Document 2RKdjw6DGkepy4bpDNJorEkJR

LEUKEMIA ASSOCIATED WITH BENZENE EXPOSURE E. C. Vigliani Clinicn del Lavoro "Luigi Devoto" University of Milan Milan, Italy Benzene has been known for almost a century as a powerful bone-marrow poison, leading to aplastic or hypnplastic anemia. It is now a rather widespread belief that any chemical capable of inducing severe bone-marrow damage must be assumed to be a potential leukemogen.' Actually, evidence has been accumulating over the last few decades that benzene produces not only aplastic anemia, but also leukemia, and that the fatal cases of leukemia outnumber those of true aplastic anemia. In 1928 Delore and Borgomano' described the first case of "benzene leukemia," an acute leukemia in a worker so heavily exposed to benzene that none of his fellow workers could stand more than two months without becoming ill. Shortly after this first description, other cases of leukemia attributed to benzene were published. In 1932, Lignac gave 0.001 ml benzene in olive oil weekly to 54 white mice over a period of 17-21 weeks, and succeeded in producing six leukemias and two infiltrating aleukemic lymphoblastomas, whereas no cases of leukemia developed among 1465 mice taken as controls. Subsequent attempts to reproduce leukemia by injecting laboratory animals with benzene gave inconclusive results, because cases of leukemia also developed in the control animals almost to the same e ~ t e n t . ~ Since then, reports of acute and chronic leukemia in man attributed to ben- zene poisoning have appeared in the literature in increasing number. In 1938 Penati and my~elf,~.iCn a critical survey of the available literature from the period 1928-1938, found, in addition to about 60 cases of fatal aplastic anemia, ten cases of benzene leukemia and also four other cases which fitted into neither the picture of aplastic anemia nor into that of leukemia, because of atypical findings, like, for instance, splenomegaly, reticulocytosis with erythroblastosis, leucocytosis with immature elements in the circulating blood, leukemoid reaction, and myeloid metaplasia in the spleen and liver. In 1945, in addition to a personal observation, Saitai investigated another 23 cases of leukemia attributed to benzene, according to the literature, in which it was clear that there was a predominance of the acute forms over the chronic ones. Browning collected 61 cases from the literature up to 1960, acute cases outnumbering the chronic ones; 14 were cases of acute aleukemia, and 12 were erythroleukemia. Tareeff and coworkers9 described 16 cases of leukemia ( 6 acute and 10 chronic) in workers in the USSR occupationally exposed to ben=ne for 4-27 years (average = 15 years). In three out of the s i x acute cases, a latent period of two to five years between the cessation of the exposure and the development of leukemia was noted. In the past two decades, case records of patients with acute or subacute leukemia, usually with leukopenia at some stage in the illness, have become SO numerous that they exceed those of fatal pancytopenia. This finding led us to suspect that many cases that had been considered as the acute terminal stage of aplastic anemia or as a hemorrhagic aleukemia, prior to the introduction of bone-marrow puncture, may in fact have been examples of acute myeloblastic 143 144 Annals New York Academy of Sciences leukemia, leucopenic or aleukemic or with few microhemocytoblasts in circulating blood, possibly mistaken for lymphocytes. An approximate estimation of the available literature, including some published North Italian cases of which we have knowledge, puts the number of known cases of leukemia attributed to benzene at at least 150. The most convincing cases of benzene leukemia are those occurring factories where there were outbreaks of chronic benzene poisoning. This true, for instance, of the epidemics of benzene poisoning seen in r o t o g r a m plants and especially in the shoe-manufacturing industry in Italy prior to banning of benzene as a solvent for inks and glues in 1963. Many of the that occurred in Lombardy have been studied at the Institutes of Occupatioplt Health of Pavia and Milano. In 1964, Saita and myself lo published six cases of leukemia that o c c w among 47 patients with benzene hemopathy seen at the Institute of Milano 1942. New cases have occurred since then: our experience has already Iv SHOEMAK IN FACT( I Case i1 2 3 4 5 6 I '8 i9 I1O1'+ . i No. OF CASES OF Type of Industry LEUKEMIA TABLE 1 AMONG 66 CASES OF BENZENE Cases of Benzene Hemopathy (overall no.) # . ." --HEMOPATHY* cases of 