Document 2JqbLDROnOgmK5ebemrMVVJoR

SIGNIFICANCE OF INDUSTRIAL CANCER IN THE PROBLEM OF CANCER W. C HUEFtt, HfW TOXIC HE study of occupational cancer is of eminent significance for the control of human cancer in general. As occupational cancers result from exposure to certain more or less well defined exogenous agents, they represent chance experiments on cancer in man conducted by modern industry on a. large- scale and thus are human equivalents of experimental cancers in animals.' In view of the known differences existing in the susceptibility and reactivity of various species to the numerous recognised physical and chemical cancerigenic agents, indus trial cancers possess the great advantage over experimental cancers in animals that they permit the direct study ofmany of the most important and fundamental aspects of cancer in the human organism, such as the action mechanism of the different physic^ and chemical carcinogens, the character of the local'and systemic reactions associated with the process of cancerization (shifts in the mineral, lipid and vitamin con tents of the cells acted on, qualitative and quantitative disturbances in the enzyme and vitamin activity, endocrine function, steroid metab olism, chemcimtounity reactions and metabolization and detoxication of the carcinogenic agents), influence of age, sex and race, hereditary foetors. diet, role of periods of exposure and latency and of procancerous and anticancerous mechanisms and the factors* responsible for multiplicity of cancers and systemic cancerization. It is obvious from these considerations , that a thorough, extensive and continued investigation of occupational cancers through a study of man exposed to known occupational cancerigenic agents or affected by industrial cancer would be of utmost benefit for a better understanding of the conditions which may cause cancer in man and of the measures which may prevent such developments. * There is a second important reason'* calling for an appreciably increased interest in the problem of occupational cancer in connection From the Warner Institute for Therapeutic Research. 1. Hoepcr, W. C: Occupational Tumors and Allied Diseases, Springfield. HU Charles C Thomas. Publisher. 1942; Cancer in Its Relation to Occupation and Environment. Bull Am. Soc Control Cancer 25:6, 1943: Industrial Management and Occupational Cancer. J. A. M. A. 131:738 June 29) 1946. 190  ior the ?rs result i agents, jcted by alents of Terences' ? to the 3, indusncers in uportant h as the inogens, vith the n con(f inces V. *ab- ^ of ary facous and Hifrfidtr tensive a study cted by unding easures . . -cbbiy nectson m, :ion and iCC^K.it H UPER--l\'D USTRIAL CASCEK 191 with the general problem of cancer. The rapid and enormous growth of modem industry and its vast diversification during die last five decades has been accompanied by a considerable rise in the absolute number and by the appearance of many new types of industrial cancers. This development reflects an important biologic maladjustment of civilized mas to his new artificial industrial environment and represents a striking illustration of the momentous role which exogenous environmental agents apparently play in the causation of cancer in general. Experimental and clinical evidence obtained during the last few years makes it likely that new industrial carcinogenic agents and heretofore unknown types of occupational cancers will be discovered in the next few years in American industries. This development is foreshadowed by recent observations indicating that certain types of industrial cancers which in the past were observed exclusively in European plants have made their appearance in American factories. Moreover, American investigators produced cancer in animals during the last few years by the exposure to carbon tetrachloride, ethyl carbamate, diethylene glycol, beryllium and ergot, L e., substances extensively used in industry and/or for medicinal purposes. It seems to be fair to compare present knowledge as to the causation of cancer in man with that available on the causation of infectious dis ease during the days of Pasteur and Koch. There exist good reasons for assuming that the majority of occupational carcinogenic agents are still unknown an3 that this applies especially to those occupational carcinogens which have a low potency and which therefore produce a low incidence of cancer not appreciably differing from that seen for the various types of cryptogenetic cancers among the general population. When these facts and their implications are properly and fully appreciated, occupational cancers are !x>uml to become a public health problem of the first order, which deserves to be seriously and exten sively investigated. . ' X. OCCUPATIONAL CANCEX AND CAXCE* KESSAltCH A. Carcinogenic Agents.--It nay be appropriate to recall here tliat modem cancer research dealing with physiol and chemical carcinogens started some thirty years ago as an outgrowth of the study of the causa tive agents and conditions involved in the production of occupational cancers. Although great strides in knowledge of exogenous carcino genic agents and their effects on the animal organism have bees made since that time, the constantly growing number and diversity of types of occupational carcinogenic agents have raised many new and often still unsolved problems. The existence-of wide differences in the physi cal and chemical properties of the various established or suspected car- *' 1 'i!'1.-1Wddfl'--- ----- -------------------- -A % I.TV ' !: AaSm iSS*- V)2 OCCUPATIONAL MEDICINE antigens suggests that these agents do not exert their specific pathogenic action through the same mechanism. From an analysis of the data at present available on this matter and from theoretic considerations it appears that exogenous carcinogenic factors may elicit malignant growths through one of the following three mechanisms. In the first group those occupational carcinogens may be found which apparently cause a cancerous cellular transformation by acting directly either in their original form or as metabolites or conjugates on the cellular substrate. The carcinogenic substances contained in tar, pitch, asphalt, soot, mineral oil and related substances, and those repre sented by certain aromatic amines (betanaphthylantine, benzidine, ani line) perhaps belong to this group of primary carcinogens. The second group of exogenous carcinogens consists of agents which do not possess any direct carcinogenic properties but which exert such action by changing some normal chemical constituent of the ceils or tissue fluids m such a way that it becomes endowed with carcino genic properties. In view of the long latency period of actinic cancers, excluding the possibility of a direct electronic chromosomal mutation, it seems probable that this mechanism may be active in the development of cancers caused by radiating energy. An indirect or secondary mechanism of cancerizadon may also be responsible for the occupational cancers observed in workers^ employed in chromate plants, nickel refineries, asbestos factories and arsenic operations. In a third group those exogenous agents are included which have neither primary nor secondary blastogenic properties, but which elidt functional disturbances m certain organs, such as the liver, adrenal glands, pituitary gland and the gonads. The quantitative and/or qualitative functional abnormalities thus produced may lead in turn to the development of endogenous substances or metabolites possessing carcinogenic qualities. The possibility of such a mechanism has not been extensively ocpiored and.irmainly speculative, but certain aromatic azodyes may belong to this group of exogenous cardnogws. It is obvious that adequate information on the sources and types of carcinogenesis not.only is essential for determining the scope and effect ing the control of environmental cancer and, especially, its occupational variety, but also may bring about a closer connection between the carcino genesis by the action of exogenous substances with that apparently ensuing from endogenous factors. . ' B. .SVjt.