Document bar6a83GQmGQ7L2gVKb20RZ2g

i CHRONIC EXPOSURB TO BENZENE (BENZOL). 111. THE PATHOLOGIC RESULTS*t L t TRACY B. MALLORY, EDWARD A. GALL AND WILLIAM J. BRICKLEY Department of Pathology and Bacteriology, Massachusetts General Hospital, and the Ofice of Me Medical Examiner for SuffolkCounty, Northern Division, Boston, Massachuaeits pathogenesis was to a large extent prolonged exposure to benzene from elucidated by the classic experimental which histologic material is available and clinical studies of Selling (46, 47) therefore permits a broader perspective from 1910 to 1916, the paucity of of the anatomic features of the human pathologic studies of human material disease than has heretofore been has repeatedly been noted (7, 19, 20). possible. A considerable body of experimental It is probably not unfair to assume evidence has, it is true, served to some that the present consensus regards extent to offset this lack (2, 12,21,22, chronic benzene poisoning as typically ',i has in general been limited to the effects of acute poisoning, whereas the F human disease is preeminently chronic i in character. Dispersion of material k has unquestionably prevented any one pathologist from studying a consider- able group of cmes, and incompleteness of most case reports from the path- 1 * Received for publication July 15, 1939. t The substitution bv the editorial staff anemia-a syndrome characterized hematologically by severe refractory anemia, leucopenia, thrombocytopenia and the usual clinical signs and symptoms which accompany such disorders of the blood picture such aa weakness, pallor, purpura and extreme susceptibility to infection. As the underlvina basis for such the bone marrow har; unquestlonably 5 tiongas the American Chemical Soci6ty and yv"' --v"bvb'I' : the American hledical Association. In aplastic marrow has b individuals reported upon in these papers were exposed. - Control of poisoning with this agent reqmres education of the layman and the m e af a term reedilv confusable with the rela- have presented abun that the pres,~mnt;,,m n~ 1,+.,;, -OW not always warranted under confusion, seems to us unfortunate. sew 01 m e case8 citea DY tnese autnom 366 --- -_-.-f.I - 356 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [uol. $1, no. 8 showed any diminution of bone mar- other 8 cases, some of them already row activity, whereas the majority published elsewhere in exiensu, brief exhibited marked medullary hyper- clinical abstracts are given. The sex plasia. In benzene poisoning, also, and age of the patients, the nature of hyperplasia of the bone marrow has their employment, the presumptive occasionally been noted in isolated duration of contact with benzene and case reports (1, 14, 19, 20, 38) and the interval between the last contact , Rhodes (39) states that in many of and the death of the patient or the his cases of refractory anemia with time of biopsy are recorded in table 1. hyperplastic marrows exposure to ben- As the series of cases accumulated zene or other myelotoxic agents was it became gradually apparent that recorded. That in chronic benzene significant changes were regularly to poisoning such a combination of a be found not merely in the bone mar- clinical "aplastic" anemia associated row but throughout the hematopoietic with a markedly hyperplastic marrow system, including liver, spleen and and even extensive extramedullaqy lymph nodes. No consistent changes hematopoiesis is no coincidence but a were noted in any other organs except characteristic stage of the disease, aa frequent purpura of skin, mucous Hamilton prophesied, is amply borne membranes and serous surfaces. The out by the cases here reported. brain was grossly negative in all cases On 14 of the 19 cases reasonably examined except Case 14, which complete postmortem examinations showed several subarachnoid hemor- were performed. On 4 cases only a rhages, evidently part of a generalized sternal biopsy was obtained and in 1 purpuric process. case our material consisted of a spleen No effort has been made to describe removed at operation and a post- in detail the various septic complica- mortem biopsy of the tibial marrow. tions of the terminal state. It was Three additional bone marrow biopsies consistently noted that pneumonic were obtained on Cases 5,8 and 14 at and other exudates contained rela- intervals of 2 to 13weeks before death. tively few polymorphonuclears, and in In each of the autopsied cases histo- a few instances granulocytes were logic material was available from virtually lacking. Hemorrhage was several specimens of bone marrow usual in infected foci and necrosis and including both long and flat bones as gangrene were not uncommon. well as from the usual thoracic and In the following description of the abdominal viscera, including spleen changes in the hematopoietic system and liver. Lymph nodes were pre- the nomenclature probably deserves a served in only 6 cases. The significant word of comment. In general the positive gross and microscopic findings terminology of Sabin and her CO- are recorded in the protocols which workers has been employed (8,10, 11, appear in the appendix. The clinical 40,41). In the red cell series erythro- histories and pertinent laboratory data blast, normoblast and erythrocyte of the majority of the cases will be have been used to signify ascending found in Dr. Hunter's paper, immedi- stages of differentiation. In addition, stdy preceding this one. On the certain relatively large cells 18 to 3 0 ~ CHROMIC I in diameter with large, round, v nuclei containing scanty chi and prominent nucleoli, an abundant basophilic, vague limited cytoplasm have been rc met. They are unqueationablj cal with the cellsidentified by E (36)as primitive erythrogenic e and termed by him "megalo In view of the coptrovemy c( about this term (25, 50)) M chosen the less committal ex "stem cells." In certain of tl these stem cells have exhibited reproductive activity and k times produced giant multini elements having no counter normal tissues. BONE MARROW The most marked lesions r appeared in the bone marrow. in the study of the series it apparent that the clinical prm of medullary aplasia was n ranted in the majority of case$ Six: showed severe hypoplasia none was there complete Three cases exhibited an mately normal degree of ce despite qualitative deviation showed definite increase in cel and in five there was markec plasia. Two cases in which a c of leucemia was made will be a In cases with severe hypoplr ed increase in iat was ( the marrow of the stern vertebrae simulated at iin row from the mid third ur of normal individuals 1 sinusoids were dilatc rocytes and hemosidei cytea but the majori iD TOXICOLOGY [vol. 81, no. nployment, the presumptive 1 of contact with benzene and rval between the last contact death of the patient or the biopsy are recorded in table 1. e series of cases accumulated ne gradually apparent that it changes were regularly to I not merely in the bone marthroughout the hematopoietic including liver, spleen and odes. No consistent changes ed in any other organs except purpura of skin, mucous ies and serous surfaces. The 3 grossly negative in all cases I except Case 14, which ieveral subarachnoid hemorridently part of a generalized process. Irt has been made to describe the various septic complicathe terminal state. It was `ly noted that pneumonic r exudates contained relapolymorphonuclears, and in lstances granulocytes were lacking. Hemorrhage was lfected foci and necrosis and were not uncommon. Following description of the L the hematopoietic system clature probably deserves a comment. In general the s been employed (8, 10, 11, n the red cell series erythromoblast and erythrocyte used to signify ascending ifferentiation. In addition, ttively large cells 18 to 30p Od. zm1 CHRQNIC EXPOBDBE To BENZENE.IIL 35? - in diameter with large,round,veaicnlsr collapsed and empty. Scattged nuclei containing scanty chromatin throughout the tissue, however, were and prominent nucleoli, and with 51I1&11 focal isw of i n & a abundant basophilic, vaguely de- hematopoiesis of which two-thircs or limited cytoplasm have been regularly more of the component elemenb were met. They are unquestionablyidenti- nucleated red blood cells (figs. 1, 2). cal with the cells identified by Peabody In one case (Case 14) eosinophilic (36)as primitive erythrogenic elements and neutrophilic granulocytes were and termed by him "megaloblasts." present in numbers equal to the In view of the controversy centering erythrogenic cells, but in general about this term (25, 50), we have granulocytes were few in number and chosen the less committal expression megakaryocytes were rarely encoun- "stem cells." In certain of the cases tered. Mitotic figures were likewise these stem cells have exhibited marked infrequent. Despite the generalized reproductive activity and have at hypoplasia a few stem cells, apparently times produced giant multinucleated identical with the "megaloblasts" of elements having no counterpart in Peabody, were regularly found. In normal tissues. Case 16, although normoblasts pre- BONE MARROW dominated, there were many small clusters of mono- and multinucleated The most marked lesions regularly plasma cells. (It is interesting that appeared in the bone marrow. Early in this case the blood serum protein in the study of the series it became was 8 gm.%, and there was a strongly apparent that the clinical presumption positive formol-gel test; x-rays of the of medullary aplasia was not war- skeleton were negative, there was no ranted in the majority of cases. Only Bence-Jones protein in the urine and six showed severe hypoplasia and in the patient is still alive.) none was there complete aplasia. With increasing cellularity-to a Three cases exhibited an approxi- normal or moderately increased level mately normal degree of cellularity in the next two groups of cwes-a despite qualitative deviations, three considerable change in the general showed definite increase in cellularity, picture occurred. Several of these and in five there was marked hyper- marrows showed the development of a plasia. Two caws in which a &agnosia fine, fibrillar, eosinophilic substance of leucemia was made will be discussed in and about the sinusoids (fig. 4). separately. The reactions of this substance to the In cases with severe hypoplasia such aniline blue connective tissue stain marked increase in fat was observed were variable, but frequently a Si@- that the marrow of the sternum, ribs cant amount of the material showed and vertebrae simulated at h t glance the morphologic and tinctorial proper- marrow from the mid third of the ties of collagen and in two cases there femur of normal individuals. Occa- was frank fibrosis (fig, 5 ) with complete sional sinusoids were dilated with replacement of all the marrow fat by erythrocytes and hemosiderin-laden dense collagen. This fibrous tissue phagocytes but the majority were seemed to replace the fat cells rather * 358 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [YoZ. 61, no. 8 than the hematopoietic elements while multiple (2 to 10) nuclei. The ap- the sinusoids appeared to be com- pearance of a large proportion of them pressed or obscured by it with result- was indistinguishable from the Stern- ant distortion and obliteration of the berg-Reed cell of Hodgkin's disease. normal architecture. The similarity at one extreme to a The increased cellularity of this ordinary megakaryocytes and at the group of cases was associated with a other to Sternberg-Reed cells is con- alight relative decrease in the pro- sistent with the thesis of Medlar (30, . portion of normoblasts and a 31) that these elements are genetically corresponding increase in the number related. It cannot be denied that in of granulocytes (figs. 3, 4). Myelo- several of these cases the pleomorphic cytes outnumbered mature p o l y m o ~ hypercellularity, the multinucleated phonuclears but never became as giant cells, the fibrosis and the numer- . numerous as in n o m 1 =ow. ow mitotic figures simulated decep- Megakaryocytes became much more tively the neoplastic process termed evident and in one case totaled 6% of Hodgkin's sarcoma (24). The sole all the marrow elements. Clasmato- histologic feature restraining such a cytes also increased considerably and diagnosis was the unmistakeable inter- frequently, though by no means al- admixture of erythropoietic elements. ways, showed a considerable hemosiderin content. Proportionately the SPLEEN greatest numerical increase occurred As in the case of the bone marrow, in the large basophilic stem cells which the spleen also was always somewhat occurred in clusters, usually intra- abnormal and frequently the site of sinusoidal, mith numerous mitotic remarkable cellular activity. Al- figures. though splenomegaly was rarely ap- In the final group of marked hyper- parent clinically the organ was often plasias still further increase in the enlarged a t autopsy, and in Case 10 it proportion of these stem cells occurred. weighed 1800 gm. In several cases proliferative activity Minimal microscopic change (fig. 7)) reached extreme proportions, mitotic generally associated with hypoplasia figures became very numerous and of the bone marrow, was evidenced by multipolar mitoses not infrequent (fig. marked prominence of the sinusoidal 6). Peculiar multinucleated elements littoral cells. These were both larger unlike any component of normal mar- and more numerous than normal and row became very conspicuous. They projected rather deeply into the lumen differed from megakaryocytes in that of the sinusoids. The pulp cords were their nuclei uniformly retained vesicu- broadened with an increase in red cell larity, apparent immaturity, and content and a decrease in lymphocytes frequently exhibited monstrous and polymorphonuclears. Clasmato- proportions. In contrast to the multi- cytes were increased in number both lobularity of nuclear material ordi- within the sinusoids and m the pulp narily observed in normal megalcaryo- and frequently contained phago- qet!snu-b?JyQfthesec e l l s s h o w ~cytosed red cells ormasses of hemo- hisamefusion or no fusion at allof their siderin. Even in these cases with Oel. 18.981 CHRONIC E minimal changes, with a single tion, welldehed foci of hematc were easily recognizable. With progressing severity lesion these foci became more ous and larger, although for t h part they remained intraainl The proportion of undiffere elements increased and in the of stem cells with which the si: were gorged mitotic figures ' numerous, multipolar mitosl peared and atypical multinu cells became prominent. The and type of differentiation considerably from case to w e 1 always predominantly eryth except in the one case of 1 Ieucemia. In most cases, how few myeloid elements and numbers of fairly normal megakaryocytes were seen. With still further progressio~ lesion (figs. 15, 16) the immatl were no longer confined to the SI but began to invade the pulp a the periphery of the corpuscle ually obscuring the architectur ese marked cases (figs. 9,17) tion and exceptionally ni polar mitoses which, as in the bone marrow picture alrei general, though by nc parallelism could be tr bone marrow and `le (2 to 10) nuclei. me ~e of 8 large proportion of distinguishable from th eed cell of Hodgkin's a l a i t y at one extreme to; meg&aVocytes and at the 10 Stenberg-Reed c e b is conwith the thesis of Medlar (30, t these elements are genetically I t cannot be denied that in of these cases the pIeomorpGc 'llUhfitY, the IllUltinucleated the fibrosisand the numer- ;Otic figures simulated decephe nmplatiC process termed l's sarcoma (24). n e sole ic feature restraining such was the u e t a k e a b l e inter- re of erythropoietic elements. SPLEEN the Case of the bone marrow, a h was always somewhat 1 and frequently the site of )le cellular activity. u- gplenomegdy W ~ U rarely a p inically the organ was at autopsy, and in Case 10 it 1800 gm. microscopic change (fig. 7), associated with hypoplda le -OW, WaS evidenced by IrOhnenCe of the sinusoidal These were both h r n w e r o w than noma1 and rather deeply into the lumen WAS- n e pulp cords were with an increase in red cell Id a decrease in lymphocytes Qorphonuclears. Chmato! increased in number both SinUSOids and in the pulp JentlY contained phaged cells O r m a s S e s of herno- hen in these cases k t h (2xmmvrc~To-. III. m i n i m a l t h m g e s , ~ t h s e i n g l e h~ematopietkaetiuitig. c e s e 4 , k - tion, wendefined foci of hematopoiesie e m , ahowed marimal h- of were e d y recognidle. the 11uvr0w and only traces of s p h k With progreasing =verity of the erythropekk, w h e m in-mae 8 h8e lesion these foci became more numer- most marked splenic erythropaleeis ow and larger, although for the most observed in the series (in fact fat part they remained intrasinusoidal. beyond any that the authors have ever The proportion of undifferentiated observed) was associated with dis- elements increased and in the masses tinctly diminished marrow cellularity. of stem cells with which the sinusoids Fibrosis occurred sporadically in both were gorged mitotic figures became spleen and bone marrow without numerous, multipolar mitoses ap- definite relationship. It WM marked peared and atypical multinucleated in the marrow in Case 8 but scanty in cells became prominent. The degree the spleen. It reached a maximal and type of differentiation varied grade in the spleen in Case 10, whereas considerably from case to caae but was the marrow showed very little. In always predominantly erythrogenic the spleen s i m c a n t fibrosis was except in the one case of myeloid found only in association with very leucemia. In most cases, however, a active and atypical hematopoiesis, few myeloid elements and varying whereas in the marrow it was MO- numbers of fairly normal looking ciated with varying grades of cellu- megakaryocytes were seen. larity but not with either extreme With still further progression of the aplasia or extreme hyperplssia. lesion (figs. 15, 16) the immature cells In cases with minimal splenic were no longer confined to the sinusoids changes the Malpighian corpuscles but began to invade the pulp and even were ordinarily small but intact. the periphery of the corpuscles, grad- With advance of the PrOCm they ually obscuring the architecture of the tended to become obscured, in part by organ. In certain, though not all of intrinsic degeneration and subsequent these marked cases (figs. 9, 17),fibrosis fibrosis (fig. 171, in Part by Perifol- of the pulp became apparent which, as licular hemorrhage and in some it progressed, still further tended to instances by invasion of proliferating distort and destroy the usual histologic elements from the surrounding pulp. landmarks. In the most marked in- These invading cells sometimesformed stance (Case lo) (fig. 9) this was a wide collar about the follicle and associated with extreme unmerentia- tended to obscure its delimitationfrom tion and exceptionally numerous the surrounding pulp. No frank atypical giant ceils (fig. 8) and multi- lymphoid hyperplasia was observed polar mitoses which, as in the similar though in some of the severe cases a bone marrow picture already de- high proportion of the persisting cells scribed, closely simulated so-called in the shrunken and deformed cor- Hodgkin's sarcoma. puscles were lymphoblasts. A general, though by no means The greatly enlargedspleen removed exact parallelism could be traced be- surgically from Case 19 was markedly tween bone marrow and splenic hematopoietic and differed in no essen- tial way from the postmortem organs sinuses and concomitant diminution of other caaes. in the lymphoid pulp. The sinuses LIVER were frequently packed with active clasmatocytes (fig. 10) to give the Changes in the liver were much leas picture which has been termed "sinus striking than those noted in either catarrh" (17). In 2 cases interlacing the spleen or bone marrow. Kupffer cords of these cells packed the sinuses, . cells were invariably prominent and and in the interstices large numbers of usually loaded with hemosiderin. erythrocytes and free clasmatocytes Central necrosis of varying extent was were seen. There was active phago- frequently present .but always ap- cytosis of red cells both in the peared to be of short duration, judging sinuses and in the remaining nodal from the acuteness of the reaction, and parenchyma. probably did not often much antedate Lymphoid cords showed slight to the agonal state. It would seem more almost complete loss of lymphocytic reasonable to correlate it with the content associated with a marked terminal infection so generally present grade of edema and loss of follicular than with any direct effect of benzene identity. In several nodes there was upon the liver. It showed little cor- focal evidence of partial lymphoid relation with icterus, being absent in regeneration accompanied by the ap- frankly jaundiced patients and present pearance of pale elements in patients showing no trace of icterus. identified as stem cells and lympho- In the majority of cases showing blasts. Few of these immature cells marked erythropoiesis in either bone appeared in the sinuses, the majority marrow or spleen small foci of intra- being confined to the pulp. Meta- sinusoidal erythroblasts and normo- plastic transformation to myeloid blasts appeared. In Case 10 relatively elements was occasionally evident, large numbers of stem cells were myelocytes, normoblasts, and even present and few normoblasts were megakaryocytes being noted in re- observed. As in the other organs of generating lymphoid cords. Accom- this patient a marked tendency to panying apparent increase in paren- giant cell formation was apparent chymatous substance there was an (fig. 18). increase of stromal fibrous tissue and LYMPH NODE6 compression of previously dilated sinuses. Lymph nodes were only occasionally Lymph nodes were unfortunately noted to be grossly enlarged but fre- not available in the cases demonstrat- quently were prominent st autopsy ing the most advanced lesions in the because of a dusky pinkish hue which spleen and bone marrow. Through made them stand out prominently the kindness of Dr. Ellis Kellert of from the surrounding fatty tissue. the Ellis Hospital Laboratory, Sche- Sections were available for study in nectady, New York, however, the _ _ only 6 c&~e6but the findings varied authors have been privileged to ex- considerably. Minimal changea can- amine a section of lymph node from sirrted of marked dilatation of the another caae of chmnic benzene poi- Honing in which the appearanc liver, spleen and bone man exactly similar to that noted Case 10, which resembled Hc disease. In this lymph node chymatous regeneration and plaaia were sdiiciently excez compress the sinuses and obsc architecture (fig. 11). The nc qined a loose fibrous stron intermingled lymphocytes, 1 , stem cells, normobk ucleated giant cells (E ne of which showed extre~ THE LEUCEMIA6 Two cases in this series different from the rest tha description has been reservec separate paragraph. Case 15 $87) as may be learned by n to Dr. Hunter's paper, hsc exposed to benzene for 10years, heavily and the succeeding lightly, and had from the star emplopent shown hematolog dence of benzene intoxication. lsst 3 months of his life he de? the typical picture of an acuteI leucemia. At autopsy the teristic findings of leucemia wer fest with m u s e myeloid infiltrr the liver, spleen and bone n An unusual manifestation was bed tumor nodule, 4 cm. in di h the liver which on micr -mination proved to be tumor (figs. 12,13) co erentiated myeloid cell d atypical multinucleat invaded, disrupted and the liver substance. thought that the bone 1 ed rather more persistent ND TOXICOLOGY [ool. h2, I and concomitant lymphoid pulp. The s een. There was active phamof red cells both in the and in the remaining nodal hyma. phoid cords showed slight to complete loss of lymphocytic t associated with a marked. of edema and loss of follicular y. In several nodes there was ?videme of partial lymphoid sation accompanied by the a p ce of pale staining elements ed as stem cells and lympho- Few of these immature cells ed in the sinuses, the majority confined to the pulp. Meta- transformation to myeloid ts was occasionally evident, ytes, normoblasts, and even iryocytes being noted in re#inglymphoid cords. Accomg apparent increase in paren;ous substance there was an 3 of stromal fibrous tissue and e o n of previously dilated ph nodes were unfortunately tilable in the cases demonstratmost advanced lesions in the and bone marrow. Through tdness of Dr. Ellis Kellert of is Hospital Laboratory, Sche- r, New York, however, the have been privileged to ex% section of lymph node from B case of chronic benzene poi- CHRONIC ExmsmtE To BE"E.111. 