaust fumes hi these engines when operating perfectly and thereby generating products of complete com- ,,.bostioo contain little or no ingredients of pofe~tfitial cancerigenic qualities (Bloch and Wid- ^tner; Probst). Mention, moreover, was made Uof the fact that there does not exist a-parallelism (/.between the rise in automobile traffic i n d i f f e r - countries and the increase in lung cancer Lehmann: Konrad and Franck; Syreck). and ^ t h a t occupations particularly exposed to engine 'exhausts, such as policemen, street cleaners, garage mechanics, and automobile drivers, do not show an excessive incidence of lung cancer (Passey and Holmes; Probst; Katz; Brandt). Experimental attempts to produce cancer of the skin or of the lung by exposing mice to exhaust gases or to extracts from the fumes of such engines gave negative results (Campbell; Sm ith: S chm idtm ann: Twort and Twort) in the hands of most investigators, although Pessano reported the development of metastasizing can cers of the lungs in rats following prolonged and intense exposure to combustion products of fuel oils. In evaluating the experimental evidence it m ay be well to note th at the products of exhaust of a well functioning gasoline or Diesel engine differ doubtlessly in many respects from those of an engine with imperfect performance, which generates considerable amounts of soot and other matters of incomplete combustion at high temperature. Since engines with defective com bustion are rather frequently met, future at tention should be focused on the potential can cerigenic properties of exhaust fumes emitted from imperfectly operating gasoline and Diesel motors, before definite conclusions as to the existence of an environmental and occupational lung cancer hazard from this source can be reached. (c) T ar Dust and Fumes: The existence of an environmental Jung cancer hazard from the inhalation of dust, mist and fumes of ta r and ta r oils generated during the construction and use of tarred roads has been a m atter of con siderable speculation, since such a hazard, if present, would be of great practical importance (B randt: Kling, Samssnnov and Heros, and others). However, this concept finds little sup port from the epidemiologic studies of Lehmann; Husted and Blllmann; Fischer, and Kennaway and Kennawnv. There was no consistent rela tion between the lung cancer frequency and the extent of tarred roads in different countries, nor was there any excessive lung cancer in cidence among workers especially exposed to the inhalation of ta r dust and fumes in several countries (Hugounenq; Husted and Billmann; Mullschitzky). More recent observations, however, indicate, that the inhalation of hot tar fumes, such as those encountered in the operation of gas gen erators in connection with the production of illuminating gas and coke, is associated with an increased liability to'lung cancer. It was shown that retort workers seem to be especially subject to pulmonary malignancy (Kuroda and Kawahata: Kawahata; Sunderland). According to Japanese experience the gases emitted from the stoking holes contain 0.7 c/a t a r r y m atter. W ith in a a i x - y e a r p e rio d there c a m e to observation 21 cases of lung cancer among a total of 100 workers employed for more than 10 y e a r s r In 14 of the 21 cases the age of the patients was from 35 to 15 years, thus showing a definite Pa.ge S i INDUSTRIAL MEDICINE and SURGERY February, lo.Sl shift into a younger age group than that found for lung cancer in the general population where the majority of cases occurs in the group of from 45 to 65 years. Similar observations have recently been made among gas house retort workers in Canada. Kennaway and Kennaway noted that gas stokers and patent fuel workers* who have a similar exposure to tar fumes and dust have a more than nine-fold incidence rate of lung cancer. These relatively meager findings in man are repeated by the experimental evidence obtained in mice and other species exposed to tar dust or subjected to cutaneous, intrapulmonary or in travenous administration of tar. Campbell's experim ents showed th a t mice ex posed to dust from tarred roads developed cancer of the skin and of the lungs. Similar experi ments of S taufer: Barnewitz: and Bonne, using mice, however, were negative as to the develop ment of lung tumors, although resulting in some of the animals in the development of cutaneous carcinomatosis. Inhalation experiments with dust from tarred roads in which rabbits, guinea pigs and rats .were employed were equally un successful in regard to pulmonary tumor for mation (S ta u fe ri. Intratracheal insurtlation of powdered ta r into mice, and guinea pigs yielded negative results (Bonne; Schabad). Kimurau on the other hand, using *the same experimental method in rabbits and guinea pigs, reported the development of lung cancers in both species. Nakano obtained a similar result in rabbits in jected intravenously with a .solution of tar in lanolin, while Tedeschi, as well as Simouds and Curtis, observed merely atypical proliferations of the bronchial epithelium of rabbits after re peated intravenous administration of tar. A similar result was obtained after the direct in troduction of tar into the pulmonary parenchyma of rabbits (Gerschin and Pigalew). Since none of the so-called carcinomas produced by insuf flation, or intravenous or intrapulmonary in jection of tar gave rise to mtastass, it is doubt ful. whether any of the reported atypical pro liferations of the bronchial and pulmonary par enchyma were actually malignant. It is noteworthy, on the other hand, th at the cutaneous application of tar to mice was fol lowed by the appearance of adenocarcinomas of the lung (M urphy and S tu rm ; Koose and Cordes; Lynch; Schabad; Watson and Mellanby; Campbell; Samssonow, Puccinellil. Pucinelli as well as Moller obtained, with the same method, lung cancers in rats. These remote cancerigenic effects of cutaneouslv applied ta r on the lung suggest the possibility that in man also cancer of the respiratory tract may result from con tact with environmental cancerigens by other than the respiratory route. , (d) Tar Fumes from Tobacco Smoking. The tobacco smoking