--The observations made m occupational cancer in man and its experimental equivalents.in animals show unmistakably that any differences in the sex distribution of such tumors are not sex conditioned but are the results of variations iu exposure. The great predominance of W j wT'V'jw''* 6 -c :au at ons it owths C HUEPER-iSDUSTRlAL CASCER 193 males among persons affected by occupational cancers is mainly attribu table to the fact that industry has employed, until relatively recently, men almost exclusively in such hazardous operations. Only during periods of abnormal strain in the available manpower have women been used on a larger scale in operations inyolving exposure to carcinogenic agents, such as aromatic amines, tar, pitch, mineral oil, and related substances. The temporary nature of such an employment in addition to the lack of subsequent medical supervision of these women mainly accounts for the fact that in most instances of occupational cancer little information is available as to the incidence and occurrence of such neoplasms in the female sex. Wherever, on the other hand, occupational carcinogenic agents acted on members of both sexes cancers appeared in both, males and females, according to their relative number exposed and to the degree of exposure sustained. Thus cancer of the skin due to roentgen rays has been seen in men and women. Inversely, operations with carcinogenic hazards in which mainly female workers were present exhibited a prevalence of occupational cancer among women. The occurrence of cancers of the bone among girls working in luminous dial plants exemplified this relation. These observations on the sex distribution of occupational cancers suggest that environmental factors may play an important role in the causation of the numerous.cryptogenetic cancers affecting certain organs (lungs, larynx, gastrointestinal tract and skin) which have extensive contact with exogenous agents, because these cancers occur much more frequently in males dun in females. C. Age and Life Span.--The claim has been repeatedly advanced that an age factor represented by the relative age or the average life span of a particular species has a significant part in determining the degree of susceptibility to cardnogenic agents and the relative speed of tissue caaeerizatxm as expressed by the latest period. Clinical and experi mental evidence obtained on exogenous occupational and experimental cancers, however, does not lend support to this contention. It is the age at onset together with duration and intensity of exposure which controls the manifestation age of occupational cancers. Depending on these fac tors industrial cancers have been observed in persons* between the ages of 10 and 80 years. Although the dogma of the parallelism between the biologic dynamics between senescence and cancerizasion receives some support when comparisons on these points are made between man and mouse, it loses most of its validity when applied to other species and different types of exogenous cancers. Taumtsr'T f 194 occur.ITIOX.IL MEDICIXE Ultraviolet ray cancer of the skin, tor instance, can be elicited with out difficulties in mice and in rats, but not in rabbits; cutaneous cancer develops readily in mice after the application of a benzolic solution of methylcholanthrene. but not in rats: the skin of rats and monkeys does not respond with any appreciable speed or permanence to the carcino genic action of tar, although the skin of mice reacts rapidly, consistently and persistently to this agent with the development of cancer. Thus, regardless of the relative length of their average life spans, certain species are either completely refractory or abnormally resistant to carcinogenic agents which elicit easily in mice carcinogenic rcsjxmscs under equal conditions of exposure. Observations on occupational cancers in man show, moreover, that in some persons only comparatively short exposure time (six to twelve months) are necessary for eliciting the development of aniline cancers of the bladder or chromate cancer of the lungs. If the aforementioned dogma of the biologic dynamics of cancer genesis in relation to speed of senescence is applied to such cases one is forced to assume that some men apparently possess organs which age in an extraordinarily short time, while others with exposure times of twenty to thirty years undergo senescent changes in slow motion. Inasmuch as it has been established that different species metabolize carcinogenic agents by different methods into different metabolites, it appears to be more plausible that the observed discrepancies in the speed of tissue cancerizadon In various species are related to their dif ferent special metabolic activities and not to their senescent dynamics as expressed in average spans of life. It may be noted in this connection that the observation of species- specific differences in the susceptibility to various physical and chemical carcinogens may make it necessary to qualify is the future the term "carcinogen" by adding the species which reacts or react with the development of cancer to a certain "carcinogenic" agent The importance of this consideration for the testing of occupational carcinogens in ani mals is obvious. ' . ' . "v-'U"'."'' . D. Hedify.--Although it is possible that hereditary, factors'may determine in part the length of the period of latency and of the time of exposure necessary for eliciting an occupational cancer in the individual case, there is no concrete evidence that a genetic predisposition plays any important role in the incidence of these tumors. The intensity and type of exposure and the potency of the carcinogenic agent involved appear to be the main factors in this respect. Whenever these conditions are favorable to the development of a cancer, there is found an early occurrence, a high incidence and a marked multiplicity of occupational cancers. Titus, aniline cancers of the bladder appear in 30 to 90 per : .,1cancer ;ion ot s does ircinosieutly Thus, pecies ogenic equal that wclve Jnccrs.' ioned ed of some short lergo >oIize a, .it the ( UUCPEK--ISDVS7RML C.tXCEK 19S cent of the massively exposed workers. Cancer oi the lungs kills 80 per cent of the Schnceberg miners and between 40 and 50 per cent of the Joachimsthai miners exposed to radioactive material. Cancer of the same organ, on the other hand, is found in only 4 per cent of the dead and living chromate workers and in 12 per cent of the asbestos workers who came to autopsy. . Attempts have been made to attribute the high incidence of pul monary cancer among the Schneeberg miners to a familial hereditary predisposition prevalent among the population of this region. This purely speculative concept has no factual basis and apparently was developed without any reliable knowledge of the actual conditions in Schneeberg concerning the incidence of marriages among close relatives. If an analogy with the genetic background of certain mouse strains showing a comparable incidence of mammary cancer is permissible, one would have to assume that the people of Schneeberg must have propagated by incest for the last three hundred to five hundred years. Such a proposition, however, is obviously outride the realm of science or good sense. E. Procancerous and Anticanccrons Mechanisms.