384 soning m which the appearance of the mgenic t k u e than m a be expesbd liver, spleen and bone marrow was in a l d of this type. exactly similar to that noted in our Theaecondcssewaaaboyaftmehq Case 10, which resembled Hodgkin's a painter's son,who played frequedy disease. In this lymph node paren- in his father's shop and had amused chymatous regeneration and meta- himself by frequently r e p a h a hie plasia were sufficiently excessive to toys in Werent colors using a paint compress the sinuses and obscure the remover known to contain benzene to architecture (fig. 11). The node con- remove the preceding coat of psint. tained a loose fibrous stroma with He developed a clinical picture of , intermingled lymphocytes, lympho- aplqtic anemia but sternal puncture 1 blasts, stem cells, normoblasts and in one hospital and sternal biopsy in ' multinucleated giant cells (fig. 19), another, which we were privileged to 1 none of which showed extreme pre- examine through the courtesy of Dr. dominance. k l e Chapman, revealed a typical 1 i THE LEUCEMLM leucemic replacement of the marrow with very unWerentiated cells of Two cases in this series are so the lymphoblastic series. No features diferent from the rest that their suggestiveof a benzene reaction on the description has been reserved for a part of the erythrogenic series could separate paragraph. Case 15 (FTH- be made out. l #87) as may be learned by reference to Dr. Hunter's paper, had been DISCUSSION exposed to benzene for 10 years, 4 yeam Since all but three of the cases in- heavily and the succeeding 6 years cluded in this report were fatal-and lightly, and had from the start of hia a speedy demise is to be expected in employment shown hematologic evi- one of the remainder if our diagnosis dence of benzene intoxication. Inthe of acute aleucemic leucemia is cor- last 3 months of his life he developed rect-it is evident that the earlier the typical picture of an acutemyeloid phases of benzene poisoning are not leucemia. At autopq the charac- exemplified. None of the casea had teristic hdinga of leucemia were mani- less than 6 months' contact with the fest with H u s e myeloid infiltration of fumea and only 4 cases had leas than the liver, spleen and bone marrow. a year's exposure. Eight were sub- An unusual manifestation waa a local- jected to contact from 1 to 4 years and .ized tumor nodule, 4 cm! in diameter, the remaining seven for 4 to 12 years. in the liver which on microscopic Nevertheless a wide variation in tissue examination proved to be a true response has been recorded. Exclud- i leucemic tumor (figs. 12,13) composed ing for the time being the two leu- of undifferentiated myeloid cells, stem cemias, one can divide the remaining cells and atypical multinucleated cells cases into two groups-six cases with which invaded, disrupted and had re- marrows less cellular than normal placed the liver substance. It was (Cases 1,3,6,11,14 and 16) and nine also thought that the bone marrow with frank hyperplasia (2, 4, 5, 7, 9, showed rather more persistent eryth- 10, 12, 13, and 18). Two cases are ~ 362 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [uol. g2, no. 8 di6cult to classify and appear to possible before an assessment of its occupy a somewhat intermediate posi- importance in comparison with vari- tion: Case 17 because the cellularity ability of host reaction can be d e . was within normal limits though a Nevertheless, inadequate as our data slight shift to the left in degree of are, they do permit an attempt to Merentiation suggests a hyperplastic analyze some of these factors and tendency, and Case 8 with a definitely suggest some tentative conclusions hypoplastic marrow but the most which are of interest. active and extensive extramedullary Among the factors which might in- hematopoiesis of the series. fluence the reaction of the marrow, in- Benzene, therefore, is a toxin which tensity of exposure must be considered. under varying conditions can produce By analogy with other toxins it seems diverse reactions in exposed indi- reasonable to suppose, if intensity is of viduals. Is it possible to determine importance, a high degree would pro- any of the factors responsible for this duce an overwhelming aplastic result, diversity? a lower intensity a stimulating hyper- Biologically toxic agents can be plastic one. Unfortunately, the avail- roughly classified into two categories: able data are scant. Case 17 (FTH- substances which with adequate exhi- #El), a telephone operator, was in bition will produce their effects upon the habit of cleaning off paint marks all individuals exposed, and a second from the switchboard with a paint group which in minute dosage will remover shown to contain approxi- produce devastating effects upon occa- mately 50% benzene. Since the proc- sional individuals that cannot be ess did not take more than 3 to 1hour duplicated in the majority of appar- per day, the degree of daily exposure ently similar beings by an exaggeration cannot have been great. Neverthe- of the dosage. To which category leas she showed a marked hypoplasia benzene belongs is still uncertain. at autopsy. Cases 7, 8 and 16 were Possibly adequate exposure would workers in the same factory. Case affect all individuals but clinical 7 worked for 12 years before illness experience strongly suggests that the compelled him to give up his position. eEect of minimal dosage is extremely Case 8 took over his job but w&sable variable and that individual idiosyn- to hold it only 14 years before weak- crasy is of great importance. Animal ness compelled him also to give up. experimentation in various investi- Case 16 assisted Case 8 and worked gators' hands has confirmed the vari- over the same vat with him. In- ability of host reaction even under tensity of exposure must have been uniform controlled conditions but has approximately equal in these three given us no explanation of the mech- workers, yet Case 7 showed at autopsy anism. Clinical investigation has yet marked medullary hyperplasia, Case 8 %omzatch the surface of the problem. an aplastic marrow but a hemato- Dossge--both intend^ and duration poietic splenic tumor, while cme 16 of exposuremust be estimated with (still living) showed on sternal biopsy far greater accuracy in many more a definitely rliminiRhed cellularity. individuals than hss heretofore been 60f a r our evidence goes it does not Ocl. l8S8] CHRONIC E: suggest that intensity of expos the determining factor in the marrow reaction. Duration of exposure, howevei seem to be of importance. Chc the lists of the two types of againet table 1 it is apparent th 8 cases with fatal outcome with than 1year of initial exposure SI -m l M M F M M F 1M 2M 32 M 34 M 35 F 79 M 80 M 81 F 87 M 88 M 10 M M -M 22 64 20 25 46 44 48 45 45 43 18 54 51 63 28 57 57 41 12 Rub1 Artif Rub1 Artif Cobt Rub1 Artif Artif Artif Artif Rubt Artif CobE Telej Artif Artif Arti6 Furn Schoc ) Necropsy, (B) Biopsy, (A) 1 Case number in Dr. Hunter's 81 1 *** Used paint remover containing converse does not, however the two series suggest that mtentxi@ of exposure is the determining factor m the bone marrow reaution. ~ Duration of exposure,however, does seem to be of importance. Checking the lists of the two types of cases against table 1 it is apparent that the 3 cases with fatal outcome within less than 1 year of initial exposure showed and iaa active ertnrnnedullary hem- atopOieeie; k d -thecases wi& less thz$xrs year's exposure showed hypoplasia d most af the cases with prolonged exposure hyperplasia, one is tempted to conclude that the initial effect of benzene on the bone marrow is to depress it, whereas the later effect is to - TABLE 1 - - - -CA8. llgl A011 INDOLITBY DUBATION OI CONTACT I N T ~ B V A C8INC11 LA8T CONl'ACl' 1 M 22 2 M 54 3 F 20 4 M 25 5 M 46 6 F 44 7 1 M 48 8 2 M 45 9 32 M 45 Rubber factory Artificial leather Rubber cement Artificial leather Cobbler' Rubber factory Artificial leather Artificial leather Artificial leather 6 months 9 months (N) 7 years I month (N) 8 months 1 month (N) 3 years 1 month (N) years 1 month (N) 4 years 6 months (N) 12 years 5 months (B) I+ years 4 months (N) 3 years 14 years (N) 10 34 11 35 12 79 13 80 14 81 15 87 16 88 17 10 18 -19 - 1M F M M F M M M M M 43 18 54 51 63 28 57 57 41 12 Artificial leather Rubber factory Artificial leather Cobbler. Telephone operator** Artificial leather Artificial leather Artificial leather Furniture finisher*** Schoolboy*** years ? (N) 7 months 1 month (N) 3 years 3 months (N) 2 years ? (N) 5 years 3 months (N) 4 years 6 years (N) 1 year 2 years (A) (B) 5 years 5 months (A) (B) years 2) months (N) ? 2 months (A) (B) (N) Necropsy, (B) Biopsy, (A) Alive. Case number in Dr.Hunter's series. * Used benzene as solvent for rubber cement. ** Used solvent containing 50% benzene for eradicating namea on switchboard. *** Used paint remover containing benzene. depression of maxrow activity and that no case with a hyperplastic marrow had been exposed for less than 2 years. The converse does not, however, hold true, for 2 cases with prolonged ex- posure (6 and 14) showed aplastic marrows. Case 8 with 13 years' exposure appears to occupy a middle ground between the Go series with its definitely hypoplastic bone marrow stimulate it. This may or may not be true, but no such conclusion is warranted by the data a t our dispod. An equally tenable hypothesis would be that benzene may cause either hyperplasia or aplasia, the former enabling the patient to carry on for many years despite continued exposure, the latter leading to a prompt fatality if the patient is not quickly . 