habit provides an additional environmental source through which tarry ma terial in the form of hot fumes comes in contact w ith the tissues of the respiratory tract. In view of the existing tendency to relate the recent increased, frequency of lung cancers to the action of a single, widely distributed can cerigenic agent, it was to be expected th a t some investigators would point to the parallelism be tween the phenomenal growth in the cigarette smoking habit and the rising incidence of can cer of the respiratory tract during the last three to four decades <Bogen and Loomis; Schiirch and W interstein; Hruby and Sweany: Roffo; McNally; Lickint; Muller; Arkin and Wagner; F errari; Mertens; Ochsner. .Dixon and DeBakey; Fulton: Grace; Hoffman; Schrek; Baker; Ballard and Dolgoff; Wynder and Graham: Jackson and Jackson: Hermann and others). While some of these investigators (Roffo; Wynder and Graham) went so far as to attribute the chief responsibility for the development of lung can cer to cigarette smoking, others claimed that the inhalation of tobacco smoke is merely one of the factors that is involved (Hoffman'). In analyzing the statistical evidence advanced in support of these contentions, it becomes ap parent th at in no instance have occupational or environmental exposures to the various known or suspected cancerigenic agents been consid ered. The complete exclusion of these factors when investigating tabagism must lead to seri ous errors. It is. moreover, evident that the present trend in the sex ratios of lung cancer and of cigarette smoking run in opposite direc tions-- that is, while the sex ratio of lung cancer becomes more heavily weighted in favor of the male sex, that of cigarette smoking doubtlessly favors increasingly the female sex. The claim of Roffo th a t the spectrographic examination of tobacco ta r demonstrates the presence of can cerigenic arom atic hydrocarbons, such as 3.4 b e n z p y re n e , has not been substantiated by Coop er, Lamb, Sanders and Hirst, and Schiirch and W interstein. It is obvious, on the other hand, from measurements of the temperatures ob tained in pipes, cigar3 and cigarettes during the smoking process that temperatures are reached (400 to 700C) which might cause the production of aromatic compounds of canceri genic nature through thermo-cracking (Flory; McNally; Cooper, Lamb, Sanders, and H irst). Attempts to produce career of the lung in mice by the inhalation of tobacco smoke have failed (Lorenz, Stewart, and Daniel). The results of cutaneous applications of tobacco tar to the skin of mice and rabbits have been contradictory. While Roffo claimed ra th e r uniform and con sistent cancerigenic action of various tobacco tars in mice and rabbits, the great majority of other experimentalists either obtained only carcinomatoid growths in the ears of rabbits and an occasional skin cancer in mice <Cooper. Lamb, Sanders and Hirst; Campbell; Flory: Lu-Fu-Hua; Schiirch and W interstein; Chihamatsu i or no tumors at all (Bogen and Loomis: Hoffmann; Schreus and Zurhelle; Mertens i. Vou 20, No. 2 INDUSTRIAL MEDICINE and SURGERY Page 55 -->. It appears from the evidence reported th at oil operation. An inhalation hazard from lubri ^ y d the present time only suggestive epidemic^.. cating oil mist and fog (c u ttin g oil) has been 4 /logic data exist connecting the inhalation of tar incriminated in the excessive incidence of lung f fumes in tobacco smoke and thereby the smok cancer among French turners, millers, planers, ing habit with the development of lung or larynx mechanics, aifd fitters (Huguenin, Fauvet and cancer in man (Hueper). It is unlikely, more Bourdin; Touraine and Bour; Kling, Samssonow over, th a t this type of respiratory contact with and H ros). S tatistical data cited previously a variety of vegetable ta r plays a dominant role Indicate th a t painters who are exposed to the in the production of lung cancer, since experi inhalation of mists from petroleum fractions mental observations place tobacco tar at best used in paints have an excessive lung cancer among the weak exogenous cancerigens. incidence rate. No information on this point is It is essential in any consideration of this available in regard to printers and construction question to take cognizance of the fact that all workers who spray impure paraffin (H u m p e r tobaccos grown in the European and American dinck; Meyer-Brodnitz ) and in workers in countries are apt to be contaminated with resi- match and water-proofed paper factories using dues of arsenical insecticides. The smoking of impure paraffin for impregnation. k |Y such a tobacco, therefore, would entail the in- While there does not exist any information 1* S f u ' halation of arsenical vapors or fumes which by on the pulmonary effects of oil mists and fogs themselves seem to represent a respiratory can- (nebulized oil) in experimental animals, Scha- cer hazard. bad, Campbell, Twort and Lyth; and Kling, Samssonow and Hros reported an increase of Although the exposure to tobacco dustludnoges tum ors in mice following the cutaneous not entail contact with ta rry combustion prod application of shale oils and lubricating oils of ucts of tobacco, mention is made in this connec petroleum derivation. There was. however, no tion of the claim that the inhalation of tobacco direct correlation between the degree of cutane dust ( tobacco workers, cigar makers, tobacco ous cancerigenicity of these oils and the extent dealers) creates an increased liability to lung of pulmonary tumorigenesis. cancer (Seyfarth; Krompecher; Heilmann; Beh- () Isopropyl Oil: The only aliphatic chemi la; Benda; Ferenczy and Motolcsy; Brinkm ann; cal th at may be involved in the development of m r - Enger; Langbein; Borst; Jaeger and Kolb; cancer of the nasal sinuses and of the lung Rottmann; Koelsch; Wacher and Schmincks; when inhaled as a vapor is apparently isopropyl Lickint). Lehmann, however, pointed out th at oil which is a crude product of the m anufacture 1 persons engaged in the tobacco trade are, in of isopropyl alcohol. Although neither the ac general, heavy smokers. The entire statistical tual existence of these occupational respiratory evidence as to a lung cancer