--Recent observa tions made on occupational and experimental cancers have demonstrated the existence of factors which may enhance or impede the development and growth of cancers. However; a sharp distinction must be made between those agents which act in conjunction with a carcinogen and thus during the process of cancerizadon and those which influence the growth activities of an established cancer for which the continued action of a carcinogen is unessential. The last-mentioned factors are called procaronotic when they favor the proliferation and spread of cancer cells and anticardnoric when they have an antagonistic effect in this respect. Factors of the first group are cocarcinogens when they represent an integral part of a carcinogenic complex* procarcinogens when thief aid in the initiation of the transformation of normal into malignant cells and anticardnogens when they interfere with this process. . A constitutional anticarcinogeaic factor is, for instance, responsible for the much higher resistance of the skin of members of the colored races to the carcinogenic action of solar rays than that seen in members of the white race and, particularly, those with fight complexion, blue or gray eyes and blond or red hair. Similarly, colored persons are much less susceptible to cardnogenic tar, pitch and mineral oil than are white persons. It is likely that the higher degree of pigmentation of the skin in the colored races and the greater natural oiliness of the skin of Xegroes account for these differences. i I9o OCCUPATIONAL MEDICINE The assertion was recently made that pticumonneoniosis acts as a cocarcinogen to other factors, such as radiating energy or arsenic, in the development of cancer of the lungs in Schneeberg miners. Inasmuch as nonspecific pneumonoconiosis does not exhibit any demonstrable causal relation to cancer of the lungs and is not essential to pulmonary action of other carcinogens (chromates, nickel carbonyl, tar and arsenic) the alleged cocarcinogcnic role of pneumonoconiosis in the cancer <( the Schneeberg miners appears to be highly uncertain. It is interesting to note that the role of all these factors is evidently not a fixed one, but varies with the circumstances. For instance, hyper keratosis may play in rats a procardnogenic pan in the initiation of cutaneous cancer caused by methylcholanthrene, while it assumes an anticardnogenic role in the development of cancer of the skin eaused by ultraviolet rays. Roentgen rays, rays from radioactive substances and benzene and arsenic are well established carcinogens when acting in small doses over long periods of time, while they are powerful anticardnotic agents when anployed therapeutically in large doses given within a relatively short period. F. Multiplicity of Cancers.--A multicentric development of cancer is frequent with occupational carcinogenesis. While primary multiplicity of cryptogenetic cancers has been recorded in 0.5 to 3 per cent this phenomenon has been observed in 15 to 30 per cent of industrial car cinomas (arsenic cancer of the skin, 15 per cent; tar cancer of the skin, 20 per cent; paraffin and oil cancer of the skin, 15 per cent; aniline cancer of the bladder, 25 per cent; roentgen cancer of the skin, 30 per cent). Systemic multiplicity of occupational cancers has been noted in several cases of aniline cancer, m which the bladder and/or the ureters and kidneys were the sites of primary cancers. Exposure to aromatic amines, arsenic, tar and paraffin oil and radioactive substances has been associated hi a few instances with hetero-organic multiplicity of cancers, affecting simultaneously or successively organs of different systems, such as the skm, the lungs, the stomach, the bladder, and the kidneys. The excessive frequency of primary muItipBdty of occupational cancers is evidently an expression of a relatively powerful carcinogenic stimula tion. The occurrence of hetero-organic multiplicity is of particular interest, as it throws some light oh the so-ofled tissue spedfidty of certain exogenous carcinogenic agents. It seems to be a general principle that cancerous growths ensue most readily ax those sites where the carcino genic agent is present in an optimal concentration and for the most prolonged period. The site, intensity and length of exposure, the speed of absorption of the carcinogenic agent from the site of primary contact and the organs of deposition, of metabolic conversion and of excretion. 1 a enjc, in ssmuch istrable mooary rsenic; icer ui identiv hypertion of nes an ;scd by * end ing in i anti given *i -fM i ie hueper--industrial cancer 197 in addition to the character of the metabolites formed, represent the factors which determine mainly the location or the carcinogenic responses to a given carcinogenic agent. These selected illustrations of the more important scientific aspects of occupational cancers may suffice in demonstrating the eminent sig nificance which these tumors have in connection with the general problem of cancer. U. OCCUPATIONAL CA.VCSKS AS A PUBLIC HEALTH PROBLEM It is only in rather recent years tluu industry and public and indus trial health organizations have become aware, in this country, that occupational cancers represent a public health and an industrial medical problem deserving serious attention. F. Hoffman complacently noted about this matter in 1928 that the scarcity of recorded industrial cancers in the United States was attributable to the fact that the workers in America are unusually intelligent and susceptible to educational influence, desire to know the truth and facts of a given situation and frequently govern their conduct accordingly. Hoffman added that this observation applied to no particular dass of workers more than to those who were connected with the chemical industries in which occupational cancers were unusually frequent in other countries. A look at the record brings out the following facts: Although the United States ins been Jor several decades the leading industrialized country and has recently* accentuated this position `through the develop ments and die outcome of the last war, It Is obvious that this country does not equally excel in regard to the study, control, preven tion and legislative measures of industrial health hazards, especially those causing occupational cancers. By the end of 1945 only thirty-two states had passed some form of eom|*nsation law covering occupational diseases. Since the majority of such laws either contain time limita tion clauses as to the filing