364 a,JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (00l. y. 6 removed from contact. The experi- periods varying from 6 months to 2 merits of Schilowa (44)may be cited years. Two of these fall in the in partial confirmation of such a plastic and three in the aplastic m. hypothesis. In several series of dogs The interval since exposure may thup identical dosage produced hyperplastic fore be eliminated as the deb- changes in some, aplasia in others and cause of the varying bone mw no effect in still other animals. pictures. Since the peripheral blood often Correlation with age and 8uc fe\*q reflects imperfectly or, in our present somewhat more interesting &-. state of knowledge, even misleadingly Eliminating as before from our hm the state of the bone marrow, the ac- the leucemias and the indekrplipate t u 1 progression of medullary changes Case 8, we find 4 patients Mow can only be determined by repeated age of 30 and twelve above it. of the m o w punctures or biopsies. Our former, three showed aplasia a d m b own material is insuflicient to warrant one hyperplasia; in the older group any conclusions. Biopsy was per- contrast nine showed hyperp- and formed on Case 5 eight weeks before only three aplasia. S u r p r s x h at death, on Case 8 two weeks ante- first glance, with their suggestim thst m o h m and on Case 14 thirteen weeks the older marrow8 are more c a p a h af and again 5 weeks before exitus. a proliferative reaction than &, Case 5 belongs to the hyperplastic younger ones, these figures do uot group, Case 14 to the aplastic and stand analysis. Only one of the M- Case 8 was the intermediate one. In viduals below thirty had been e - q m none of the three cases was there a for more than a few months, w & m q significant difference between the bi- all of the group above thirty lad had opsy specimen and the subsequent from 1 to many years of exposun.. autopsy findings. Finally, in the two In relation to sex, the figures,thowb surviving cases, cases which despite too few to be conclusive, are distiuctb fairly prolonged exposure may be con- more suggestive. Taking the .we sidered t o be at a relatively early group of 16 cases we find 12malm and stage of the disease since their appar- 4 females. Ten of the males ,&<I& ent cure indicates that the process W&S hyperplasia and only two aplersiy. still reversible, Case 16 showed well All four females showed a@- marked hypoplasia and Case 17 slight Among the males the only two sho\\<w hyperplasia. aplasia had exposures of 6 months snd Another matter worthy of analysis 1 year respectively. Among the 4 is the relationship between the state of females are the only two cases in the the marrow and the interval since the entire series with aplastic m m \ \ i~n last contact with bensene. Eight the face of prolonged (4 and 5 )-\ cases died within 3 months of their exposure. The number of feis. k t exposure, and of these, five showed of course, too small to j-uy d e hyperplasia and three relative aplasia. generalization. That females also At the other extreme, five cases had react to prolonged exposwe t o w had no contact with the agent for withextremeandatypical hyperptasi. ds V- from 6 months to IC and three in the aplastic of the varying bone mam res. rrelation with age and sex rev& what more interesting results. nating as before from our figures 3ucemias and the indeterminate 8, we find 4 patients below the f 30 and twelve above it. Of the r,three showed aplasia and only yperplasia; in the older group in ast nine showed hyperplasia and three aplasia. Surprising, at:lance, with their suggestion that der II~LLITOWSare more capable of oliferative reaction than the :er ones, these figures do not analysis. Only one of the in&1s below thirty had been exposed ore than a few months, whereas the group above thirty had had 1 to many years of exposure. *elationto sex,the figures,though w to be conclusive, are distinctly suggestive. Taking the m e of 16 cases we find 12males and ales. Ten of the males showed PUand only two aplasia. our females showed aplasia. g the males the only two showing 5 had exposurea of 6 months and x respectively. Among the 4 :S are the only two cases in the series with aplastic marrows in :e of prolonged (4 and 5 years) re. The number of females is, me, too small to justify wide hation. That females also can 0 prolonged exposure to benzene xtreme and atypical hyperplasia CaRowIC -To Bm- ut 365. i s s h o ~ b y t h e ~ o f l b l hoftac~uhrnyelaidhcerda ( h e 15) cited. A tendency, however, of the and another of acute aleucemic leum l e to react with hyperplasia, of the cemia (Case 19). It is interesting ta - female with aplasia is suggested and note, since the issue of sex hss already m y help to explain, since the hyper- arisen in relation to the hyperplastic plastic form of the disease has not yet anemias, that 8 of the 10 patienta - same sex. benzene poisoning can be terminated without mention of the close similarity of many of these hyperplastic marrows, composed predominantly of immature erythrogenic elements, to the bone marrows described by Martland (24a) among the unknown thousands exposed to a solvent so widely used throughout the industrial world (33, 43) do not constitute in themselves an impressive figure. They gain in significance, however, when viewed in the in chronic radium poisoning. A still light of certain other observations. more surprising, though probably a c i - Most important is the experimentd dental parallelism exkk in the pro- work of Lignac (27, 28). Working longed latency between exposure and with a strain of mice ordinarily free the development of symptoms or from diseases of the hematopoietic detectable signs frequently observed system, he observed the development in the two conditions. The authors of leucemia and malignant lymphoma can do no more than express their in 8 of 33 animals following minute amazement that a simple, volatile repeated doses of benzene over a long organic chemical, readily eliminated period of time. This observation still via the respiratory tract can initiate a lacks independent confirmation. train of pathologic sequences which Also suggestive to anyone who has can progress for months and even studied even superficially cases of the years after exposure has ceased. hyperplastic type which have been A still more controversial field is presented in this article are the evi- entered in considering the relationship dences of what, for want of a better of chronic exposure to benzene to the term, may be called a neoplastic development of leucemia or other tendency. The degree of anaplssis, neoplastic conditions. Penati and the rapidity of growth aa judged Vigliani (37) in a recent review of the by the number of mitotic figures, literature were able to collect 10 c88e9 the development of cells having no of leucemia in patients who had veri- counterpart in normal tissues but fied histories of exposure. Virtually common to a variety of malignrtnt all varieties of the leucemic state have tumors are phenomena characteristic been recorded: chronic myeloid (52), of neoplasia which the authors have chronic lymphatic (14), acute leu- never heretofore met in such marked cemia (9), acute aleucemic leucemia degree in non-neoplastic states. Cer(49). To these we have added a case tainly no more favorable conditions * 366 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (uoZ.M, M.8 for the development of neoplasm can be imagined than prolonged and intense stimulation of reproductive activity and simultaneous arrest of mm. The bleeding time was 36 minutes, the clotting time 38 minutes. Fragility of red cells was normal. There was no clot retraction in 48 hours. The patient was given five transfusions maturation. but bleeding from the mucous membranes The evidence that chronic exposure to benzene produces leucemia in human beings is still incomplete but it is accumulating at a rate and to a became profuse. The red cell count fell to g00,OOO and the patient died on the 39th hospital day. Necropsy: Skin: Marked pallor, scattered small purpuric spots. volume which Eommand serious con- Serous Cwities: Pebchial hemorrhages : sideration. of pericardium. Lungs: Marked edema and congestion. PROTOCOLS* Liver: 1415 gm. Kupffer cells markedly increased in prominence and 6lled with Case 1 . F. W.A., 22, male. A 22 year hemosiderin. Portal islets negative except old American laborer entered the hospital for alight hemosiderosis. Central lobular complaining of purpura. necrosis moderate with polymorphonuclear Three year8 ago the patient worked in a exudate. rubber factory for a period of several Spleen: 70 gm. Corpuscles are present months. Following this he suffered inter- in normal numbers but are quite small and mittently from headache, dizzy spells and (miashapen. Content normal. Architec- occasional epistaxis. One year ago, while ture is preserved and there is minimalhemo- at sea, he suddenly became quite weak and siderosis. Splenic cords are widened and pallor was noted. He returned ashore, show slight fibrosis. Littoral cells are rested for 3 months, and 9 months prior t o unusually prominent and project into sinu- admission he again returned to work in a soids. Sinusoids contain scattered stem rubber factory, where he was exposed to cells, normoblasts and rare myelocytes. benzene fumes. After 6 months of this Bone Marrow: Architecture preserved, work he began to suffer from throbbing with marked increase in fat and minimal headaches, palpitation and profound weak- cellularity. Fibrosis is absent and hemo- ness. He stopped work but the symptoms siderosis slight. Sinusoids are collapsed continued and he developed dyspnea and but there are small intrasinusoidal foci of migratory joint pains. For about 2 weeks hematopoiesis in which normoblasts pre- there was constant oozing nosebleed, the dominate. stools became tarry, the gums bled readily and multiple black and blue marks appeared Case d. W. D. S., 64,male (5). on the skin. These features were evident A 54-year-old factory worker entered on examination at entry. There was very complaining of bleeding from the gums. marked pallor. Lymph nodes, liver and For 7 years the patient had operated a spleen were not felt. spreading machine in an artificial leather Laboratory Findings: The red blood factory, in the process of which he was con- count w m 1,200,000, with 30% hemoglobin. stantly exposed to benzene fumes. About The white cells numbered 2,600, with 39% a year before entry he first noted occasional polymorphonuclears, 50% lymphocytes, 9% bleeding from the gums and B slightly monocytes, 1% eosinophils and 1% baso- productive cough. For about 2 months phils. There were no immature cells or there was slight swelling of the ankles and nucleated red cells. Reticulocytes num- pufEness of the eyelids associated with bered 0.9% and the platelets 46,OOO per cu. polyuria and polydipsia. For 6 weeks there was constant bloody oozing from the gums. * Cases included in the clinical studies Exnminstion on admission showed pallor, by Dr. F. T. Hunter are denoted by the marked hemorrhagic oozing from the gums perenthetic expression (FTHu). and numerous purpuric spots on the skin. CHRONIC E The tip of the spleen was barely 1 and the liver edge extended 6 cm. the costal margin. Labmatory Findings: Urine wa tive. Red blood count was 1,900,O 45% hemoglobin. The white ceT bered 2,800, with 16% polymorphor 52% lymphocytes, 8% monocytes, 4' ophils and 14% basophils. The marked stippling of red cells, oc nucleated red cells and rare myel Platelets were markedly reduced bers. Reticulocytes were 2%. '1 time was over #) minutes and there clot retraction in 48 hours. The index was 8 unite. The patient was given five tran without improvement. He died on Necropsy: Skin: Icteric, mdti] techial hemorrhages. Edema bot Lungs: Pulmonary edema and rhagic bronchopneumonia witb rei . cells and fibrin but relatively fe1 morphonuclears. Liver: 2095 gm. Kupffer cells m prominent and filled with hemc .Islets negative. Within the s i n w scattered immature blood cells and ate numbers of clasmatocytes. Spleen: 480 gm. Corpuscles in =umbers but compressed by Burn m&lars consisting of denae aggrega indeterminate stem cells accompai afew normoblasts and phagocytes. cords are widened and contain hemc extravasation and hemosideri phagocytes. Lining cells of sinusc prominent. Many of the sinusoi filled with stem cells, erythroblas ! occasional normoblasts. There a some clssmatocytes with both red an .cells ingested. Architecture is gc preserved save for a few foci in which ,.of stem cells obscure the structure. " 8 Bone Marrow: Markedly increase t y in both rib and femoral marro remains and there is no evid is. Architecture is oblitera "... TOXICOLOGY [oo~.11, The bleeding time was 36 mi )tting time 38 minutes, Fragili 11s was normal. There was no tion in 48 hours. : patient was given five transf ceding from the mucous membr e profuse. The red cell count 000 and the patient died on the 39 a1 day. roPSY: Skin: Marked pallor, sc small purpuric spots. ).icuasrdC.i.uamtd.ies: Petechial h e m o r r h a g a gs: Marked edema and congcstioe 'r: 1415 gm. Kupffer cells marke ,ed in prominence and filled w i derin. Portal islets negative exce :ht hemosiderosis. Central lobd s moderate with polymorphonucle e. en: 70 gm. Corpuscles are presen la1 numbers but are quite small and Den. Content normal. Architecmeserved and there is minimal hemo.s. Splenic cords are widened and slight fibrosis. Littoral cells are Ily prominent and project into sinuSinusoids contain scattered stem innoblasts and rare myelocytes. Marrow: Architecture preserved, arked increaae in fat and minimal ity. Fibrosis is absent and hemoB slight. Sinusoids are collapsed re are small intrasinusoidal foci of Doiesis in which normoblaate prea. 8. W.D.S.,54, male (6). -year-old factory worker entared ning of bleeding from the gums. ' years the patient had operated a ig machine in an artificial leather in the process of which he was conexposed to benzene fumes. About sfore entry he first noted occasional from the gums and a slightly ve cough. For about 2 months LB slight swelling of the ankles and of the eyelids associated with and polydipsia. For 6 weeks there itant bloody oozing from the gums. ition on admission showed pallor, hemorrhagic oozing from the gums ierous purpuric spots on the skin. CHRONIC lzXPwmmT0.