hazard from to- cancers nor the n a tu re of the causal agent is h** f.'V bacco dust is unreliable and requires confiarsmayet entirely established, the observations t'rt tion before such allegations can be entertained made in two plants known to us are of sufficient i. * seriously, significance to deserve further study. If con ie) Petroleum and Shale Oils: Inhalation of firmed these findings would open a large new processed mineral oil mists and fogs occurs for field of environm ental chemical agents (s tra ig h t occupational as well as medical reasons. The chain and cyclic aliphatic hydrocarbons) th a t .question, therefore, has arisen as to whether would require intensive scientific and epidemio such exposures may result in the production logic investigations for evidence of potential of cancers of the respiratory tract. Kennaway cancerigenic properties. and Kennawav stated that there exists a rela tively high incidence of laryngeal cancer in mule spinners who, during their work, inhale a mist of cancerigenic shale oil used in lubrication of the spindles. While the use of mules has long been discontinued in the United States in textile manufacturing using fibers of vegetable, animal or synthetic chemical origin, mules are still em INORGANIC CHEMICALS: Observations made dur ing rather recent years in the occupational field indicate th a t respiratory exposure to in haled dusts, fumes, vapors and gases of various metals or metal compounds seems to convey an excessive liability to cancer of the respiratory system. if..:. ) ployed in asbestos mills for the production of asbestos threads having a minor addition .of other fibrillar material (cotton, rayon). Southara noted that mule spinners exposed to a spray of shale oil occasionally develop not only cancer of the scrotum but also of the stomach and lung. Scott, on the other hand, stated th a t he had not seen a single case of lung cancer in shale oil workers, of whom those e m p lo y e d in the press rooms of paraffin departments may be come exposed to the inhalation of oil fogs. Roesch reported a case of triple cancer (lung, skin, stomach ) in a paraffin worker of a lignite (a) Arsenic: While cancer of the skin through medicinal, environmental, or occupational con tact with inorganic or organic arsenicals has be come a well recognized fact, (H ueper; Neubauer), cancer of the respiratory organs fol lowing exposure to arsenical dust, fumes or spray or after medicinal ingestion of arsenicals represents a sequela of more recent observation and of less firmly established nature. The total number of lung cancers after medicinal or occu pational exposure to arsenicals stands at present a t 13 cases with one additional case listed as iti a -w-i - mm 8gs 38 v 5 Y- V .-- 1#^ .tK-j -V* . sry. t* A- : .lag If?: &r Pape 56 INDUSTRIAL MEDICINE and SURGERY y -u rm n ,, m .u \ Lust. Cancer Mortality in S everal Co unties or Mo n t a n a , 1947-1948 .___________ Coaaty Total Pormitkm mo La4r u.rr C ***+ Calk tin Major la^aatry Cot>*r Smettine Cmpr Miai af Cootxr Mi a i n r Sarxltinr Acncuttur# Number Lacmc CaAcer* U n 0 z^ . * 10 & 1 0 Total 21 21 Total CaJfccjrr DUM 94 29* 1 n *" Lune Caimer Mat 10. & Krmak 0.0 1- 12.7 7J ro 0.0 Aarumi Lane Can*r tVath ZLtU/lOO.'tfV) Mai Fmeaie 1U.7 4A.G J.o 12.3 3.2 Th mtimatad erud 4cath rat* for ione mnrrr vnoftf whit* crvaUa in the entir* l/nited SUtr in 1947 i* )u.9 t>r 1U.IKW cancer of the larynx. Two of these cancers oc curred after medicinal use of arsenicals (Semon: Montgomery and W aisman: Russell and Klaber), the other followed after occupational ex posure to dust of arsenical pesticides, (manu facture and use) (sheep dip manufacturers, vineyard workers) o r sm elter fumes ("Merewether ("four ca ses); Hopkins and Studdiford ("one c a s e ); Saupe ("two ca s e s ); Frommel lone case); von Pein (one ca se); and F aning (five cases of lung (three apparently identical with M erew ether'si, one case of larynx). In the ma jority of the lung cancer cases of apparently occupational origin there co-existed cutaneous lesions characteristic of chronic arsenicism. The cancers of the respiratory tract observed by Hill and Faning among sheep dip manu factu rers represented 31.8r <- of all cancers ob served in this group (engineers? packers, chem ists) . These occupational observations are of dis tinct environmental importance, since reports from Germany have related serious arsenical injuries in domestic and wild animal life living within the fume zone of silver and lead smelters to arsenic containing fumes released into the air from- these plants (P rell). Nieberle also re ported from the same region the endemic occur rence of adenocarcinomas of the nasal sinuses in a flock of sheep, and stated that "a certain connection of this disease with the locality and with an injury by arsenic can scarcely he ex cluded." Similar environmental and industrial health conditions may exist in this country for those p arts where arsenic containing flue dust or a r senical insecticides have been and/or are re leased into the air in appreciable quantities. Recent observations made in regard to the lung cancer incidence in certain counties in Montana where huge quantities of arsenical fumes in past years entered the air from copper smelting operations mav be of significance in this respect (Lull, W allach). Mortality and morbidity records for the years 1947 and 1948 revealed th a t 30.8' ( (21 cases) of all m a l e cancer deaths total cancer 98 deaths) were listed as due to, cancer of the re spiratory tract in P eer Lodge County where about 25rc of the population (13,627) is engaged in smelting of copper ores containing 0 . 5 arsenic, and where from the past industrial history of this region an occu pational as well as environmental arsenic hazard may be assumed to exist. In the adjacent Silver Bow County where ex tensive copper and zinc mining activities are-car ried on, the proportion of lung cancer deaths to cancer deaths was 22.6', 127 cases) for males and 1.5cr (two cases) for females ("total number of cancer deaths 259, total population 53.207). There was in contrast in the adjoining Gallatin County which is agricultural in character, and which has a population of 18,269. one male lung cancer death, while again in Cascade County with a population of 41.999 and with copperarsenic ore mining and smelting activities the proportion of lung cancer deaths to all deaths from cancer was 12.7G- for males ("20 cases) and a t 3 . 