of compensation claims or apply only to a limited and well defined number of hazardous agents or operations, they provide inadequate or defective coverage against the hazards of .industrial cancer. ~ This situation deserves serious consideration, as the enormous and rapid expansion of the industrial activities engendered during the war ..was not infrequently carried on under unfavorable conditions, such as inexperienced management and. workers, emergency construction of plants and use of hazardous substances under the pressure of war without the possibility of instituting proper precautions. * It stands to reason that the chances of exposure to occupational carcinogens faced by tlie industrially -employed population of this country were increased by these circumstances during the last few years. Tlie results of such C. li* < K L LI T/O.W II MEDICIXZ exposures in the form of cancers, however, will tiot become manifest before ten to thirty years hence in the majority of persons thus exposed, that is, at a time when many workers have taken up employment ot very different types and most of the women workers have abandoned their industrial activities and either returned to or taken up housework. It is obvious that the industrial origin of many of the then occurring occupa tional cancers will not be correctly recognized, and this will be particu larly true in regard to occupational cancers developing in former industrial employees of the female sex, unless the knowledge concerning and the interest in the occupational genesis of cancer become consider ably more widespread among die members of the medical profession than is the case at the present time. As industrial cancers are not notifiable diseases in most of the states and as American industries have shown so far great reluctance in placing their cases of occupational cancer on record, there exist in this country only incomplete data as to the actual number and variety of these dis ease conditions, their causes and the agents and operations responsible for their development. This evident lack of proper appreciation of the importance of industrial cancer in the United States stands in sharp contrast to the unrestricted and wide publicity which these minors hare received for many years in other industrialized countries, such as England, Germany and Switzerland,'in which industrial cancers are compensable and notifiable industrial diseases and from which for this reason rela tively reliable and complete official information concerning them is available. In view of the continued ignorance concerning the causation of the great majority of cancers occurring among die population in generaljt is regrettable that no competent and extensive investigations exist in regard to the possible role which industrial or related exogenous agents might play in the causation of some of these tumors. The demonstration of such a relationship, if it exists at all, will not be an easy task, as it is likely that any carcinogenic substances which might be isadvertendy contained in the numerous articles of daily use possess a potency of rela tively low order. There is, moreover, no good reason to assume that such agents are numerous and enjoy a wide distribution, as the majority of the definitely identified chemical carcinogens are rather specific, representing usually only a few compounds among a large group of noncardnogenic related derivatives The first step for an effective future control of the hazards of indus trial cancer in this country should be a comprehensive and thorough survey of all industries producing or handling known or suspected car cinogenic agents, including those occurring in the form of contaminants, by-products or waste products. Wherever cases of definite or suspected HUEP ER--lSDUSTRl.lL L.iSCliR m industrial cancer arc found the., following data should be obtained: type of operation; character of carcinogenic agent or agents; absolute and relative number of workers affected; sites, types, length and inten sity of present and previous exposures to carcinogenic agents; local and general precancerous symptoms and reactions; latency period; organ or organs involved; incidence of multiplicity and histologic types of cancers; age, constitution, sex and race of persons affected; diagnostic, preventive, prophylactic and therapeutic measures taken and sociologic, sanitary and technical aspects (physiol, chemical, engineering). If occupational cancers should be found among the workers of a certain operation in one plant and should be absent apparently among those of a similar operation somewhere else, efforts should be made to ascertain any underlying differences (type and intensity of exposure; sex, race and rate of turnover of labor; details of manufacturing proc esses; type of precautionary measures; length of time operations were established; raw products used; intermediary and by-products gener ated; climate, and diet). Special attention should be paid is this connection to those American industries which have apparently remained free or almost free from occupational cancers, although numerous cases have been reported from similar establishments in other countries (pulmonary and nasal can cers in nickel refinery workers and pulmonary cancers in chromate workers, asbestos workers andrarseaic workers). A thorough restudy of the potential cancer hazard to manufacturers and handlers of arsenicals seems to be especially indicated, as recent observations made by clinicians in this country and in Europe as well as governmental data from England show that not only an alimentary 2nd therefore mainly habitual and medicinal exposure to arsenical*, but also a respiratory and cutaneous contact, wliich is prevalent in industry, may cause the devel- -opment of cancers of chc-sldn and the. internal organs (lungs, alimentary Jract). It is not probable that .any occupational cancers of the skin or lungs and leukemias would be found at this time among the many persons who came in contact during recent years with radioactive gases and dust, because a much longer latency period is required in general before ..such complications become manifest. However, all persons who have sustained such exposures should remain under close medical super- .^vision for the next twenty or thirty years/ ' * There can be no doubt that an evaluation of the data obtained in such a survey will permit conclusions which can be translated into definite research problems of an experimental or clinical nature and into useful recommendations for medical, sanitary, technical and legal measures. An effective control of occupational cancers requires the dose and hanaanioss cooperation of many and diverse parties (physicians, chem- --------- tFri'Tvmr 200 OCCUPATIONAL MEDICINE ists, physicists, engineers, biologists, public health officials, law making and enforcing agencies and industrial management). If such collabora tion can be obtained, the great majority of industrial cancers known today may disappear within the next twenty to thirty years from the list of industrial diseases. The continued occurrence of occupational cancers, on the other hand, represents a challenge not only to the intelligence but also to the soda! conscience of human society, because industrial cancers may be compared with a biologic bomb having a delayed time fuse which may be placed in the body of the victim with out his knowledge and realization and which may display, its deadly effect many years later when the conditions connected with its intro duction are often forgotten. _ .. . ,,...nc;u a.mi connmit'fi mi S ca.