-B 111. 3627 The tip of the spleen wa8 barely palpable and the liver edge extended 6 cm. beneath the costal margin. Laboratory Findings: Urine was nega- are rare,mitotic abrmdant, mtd oc- caaional giant cells with menatroue n. .e maybeeen. P h a g o c y t e p = i i h ~ - are abundant. tive. Red blood count was 1,9OO,ooO, with 45% hemoglobin. The white cells numbered 2,800, with 16% polymorphonuclears, 52% lymphocytes, 8% monocytes, 4% eosin- Cape 3. E. M., 20, female (23, 4; 6). A 20-year-old Canadian shoe factory worker entered the hospital complaining ophils and 14% basophils. There were of nosebleed. marked stippling of red cells, occasional Eight months before entry the patient nucleated red cells and rare myeloblasts. began to work at applying rubber heels. P- latelets mere markedly reduced in num- The cement solvent which she used in her bers. Reticulocytes were 2%. -Bleeding daily work showed on analysis a content time was over 20 minutes and there was no of 80% benzene. After 4 months she noted clot retraction in 48 hours. The icterus nausea and easy fatigability which pro- index was 8 units. gressed rapidly during the ensuing month. The patient was given five tranefusiona Two months before entry purpuric phe- without improvement. He died on the 28th nomena appeared. There was first epi- hospital day. ataxis, next menorrhagia, and h a l l y Necropsy: Skin: Icteric, multiple pe- bleeding from the gums. Uncontrollable techial hemorrhages. Edema both lower epistaxis brought her to the hospital, where extremities. examination showed pallor, a foul breath, Lungs: Pulmonary edema and hemor- Vincent's infection of the gums, and pur- rhagic bronchopneumonia with red blood puric spots on the skin. cells and fibrin but relatively few poly- Laboratory Findings: Red blood count morphonuclears. 1,715,000, with 40% hemoglobin. The white Liver: 2095 gm. Kupffer cells markedly cells numbered 1,200, with 16% polymor- prominent and filled with hemosiderin. phonuclears, 76% lymphocytes and 8% Islets negative. Within the sinusoids are monocytes. Platelets were greatly dimin- scattered immature blood cells and moder- ished and no reticulocytes were seen. The ate numbers of clasmatocytes. bleeding time was 16 minutes and the Spleen: 480 gm. Corpuscles in normal clotting time E to 19 minutes. numbers but compressed by surrounding Despite 12 transfusions in 19 days the collars consisting of dense aggregations of course was progressively downward. The indeterminate stem cells accompanied by patient developed otitis media and broncho- a few normoblasts and phagocytes. Splenic pneumonia and death followed profuse p d - cords are widened and contain hemorrhagic monary and vaginal hemorrhages. extravasation and hemosiderin-laden Necropsy: s k i n and scbae: Icterio. phagocytes. Lining cells of sinusoids are Petechial hemorrhages of serous cavities prominent. Many of the sinusoids are and mucous membranes of stomach and filled with stem cells, erythroblasts, and bladder. occasional normoblasts. There are, ala0 Lungs: Show large foci of hemorrhagic some claamatocytes with both red and white pneumonia without polymorphonuclear re- cells ingested. Architecture is generally action. preserved save for a few foci in which masses Liver: 1220 gm. Kupffer cells moder- of stem cells obscure the structure. ately prominent, minimal hemosiderin con- Bone Marrow: Markedly increased cellu- tent. Islets and sinusoids are negative. larity in both rib and femoral marrow. No Parenchymatous cords show slight central fat remains and there is no evidence of fraying. fibrosis. Architecture is obliterated by SpEeen: 1% gm. The corpuscles are nor- large clustera of stem cells, erythroblasts mal in number but are unusually small and normoblasts, although moderate num- and are surrounded by broad hemorrhagia bers of myelocytes and polymorphonuclears collars containing moderate numbers of may also be observed. Megakaryocytes phagocytes. Architecture is preserved but sinusoids are small. Littoral cells prominent. There is no hematopoiesis. Pulp cords are broad, hemorrhagic and contain scattered lymphocytes, plasma cells and monocytes. There is a small amount of hemosiderin. Lymph Nodes: Slightly enlarged and considerably redder than normal. No IWCtions available. Bone Marrow: Femoral marrow is totally fatty with minimal evidence of hematopoiesis. Marrow elsewhcfe is mostly fatty and sinusoids are collapsed. There are scattered small clusters of intrasinusoidal normoblasts and occasional phagocytes. Case 4. N.A., 25,male. A 25-year-old Greek factory hand entered the hospital complaining of fever and weakness. For 3 years the patient had worked in a leather factory using a spray containing benzene. Eleven days before entry he developed chills, fever and a severe headache. During the week preceding entry there was frequent vomiting of blood-streaked material which gradually became coffee ground in character. There was a hacking cough, and 2 days before entry jaundice and herpes labialis appeared. Examination showed the patient to be pallid but deeply icteric. The liver and spleen were not felt. Laboratory Findings: The red blood count was 3,300,000,with 70% hemoglobin. The white cells numbered 3,800,with 1% polymorphonuclears, 98% lymphocytes and 1% myelocytes. Platelets were markedly reduced and an occasional nucleated red cell waa seen. Red cell fragility waa normal and the clotting time was 9 minutes. The van den Bergh showed 13.5 mg.% of bilirubin and a liver function test (bromsulphalein) showed 85% retention of dye at the end of 1 hour. (The white cell count was reported as being 16,000 and 12,000 four and three days respectively before entry. Almost all of the cells were lymphocytes.) The patient was given 5 transfusions without benefit and died on the 14th hospital day. Necropsy: Skin: Pallid and markedly icteric. Liw: Coneiderable increase in perip a l fibrosis with infiltration by lympho- cytes. Proliferation of bile ducts but no evidence of necrosis. Scant normoblastic hematopoiesis in sinusoids. Spleen: Corpuscles are small and dimin- ished in number. Architecture is preserved but splenic cords are widened, hemorrhagic and contain large deposits of hemosiderin. Sinusoids show prominence of the littoral cells, rare clusters of normoblasts and an occasional megakaryocyte. Lymph Nodes: Architecture preserved but there are no follicles or germinal centers. Cords are negativc. Sinuses are markedly dilated and filled with strands of phagocytic cells intermingled with which are large numbers of red blood cells and free clasmatocytes filled with debris, erythrocytes and polymorphonuclears. Bone Marrow: There is a maximal cellularity with no fat present. Predominant cells, 95% of elements present, are normoblasts. Granulocytes and stem cells are minimal but there are moderate numbers of megakaryocytes. Phagocytic cells and hemosiderin are sparse. Case 6. L. C.,46, male (6a). A 46-year- old Italian cobbler entered the hospital complaining of headache and dizzy spells. For 7 years the patient had cemented leather soles with a rubber cemcnt believed to contain benzene. Five months before entry he began to tire easily. Two months later he had palpitation with the slightest exertion and headaches. He noted thereafter increasing pallor, frequent epistaxis, and bleeding from the gums. Examination showed pallor, and purpura of the skin and mucous membranes. There were systolic and faint diastolic murmurs over the base of the heart. The liver and spleen were not felt. Laboratory Findings: The red cell count was 1,050,~w, ith 30% hemoglobin. The white cells numbered 1,400, with 36% polymorphonuclears, 49% lymphocytes, 2% monocytes, 3% myelocytes, 8% myeloblasts, and 2% unclassified cells. Platelets were very few in number. A sternal biopsy done 8 weeks before death was inadequate in amount but showed hyperplania and a shift to the left in both the red and white cell series. Nucleotide therapy for 80 days produced no im- r provement. The patient grew pro1 worse, the stools became tarry, a of the left buttock developed an1 suddenly 10 weeks after admiasi episode suggestive of pulmonary e Necropsy: Skin: Few scattered spots. Lungs: Acute pleuritis on right cc. fluid. Right lung almost c( consolidated by hemorrhagic pneumonia with exudate coneistin4 serous fluid, red cells, phagocy relatively few polymorphonucles two small acute infarcts. ' Inferior Vena Cwa: Adherent f thrombus extending from right iliac vein. t Liver: 1700 gm. Central thre of all lobules shorn marked fra. disintegration of cell cords. Mc increased prominence of Kupffer ( ' engulfed hemosiderin. Islets Rare small clusters of normol: sinusoids. Spleen: 50 gm. Architecture I and corpuscles normal in numl slightly compressed. Cords are ately broadened and contain small of lymphocytes, monocytes, and patchy fibrosis. There is con hemosiderosis. Sinusoids contair ate numbers of phagocytes and of early hematopoiesis in which nor predominate although small nux myelocytes are also present. Lymph Nodes: Slightly enlarged, pink. Follicles are barely evide minal centers are absent. Archit preserved. Sinuses filled with ph as in Case 4. Cords are various1 .atous with infiltrating monocytes o . foci of plasma cells, myelocytes anc hlaats. There are occasional me1 cytes and moderate numbers of figures. Bone MUTTOWV:ertebrae, ribs I how no fat and a barely evide d of thin fibrous stroma. Ce reased numerically over the t. There are many large em cells although two-third w content consists of nom totic figures are abundant and 1 derate numbers of myelocytes, 3 TOXICOLOGY [uol. 82, m; *oliferation of bile ducts but of necrosis. Scant normoblas ieais in sinusoids. Corpuscles are small and dimi unber. Architecture is c cords are widened, in large deposits of show prominence of the littoral clusters of normoblasts and an megakaryocyte. Nodes: Architecture preserved are no follicles or germinal cends are negative. Sinuses am dilated and filled with strands of z cells intermingled with which numbers of red bIood cells and matocytes filled with debris, ;es and polymorphonuclears. arrow: There is rr maximal celluh no fat present. Predominant of elements present, are normoranulocytes and stem cells are u t there are moderate numbers of tcytes. Phagocytic cells and in are sparse. L. C., 46,male (6a). A 46-yearn cobbler entered the hospital I g of headache and dizzy spells. ream the patient had cemented ea with a rubber cement believed I benzene. Five months before egan to tire easily. Two months ad palpitation with the slightest nd headaches. He noted therelasing pallor, frequent epistaxis, ng from the