5 (five cases) for females, with a total num ber of 299 cancer deaths. These ob servations are of only limited value since they cover too short a period of time, too small a number of cases, and no detailed data on the occupational and environmental aspects of the individual lung cancer cases. However, the high frequency of lung cancer in counties where ar senic contamination of the environment is known to exist is of sufficient importance to call for a thorough and extensive study of the presence of a potential arsenic lung cancer hazard in all those regions in which existing occupational and environmental conditions warrant such in vestigations. Such epidemiologic studies are especially in dicated because of the difficulties encountered in the production of arsenic cancers in experi mental animals and because of the complete lack of any investigations of the pulmonary cancer aspects of arsenic hazards by experimental m eth ods (Neubauer; Hueper). (b) Asbestos: There occurs respiratory con tact with three different types of silica comIKiunds, namely, inorganic crystalline or amor phous silicates, organic silicones aud asbestos. Since silicotic pneumoconiosis is characterized hy a chronic granulomatous inflammatory re- - Vol. 20, No. 2 INDUSTRIAL MEDICINE anu SURGERY Page j ;. . b " ~ "'v Ct' n' ar*d thus sterns to fulfill remarkably well \he baaie requirements of the chronic irritation ^theory of cancen genesis. several investigators sas have incriminated this frequent type of occu pational pneumoconiosis in the development of cancer of the lung (Fine ami Jaso; Anderson and Dible; C harr; Klotz; Diblel. There are in fact some 50 cases on record in which cancer of the lung or larynx and silicosis were co-exist ing (Dible: Fine and Jaso; Klotz and Simpson; Maxwell; Sladden; Middleton; Sweany,. Porsche :IrSiry**. **** ^>ou^ a s s l Vorwald and K a rr; Allen; Sokoloff; Pancoast and P enderg rass; Simons; Schno- rer; Charr; H arris). However, the great ma &I 1?9. jority of investigators have come to the con clusion that there does not exist any causal re lation between silicosis and pulmonary or laryn geal malignancy (Vorwald and K a rr; Allen; Fell; H arris; Pancoast and Pendergrass; Saupe; Schulte; Schulis Berbllngerl. Schulte R q . 4. Atypic.*i qiaad u U r pi+K+JiAJ formatio* in fibrottc and cbi'+m ctHy intlflmd lur with o b w vtom body#* within dw*qHMnt*d pith*li*i c*Ht loe*+d within of , cystic qUnd-M n formation*. and Schulz noted that coal miners in th e R uhr district, among whom silicosis is frequent, have no unusual frequency of lung cancer, while Allen recorded a similar observation for the coal : - r miners of Pennsylvania. Corresponding nega- / ; five observations were made by Vorwald and ' ' Karr on individuals who came to necropsy with I - silicosis at the Saranac Laboratory and have f been reported by the Miner's P hthisis Medical ' Bureau of South Africa based on studies made C^Vimong the South African gold miners in the Ijohnnnesburg district. Iw_ ' These conclusions ure supported by the re- v.-- suits of experimental investigations, in which mice, rats, guinea pigs, rabbits, chickens and TJi' cats were exposed to the inhalation of silica R q . 5. ' U dust iCampbeil; Vorwald and K a rr; Willis anSdq u ^ m o o i c i n c t f o f (unq w ith * tb ito iii b o d io t * d jic n t to tp ith o lia i coil p qj. Brutsaertj. A fundamentally different situation, on the other hand, seems to prevail in regard to the causal relation between asbestosis and cancer of the lung. Because the recognition of asbestosis as a special form of pneumoconiosis is of ra th e r recent date, the analysis of 18,280 death cer tificates for-cancer of the lung and larynx in IJ males from England and Wales from 1921 to 1932 did not reveal any cases of lung cancer in asbestos workers (Kennaway and K ennaw ay). Since 1935. however, an appreciable num ber 1551 of cases of asbestosis complicated w ith cancer of the lung have been recorded from England, Germany, Canada and the United States (Lynch and Smith; Lynch; Lynch and Cannon; Egbert and Geiger; Gloyne: Wood; R q . 6. Horning; Welz; Wedler; Nordmann; Merewether; Luton and Champfix; Linzbach and C o m b in a tio n oi it y p i e j l g U n d u L r form ntiont in d iq iw m o u i coil e * rc in o m j in jsb n sto tie lung. Wedler; Dominici; Baader; Homburger; Holleb I and Angrist; Desmeules, Rousseau. Giroux and Sirosis: Cureton) (F igs. 4, 5 and 6). "X The proportion rate of lung cancer in per V-oas with asbestosis who came to necropsy ,U_ ^ / s t a n d s between 13 and 15G. The exposure time l ' ranged from three t0 27 years ' average 15 &` years ). The latent period a fte r cessation of exposure w a s f r o m 10 to 12 y e a r s . M u l t i p le c a n c e r s w e r e f ou nd in several cases, a n d both male a nd fe male worker- were affected. The male-female .-.ex r ati o, a e e u r d i n g to M e r e w e t h e r is 2. 4: 1. while the mean age is ab o u t 52 years. Although Warren rather recently m aintained that 'he con- iff # 'OSS $n L -e-,,. -v> "x &- 2 * - 'Ji , _ . V 'Sk *; l iM l ' rA V>.-' . 'Acv > 1--< : ; ':v -' ` : 't - 'M w- ' N-Ti ; `-r .U' 7 ; Jr'4*. 7 .rs ? ) ' 'r; (.