^es :or more :bnn jwo months is convincing evincive ;hnt the rcmi>* -ion was imitjccf) rnrher than jjK.tiuncims. (t >h<niki in.- remembered. however. that it rrcnttnem is continued for more than eighteen months and then discontinued, the resultant remission might well he a natural one. It has been >uggcstetl that thiuurneil could not induce a relatively long remission Ixreause it produces in the gland a hyperplastic but iunetinnally inefficient '.tate. It has been recognized that 3 'hyperplastic state of the thyroid can exist in a patient experiencing a relatively permanent remission of his thyrotoxicosis. This has been demonstrated by the structure of the remnant of die thyroid gland after thyroidectomy by Rienhoff" and Brandi. They examined sections of the thyroid gland removed several months after thy roidectomy and found the characteristic evidence of stimulation of the thyroid. Even though this state of hyperplasia persists. Preston and Tiiompsonu con cluded that a single thyroidectomy may accomplish control of the toxic state sufficiently to avoid subsequent operations in 35 per cent of the patients. Treatment with thiourea! has the same effect as thyroidectomy, at least temporarily. This is accom plished by reducing the function of the thyroid tissue hy interference in the iodine concentration and oxida tion process of the gland. It is entirely possible that the hyperplastic state of the thyroid induced by thiouracil changes to a state of normal 'involution after a variable time. Evidence in support of this is to be found in the report of Shirer and Cohen.** who observed a normal morphologic picture in a thyroid gland removed from a patient previously treated unsuccessfully for seven months with thtoareal. Further evidence of the active effect of thiouracil m producing a more permanent clunge in thyroid func tion is found m the case reported by Barr,*" and in 1 observed in our series in which a thiouracil induced picture of myxedema recovered slowly over a period of six months after treatment with thiouracil was dis continued. ' In oar opinion this evidence indicates that thiouracil does more than iodine in that it produces a change in the thyrotoxic state which persists after the admin istration of the drug is discontinued. CONCLUSIONS Thiouracil may be used in about one third of the thyrotoxic patients only as preoperanve treatment, since these patients possess nodular goiters which might develop a malignant condition. Another 7 per cent of the total number win require thyroidectomy on account of complications which occur during thiouracil therapy. The most serious of these complications to be kept m mind is agranulocytosis.* About 15 per cent of the patients with thyrotoxicosis will leave the physician's care for personal reasons of the (tttient. which arc in some instances related to difficulties encountered in thiouracil therapy. In the remaining 45 per cent of the total group, mane up ol titose with toxic hyjierplastic goiter, thiouracil therapy may be discontinued at the end of a little over an average of ten months with the prospect that dO to 30 per cent of the patients will experience a relatively persistent drug induced remission. For this IS. Rtcnfceff, owd by Ftu.* It. Pt>--, T. WH uS Tfaowpiiw. 'V. 0.: Pmmnn and Rmrww ( Tttbc Gan* F0wri*c SabttUl Tfam*dcctor. Arch. Im. Ot 1019 <JM> 1942. _ 12. Shim, /. W,, nd Cata. X.: Tfat Effect* of Tfaioaracil n tht TtfwM Oaa An. 1st. il4. 33*790 (Nw.J 19*}. jc.d..cu group, at icast during the period ot observai "'inch has continued to date, tins resuit :s as sanstac: dun ot subtotal thyroidectomy. The majority patit-nta vvttit thyrotoxicosis, however, must be trea; lw surgical means. Those receiving thiouracil mi continue treatment with the drug tor indefinite perio For these reasons surgery is still the treatment of choi in the management ot this condition. Thiouracil ,-uperior to iodine, however, as it is more specific its action and induces a more complete and permane remission in patients with this disorder. In the trea mem of selected cases of thyrotoxicosis, therefore, thi uracil treatment must be considered as a form of therup which has promise, and ultimately it may prove to fc as satisfactory as thyroidectomy in this group of patient*. INDUSTRIAL MANAGEMENT AND PATIONAL CANCER W. C KUCTtt, MA. OCCU The term "occupational cancer" applies to malignant tumors which originate in persons during the course of and as the result of the regular and usually prolonged exercise of certain occupational activities which entail contact with some exogenous, physical or chemical car- i cinogenie agent acting in proper intensity. Occupational. cancers are in general elicited by specific factors which ; form as integral part of the ordinary working conditions . and thus are not the result of some unforeseen, acd-: dental injury sustained while at work. i Although a few of the cancers so far recognized as ; of occupational origin have been known or have existed - without correct recognition prior to the advent of the modem industrial era, such as the soot cancer of the j chimney sweeps and the cancer of the lung of the cobalt j and uranium miners is Schneeberg and JoachimsthaL : the great majority of occupational cancers appeared after ; the start of the Wesem industrial development and as : a result of it. During the last century there occurred not only a constant rise in the absolute number of these j malignant growths but also a decided increase in the types of organs affected by them, m the number of i exogenous occupational agents involved m their pro- j duction and in the variety of manufacturing establish- ( ments in which workers were afflicted with them. t An analysts of the available data on occupational \ cancer has shown that the type of the resulting tumor, the length of the latest period preceding its manifests' t tion, the organ affected and the age of the person t involved depend on the diameter of the carcinogenic j agent, the type and intensity of exposure and the age f of the person when the first exposure takes place. The l soot cancer of the scrotum found in chimney sweeps, for ' instance, was observed some hundred and twenty-five ^ years ago even in children, since boys as young as * 4 years were used in England at that time for denning ' chimneys. The exposure to the carcinogenic soot dur ing this ujwration was severe, and the degree of clean- \ liness among these unfortunate youth was very low. i When, during the middle of the last century, the English * government repeatedly raised the age limit of the apprentices of this trade, there followed a gradual rise ' of the age range at which the scrotal cancers appeared * among chimney sweeps. At the same time the insritu- ; tion of better hygienic conditions and the improvement j of working tools and of chimney construction reduced j tM Wuxr Iartimt far Tfa*rsf*tic Utmrcfc Vqiuvc I-H ,Su* 9 OCCUPATIONAL CANCER--HUEPER 739 > the decree of exposure to soot. As the result of these causes a destruction of the