guma. Examination dlor, and purpura of the skin m membranes. There were s y 5 'aint diastolic m u r m m over the Le heart. The liver and spleen elt. !wy Findings: The red cell count )o, with 30% hemoglobin. The s numbered 1,400, with 36% onuclears, 4995 lymphocyks, 2% , 3% myelocytes, 8% myelo- ,295 unclassified cells. Platelets few in number. al biopsy done 8 weeka before nadequate in amount but showed B and a shift to the left in both d white cell aeries. Nucleotide or 30 days produced no im- 3m ' provement. The pstiant grewprogrm&vuly worse, the stools became tsrry, an abscaa of the left buttock d s v e b d end ha diedsuddenly 10 weeks after admission in an episode suggestive of pulmonary embolism. Necropsy: Skin: Few scattered purpuria spots. Lungs: Acute pleuritis on right with 500 cc. fluid. Right lung almost completely consolidated by hemorrhagic bronchopneumonia with exudate consisting of fibrin, serous fluid, red cells, phagocytes, and relatively few polymorphonuclears. Also two small acute infarcts. Inferior Vena Cava: Adherent granular thrombus extending from right internal iliac vein. Liver: 1700 gm. Central three-fourth of all lobules show marked fraying and disintegration of cell cords. Moderately increased prominence of Kupffer cells with engulfed hemosiderin. Islets negative. Rare small clusters of normoblasts in sinusoids. Spleen: 50 gm. Architecture preserved and corpuscles normal in numbers but slightly compressed. Cords are moderately broadened and contain small numbera of lymphocytes, monocytes, and minimal patchy fibrosis. There is considerable hemosiderosis. Sinusoids contain moderate numbers of phagocytes and evidence of early hematopoiesis in which normoblasts predominate although small numbera of myelocytes are also present. Lymph Nodes: Slightly enlarged, soft and pink. Follicles are barely evident; ger- minal centera are absent. Architecture is preserved. Sinusea Wed with phagocytes as in Case 4. Cords are variously edematous with infiltrating monocytes or contain foci of plasma cells, myelocytes and normoblasts. There are occasional megskaryocytea and moderate numbers of mitotic figures. Bone Marrow: Vertebrae, ribs and sternum show no fat and a barely evident background of thin fibrous stroma. Cellularity is increased numerically over the normal content. There are many large clusters of stem cells although two-thirds of the marrow content consists of normoblaste. Mitotic figures are abundant and there are moderate numbers of myelocytes, mature cyton and.-p The femoral and t i b i a l - ~ b W S - e h e w 8 ~ h d f & ~- tion with increased cellularity qualitatively similar to that in the vertebrae but quanti- tatively not quite asabundant. Case 6. M. McK., 44, female (6b). A 44-year-old Canadian factory worker entered the hospital complaining of weakness and headache. For 4 years, until 3 months before ad- mission, the patient had been employed in a rubber factory and had been exposed to benzene fumes. Three years before entry she had noted soreness of the gum and tongue. One and a half years later there waa numbness of the hands and toes. For 8 months there had been dyspnea on exertion. Seven weeks before entry a hemorrhoidectomy was performed and at that time her physician noted that she had anemia. Ex- amination showed pallor and retinal hemorrhages. Vibratory sense was impaired. The liver and spleen were not palpable. . Laboratory Findings: The red blood count was 1,150,OOO, with 40% hemoglobin. The white cells numbered 1,200,with 28% polymorphonuclears, 32% lymphocytes, 28% myelocytes, 4% myeloblasts and 8% monocytes. Platelets were greatly reduced. The bleeding time was 30 minutes. Repeated transfusions (40) produced only transient improvement. Purpuric manifestations became progressively more severe and she paaaed blood copiously in the urine, stools and per vaginam. She died 5 m o n t h after entry with symptoms suggesting peritonitis. Necropsy: Skin: Bloated by marked accumulation of subcutaneous gas. Terminal gaa bacillus septicemia. Cecum: Severe acute and chronic typhilitis with ulceration, probably the portal of entry for the terminal infection. Liver: le00 gm. Contains bubbles of gas. Extensive marked postmortem degeneration of hepatic cords. Islets negative. Hemosiderin in Kupffer cells is markedly increased in amount. Sinusoids contain rare small clustera of normoblasts. Spleen: 125 gm. Corpuscles normal and architecture preserved. Pulp cords show marked hemosiderosis and moderate fibro- 370 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [vol. 81, m.8 sis. Sinusoids show prominent littoral cella with abundant phagocytosis of hemosiderin and contain a few small clusters of normoblasts. Bone Marrow: Vertebral and femoral marrow fatty. Sinusoids are dilated and filled with erythrocytes and thin fibrous strands. There are scattered and occasion- ally clustered normoblasts and .moderate numbers of hemosiderin-laden phagocytee. are normoblasts, erythroblasts and stem cells frequently forming large nodular clusters. Granulopoiesis is scant and there are very few true megakaryocytes present. CaseB. P. F. M., 47, male. (FTH132) Necropsy: Skin: Pallid; multiple crusted hemorrhagic and occasionally purulent lesions on extremities. Multiple petechial hemorrhages and decubitus ulcers. h n q s : Focal abscess formation with Case 7 . E. G. T., 48, male. (FTH11) necrosis. Biopsy: Bone Marrow: There is no fat Pericardium: M) cc. of hemorrhagic 5.uid. or fibrosis. Marrow is intensely cellular Liver: 2,000 gm. Kupffer cells very with erythrogenic activity predominating. prominent and filled with hemosiderin. - White cell elements are greatly diminished Scattered immature blood cells in the and there are relatively few mature cella. sinusoids. There are large clusters and fused nodules Spleen: 200 gm. Architecture pre- of normoblasts and stem cella with abundant mitotic figures. Very slight hemosiderosis is apparent. Case 8. L. M., 46, male (16). (FTH 1 2 ) Necropsy: Marked pallor of skin and mucous membranes. Many purpuric spots measuring up to 6 cm. Large amount of tarry material in intestinal tract. Liver: 2,000 gm. Central lobular necrosis with scant polymorphonuclear and marked monocytic reaction. Kupffer cells very prominent and filled with hemosiderin served, corpuscles present but diminished in number. Pulp cords thin and hemor- rhagic. Sinusoids filled with moderate numbers of stem cells, erythroblasts, plasma cells, normoblasts and clasmato- cy-. There are occasional granulocytes and rare megakaryocytes. Bone Marrow: Fat considerably diminiehed and replaaed by marrow cells. Latter exceed the normal in number and are predominantly erythrogenic, consisting of normoblasts, erythroblasts and stem cells, frequently in clusters. Megakaryocytes as in Case 1. Islets negative. In the sinusoids are small numbers of scattered and clustered stem cells and normoblasts. Rare megaksryocyte seen. Splecn: Architecture preserved but corpuscles few and obviously compressed. Pulp cords thin and contain few cells but much hemosiderin. Sinusoids are enor- mously distended with large numbers of stem cells, erythroblasts and normoblasts. There are numerous mitotic figures, frequently multipolar in character, and moderate numbers of multinucleated giant cells resembling megakaryocytes. Only a rare granulocytic element is seen. Bone Marrow: Architecture obliterated by dense fibrosis without evidence of fat or and granulocytes considerably diminished in numbers. Hemosiderosis, slight. Case 10. F. B., 43, male. (FTH #34) Necropsy: Liver: Extensive early central necrosis. The Kupffer cells contain moderate amounts of hemosiderin. Islets contain small foci of hematopoiesis, usually erythrogenic but occasionally granulocytogenic. Sinusoids contain many discrete cells and occasional clusters of normoblasts, large stem cells, and giant multinucleated cells with bizarre irregular nuclei and abundant basophilic cytoplasm. There are many unipolar and multipolar mitoses. Moderate numbers of phagocytes are evident but there are very few granulocytes. husoids. There are large deposita of Spleen: 1800 gm. Architecture obliter- lceemlloueliadreitryiniaasnldighntulmy elereosusthcalnsanmoramtoaclyatensd. caotelldagenb.y Cdoerpnuses,clesirraergeulfaerwly inarnruamngbeedr .__ _ imegular in distribution--some areas are and markedly ahrunken and miesllapen, u y cellular and others +elptiwfy consisting for the most part of a few scatm y oellulor. Predominant elamente tered 1ymphocJrtee about the central - CHRONIC stenole. There is abundant ii extracellular hemosiderosis throughout the entire organ. 1 formed, compreeeed sinusoids pt both the sinusoids and fibrosed large numbers of cells similar to t1 in the liver sinusoids (i.e. both er) a d myelogenic cells). The moa cells are huge elements with phagocytic cytoplasm. Nuclei mom with prominent nucleoli f cella contain 2 to 10, either se `fused. Mitotic figures are nun Bone Marrow: Marrow fat il aced by hematopoietic cells 811 re is abundant hemosideroi a few granulocytic myelocytes I morphonucleam. Many large 8 with multiple megakaryocyte-L mapparent and are accompanied Case 11. C. M. L., 18,female. ( Necropsy: Skin: Marked yell0 lor with many hemorrhagic areas 1 Serous Coats: Many ecchymosc cc. blood-tinged fluid in the 1 Appendiz: Small, 1 cm., hen necrotic lesion in middle third of Lung: Hemorrhagic bronchop with focal necrosis without palp clear reaction. Liver: 1400 gm. As in Case 2. Spleen: 120 gm. Architect1 served. Corpuscles normal in nu size but contain numerous stem ticularly aggregated to form a pal collar a t the periphery of the nodu soids widened and contain model bers of phagocytic clmmatoc, erythrogenic cells (stem cells, eryl and normoblasts). . L y n p h Nodes: Enlarged up to mottled reddish gray in appear81 licles and germinal centers as il Sinuses are dilated and contain I clasmatocyte8 and scattered la oells. Both of these cella are a ID TOXICOLOGY [vol. 81, no. noblasts, erythroblasta and stem rquently forming. large nodular Granulopoiesis is scant and there few true megakaryocytes present. p. P. F. M., 47, male. (FTH#32) psy: Skin: Pallid; multiple crusted agic and occasionally purulent in extremities. Multiple petechial ages and decubitus ulcers. 1: Focal abscess formation with wdium: 50 cc. of hemorrhagic fluid. * 2,000 gm. Kupffer cells very nt and filled with hemosiderin. d immature blood cells in the 8. n: 200 gm. Architecture pre: corpuscles present but diminished 3er. pulp cords thin and hemorSinusoids filled with moderate I of stem cells, erythroblasts, cells, normoblasts and clasmatoThere are occasional granulocytes 3 megakaryocytes. Marrow: Fat considerably dimind replaced by marrow cells. Latter ;he normal in number and are pitly erythrogenic, consisting of lasts, erythroblasts and stem cells, tly in clusters. Megakaryocytes nulocytes comiderably diminished bere. Hemosiderosis, slight. 10. F. B., 43, male. (FTH 2%) .1 ~ Liv:er: Extensive early central The Kupffer cells contain moderu t aof hemosiderin. Id& contain ci of hematopoiesis, usually erythrout occasionally granulocytogenic. is contain many discrete cells and d clustera of normoblasts, large 118, and giant multinucleated cells 5arre irregular nuclei and abundant Iic cytoplasm. There are many r and multipolar mitoses. Moderhers of phagocytes are evident but *every few granulocytes. 