* O fi-?' NV '1t#' O Vi i N-*5'-. Page J,S INDUSTRIAL MEDICINE a.nd SURGERY F e b r v a n j, Ot A ge D istr ibutio n of A sbestosis C ancer A ft: U mi : *0*441 2 41-AO 7 It u n otew orthy th a t th raiwevr la you. 5 l-< 0 4 4U70 li m *nif*uiott ac* It-S O y*mr* of aaberU* E xrosu xx T ime or Asbestosis Cancer O ms 1 -i t-1 * 11-1 2 12 lt-2 0 3 21-1 2S-i* J W ) section between asbestosis and lung cancer is of coincidental nature, the actual existence of a causal relation appears to be very likely (Leeoeur; Koeisch; Salta; Hueper; Teleky: Edi torial) ; Gross I. The reason for the different behaviour of silica and asbestos in regard to pulmonary caDcerigenesis is unknown. The various metallic constituents of asbestos may possibly play a role. While the experiments of Vorwald and Karr performed on guinea pigs that were exposed to asbestos dust gave negative results, those con ducted with mice by Nordmann and Sorge ap parently yielded positive results, since a few of the animals surviving the inhalation of as bestos dust sufficiently long showed at autopsy pulmonary lesions interpreted as squamous cell cancers of bronchiogenic nature. All spontane ous pulmonary tum ors occurring In mice, on the other hand, are of glandular type and alveo lar origin. (c) Chromium: Another member of the group of respiratory metal cancers is the cancer of the lung observed in the manufacture of chromates and chromium pigments (zinc chromate). Whiie the first two cases of chromate cancer of the lung were observed in 1914 in Germany (Leh m ann), it was not nntil 1936 that their number had become sufficiently large for establishing definitely the causal relation between exposure to chromate dust and lung cancer in German chromate plants (Alwens and Jonas; Alwens, Bauke and Jonas; Bauke and Alwens; Bander; Gross and Koeisch r G ross; Pfeil; Teleky; Bauer; Carozzi; Koeisch; Lecoeur; Saita; Staemmler: Teutschlaender; Kennaway and Kennaway). While the exposure in the chromate plants was to dust of chromite ore and of monochromata and bichromate salts of sodium or potassium, the respiratory contact in the chromium pig ment manufacture which resulted in lung can cer was in all cases (eight) to zinc chromate i zinc yellow) (Gross and Koeisch). B aader noted moreover th a t1 there were nine cases of lung cancer on record among workers of the chromate consuming industries in Germany. The more recent observations of similar na ture among American chromate workers cover so far only chromate m anufacturing operations. In neither country is there any information available as to the existence of lung cancer hazards for workers employed In chromium plating operations, in the manufacture of inks and paints, in printing, painting, dyeing, dye Rg. 7. RmiftA coil careino of tho lung in ekconmf* orlf wjtfi bioc ekrwnit dcpotfH in ef*+ lung tiuuo. Fig. 8. Spodogrtm of lung wttR cRromrt pnnumoeonioti *Row ing tRo bloel cRromrt dpoiti within tK* whit min er! d)ton of tRo thd lung wetion. making establishments, and in the production and processing of metallic chromium and chro mium alloys. It is remarkable that, according to Goldblatt and WagstafT, the English chromate industry apparently has remained free from these respiratory cancer hazards. Gross esti mated that the chromate lung cancer incidence rate among the approximately 1,000 effectively exposed German workers stands at 3 .9 ^ . It ap pears to have risen in more recent years to about o cc, since Raader placed the total num ber of chrom ate cancers in Germany a t above 50. No similar figures are available from this country. However, the epidemiologic studies of Machle and Gregorius have shown that the lung cancer incidence rate among American chromate workers is from 10 to 40 times th a t of a com parable industrial group, or an average of 16 times the expected rate. A recent analysis of the final f a t e of some 150 former chrom ate workers engaged in chromate production for at least six months, and having passed a latent period of more than four years, demonstrated th at of 25 deaths that had so far occurred in this group, five viere caused by cancer of the respiratory tract *20' , ) (Figs. 7 and 8i. VOU'20, NO. 2 INDUSTRIAL MEDICINE and SURGERY Page 0 Acs Distribution o r Chromate Cancers or t h e Lunc < U 3 1-1 U -& 5 1 . 1 .7 0 71 i i U i b o n T o n T otal B a u 1 ( It It M 1 6 12 14 T 1 l 11 22 14 21 1 n i r di Cri buto i o f th o c h r o m a i idaaond ( K r t u v i r ami K r tiu w k j > M fW o 1.214 Hra* p a n o f a a i M ab~d by M ti. G ir , 44 A ew rw aa 42 41.7 100 u p r a c tic e Uy w ith that w t n in a v i tioio% j th a t n a E rrosuR X P erio d o r C h r o m a te Of th e L ung Cancers 1 1 - 2 0 21-30 31-40 41 and a b ov Y n n 10 18 I 12 l G erm an 15 rear* |0 22 Ji 2 A m r x n 16.8 Tb* to u nnnabwr o f ob*nrfd ( n o f ch ro m a l c a n c e r o f the h io c fro m b o th th U n ite d S ta t e s and G e rm a n y ia now weU ab ove 100, s in c e a d d itio n a l eaaes h ave been diaeovered after the above Artzraa w ere rrp o rtn i. Although ulcers and perforations of the- nasal septum are frequently observed in chromate workers, there is only one case of carcinoma of the nares in a chromate worker on record (New man i . The statement of Machle and Gregorius that apparently the monochromate only is cancerigenic does not seem to be supported by obser vations made in German plants where in Lever kusen 10 cases and in Uerdingan 14 cases were found among workers in dichromate plants, -uch a selectivity of monocnromate is, more- Yer, scarcely conceivable from a biochemical 'ewpoint since both monochromates and bi chromates are readily ionized in the body. Whether chromite ore dust represents a cancerigenic factor in chromate workers is still an open question although it may produce a chemi cal pneumoconiosis (Lukanin.'. Likewise it is uncertain whether chromium plays an essential role in the production of other human cancers, although Dingwall and Beans some 15 years ago demonstrated spectroscopically chromium in various human cancers. The exposure of rabbits- and cats for several months to chromite and chromate dust present in a chromate- factory did apparently not elicit any cancerous responses (Lukanin). The im plantation of metallic chromium into the marrow cavity of the fem ur of rabbits (Vollmann', on the other hand, gave rise in animals surviv ing for more than three years to cancers at the site of deposition and in the lung (Schinz). (d> Nickel: The occurrence of cancers of the nares, nasal sinuses and of the lung among workers in Clydach, South Wales, engaged in processing Canadian coppernickel matte of the Sudbury mines by the Mond nickel carbonyl process was first observed in 1924 (B a a d e ri. During the following 15 years several reports on the continued appearance of such cancers ">vere made by various in v estig ato rs t Grenfell: 'ooper; Stephens: Bridge; Amor*, M erewether). Up to 1939 there were recorded with the