blood-forming tissue and hanges the scrotal cancer of chimney sweeps in England results in a fatal anemia when acting in large doses, but. ya appears at the same age as that found in members it may elicit leukemic responses when acting in small ,i the general population affected by cancer of the doses and in suitable intervals on the blood-forming ( scrotum of unknown etiology. Only the increased tissue. : incidence of this particular type of tumor among chitn- In most cases of industrial cancer, experimental ; ney sweeps has remained as evidence of the action of research on cancer has succeeded in demonstrating the ' an occupational carcinogenic' agent. specific carcinogenic agent involved by using these ' However, not all occupational cancers have followed such a favorable development. Whenever the managers of new plants and their medical advisers have neglected to profit, in the construction and operation of their estal>- agents to reproduce similar tmnors in animals. Definite proof of carcinogenic properties have thus been obtained for arsenic, tar. pitch, soot, crude mineral oil, crude jarafim oil. anthracene oil. shale oil. some fuel and lubricating oils, creosote, benzene, aromatic amines, lishments, from the adverse experiences previously had ultraviolet rays, roentgen rays and rays from radio by other manufacturers in the same fields, there has active substances. In recent years, however, cancers ; appeared some ten to fifteen years later a renewed, acute of the lung lave liven noted among workers in chromate ; and sometimes epidemic-like occurrence of occupational plants, nickel refineries and asbestos-manufacturing ; cancers in these industries. Such a course of events establishments. These tumors are either suspected or i is exemplified by the incidence of cancers of the urinary .. bladder in workers of the aniline dve industry. These tumors were first observed in 1895 in German dye . works and were later found among the chemical workers ( of other countries, such as Switzerland. Italy, England. Japan and the United States. The time of appearance of cancers of the bladder of this origin followed closely the time of large scale development of chemical indus recognized as being of occupational origin. An inter esting feature of these cancers is represented by the fact that the cancers of the lung in chromate workers were observed only in several German .plants, while the can cers of the lung in nickel refinery workers were found exclusively in English plana where the nickel carbonyl process was used. Although the same process is employed in some nickel refineries located in Canada * tries in die countries mentioned. Thus the first cancers and the United States, caneers of the lung lave not been of the bladder in chemical workers of this country were noted among the workers employed here if full credence noted in 1932. that is, approximately fifteen years after can be given to (he meager information available on . the American dye industry had .reached large propor- this matter. Cancer of the lung in asbestos workers, on rions. Within the short period of six years thereafter the otlier hand, has been reported from Germany, {(' nost 100 cases of this industrial cancer occurring England and the United States. The actual causative * nen of relative youth were placed on record from agent in the production of cancers of the lung in chro single chemical concern, attesting to the presence mate. nickel and asbestos workers is still unknown. of a relatively massive exposure of the workers to the . The rapid increase in the number of recognized and causative agents--that is, betaaaphchylamtne and benzi suspected agents causing industrial cancers which have dine The full significance of this incidence figure occurred during the last forty years makes it more likely becomes apparent from the tact that there were only that new and heretofore unsuspected carcinogenic agents sbout 300 cases of this particular occupational cancer of an industrial nature wilt be discovered during the reported, according to the statistics of the Gentian gov coming years. Such a development is foreshadowed ernment. from the entire German chemical industrr by observations made during recent years by American within a period of forty years, that is. from 1895 to 193$. investigators. It was found that cancers of the liver .Although no authentic data are available as to the occur developed in mice exposed to carbon tetrachloride, a rence and the incidence of tumors of the bladder among commonly used organic solvent. The inhalation of die workers of other American chemical concerns, the ethyl carbonate (urethane), which is employed for anes existence of such cases is known. thetic purposes, resulted in the appearance of cancers Cancers resulting from contact with radiant energy-- of the lung in mice. Tumors of the bladder were that is. the rays from radioactive substances and roent formed in rats fed diethylene glycol, which is one of gen rays, illustrate strikingly the influence which the the newer widely used organic solvents. Tumors type and intensity of contact exert cm the formation of of the peripheral nervous tissue were sees in the ears the ensuing tumor. It appears that the inhalarion of of rats to which crude ergdt. a drug extensively used radioactive gases or radioactive dust causes cancer of the is obstetric practice. lad been fed over long periods. lung, such as that sustained by miners in Schneeberg Occupational carcinogenic agents produce cancers in and Joachimsrhal. whereas the local action of radioactive numerous organs. Cancers of the skin are elicited by and roentgen energy on the skin causes the development contact with arsenical*, tar. pitch, soot or carbon black, of cancers of die skin, such as those seen in radiolo crude mineral oil. lubricating oil. shale oik crude paraffin gists. roemgerwrfogists. their assistants, and in x-ray oil. anthracene oil. aotar and ultraviolet rays, roentgen tube manufacturers, physicists and engineers. The rays and rat's from radioactive substances. The number ingestion.of radioactive natter, on the otlier hand, causes of industrial cancers of this organ runs into several the development of cancers of the bones, such as those thousands. Cancers of the nasal passages have been observed several years ago in girls who applied luminous noted after occupational exposure to chromates, nickel J to dials. However, in more recent years cancers carbonyl and radioactive substances. Cancers of the \ blood, known as leukemias, lave been noted in bronchi and lung lave lieen traced to an industrial expo inu casing number among physicians and radium chem sure to arsenical*, chromates, nickel carbonyl, soot. tar. ists exposed frequently to relatively. small doses of asltesto* and radioactive substances'. Cancers of die lip roentgen rays or rars from radioactive matter. Tlvesc - liave aiqwared following contact with tar and after pm- .deleterious effects on the blood-forming tissue lave their longed exposure to .-olar rays, while cancer* of the mouth cancerous equivalents in the leukemia* observed among ami of the tongue seem to i eriologically related to att - persons exposed to benzene. Tins organic solvent, like Industrial contact with tar and arsenical*. Cancers of frwntmm *# " f--~. * * >>. 