Document 3eEY9D3R1qdYO5MMO6jbLenXx

OCCUPATIONAL TUMORS AND ' ALLIED DISEASES By W. C. HUEPER, M.D. ASSISTANT DIRECTOR AND PRINCIPAL PATHOLOGIST WARNER INSTITUTE FOR THERAPEUTIC RESEARCH NEW YORK CITY \ M m rLE>fwi 1942 CHARLES C THOMAS - PUBLISHER SPRINGFIELD ILLINOIS BALTIMORE * MARYLAND F | AHE amount of factual information and the scientific as well as practical X significance of tumors of occupational origin have increased rapidly during the past two decades. This development, however, so far has not found an adequate and comprehensive presentation in the medical textbooks dealing with industrial diseases or with cancerous growths. There is thus a place and a need for a separate and detailed treatise on occupational blastomas and related diseases. It is the principal aim of this book to furnish an extensive source of informa tion concerning the various aspects and the different types of these neoplastic disorders which have come to claim an ever-increasing importance as a part of the problem of cancer in general. A reference book is now offered in which the pertinent data, often not readily accessible and widely scattered in journals, books and separate communications of a diverse character, have been compiled. An attempt is made to analyze critically and to integrate the evidence obtained from different sources, and to correlate and evaluate the various observations made and theoretical conceptions advanced, so as to forma'well balanced and, when possible, coherent picture of the subject under discussion. The treatise may appeal and serve, therefore, as a guide to all those directly or indirectly interested in and charged with the supervision of industrial and public health hazards or concerned with the diagnosis and treatment of neo plastic diseases. The book is addressed to the a) medical profession, particularly those of its members who are engaged in the clinical management and scientific study of cancer and of occupational diseases, including their medico-legal aspects. b) governmental agencies charged with the safeguard of public health, the supervision of working conditions in industry and commerce, and the sanitary control of the various types of merchandise, especially foodstuffs, wearing ap parel, drugs, cosmetics and the innumerable chemicals contained in articles used in the household, agriculture, etc. c) legislative bodies formulating the laws which regulate the activities of the above mentioned governmental agencies, and of the private parties con cerned with occupational hazards causing the production of industrial cancers. d) vcorkmerds compensation boards, industTial COIlliniSSioiIS. etc, e) legal and judicial profession. f) industrial managers and engineers. g) life insurance and accident insurance companies. b) research workers in biology, chemistry and physics. vill OCCUPATIONAL TUMORS AND ALLIED DISEASES An appreciable unevenness exists in the presentation of the various aspects of the individual occupational neoplasms. This is in part due to the fact that marked differences exist regarding the amount of information available for any particular type of tumor, and in part to the irregularity with which our knowledge has progressed at different times and at various points. The ap parent great complexity of the subject matter, the existence of an appreciable number of disconnected or controversial observations, and the rapid and con tinuous expansion of the borders of our knowledge, may necessitate not only modifications in the interpretations of observations recorded, but also demand that final judgment must be suspended on certain points until some future time. The extensive bibliographies conform to the reference character of the book. A fairly complete list of references is offered for the majority of in dustrial neoplasms discussed. A restricted number of publications, selected according to their relative scientific or practical value or because of some special feature, is given with those industrial tumors for which a very abundant lit erature exists. The bibliographies, in these cases however, are also of great fullness and representative in character. No attempt has been made to cover the literature comprehensively, which has been accumulated concerning the traumatic causation of neoplasms, as a great number of publications dealing with the subject are of little value. It is obvious that in the difficult task of collecting data from many sources and about widely differing aspects, errors or omissions may have occurred. The indulgence of the reader is asked in this matter and the hope is expressed that his suggestions and criticisms may assist in remedying such defects and in improving the work in the future. I wish to express my sincere gratitude to William R. Warner & Company, Inc., and especially to Mr. G. A. Pfeiffer, President, and Dr. Marvin R. Thompson, Director of the Warner Institute for Therapeutic Research, for the continued interest shown in the progress of this work and for the en couragement extended to it until its ultimate publication. W. C. H. January i, 1942 Scarsdale, N. Y. CONTENTS vhi . Symptomatology ......................................................................... ix. Histology ........................................................................................ x. Pathological Relations (Ratio of Benign to Malignant Tumors, Multi plicity) ............................................................................................. xi. Localization and the Developmental Mechanism............................... xn. Treatment ..................................................................................... xm. Prognosis ....................................................................................... XIV. Susceptibility.................................................................................. xv. Occupation .................................................................................... xvi. Protective and Preventive Measures............................................ xvii . Medico-Legal Aspects................................................................. xyiii . Social Aspects .............................................................................. 3. Parasites-Schistosomiasis ........................................................................ I. Historical Aspects.............................................................................. . Causative Agent ............................................................................... in. Conditions of Exposure ................................................................. iv . Incidence v. Age vi. Symptomatology vn. Pathology vm. Causative Mechanism ix. Prognosis x. Preventive Measures xi . Infectious Papillomatosis of the Bladder in Rats 4. Mechanical Trauma 512 5i4 520 520 522 523 526 53' 533 534 534 534 536 537 538 539 540 543 546 546 547 548 CHAPTER VI OCCUpATIONXL AND ACCIDENTAL HYPERPLASTIC AND NEOPLASTIC DISEASES OF THE BLOOD FORMING ORGANS /. General Anatomical Considerations ..................................................... 2 . Occupational Erythrocytoses .................................................................. A. General Characteristics and Classification of Erythrocytoses ............ a. Chemical Agents ........................................................................ I. Erythrocytosis Following Exposure to High Altitudes (Reduced Oxygen Tension) ...................................................................... n. Erythrocytosis Caused by Carbon Monoxide Poisoning.......... 111. Erythrocytosis Following Exposure to Hydrogen Sulfide, Nitrose Gases and Hydrogen Cyanide........................................ iv. Erythrocytosis Following Exposure to Aromatic Hydrocarbons and Their Nitro- and Amino-Derivatives .................................... v. Erythrocytosis Following Occupational Diseases of the Lungs vi . Erythrocytosis Following Contact with Certain Metals .... Arsenic ................................................................................... 557 557 558 553 561 569 5T 573 573 xxiv OCCUPATIONAL TUMORS AND ALLIED DISEASES Germanium ................................................................................. 574 Manganese ................................................................................. 574 Iron ............................................................................................ 575 Antimony .................................................................................... 577 Lead ............................................................................................ 577 Mercury ...................................................................................... 578 Cobalt .......................................................................................... 578 vii. Erythrocytosis in Phosphorus Poisoning................................... 579 vm. Erythrocytosis Following Introduction of Gum-Shellac .... 580 6. Physical Agents ............................................................................... ^8o I. Erythrocytosis Following Exposure to Actinic Agents................. II. Traumatic Erythrocytosis .......................................................... 3. Polycythemia Vera ...................................................................................... A. Trauma and Polycythemia Vera .......................................................... B. Experimental Polycythemia Vera.......................................................... 4. General Conclusions on ErythrocytoticReactions ........................................ 