'n: 1800 gm. Architecture obliterIY dense, irregularly arranged 1. Corpuscles are few in number wkedly shrunken and misshapen, ng for the most part of a few scatlymphocytes about the central Oct. 1 i m l CHRONIC EXPOSURE TO BENZENE. III. F- -. Wextteraricoellel.ulaTrhereheims easibduenrodcatin8t instrcaa-ttaendd ilynmmphoodimd aatoerder.mmbars in the edemstotts - - ____ throughout the entire organ. A few deformed, compreaeed sinusoids persist. In both the sinusoids and fibrosed pulp are large numbers of cells similar to those noted in the liver sinusoids (i.e. both erythrogenic and myelogenic cells). The most striking cells are huge elements with abundant phagocytic cytoplasm. Nuclei are enormous with prominent nucleoli and many cells contain 2 to 10, either separate or fused. Mitotic figures are numerous. Bone Marrow: Marrow fat is entirely replaced by hematopoietic cells and fibrosis. There is abundant hemosideroaia. Cells are relatively densely packed and consist preponderantly of about equal numbera of normoblasts and erythroblasts. There are also large numbers of stem cells and a few granulocytic myelocytes and polymorphonuclears. Many large stem cella with multiple megakaryocyte-like nuclei are apparent and are accompanied by multi- Case 11. C .M. L., 18,female. (FTH #35) Necropsy: Skin: Marked yellowish pallor with many hemorrhagic areas measuring Bons Marrow: Both femoral and vertebral marrow fatty and hypoplastic IYI in Case 1. Case 1% A. S., 54, male. (FTH #79) Necropsy: Skin: Pallid and icteric with many scattered small hemorrhagic areas. Severe gangrenous process in mouth and pharynx. Heart: Overlying the epicardium is a patchy layer of necrotic fibrin under which is a layer of 1 to 5 large basophilic phagecytic cells, the exact nature of which is indeterminate. Liver: Swollen Kupffer cella filled with hemosiderin. Moderate central necrosis with some polymorphonuclear reaction. Spleen: Architecture partially obscured. Corpuscles generally very small, some o d y recognizable by the presence of the central arteriole, the lymphoid structure having been entirely lost. Such follicles as retain cellularity are now composed only of lymphoblasts, stem cells, and occasionally plasma cells. A few are entirely replaced by fibrous scar. Hemosiderosis ie marked. Billroth's cords are markedly widened by hemorrhagic extravasation, hemosiderin Serous Coclts: Many ecchymoses and 300 cc. blood-tinged fluid in the peritoneal cul-de-sac. * Appendiz: Small, 1 cm., hemorrhagic, necrotic lesion in middle third of appendix. Lung: Hemorrhagic bronchopneumonia wclietahr forecaacltinoenc.rosis without polymorphonu- filled phagocytes, or thin strands of fibro- blasts. Sinusoids show prominence of littoral cella with focal normoblastic and granulocytic hematopoiesis. Lymph Nodes: There is increased trabec- u l r fibrosis and vascularization. Sinuses are widely dilated and filled with broad interlacing cords of spindle-ehaped epi- Liver: 14OOgm. AeinCase2. thelioid cells,many of which arephagocytic. Spleen: 120 gm. Architecture preserved. Corpuscles normal in number and, size but contain numeroua stem cella, par- ticularly aggregated to form a pale staining collar a t the periphery of the nodule. Sinusoids widened and contain moderate n u bera of phagocytic clasmatocytes and erythrogenic cells (stem cells, erythroblasts and normoblasta). Lymph Nodes: Enlarged up to 1 cm. and mottled reddish gray in appearance. Follicles and germinal centers as in Case 4. Sinuses are dilated and contain many free clasmatocytes and scattered large stem cells. Both of them cells are also found Lymph cords are shrunken and in some areas nonexistent. Residual lymphoid tissue is evident as small patches of l p phocytes, among which are phagocytic clasmatocytes and occasional cluster8 of lymphoblasts and stem cells without m y evident germinal center arrangement. Bone Marrow: Fat cells are msrkedly diminished in rib and vertebrae and sinu- soids are filled with either fibrillar fibroua tissue or large numbers of hemosiderinpacked phagocytes. There are Scattered denselycellular areasof focal hematopoieais, predominantly erythrogenic, with small nodules of stem cells. Granulocyte forma- . I 372 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [uol. $1, no 8. tion is minimal and composed mainly of myelocytes and eosinophilea. Femoral marrow contains more fat and fewer cella than any of .the other areas examined. Case IS. A. V., 51, male. (FTH #80) Necropsy: Liuer: Hemosiderosis of the Kupffer cells and moderate central necrosis. Spleen: Architecture preserved. Corpuscles normal in number and size but e with a collar of immature cells at the periphery. Pulp cords are broad and a l e d with large axhounts of hemoeiderin and numbers of phagocytes. 'The sinusoids are filled with hematopoietic elements ' which resemble those seen in Case 8, with a predominence of erythrogenic elements, many stem cells and multinucleated celle. L y p h N o h : Architecture is preserved and the sinuses are widely dilated. Some contain strands of phagocytic cells attached to and continuous with the lining cells and others contain discrete phagocytes, moderately large numbers of stem cells, and significant numbers of myelocytes. Lymphoid cords are large and edematous. Lymphocytic content is small but there are moderate numbers of stem cells, myelocytes, eosinophiles, apparent lymphoblasts, and active phagocytes without orderly arrangement. Bone Marrow: Vertebral marrow shows replacement of fat by large dilated interlacing sinusoids. Many of these are filled with erythrocytes, but the majority contain a variety of elements, most of which are stem cells with evidence of differentiation to myelocytes and to a less extent normoblasts. These are frequently arranged in clusters. Hemosiderin, clasmatocytes and normal megakaryocytes are present. There are, however, large numbers of multinucleated giant cells with bizarre mitotic figures similar to those described in Case 10. Femoral marrow is similar qualitatively but is somewhat less cellular and exhibits a background of loose edematous fibrillar tiwue. Case14. S. M., 62, female. (FTH #Sl) lV.ropsy: Brain: Several subarachnoid - Batamr$rc;se o ~ e rceiabitlm a d in hd gmglia, the largest measuring 4 x 2.6 cm. h i v i n g the thdamm m d left lentiaular nucleus. Also minute hemorrhages in brain stem. Skin: Pallid and icteric with numerous small purpuric hemorrhages. Bladder: Contains large ecchymotic areaa. Pericardium: Contains 150 cc. of bloody fluid. Liver: Normal size. Histologically negative. Spleen: Weighs 125 gm. Architecture is preserved but follicles exhibit a variable degree of central degeneration terminating in apparent fibrosis. Surrounding each follicle is a thick collar of lymphoblasts. Hemosiderosis is marked. Sinusoids show prominence of lining cells and occasional small clusters of stem cells. Lynph Nodes: Lymphocytic content diminished but architecture preserved. There are numerous subsinus aggregations of lymphoblasts. Sinuses are widely dilated and a l e d with phagocytes. Bone Marrow: All marrow areas are fatty and show collapsed, empty sinusoids. Each oil immersion field, however, contains one or more sinusoids with compact clusters of 10 to 100 cells which are predominantly normoblasts but are accompanied by moderate numbers of myelocytes, stem cells, and phagocytes with hemosiderin content. Case 16. W. M., 28, male. (FTH #87) Necropsy: Skin: Pallid, numerous hem- orrhagic areas. Phlegmon of subcutaneous tissues of neck. Lung: A diffuse hemorrhagic and fibrinous pneumonia with focal necrosis. There are very few granulocytic elements comprising the cellular exudate which con- sists for the most part of mononuclear phagocytes. Liuer: There is a uniform degree of central lobular necrosis. Sinusoids con- tain large numbers of myelocytes, eosin- ophiles, and neutrophilic granulocytes and moderate numbers of primitive stem cells. These are all particularly massed in the aenter of the lobules, where the sinusoids are widely dktended with them. In the extra-endothelid spaces between sinusoids a d liver cells tbm is widespread infiltra- tion by theee elementa accompanied by large n& of phagocytes. The ielets Oct. I8381 CHRONIC E3 exhibit a slight infiltration with L cells. A 4 cm. soft, yellowish nodule in the gross consists of enormous nv of infiltrating cells distorting and di6r the liver parenchyma. These elc are relatively less differentiated thar noted elsewhere in the liver and Hhov numbers of stem cells and multinuc giant cells with multipolar mitoses to those noted in Case 10. Spleen: Considerably enlarged, ' not recorded. Corpuscles are few ir ber and quite small. Pulp architec partially obscured. Recognizable co broadened and filled with-erythrocyl hemosiderin. Sinusoids are packec large numbers of myelocytes, sten: and multinucleated giant cells. I pulp is not evident and there is onl) phagocytosis. - Bone Marrow: Fat is entirely obli, by dense cellularity. Predominan &e large myelocytes with intern eosinophilic and neutrophilic pc phonuclears, normoblasts and numbers of stem and giant cells. are numerous mitotic figures and sc throughout are small clusters of cells and erythrocytic precursors. . Case IS. H. L. C., 57, male. Biopsy: Bow Marrow: Fat con markedly increased and there is I degree of fibrosis. Cell content eiderably diminiehed and there a1 16tered coalescing foci of hemato These consist predominantlyof norn with a few erythroblasts. Megakar are normal and there are diminishe ' bers of granulocytes with eosinophil -tively increased. A striking and feature is the presence of increased I of plasma cells frequently aggregal . L. G., 57, male. (FT Bone Marrow: The degrc essentially normal. 1. e maturation and the relat of white to nucleated red blc pproximately that of normal re are, however, moderately ii bers of eoeinophilic elements a D TOXICOLOGY [ool. #I, 4 8 0 minute hemorrhages in b Pallid and icteric with numero puric hemorrhages. r: Contains large ecchymotic, vdium: Contains 150 cc. of bloody Normal size. Histologically neg- Weighs 125 gm. Architecture ed but follicles exhibit a variable central degeneration terminating ent fibrosis. Surrounding each a thick collar of lymphoblasts. rosis is marked. Sinusoids show :e of lining cells and occasional iters of stem cells. Nodes: Lymphocytic content di- but architecture preserved. numerous subsinus aggregations )blasts. Sinuses are widely difilled with phagocytes. Karrow: All marrow areas are show collapsed, empty sinusoids. nmersion field, however, contains .e sinusoids with compact clusters x)cells which are predomin ts but are accompanied rs of myelocytes, stem s with hemosiderin co W. M., 28, male. (FTH #87) y: Skin: Pallid, numerous hem.ern. Phlegmon of subcutaneous neck. L diffuse hemorrhagic meumonia with focal necr very few granulocytia eleme the cellular exudate which con ;he most part of mononucle I. 'here is a uniform degree of d a r necrosis. Sinusoids connumbers of myelocytes, eosind neutrophilic granulocytes and lumbers of primitive stem cells. all particularly massed in the he lobules, where the sinusoids distended with them. In the helial spaces between sinusoids 311s there is widespread infiltraLese elementa accompanied by bera of phagocytee. The isleta CHRONIC ExpoBuIyE TO BENZENIZ. 111. 373 exhibit a alight infiltration with aimiisr teradfociinwhichstemcdhorcells. A 4 cm. soft, yellowish nodule noted are aggregatedinto emall clusters. in the gross consista of enormous numbera ofinfiltratingcelledistortinganddiarupting Cose 18. 