Chief Inspector of Factories 34 eases of nasal sinus cancer and 24 cases of cancer of the lung. These figures have risen to 47 cases of cancer of the b o m and 82 cases of cancer of the lung fo r the period of 1923 to 1948 (M erew ether). No simi lar observations have been made or recorded so far from German. Canadian and American nickei refineries using the same process. According to Amor, the average employment period for the nasal sinus cancer cases was 19.4 years (ra n g e : 6.0 to 30.0 years) and th a t of the lung cancers 21.4 years (range 7.0 to 32.0 years). The average exposure time to dust was 11.3 years for the nasal sinus cases (ran g e 3.0 to 26.0 years) and 11.6 years for the lung cancer cases (ran g e 1.0 to 33.0 y e a rs ). With a few exceptions all workers who developed nasal or pulmonary cancer? had entered employment be fore 1924 (M e rew ether). The average age at death was 51.0 years for the nasal cancer cases (range: 86.0 to 66.0 years) and 53.0 years for the lung cancel1 cases (ra n g e : 48.0 to 66.0 years). As to the causative agent. Amor emphasizes that only one case has been observed in a worker who had contact with nickel carbonyl, while all others had been exposed to arsenic-containing dust originating from commercial sulfuric acid contaminated with arsenic and used for the extraction of copper. The absence of similar cancers among the nickel refinery workers in Canada is explained in the opinion of Amor therefore by the fact that in Canada the sul furic acid extraction process is not used. The concept of an arsenical origin of these respiratory cancers, however, is not supported by the apparent absence of arsenical derm a toses and cancers of the skin among the affected nickel refinery workers. Such manifestations rather regularly accompany the cancers of the lung' in arsenic workers and thus represent a part of the environmental arsenic lung cancer pattern. There is, moreover, no evidence from any other source that the industrial use of com mercial sulphuric acid usually containing a r senical impurities has given rise to cancer of the respiratory tract. Exposure to arsenical dust, while having frequently caused ulceration and perforation of the nasal septum, has not given rise to nasal cancers. The cancers of the nares and nasal sinuses in the nickel workers involved the middle t u r binates and the ethmoids and were histologically of squamous, undifferentiated or papillary colum n ar cell types. One columnar cell cancer involved the nasopharynx. The four pulmonary cancers that were studied histologically were of small round cell or squamous cell types. The inhalation experiments conducted by Campbell on mice exposed to arsenic-containing nickel dust obtained as concentrated matte from the Mond Company gave results of doubtful sta tistical significance, since the ratio of lung tu mors in the test series and in the controls was 14 :8. It is uncertain whether these experiments actually duplicate the conditions of exposure m i fi--. *1' *\ . ...V .- -,.-..i.-.T r | _,. ra-, - , ,y -- .. . y . J W- Attf* 0 INDUSTRIAL M EDICINE aud SURGERY February, is.u sustained by the workers in the nickel refineries, since the nickel-copper matte manufactured in Canada and used in England contains only min ute amounts of arsenic. The origin of the ar senic. according to Amor, is not from the m atte but from the sulfuric acid used. Since cancers of the respiratory tract seem to continue to occur in English nickel refinery workers, there is sufficient indication to investi gate thoroughly their causal aspects by epi demiologic and experimental methods for prac tical as well as scientific reasons. Definite in formation should be obtained w hether these cancers are of arsenical causation as claimed by Amor or are attributable to the inhalation of nickel carbonyl vapors and thus represent a separate type of metal cancer. A study of the respiratory cancer incidence in workers engaged in nickel plating, m anufacture and use of nickel pigments and alloys, and in the polishing of nickel mai- aid in clarifying the presently con troversial tiologie aspects of the cancers oc curring among the mp|ier-nicke| refinery workers. PHYSICAL AGENTS'. a X - r a d i a t i o n ; D e s p ite the large number o f oersons whose lungs have been subjected to intensive irradiation by x-rays for medicinal reasons (cancer of the breast or lung), there is not a single case of medicinal x-ray cancer o f the lungs on record. Chronic radiation pneumonitis, on the other hand, has been of relatively frequent occurrence. Apart from the extensive hyalinizing and fibros ing changes characterizing this process, there occurred swelling and transformation of the al veolar epithelium into cuboid! and columnar cells and cellular monstrosities, and stratifica tion, giant cell formation and squamous cell metaplasia of the bronchial epithelium (B auer and Schaer: Warren and Spencer: Warren and Gates: Widmann; McIntosh and Spitz: Leach, Farrow and Foote; Jacobsen: Freid and Gold berg; Bauer). -Engelstad produced similar re actions in the pulmonary parenchyma and bron chial epithelium of rabbits without obtaining cancerous responses. Warren and Gates reported corresponding acute lesions iu rats. The development of a squamous cell cancer of the larynx on the basis of a chronic x-ray in ju ry produced by 86 x-ray treatm ents given fo r a skin disease of the neck was reported by von Eicken. (b) Radiation of Radioactive Substances: T here are only two cases on record in which prolonged inhalation of radioactive gases and dust by a laboratory technician and a chemist engaged in the production of medicinal radium preparations or in the manufacture of luminous paint, respectively, fTonges and Kalbfleisch; KalbHeisch: Belt: Uoenecke) caused fatal fibro sis of the lungs. The high incidence o f . pul monary cancer among miners in Schneeberg and Joachimsthal where radioactive ores are mined & -- v ;V Rq. 9. Highly an*plii*ic etttinom t in * $cnnorg m in*r showing many g r o ttiq u c*lii which jf* commonly sn but not <peit~c for *n mucowl fining. and the air in the mine ducts contains radio active gases and dust strongly indicates that a prolonged exposure to