580 583 ^84 584 ggg ^35 5. Occupational and Accidental Leukoblastosesand Leukoblastomas .............. A. General Aspects and Classification ................................................. B. Occupational Leukoblastoses and Leukoblastomas.................................. a. Chemical Agents ............................................................................. 588 ggg ggg gg^ I. Benzol ........................................................................................ Chemical and Technological Aspects ........................................ Toxicological Aspects ................................................................ 594 gg^ 594 Leucocytotic, Leukemoid and Leukemic Reactions .................... 594 Etiological Aspects ..................................................... v ... 597 Preventive, Precautionary, Technical and Sanitary Aspects . . 598 II. Benzol Derivatives and Other Aromatic Compounds........... 599 b. Physical Agents ............................................................................... 602 1. Roentgen-Rays and Radioactive Substances.............................. 602 Hematological Reactions ............................................................ 602 Exposed Occupations ................................................................ 603 Leucocytotic, Leukemoid and Leukemic Reactions..................... 604 Exposure Time, Age, Occupational Distribution, etc................... 608 Diagncstic Aspects .................................................................... 608 Etiological Aspects ..................................................................... 609 Experimental Roentgen- and Radium-Leukemia ...................... 611 Medico-Legal Aspects ................................................................ 612 n. Trauma...................................................................................... 613 Leukemia (Psychic Trauma, Mechanical Trauma) ................... 613 Aleukemia .................................................................................... 62 i Myeloma, Chloroma, and Reticular Cell Sarcoma of Bone ... 621 C- General Conclusions of Leucocytotic Reactions .................................. 626 DISEASES OF THE BLOOD FORMING ORGANS ,, 5 9j Many of the recent advances in our knowledge of anemic conditions have come from occupational and medicinal toxicology, dealing with such diverse conditions as chronic benzene poisoning, toxemia of amino- and nitro- derivatives of aromatic compounds, lead hazards, injuries resulting from exposure to roentgen-rays and radioactive substances, and similar industrially important and medicinally used agents ( Lance: '}. Accumulative evidence, during late years, suggests the possibility of a similarly important role, which investigations of the occupational leukopoietic hyperplasias may plav In regard to tile elucidation of the causation and developmental mechanism of the crypto- genetic leukoblastoses and leukoblastomas. The urgent need of such studies is emphasized bv reports concerning the sudden and rapid increase of leu kemias during the iast fifteen vears. Curschmann observed, m :he university clinic in Rostock, that chis disease, relatively rare ( one case among 1,000 hospital patients) in former times, hac become much more frequent since 1905. During the decade ?receding iQ-j approximately one to three cases of leukemia came under observation during one year in the clinic. After this date the number of leukemias admitted to the clinic rose to three to In addition to this absolute and (in the opinion of Curschmann) actual increase in the incidence of leukemias there occurred a remarkable shift in the type of leukemias observed. Since 1925, the acute variety of leukemia, formerly extraordinarily rare, became relatively common, representing more than 33 per cent of the total number of cases (eightv one) studied from xpij to 1930. While Curschmann's analysis of the cases did not reveal any relation of this increase to some tvpe of exogenous or endogenous factor icccupation, trauma, infection, tuberculosis, syphilis, malaria, and septicemia), there still remains, as the most probable explanation of this phenomenon, the supposition that some new undetermined exogenous factor or factors have been active in late years. It is less iikeiv that the biological condition of the patient popula tion of the clime should have change:! in such a radical fashion. This con clusion is supported bv the fact, that during the same period a similarly spectacular increase of other blood dvscrasias, especially of the agranulocytic and aplastic anemic varieties, has taken place, which