9. S., 41, male. A 41-year old - the liver parenchyma. These elementa Ruesian furniture finisher was admitted are relatively less differentiated than those complaining of breathlessness. noted elsewhere in the liver and show large The patient had been a furniture finisher numbers of stem cells and multinucleated for 20 years during which time he had fre- giant cells with multipolar mitoses similar quently been exposed to benzene in paint to those noted in Case 10. remover. For about 6 weeks beforeentry Spleen: Considerably enlarged, weight there mas fatigability and progressive weak- not recorded. Corpuscles are few in num- ness. Four weeks prior to admission the ber and quite small. Pulp architecture is patient was compelled to give up work but partially obscured. Recognizable cords are thereafter suffered from dyspnea with the broadened and filled with erythrocytes and slightest exertion. He developed dizziness, hemosiderin. Sinusoids are packed with throbbing headaches, nausea and marked large numbers of myelocytes, stem cells, 1 and multinucleated giant cells. Splenic pulp is not evident and there is only slight phagocytosis. I Bone Marrow: Fat is entirely obliterated palpitation. He had suflered from occasional nosebleed. Examination showed a very marked lemon yellow pallor of the skin. There were small retinal hemorrhages and scars. '1 by dense cellularity. Predominant cells Laboratory Findings: The red blood are large myelocytes with intermingled count was 1,38o,O00, with 50% hemoglobin. eosinophilic and neutrophilic polymor- The white cells numbered 2,900, with 21% phonuclears, normoblasts and large polymorphonuclears, 26% lymphocytes, 1% , numbers of stem and giant cells. There eosinophiles, 6% monocytes, 38% myelo- 1 are numerous mitotic figures and scattered cytes, 2% basophils and 870 unclassified throughout are small clusters of plasma cells. The platelets were reduced. Oc- ! cells and erythrocytic precursors. casional megaloblasts and normoblasts were seen. Reticulocytes were 2%. The bleed- Case 16. H. L. C., 57, male. (FTH ing time was 15 minutes and the clotting % 88) time 14minutes. Clot retraction was poor. Biopsy: Bone Marrow: Fat content is On the 14th hospital day a splenectomy markedly increased and there is a slight degree of fibrosis. Cell content is considerably diminished and there are scattered coalescing foci of hematopoiesis. These consist predominantly of normoblasta with a few erythroblasta. Megakaryocytes are normal and there are diminished numbers of granulocytes with eosinophiles relatively increased. A striking and unusual feature is the presence of increased numbers of plasma cells frequently aggregated into clusters. was performed. The patient progressed downhill, however, and died on the 46th day in the hospital. Resection: Spleen: Malpighian corpuacles persist but are markedly compressed and distorted. Pulp and sinusoids are gorged with large clusters of stem cells, erythroblasts and normoblasts. The appearance is similar to that noted in Case 8 but scattered among the erythrogenic foci are moderate numbers of myelocytes and neutrophilic and eosinophilic polymorphonuclears. Mitotic figures, though present, Case 17. L. G., 57, male. (FTH #lo) Biopsy: Bone Marrow: The degree of cellularity is essentially normal. There ie adequate maturation and the relative proportion of white to nucleated red blood cells is approximately that of normal marrow. There are, however, moderately increased numbers of eosinophilic elements and scat- are not overly numerous and there are only small numbers of multinucleated giant cells. Hemosiderin is distributed generally, for the most part within large phagocytic mononuclears. Necropsy: Bone Yarrow: (Femur) Much of the marrow is fatty but there are large areas with dense cellularity in which prac- 374 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [uol. $1, M. 8 tically no fat is apparent. In the lese nucleolus. The cytoplasm is scanty and cellular areas an abundance of fine, e o h - homogeneous. Granulocytic elemente and ophilic fibrillar material is found filling the nucleated red cells are rare and no megainueoida. Elsewhere hematopoietic hy- akaryocyttee are apparent. Mitotic ac- peractivity is apparent with large numbers tivitp is moderate in degree. There is of mitotic figures, a predominance of young vary slight hemosiderosis. erythrogenic elements, but significant num- bem of granulocytic cella as well. Meg- SrraaaaaRY akaryocytes are unusually scanty and there -tologic from 19 - is only a minimal amount of hemosiderosis. with a history of chronic exposure to C a e 19. C.deF., 12,d e . A 12-yar- benzene (14 biopsies) old schoolboy entered a hospital com- has been described and analyzed. It plainins of weakness of nearly a year's has been shown that not merely the duration. The patient's father was a painter and t h e b o y spent much time in his father's shop, frequently using a paint remover known to contain benzene. The degree and duration of exposure could not be determined with any accuracy. Severe epistaxis - preceded his entry to the first hospital, where examination showed only pallor, a very alight generalized lymph node en- _ _ largement, retinal hemorrhages, and a aye- bone marrow but the entire h e m a b poieticsystem characteristidy changes. The picture in the bone marrow V f U k from severe hypoplasis to the most extreme hyperplasia and &medullary hematopi&, and in contrast to prevailing opinion, hyperplesis has proved the more of the two reactions. It has been tolic murmur over the heart. found only in patients with prolonged - - Labwcrtory Findings: The red cell count exposure, whereas h y p o p w may white90ce0l'l0s 0v0afried fr2o5m% 5,000to 12,000,Tthe follow either short or long contact. blood smear containing only 13to16% poly- sex appears to P b ' an important morphonuclears and many lymphoblaete. role-hyperplastic reactions being dis- A sternal puncture was interpreted as con. firming the diagnosis of aleucemic leucemia. Multiple transfusions caused moderate clinical improvement and the patient was discharged. One week after diecharge he h c t l y more Common in the =le, hypoplastic OneS in the female. certain of the hyperplastic cases de- P e a of prolifem~ve activity: of entered the Chelsea Memorial Hospital, where physical examination W M found to be unchanged. While there hi8 hemoglobin varied between 35 and 75%, rising after tranefuaions. The red cells ranged from 1,770,OOO to 4,140,000 and the white cells from 7,100 to 11,400. The blood smear anaplasia and of atypicality of the hematopoietic elements not only in the -row but in the extramedullary foci been described which can be from n e 0 P b a O d Y with difLiculty. Finally, 2 cases with contained 20 to 47% Polymorphonuclea~ typical leucemic pictures, one with and 51 to 75% lymphocytes. An occasional myelocyte was seen and platelets were frankly neoplastic tumor formation, decreased. A biopsy from the sternumwae have been rep*daJld the cumulative performed. evidence linking benzene with the __ - Biopsy: Bone Marrow: There is intense production of leucemia has been d u l a r i t y with only a rare fat vacuole hCmed. - remaining. The cells are almost all lym- _---phnhbtkk. They are relatively uniform - in appearance, measuring 7 to 10 in di- .mshr and containing vwicular nuclei - rifhin each of whioh msy be found a aingIe The authors and editors wish to thank the American Mutual Liability Insurance Chmpny for bearing the expense of the c o l d *be. CHRONIC 1. ANDEBBEN,D. H.:Benzol 7 with hyperplasia of the bone Am. J. Path., 10, 101 (1934) 2. BEYEE,G.: Chronieche Benzc ung bei Kaninchen. Beobac am Blutbild. Ztechr. f. d. gt Med., 91,410 (1933). 3. BLUMEE, G.: Aplastic anem ciated with lymphoid hyper the bone marrow. Bull. Jol kine Hosp., 16,U 7 (1905). 4. BOWDITCH, M., AND ELKINB, Chronic exposure to ben The industrial aspect. Tar 5. Case recorda of the Maass General Hoepital, Case 1332 Med. and Surg. J., 187,236 6. Case records of the Masse General Hospital, Csae 1339: 197,521 (1927). 68. Case recorda of the MBean General Hospital, Case 2036 Eng.J. Med., 811,480 (1934) 6b. Case recorda of the Maseal General Hospital, Case 21301 213, 182 (1935). 7. CASTLE, W. R., AND MINOT, Pathological physiology and description of the anemias. University Press, New Yor 8. CUNNINOEAMR,. S.,SABIN, F. DOAN,C. A.: Development o cytes, lymphocytes and mc from a specific stem cell i1 tissues. Contrib. to Embr 84, Carnegie Inst. of Wash., no. 361, 1925 (p. 229). 9. DELOBEP, ., AND BOWoMANh c h i e aigu6 au cours de l'into benzhique. J. de Med. de I 0. DOANC, . A., CUNNINQU, R. SABIN,F. R.: Experimental on the origin and maturation c and mammalian red blood Contrib. to Embryol. no. 8: negie inat. of Wash., vol. 1 1. DOAN,C. A.: The type of pha cell and ite relative proport human bone marrow and spl AND TOXICOLOGY [uol. $1, M. dus. The cytoplasm is scanty :eneous. Granulocytic elements ,ted red cells are rare and no m ~ y t e s are apparent. Mitotic is moderate in degree. There light hemosiderosis. SWY tologic material from 19 patients t history of chronic exposure to ne (14 autopsies and 5 biopsies) ten described and analyzed. It Zen shown that not merely the marrow but the entire hemato:system characteristically shorn $8. The picture in the bone w vanes from severe hypoplssis most extreme hyperplasia and kedullary hematopoiesis, and in 3t to prevailing opinion, hyperhas proved the more common two reactions. It has been mly in patients with prolonged re, whereas hypoplasia msy either short or long contact. ,pears to play an important yperplastic reactions being dismore common in the male, tatic ones in the female. In of the hyperplastic casea deDf proliferative activi ia and of atypicality poietic elements not o nguished from neoplasia ficulty. F'inallyi 2 cases leucemic pictures, one neoplastic tumor !nreported and the 1 linking benzene with t on of leucemia has been 1. ithors and editors wish to thank ican Mutual Liability Insurance for bearing the expense of the a*. -B 1. ANDQBBEN, D. H.: Benzol poisoning with hyperplasia of the bone marrow. Am.J. Path., 10,101 (1934). 2. BBYIDEG, .: Chronische Bensolvergiftung bei Kaninchen. Beobachtmgen am Blutbild. Ztschr. f. d. ges. exper. Med., 91, 410 (1933). 3. BLUMER, G.: Aplastic anemia associated with lymphoid hyperplasia of the bone marrow. Bull. Johns Hopkina Hosp., 18,127 (1905). 4. BOWDITCHM, ., AND ELKINS,H. B.: Chronic exposure to benzene. I. The industrial aspect. THIS J., 21, 321 (1939). 5. Case records of tho Massachusetts General Hospital, Case 13321. Bost. Med. and Surg. J., 197, 236 (1927). 6. Case records of the Massachusetts General Hospital, Case 13391. ibid., 197,521 (1927). 6s. Case records of the Massachusetts General Hospital, Case 20361. New Eng. J. Med., $11, 460 (1934). 6b. Case records of the Massachusetts General Hospital, Case 21301. ibid., $18, 182 (1935). 7. CASTW, W. R., AND MINOT, G. R.: Pathological physiology and clinical description of the anemias. Oxford University Press, New York, 1936 (P. 91). 8. CUNNINQHAMR., S.,SABIN, F.R., AND DOAN,C. A.: Development of leukocytes, lymphocytes and monocytes from a specific stem cell in adult tissues. Contrib. to Embryol. no. 84, Carnegie Inst. of Wash., vol. 16, no. 361, 1925 (p. 229). 9. DBLOFUPU., AND BOBQOMANNLOe:uc6mie aigu6 au coim de l'intoxication benzbnique. J. de Med. de Lyon, 9, 221 (1928). 10. DOAN,C. A., CUNNINGHAYR,. S., AND SABIN, F. R.: Experimental studies on the origin and maturation of avian and mammalian red blood cella. Contrib. to Embryol. no. 83, Carnegie Inst. of Wash., vol. 16, 1925 (p. 165). 11. DOAN, C. A.: The type of phagocytic cell and its relative proportions in human bone marrow and spleen, as identifiedbytheanprsvitdtechnique, with speeial reference to pernieioumanemia. J. Exp. Me&, 10, 558 (1928). 12. DUKE, W. W.: Causes of variation in the platelet count. Experimental results showing the effect of diphtheria toxin, benzol and tuberculin on the platelet count in rabbits. Arch. Int. Med., 11, 100 (1913). 13. ENGELFIARWD.T,E.: Vergleichende Tierversuche uber die Blutwirkung von Benzin und Benzol. Arch. f. Gewerbepath., 9, 479 (1931). 14. FALCONEER., H.: An instance of lymphatic leukemia following benzol poisoning. Am. J. Med. Sci., 186, 353 (1933). .15. Final Report of the Committee on Benzol. Chemical and Rubber Sections, National Safety Council. May, 1926. 16. GALL, E. A.: Benzene poisoning with bizarre extramedullary hematopoieais. Arch. Path., 26, 315 (1938). 17. GLANZMANNE,.: Das lymphaemoide Driisedeber. Abhandl. aus der Kinderheilk. u. i. Grenzgebiet., 96, 178 (1930). 18. 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