these agents is causally related to the occurring pulmonary malignancies (Weber: Uhlig: Thiele. Rostoski. Saupe and Schmori i : Thiele: Stocklasa and Penkavn: Stockhisa: Schmori: Scheffier: Rustoski and Saupe: Rustoski. Saupe and Schmori; Rujewski: N'eitzel; Ludewig and Lorensen: Lorenz: Lin demann: Lange; Koelsch: Hueck: Hopmann: Beyreuther; Agricola: Aucke: Arnstein: Baa der: Bauer; Epstein; Henckel: H rtung and Hesse: Fischer-Wasels; Teleky; Doubrow; Pei ler; Saupe; P.ehounek and Fort: Czechoslovakian Commission; Ziel: Woldrich: Tschelnitz: Sickl: Behounek: Pirchan and Sickl: Lowy: Humph ries; Beutel and Woldrich) (Fig. 9 '. Work in radium laboratories may represent an additional source of occupational cancer of the lung through inhalation of radioactive gases and dust. Three cases of this type have been observed in chemists (Neitzel; Lwy). Martland, moreover, reported the occurrence of a carcinoma in a nasal sinus in a luminous dial painter, who sustained a similar exposure. It is apparent from the discussion of Evans and Goodman that a similar respiratory hazard may exist for employees nf mesothorium refineries and thorium mantle factories, who inhale thoron. since the degree of atmospheric radioactivity in such plants was found to be in quantitative agreement with the experiences in Schneeberg and Joachim sthal mines (40 to COO x 10-n curies of thoron per liter of air in thorium oper ations against 40 to 1800 x 10-11 curies in Schneeberg mines and 80 to 560 X 10-u curies in Joachimsthal mines). Since Bryan and Silverman recently pointed out that electrostatic eliminators covered with a gold film containing either polonium or radium present an industrial inhalation hazard by contam ination of the air with fine particles containing radioactive ma terial, the possible development of pulmonarv cancers in workers engaged in operations where ' Voti 20, No. 2 INDUSTRIAL MEDICINE and SURGERY Page 6 l v thw* devices are used (textile, paper) might r -S u11 be kept in mind. Most oi the recent in stigators of the Schneeberg and Joachirasthai Mng cancers agree th a t their radioactive cau sation can be considered as almost definitely - established. A critical evaluation of the evidence advanced in favor of other factors, such as silica, arsenic, hisznuth, chromium, nickel and cobalt, shoves that little or no factual and valid evidence sup ports such claims. Perhaps the most objection able contention that has been put forward in this respect is the speculation that the lung cancers among the Schneeberg and Joachims- thai miners are the result of inbreeding and thus of hereditary predisposition (Mackiin). The facts are quite different. The m ajority of the Schneeberg miners reside in Schneeberg, a community of some 10,000 inhabitants located at the end of a railroad branch line, and thus are living in a remote but not isolated mountain region of Saxony, which has been for many years the most densely populated state of Germany. Even a limited type of inbreeding that would be remotely comparable to the hereditary and abnormal conditions created in inbred strains of mice is scarcely conceivable under such circum stances. A study of the names of 53 m iners listed by H arting and Hesse supports this con clusion, since there were 44 different names this group. Duplications existed seven times, C } plication and quadruplication once each. This Vegree of repetition of names is not unusually high and is plausibly explained by the fact that in some instances several members of the same family were probably employed in the mines. The occurrence of "fam iliar' cancer under such conditions is not due to heredity but due to identity of exposure to an environmental can cer! gen. Sim ilar circumstances of exposure to soot have been in past decades the reason for the appearance of scrota] cancer among several members of the same family engaged as chim ney sweeps in England. To introduce the con cept of heredity into such a picture is totally unjustifiable and merely acts to obscure or con fuse rather clearly established facts of environ mental cancerigenesis. There were approximately 400 cases of lung cancer among the Schneeberg miners between 1876 and 1930, while 42 cases of this disease came to observation among the Joachimsthal miners during 1929 to 1938 (P eller). I t ap pears from the epidemiologic studies made that between 75 and 80oc of the deaths among the Schneeberg miners and from 47 to 50r c of the deaths of the Joachimsthal miners were caused by cancer of the lung. The recorded age distribution clearly demon strates a shift toward the younger age groups \n individuals dying from lung cancer following Kiv Exposure to radioactive dust and gases. 7 The period of exposure ranged for the ma jority of the Schneeberg miners from 20 to 50 A c s D istribution of Lung Cancers in Radioactive Ore Miners *- KW> it*-* 70 Tout S tt il J* 1 IT * * 20 83 Shn*eb#rT 30 Jo*cbtmathaJ years, but waa occasionally as short as seven years. The exposure time of the Joachimsthal miners was from 13 to 23 years. No information is available on the occurrence of lung cancers among the miners employed in the Katanga mines in the Congo, which are open pit mines, in the Canadian mines at the Great Bear Lake region and in the vanadium-uranium mines in the Rocky Mountain area (Warschwa- ski; Mainsin). It seems to be characteristic of the Schnee berg and Joachimsthal lung cancers that many of them are of the small cellular or highly ana plastic type, which accounts for the fact that they were first diagnosed as sarcomas. The topographical restriction of these cancers to the lung suggests that the cancerigenic agent mainly responsible for these tumors occurs either in the form of a dust or is adsorbed to the surface of dust particles, because canceri genic vapors or gases in the absence of dust seem to cause cancers of the lungs as well as of the nares and nasal sinuses (.nickel, carbonyl and isopropyl .oil workers.). While the experiments of Schmidtmann and Lowy aimed at the production of puimonary cancers in mice exposed to radioactive dust and gases were negative, subsequent ones conducted by Dohnert, Rajewski, Schraub and Kahlau; Lorenz, Heston, Eschenbrenner