could be traced to certain types of aromatic compounds. OCCUPATIONAL CUKOBLASTOSES AND LEUKOBLASTOMAS The various agents or occupational nature, which have been related eco logically to the occurrence of leukemoid, leukemic, and leukoblastomatous reactions, may be divided into two main groups, namelv, those of more or iess well-defined chemical (benzol, tar, and crude mineral oil) or physical ( roentgen-ravs and radioactive substances) character and these of nonspecific, mechanical-traumatic or traumatic-infectious type. 594 OCCUPATIONAL TUMORS AND ALLIED DISEASES a. Chemical Agents I. BENZOL Chemical and Technological Aspects. Benzene, a cyclic hydrocarbon of the formula CsHa, is a distillation product of tar and is the principal constituent of an impure commercial product marketed, also, under the name of benzol. This substance is a colorless liquid having a characteristic odor and taste. While readily miscible with many other organic solvents, such as ether and alcohol, it is relatively insoluble in water. It should not be confused with a similarly named substance, benzine, which is a distillation product of petroleum and used for many purposes for which benzol is employed. Benzine consists of a mixture of non-aromatic hydrocarbons having the formula CH14 and C7H16. The great importance of benzol as an occupational health hazard comes from its extensive use in many industrial operations and its use as a constituent of numerous industrial products (Rep. Internat. Lab. Office; Selling and Osgood; Holstein; McCord; Schilling; Greenburg, Mayers, Goldwater and Smith; and Bowditch and Elkins). Benzol and its derivatives play an important part in the manufacture of explosives, dyes, drugs, aromatic chemi cals, lacquers, paints, paint removers, bronzing, silvering and gilding liquids, rubber cements, artificial leather, natural leather enamels, waterproof fabrics, and storage bakeries. It is widely employed as a solvent of rubber, resins, fats, oils, and alkaloids, and therefore is used in cleaning machinery, dry cleaning clothes, decorating pottery, electroplating, lithography, photography, and many other industrial processes. Toxicological Aspects. The notoriety of benzol as an industrial health hazard is principally derived from its injurious effect upon the nervous tissues (causing narcosis, lowering of body temperature, and impairment of oxidative metabolism) and upon the cells of the blood and hematopoietic organs (erythrolysis, hemorrhagic diathesis, and degeneration of the erythropoietic, myelopoietic, and ultimately lymphopoietic tissues causing leukopenia and aplastic anemia) (Weil; and Feller). These tissues develop an increasing sensitivity with repeated exposures to the toxic action of benzol (Intern. Lab. Office). This observation has been confirmed experimentally in animals by Pugliese, who reported that animals became, upon repeated exposure to benzol, intolerant to doses to which they had been previously resistant. Leucocytotic, Leukemoid. and Leukemic Reactions. Numerous observations suggest that the action of benzol upon the hematopoietic tissue is not always of a degenerative and hypoplastic nature, but that it may elicit an initial transitory or even prolonged hyperplastic, leukopoietic response. Thus, a transitory leucocytosis frequently represents the primary reaction of a benzol poisoning that results in a leukopenia (Selling and Osgood; and Intern. Lab. Office). Even the presence of a leukopenic, anemic and purpuric state, caused by benzol poisoning, may be associated with a marked myeloid hyperplasia DISEASES OF THE BLOOD FORMING ORGANS 595 of the marrow and the presence of heterotopic myeloid foci in the spleen and liver (agnogenic myeloid hyperplasia) (Weil; Gall; Anderson; Cabot; Martland; Hamilton; Erf and Rhoads; Hunter; Mallory, Gall and Brickley; Rawson and Parker; and Jackson]. In animals similar observations have Seen made repeatedly in connection with 'benzol poisoning of mild and prolonged types. The development of a leucocvtosis with hvperpiasia of the bone marrow, associated with a moderate anemia, was seen bv Schillowa in rabbits which received subcutaneous injections of benzol f'o.i to 0.05 cc. per kilo for r 1 to 15 months). From :he results 0 b tained with the experimental inhalation of benzol fumes, Paul, Friedlaender and McCord concluded that benzol in low concentration may exert a stimulat ing effect upon the blood-forming tissues, especially the erythroblastic com ponent. Similar effects were obtained by Schmidtmann, who exposed animals to benzol fumes in low concentration for a period of two hours, three times a week. The marked leucocvtosis obtained persisted for some time, was followed by leukopenia, and ultimately by anemia. There were