4v jf.t * -ih . * I' *C lowed occupational exposures in .ipmikiCK amine-. juch as nnpiuhyiamine. benzidine anti aniline* and occasion* ally to tar and arsenical*. Cancers of ilic blood. called leukemias, have resulted irotn contact with benzene, roentgen rays and rays front radioactive substance*. The latter are also responsible for the occurrence m cancer of the l>oncs. The exposure time necessary. for eliciting cancer* ous reactions in exposed workers varies greatly with the type and potency of the carcinogenic agent, with the intensity of exposure and with the susceptibility of the individual. The range is from six months to three to four decades, while the average exposure time is from five to fifteen years. In most instances occupational cancers appear in a younger age group than that found for die same cancer of unknown etiology in the general population. Age and sex factors do not, as a rule, play any role in the production of industrial cancers. The incidence rate of these tumors shows decided varia tions hot only for the different carcinogenic agents but also for the different operations and is directly propor tional to the potency of the carcinogenic agent and the intensity and length of exposure. Oncer of the bladder "thus affects from 30 to 90 per cent of the severely exposed dye workers, while cancer of die lung kills from 73 to SO per cent of the cobalt miners of the Sclweeberg mines. Carcinogenic agents eliciting occujiarional cancers of the skin, on the other hand, have a lower morbidity and mortality rate because the precan- cerous changes of the skin preceding the appearance of the tumors gives ample warning, as a rule, of the threatening malignant condition, while the ready accessi bility of the skin to therapeutic measures enhances the prognosis of cure. It is of a certain importance from an industrial point of view that the skin of colored workers is less susceptible to the cancerigenic action of solar rays and of tar. pitch and similar substances than that of white, and especially of fair-skinned, workers. * The total number of occupational cancers placed on record is small when compared with the large number ofcancers of unknown etiology. It is obvious, however, that the latter group contains an undetermined number of cancers of occupational origin, as many of diem either are not properly recognized or are nocmade a matter of public information. Although today a great deal of evidence On the causes of occupational cancer and the conditions under which it develops is available, relatively little effort has been made to spread this knowledge among parties who are vitally concerned with this information, namely the man agers and physicians of industrial concerns, although they carry the main load of controlling this preventable type of oncer. This situation is the more deplorable Iwcause the present rapid development of industry tends to extend the hazards of the known industrial carcino genic agents while at foe same time creating new ones which may cause the appearance of cancers ten to twenty years hence, unless concerted efforts are made in time to discover and control such dangers by appropriate countermeasures. It is essential chat industry should devote considerably more effort than heretofore to deter mining the cancerous or noncancerous nature of such of its numerous products as may be suspected on general grounds of cancerigenic properties. As occupational cancers are chance experiments on cancer in man. con ducted by modern industry on a large scale, which render direct, reliable and conclusive information as to the cause and mechanism of human cancer, the inves tigative study of these conditions deserves a great deal unTt; uniNderniioii dun it ;as !K-r;, ;m :iic pa-?. ! be exiHrricncc gained from the study of ocatntumuai cancer, and specially of us causative mcch.v.UMU an*' 'ts prevention and control, should prove of great vaiue in the future in fighting cancer in general at its source: that if. it should aid in the elimination of the cavises of cancer l>efore they are capable of initiating the malig nant growths. In waging this campaign it should be realized that a well planned, systematic and. probably, prolonged attack must be launched if worth while results are to t* expected. However, I am convinced that with the necessary perseverance and determination this battle against occupational cancer in particular and against cancer in general can be won. if every one concerned aids in the effort. * If industry can be persuaded to finance the foundation and maintenance of an organization exclusively devote*! to the study of the causation and control of industrial cancers, not only will industry be the main beneficiary of this move, but also it will gTeatly advance the fight against cancer in general, which is of direct concern to every one, unless it is forgotten that every tenth adult dies from this disease. * RECOMMENDATIONS FOR THE CONTROL OF OCCUPATIONAL CANCER 1. Plant management officials, industrial workers ami members of the medical profession must 1* made increasingly aware of the fact that numerous agents of our new industrial environment possess carcinogenic properties. 2. Construction and chemical engineers should design buildings, machinery and apparatus with this hazard m mind---that is. they should try to favor the closed svstem of production, the installation of adequate exhaust ven tilation, the use of building material which does net absorb carcinogenic substances, the avoidance ot nooks, crevices and ledges where carcinogenic dust can be deposited, and the employment of win and floor cover ing that can be thoroughly and'repeatedly cleaned with water and steam used in connection wtth'deansers. 3. Adequate provision must he made for the removal of carcinogenic material from waste gases, fumes, waters, dust and the like before these waste products are released into the air. public waters or ocher chan nels affording foe contact of the general population with carcinogenic industrial wastes. 4. Carcinogenic material must be packed in leak proof containers. . 3. Similar appropriate protective technical measures should guard foe persons handling roentgen rays and radioactive substances from being exposed to deleterious quantities of radiant energy. 6. These measures must lw sufficiently extensive t protect also persons working or living in the immediate environment where physical or chemical carcinogenic agents are iiandled. 7. Whenever the uSe of carcinogenic material u: industry cannot be eliminated by die use of substitutes, workers should be protected from contact with carcino genic agents by suitable protective clothing, gloves, masks and the like and by the enforced observance of adequate hygienic measures, such as the use of washing facilities, showers and special rooms for storing street clothes and for taking meals and frequent changes ot working clothes. K. Frequent and experienced medical supen'ision of the workers exposed to carcinogenic material is impera- VNoulausms'*c 9131 ACUTE SYPHILITIC NEPHROSIS--HARR ET AL. 741 live for effective control of die hazard. This supervision must also extend to workers who have left the employ ment after having been exposed to carcinogenic agents for a sufficiently long time or who have been shifted to nuncardnogenic operations. 