and Deringer gave suggestive results. Of definitely more con clusive character are the observations reported by Liaco and Finkel who obtained malignant pul monary tum ors in rats exposed to an aerosol of radioactive cerium. The gTeatly and rapidly increasing production and uses of radioactive substances of natural and synthetic character for research, industrial and military purposes that has taken place dur ing the last 25 years in this country have brought along exposures to radioactive material for an appreciable number of individuals. The conditions of such contacts are of a quality and order that the appearance of cancers of the res piratory organs in some members of this group must be anticipated. Commnh 'J'HE data presented permit the conclusion that some of the cancers of the respiratory tract are attributable to the inhalation of a number of more or less well defined chemical or physical agents. Although the total number of these respira tory cancers is relatively small when compared with the total number of cancers of this organ system, the proved environmental origin of these tumors lends strong support to .the great amount  ; 1- & u #- # : TTrfcp*i - ' ;^ ' &i; 4iH ' :*.;' fi' i'*jf}U-'-H<" i h;!r-`!'j J^ *-*-*c-->:i: tv ; *4*> = of 'J*.'.. . :T - ..'T -J' <i'-J ' ' "V Page 62 IN D U S T R IA L M E D IC IN E -AND s u r g e r y F ebruarij. 1061 of merely circumstantial evidence indicating of occupational lung cancers mistaken for many that environmental factors play a significant yeara for tuberculosis or silicosis. role in the production of pulmonary, nasal and Future studies of environmental pulmonary laryngeal malignancies. cancerigenesis m ight well include proper con The available information on the recognised sideration of local atmospheric conditions for and suspected respiratory carcinogens* moreover, air pollution with cancerigenic agents. suggests that the known numbers of environ In view of the long latent period of environ mental respiratory cancer represent only a mental respiratory cancers which ranges from fraction of the actual ones, since existing epi five to 40 years and because of the fact that demiologic studies on this point are highly de these cancers may develop many years afte r li fective. cessation of exposure to the cancerigenic exo Although all known environmental caneen genous agent, it is essential that arrangem ents have followed upon the inhalation of exogenous are made for the medical supervision and con cancerigens present in the form of dust, fume, trol of effectively exposed persons to extend be mist, fog, vapor or gas, serious consideration yond the period of employment. Likewise, it is should be given to the possibility that some or pertinent that detailed employment and exposure m any cancers of the respiratory trac t may be d ata in addition to name, birth date and place, due to agents entering the organism through and social security number are recorded and the alimentary or cutaneous route and being kept for all persons who had effective exposure either excreted through the respiratory organs to environmental respiratory cancerigens, so as or having special metabolic or chemical aifini- to ascertain in future investigations reliable and ties to these tissues. valid epidemiologic evidence on the existence The past history of the discovery of environ and extent of cancers of the respiratory tract. mental respiratory cancers has shown th at the While such procedures will prove to be tedious, first indication of their existence is usually pre and expensive, they will amply repay all efforts sented by the occurrence of a crowding of such by improving the health of our people not only tumors among members of restricted occupa through prevention of environmental canceri sH tional groups. Industrial physicians and special genesis. but through resultant fundamental con ists in pulmonary diseases might, therefore, tributions to the etiology of human cancer. make valuable contributions to the etiology and The experiences made in connection with en epidemiology of respiratory cancers by investi vironmental respiratory cancers suggest that the gating thoroughly the entire occupational his regional variations in lung cancer among the tory of th e ir respiratory cancer patients for general population may be attributable to locally evidence of a previous exposure to an environ restricted quantitative and qualitative differ mental cancerigen. Special attention should also ences in the environmental cancerigenic spec be given to all those patients who enter medical trum. care with the diagnosis of tuberculosis or sili Likewise, the evidence related to environmen cosis or both and who have been employed in in tal lung cancers indicates that the increased fre dustries where they became exposed to various quency of these tumors observed during recent cancerigenic metals, such as arsenic, uranium decades is apparently not caused by the appear ores, chromates, nickel, asbestos, and bituminous ance of one new environmental cancerigen re substances. The history of occupational res lated to occupation or habits, but rather re piratory cancers offers several vivid examples flects the action of several or many cancerigens. He Says He Did It To Save Money I LLINOIS' Governor Stevenson on December 28 ordered the liquidation of the Bureau of Industrial Hygiene in the State D epartm ent of Public Health, on recommendation of the Schaefer Commission to Study State Government. The commission pointed out that "one of the more obvious cases of overlapping and duplication of activities" between separate state agencies existed in the competing activities of the bureau and the Industrial Hygiene Unit of the Department of L abor's Division of Factory Inspection. The governor ordered the bureau liqui dated by next J une 30. the end of the present biennium. The Bureau of Indus trial Hygiene currently employs 16 persona and has a biennial appropriation of 3133,735. The commission's report recommended and the governor directed that the facilities of the health departm ent s central laboratory be marie available to the Departm ent of Labor to review findings made in the course of its inspections.