heterotopic, metaplastic, myeloid proliferations in the spleen during tile eariv stage of exposure, while in the later stages fibrosis and hemosiderosis developed. These ieucocvtotic reactions of the blood and the reported hyperplastic manifestations in the bone marrow, frequently associated with leukemoid heterotopic myeloid foci, which were observed in several cases of occupational chronic benzol poisoning In human beings and animals (experimentally pro duced conditions') > are of immediate significance in connection with the occur- rente of leukemia resulting from a prolonged occupational exposure to benzol fumes ( Hamilton-Paterson). Two cases of chronic benzol poisoning, showing a myelogenous leukemic blood picture, were mentioned briefly bv Hamilton, who stated that a third similar case had been observed by Martland. The absence of any detailed data regarding exposure and associated symptoms greatly impairs the value of this evidence. Delore and Borgomano reported a case of chronic benzol poisoning in de tail. Am acute myeloid leukemia developed in a chemist, 41 years old. This in dividual had Men exposed to benzol fumes for five years, when engaged in the manufacture of pvramidon ( containing aminopyrine). The blood examination showed 532,000 leucocytes with 80 per cent myeloblasts, 8.0 per cent neutro philic mveiocvtes, 2.0 per cent eosinophilic myelocytes, 1.0 per cent baso philic mvelocytes, 6.0 per cent polymorphonucieated leucocytes, and 3.0 per cent Ivmohccvtes. A colleague employed in the same room and exposed to the same acent died from aplastic anemia, an incident which was of essential assistance in the inter sretation of the etiologic re dyscrasias. A second case of mveio;i.du leukemia of allegedly benzoiic origin Was cited, bv Weil. This individual, a 62 year old man, was employed in a w.nere he came into contac: benzol fumes. He was 596 OCCUPATIONAL TUMORS AND ALLIED DISEASES jaundiced, anemic, and had 25,900 leucocytes, 98.0 per cent of which were of myeloid origin. At autopsy the spleen and bone marrow showed morpho logic lesions characteristic of an immature myeloid leukemia. While the individuals in the last two cases cited were exposed to relatively large concentrations of benzol fumes, Falconer reported a case of leukemia in an employee who inhaled comparatively small amounts of this substance in a can factory. This individual was employed in the transportation of can ends from a conveyor to the warehouse, and inhaled benzol fumes given off by a solution of rubber applied to the can rims. When the leukemic worker was first seen he had 8,100 leucocytes (32.0 per cent lymphocytes, 62.0 per cent neutrophiles, and 6.0 per cent monocytes), 1,530,000 erythrocytes, 50.0 per cent hemoglobin, and 62,000 platelets. After one year, following a course of treatment consisting of blood transfusions, administration of sodium cacodylate, and Blaud's pills, he improved enough to return to work. Upon subsequent examination two years later, this individual had 13,200 leuco cytes (36.0 per cent neutrophilic leucocytes, 56.0 per cent lymphocytes, 6.0 per cent monocytes, and x.o per cent eosinophilic leucocytes). From this period on there was a gradual and consistent rise in the number of leuco cytes during the next two years, ultimately reaching 140,000 cells (98.0 per cent lymphocytes and 2.0 per cent neutrophilic leucocytes). The platelets had decreased to 34,000. At autopsy there were lymphatic leukemic lesions in the bone marrow, liver, spleen, and kidney. An actual benzol hazard existed as attested by the occurrence of four additional cases of benzol poisoning among employees of this plant. In the analysis of this case, Falconer mentioned that the treatment with arsenicals might have depressed the myeloid tissue and simultaneously stimulated the lymphopoiesis, thereby introducing a complicating etiologic factor. H e felt that the evidence available, while not definitely proving the etiologic interrelation between the exposure to benzol and the development of the lymphatic leukemia, made such a connection probable, especially as there occurred a gradual transition from changes typical for chronic benzol poison ing into those characteristic for lymphatic leukemia. This latter reaction was interpreted by him as the result of an overcompensatory measure of the lymphatic tissue. A second case of chronic lymphatic leukemia in an individual exposed to benzol fumes for a period of ten years in a rubber factory was reported by Tareev. The leukemia reacted favorably to benzol medication but was re fractory to roentgen-rays and Fowler`s solution. A more recent addition to this list of leukemias, following an occupational contact with benzol, was recorded by Sabrazes and Bideau. These investigators