9. A nationwide survey by skilled investigators should be made to determine the actual, scope of the problem uf industrial cancer. Representatives of management, industrial physicians, members of the Public Health Sendee and of departments of industrial hygiene and l>ossibly also representatives of the workers should par* ticipate in such a survey. 10. Precancerous and cancerous industrial diseases slfould be made notifiable to the departments of Indus* trial hygiene of the various states. 11. Adequate compensation laws for occupational diseases should be passed for the protection of both management and workers against excessive awards or inadequate compensation, respectively, for claims that result from the production of occupational cancers. 12. Government inspectors should examine all Indus* trial plants at regular intervals to determine whether or not they meet the essential safety requirements nee* c&ary for minimum protection of the workers against the hazards of industrial cancer. 13. An institute for the study of industrial cancer should be founded and should be attached to or coordi* rated with one of the existing targe cancer research centers, in order to provide for proper integration of the results obtained by such investigations with those produced by cancer research in general. Such aif >rganization would serve industry for consultative and investigative purposes on matters of occupational oncer. 14. A committee composed of industrial physicians, cancer research workers, industrial physicists, dicausts and engineers, compensation lawyers, members of the Public Health Service and of state departments of industrial hygiene, representatives of industrial manage ment and union officials should be created, whose mem bers should act as a body of consultants and special expens to the Institute for the Study of Occupational Cancer. An and Anatomy.--Among the great artists who engaged jo dissection were Michael Angelo. Raphael and Albrecht Oarer. Greatest of all was Leonardo Oft Macs (1452*151$). This gifted and versatile artist, a man centuries ahead of Ids dme a original Ideas, who visualised ariarioo. and modem methods of warfare and who discussed many problems of engineering which were later put into practice; also made discoveries in anatomy, such as the maxillary aims and the moderator band of the heart. He was the first to demonstrate the ventricles of the brain by wax injection* and to depict correctly the ferns and its membranes within the uterus. Originally he set out to study tiw bones and muscles in their relation to art, but his interest grew, and be pursued his investigation of the deeper parts, the viscera, the brain, the blood vessels and especially die iican. He intended to publish a great work on anatomy in collaboration with 3farco Antonio della Torre ot Pavia, but this project was abandoned owing to he death of his co-worker. It is only within recent years that e value of Leonardo's contribution to anatomy has been fully appreciated. He made hundreds of sketches and mtmacript notes, many of which are preserved m die Royal Library at Windsor and here only recently appeared a print. Tins apostle of naturalism in an must also be regarded as a leading piooecr in anatomy.--Guthrie, Douglas: A History J Mcdicioc. Philadelphia. J. B. Lippmcott Company, 1946. Clinical Notes, Suggestions and New Instruments . ACUTE syphilitic nefhhosis successfully TREATED WITH PENICILLIN .. i. H. SAS* )t. M.D.; H. N. COU. M.O.; J. *. OSIVfft. M.0.; lOSCOC 0. lAS, M.0.; MAX MIIUK. M.O., * L fi. STIAUSS. M.0. Outline The nephruiic syndrome is defined as a clinical symptom vumplex characterized by profuse proteinuria, hypoatbuminoma and edema without serious renal insufficiency or hypertension, h may be seen in a variety of conditions and has been observed in connection with acme syphilis.: urotr or cask History.--J, Y,, a white man aged SI, was first admitted to University Hospitals July 18, 1945 with a chief complaint of generalized edema and genital ulcerations of approximately one week's duradon. In the early port of June 1945 several superficial lesions developed in the coronal sulcus of the penis. These gradually enlarged, with subsequent ulceration. July 2 he was seen by one of us (L. G. S.), who made the diagnosis of chancroid of the pens and started the patient on sulfathiaxole two tablets four times daily. This was continued until July 6, when the result of the serologic test for syphilis drawn at the first interview was reported as strongly positive. On July 7 he was given 0.04 Gm. of oxophenarsine hydrochloride (Maphar* sen) intravenously, with no immediate reaction. However, right to twelve hours later he had a shaking chill and tempera* tore elevation to 104 F. Within twelve hours the patient was again symptom tree. July 10 another injection of 0.02 Gm. of oxophenarsine hydrochloride was given intravenously, without ill effect. He returned on July 15 and at that time had moderate edema of the face. legs, penis and scrotum and complained of general malaise, anorexia and low hack pain. Mo urine exami nation was done at this time. On July 17, when he was seen again, the ctkma of the face, legs, penis and scrotum was more severe. The urinalysis revealed 4 plus proteinuria and an occasional red blood cell. On July 18 the edema was less severe and the urine contained only an occasional red blood criL He was then referred to University Hospitals for study. Physical Ewwiiwtum.--The temperature was 57 C (9&6 F.), pulse rate 82. respiratory rate 18. blood pressure 124/72, weight 78.1 Kg. He was wdl developed and wdl nourished. He did not appear to he m distress. There were no abnormalhies of the skeletal system. Hie mucous membranes were of normal color with no abnormal lesions. There was slight facial edema, especially nonetable about the eyes. There was no apparent edema of die upper extremities. There was moderate pitting edema of the sacrum, external genitalia, thighs and legs. The skin was normal m color and texture, with no abnormal lesions. There was a well defined, firm, freely movable nomender lymph node in the right inguinal region measuring 2 by 2 cm. There were two smaller Ivraph nodes similar in character in the left inguinal region. There was no other lymphadeaopathy. There was moderate periorbital edema. The conjunctivas were pale. Tlw corneas and scleras were normal. The pupils were equal and regular, measured 4 mm. and reacted normally V'ruM tW IhiunMifMi <4 ami SnAiUott and the Depart- iMrm d Mnlmw 4 t'niwniir ll<MHnh <4 L'k'vrtand and Western Kmerv* Cntavnity Srfaa* ,4 Medicine. The wwrfc kxriM in this paper was June umter a cewtrtct. men aielri hv the cunumtee on OiiiVi mease*, between the IMIev f Scieatilie kewarch an4 Umlupniwt and the Western Reserve Uneven**.*. I, CW. U. X.; Acute Syphilis f Kidney. As*. I. Syph. 4: 4ft (Jan.* 19J0. Baker. B. JU Jr.: The IteUlinn t SrphBts tn Xcphriti*. BttO. Inhne llsskiM Hiss, hit IN, 1UL UervtMttn. (u S*4 Uarr. W. llutkal Syphilitic Xrthr*wtJu**w As*. J, Syvh. k .VwsL lit 1, ISIS. M*wre. J. L.: The Jledrrm Treatment i SrphUis. L Z. SprieftUid. IIUmm ft Raltitnurv. Chart** C Thenssi. 1*41. Stake*, J. H.; Zeeman. Herman. ami Jncrahsun. N. K., Jr.: tt<*irra Clinical Srphtiehtey, *4. J, rhila4rl|>kia ft bnl>, \V. H. Sswmlers Cem|ny. 1*44, p. 1177.