observed a myelogenous leu kemia in a machinery oiler (20 years old), who used a lubricant containing benzol. The hands and face of this individual were constantly covered with the oil during working hours over a three year period. In asserting the exist- ence of a causative correlation between occupational exposure to benzol and myelogenous leukemia, the authors pointed out that nearly all commercial lubricating oils contain traces of benzol, especially the heavy types of oils. A case of acute aleukemic leukemia following exposure to benzol fumes was recorded by Thompson, Richter and Edsall in 1934.. Perrin, Kissel and Pierquin reported recently a case of acute benzol leucosis, while Pessati and Vigiiani were able, in 1938, to collect IO cases of benzol leukemia from the literature (8 in males and 2 in females). American investigators, studying workers employed in several artificial leather factories, shoe manufacturing plants, and fast-press rotogravure print ing plants in the New England States and New York City, added three new cases of benzol leukemia, apart from several cases with leucocytoses and leukemoid reactions. A myeloid leukemia was found in a man, 38 years old, exposed for several years to the inhalation of benzol fumes in a rotogravure printing establishment (Erf and Rhoads). Two cases of myelogenous leu kemia, one acute and the second chronic, were observed by Hunter; and Mallory, Gall, and Brickley, following prolonged exposure to benzol fumes in low concentrations. The latter investigators studied a case of acute, aleu kemic, lymphoblastic leukemia masquerading under the clinical picture of an aplastic anemia in a boy, who used to play in a painter's shop. Special attention may be called in this connection to an important observation made by Hunter. He found that the first hematological symptoms of a chronic benzol poisoning may become manifest long after exposure to this injurious agent has ceased. Langelez noted from his experience with chronic occupa tional benzol poisoning in Belgium, that not only cases of atypical aplastic anemia with hypertrophy and myeloid metaplasia of the leukemic type are observed, but also acute and chronic leukemias. Etiological Aspects. Teleky agreed with Falconer, in that a special indi vidual susceptibility and potential leukemic reactivity must be present, if exposure to benzol and subsequent benzol poisoning are to lead to the develop ment of a leukemia. This opinion is shared by Schultz, who conceded that under these conditions the claim of causative interrelations between exposure to benzol and leukemia may be granted. This conception was rejected by Schmidtmann who considered such occupational factors as purely coincidental, Schmidtmann pointed out that the transition of a leucocytosis, resulting from an occupational benzol hazard, into a leukemia has not been observed, and that the so-called "leukemias" produced in animals after experimental exposure to benzol were nothing but irritation hyperleucocytoses. A similar scepticism as to the actual occurrence of benzol leukemias was voiced by Richter, who argued that leukemias usually appear spontaneously. Such reasoning has little weight, because a term like "spontaneous" represents, along with "idio pathic," "essential," or "primary," evidence of our ignorance in etiologid respects. 598 OCCUPATIONAL TUMORS AND ALLIED DISEASES In view of this controversial situation, it is fortunate that some experimental studies exist which supply confirmatory evidence to the probability or actuality of an occupational origin of such blood dyscrasias. The development of leu kemic (three) and aleukemic (five) conditions in eight out of fifty-four mice treated with small doses of benzol over an extended period of time was observed by Lignac. There were two lymphosarcomas, one lymphoblastic leukemia, one eosinophilic aleukemia, two basophilic aleukemia, and two myeloid aleukemias. Leukemic lesions were absent in 1,465 mice which were studied for other reasons. Lignac's conclusion, in regard to the existence of interrelations between treatment and leukemia, received some support by the metabolic studies of Hess, who noted that the marked increase in aerobic and anaerobic glycolysis and the impairment of respiration of liver sections from mice treated with benzol was suggestive of a leukemic disposition. The causa tive mechanism active in the production of the experimental leukemia is, according to Lignac, as follows: small doses of benzol cause a minor destruc tive effect upon the hematopoietic tissue; this is followed by a regenerative phase; and with continued repetition of these two reactions by prolonged treatment given at proper intervals, the proliferative stimulation may become exaggerated and result in a transformation of the hyperplastic reaction into a leukemic one. The combined clinical and experimental evidence presented, concerning the causative interrelations between occupational exposure to benzol and the development of leukemia, seems to indicate that such a connection is not a mere possibility but a great probability, and even an actuality. There occurs evidently a marked variability in the individual susceptibility and reactivity to benzol. This fact may account, in part, for the different types of hematopoietic tissue responses to this substance. The dose, the duration of exposure, and the interval between the individual exposures are obviously of great significance. Preventive, Precautionary, Technical, and Sanitary Aspects. From the evidence presented and the conclusions drawn, the indication for strict medical supervision of the large group of workers occupationally exposed to benzol is inescapable. This surveyance should be constant and unremitting, and should include periodic blood examinations for the presence of quantitative and qualitative changes of the various blood constituents. It may be advisable to examine the urine for the presence of ethereal sulfates of benzol, utilizing the Obermayer method for indican and determining the inorganic sulfur portion, according to the procedure of Schrenk, Yant and Sayers. These tests are of limited value, since they are not specific for benzol poisoning and may Le influenced by various internal and external factors (Kammer, Isenberg and Berg). . The proposal of Hagen, who recommended an ample dietary supply of vitamin C for workers exposed to benzol, merits consideration. Resistance the effects of benzol is strengthened by this vitamin, as benzol poisoning is DISEASES OF THE BLOOD FORMING ORGANS 599 accompanied by the development of a vitamin C hypovitaminosis. A daily dose ranging from 75 to 400 mgm. of vitamin C is considered by Hagen as an adequate amount for therapeutic and prophylactic purposes. The most effective means of combatting this occupational hazard is of a technical nature and consists of the complete elimination of benzol fumesfrom the atmosphere of the working environment. This aim may be achieved, in many instances, by the introduction of a closed system in the production. The installation of an efficient exhaust ventilation and a frequent periodic de termination of the benzol concentration in the air of the workroom to detect leaks and defects may aid in achieving this goal. As the use of a closed system is not always practical, the replacement of benzol by the less toxic benzine or some other less harmful solvent should be considered and insisted upon. At present, no country has offidally recognized benzol leukemia as a com pensable occupational disease. Several countries include aplastic anemia and related conditions caused by occupational exposure to benzol among this class of industrial disorders. II. BENZOL DERIVATIVES AND OTHER AROMATIC COMPOUNDS A great deal of experimental evidence exists incriminating various benzol derivatives and other aromatic compounds in the production of leukemoid and leukemic conditions. Phenylhydrazine and its derivatives have been proved repeatedly as the cause of extensive, heterotopic, myeloid proliferations in the liver, spleen, kidney, and lymph nodes and of hyperleucocytoses of leukemoid character (Jaffe; Seitz; Itami; Bratley; Hueper; v. Domarus; Long; Liidke; Pappenheim; and Heck and Hall). Similar organic changes were observed after the administration of chemically related hemotoxins, such as saponin and pyrogallol. Small amounts of indol, which is known for its anemiogenic and leukopenogenic properties (Biingeler) ,was repeatedly injected into experimental mice. Leukemia developed in seventeen of the ninety-seven animals surviving for more than eight months. An aleukemic, lymphatic leukemia was observed in three mice; one had a lymphosarcomatosis, four exhibited a myeloid leu kemia, and nine showed an aleukemic, myeloid leukemia. A diversity of leu kemic responses were exhibited similar to those observed in occupational benzol leukemias. The incidence of the leukemic reactions, among the mice so treated, increased with the duration of the treatment. The organs of these animals revealed an elevated glycolytic activity and the leukemic reactions followed a preliminary stage of anemia and leukopenia. Recent investigations with different synthetic, cardnogenic aromatic hydro carbons and tar have shown that these more distant relatives of benzol possess carcinogenic properties and may elicit leukemoid and leukemic responses. The Occurrence of leukemia in 2 mice and lymphosarcoma in i mouse, out of 60 mice repeatedly injected with water soluble i.2.5.6-dibenzanthracene-9.iO-