1 I 12 1' 13 + _- * The leukemi 13. data not avai 7 These cases [kite of Occupatic oys and artificial flowers *Seen at the Institute of Occupational Health of Milano from 1942 to M , 1975; 37 men. 29 women. Number of women shown in parentheses. summarized in two reports.I1. but we can now add some more detailed infor- mation. Altogether, in our Institute in Milano from 1942 up to now. we have seen 66 cases of chronic benzene poisoning, mostly with less than 3 red cells and less than 4.000 white cells. There were 18 deaths; of these, from aplastic anemia and 1 1 from leukemia. They came from rotogr -pIleanntcsa, ssehsooeffapcotiosroineisn,gancdamotehefrroimnduosntlryie!sv:=usirncgtcbgernazveunree as a solvent (TABLE p!?:!~, mostly be 1952 and 1953, when the benzene content in inks and solvents was very often reaching 100%. Of these, eight had a severe hypoplastic anemia less than 2.5 million red cells, and two of them died; two were acute m leukemia. In one case. severe anemia developed after only four months' The benzene content near the rotogravure machines was calculated to be be- 'lj. tween 200 and five cases seen All cases 0' edge came fro workers with 1 Sixteen of the: of leukemia. t (TABLES 2 8~ The benzene c the breathing 15 to 600 ppl used containe of samples. j shoe industry FATAL CASES OF O c C u P A -- ,\piastic Aner Acute Leukec Er) throleuke .Acute Erythr Total Deal Vigliani: Leukemia and Benzene Exposure 145 TABLE 2 SHOEMAKERS USING GLUES AND ADHESIVES CONTAINING BENZENE IN FACTORY AND AT HOME, SEEN AT THE INSTITUTE OF PAVIA Exposure Type of Prevalent Type Case Age ( years) Leukemia - of Cells 1 54 40 acute stem cells 2 59 38 acute * paramyeloblasts 3 54 8 acute * myeloblasts 4 35 1 acute stem cells 5 64 46 acute * hernocytoblasts 6 44 2 acute stem cells 7 66 40 acute * stem cells 8 61 32 acute * stem cells 9 46 IO + 9 11 + 7 ? acute ,I acute ? acute erythroleukemia stem cells myeloblasts 12 + 9 ,I acute hemocytoblasts 13 + ? ? acute hemocytoblasts *The leukemia was superimposed on aplastic anemia. For cases 10, 11. 12, and 13, data not available. t These cases were admitted to other hospitals in Pavia and referred to the Insti- tute of Occupational Health. tween 200 and 400 ppm, with peaks up to 1500 ppm. A short synopsis of the five cases seen at our Institute from 1964 up to now is given later in this paper. All cases of which the Institute of Occupational Health of Pavia had knowledge came from the shoe-manufacturing industry. From 1959 to 1974, 135 workers with benzene hemopathy were seen or were reported to this Institute. ' Sixteen of them died; of these, only three died of aplastic anemia, and thirteen of leukemia, twelve of them acute myeloblastic and one acute erythroleukemia (TABLES 2 & 3 ) . (Data kindly supplied by Professors Maugeri and Pollini.) The benzene concentration in the air was measured by us in some factories near the breathing zone of workers handling glues. The concentration ranged from ' 25 to 600 ppm, but was mostly around 200-500 ppm. The glues and solvents used contained from nil up to 100% benzene, according to the different types of samples. It must be remembered that in the many cases occurring in the shoe industry, the people worked not only in the factory but also at home, doing TABLE 3 FATAL CASES OF BENZENE APLASTIC ANEMIA AND LEUKEMIA SEEN AT INSTITUTES OF oC!CUPATIONAL HEALTH OF MILANO(1960-1974) A N D PAVIA (1960-1974) Aplastic Anemia Acute Leukemia Erythroleukemia j Acute Erythremia Total Deaths Milano 7 7 3 1 18 Pavia 3 12 -1 16 146 Annals New York Academy of Sciences the same job and using glues with a high benzene content without the slightat precaution. The cases of benzene hemopathy that occurred in the Province of Milano from 1960 to 1967 and in the Province of Pavia from 1960 to 1965, and i which were compensated by the National Insurance Institute for Occupational Diseases. are shown in TABLE 4." These cases not only include many patients seen at the Institutes of Milano and Pavia, but also other cases admitted to other hospitals. Very often, leukemia develops in subjects with benzene-induced hyporegen- erative anemia or pancytopenia of more or less long standing and constitutes I ! the acute terminal stage of the disease. The leukemia might become clinically apparent only a few weeks before death: in these cases, the anemia can considered as being a preleukemic stage. Aplastic anemic occurs in subjects generally while they are still exposed to i , Ihigh concentrations of benzene; leukemia may occur at the same time, or mon or less shortly after cessation of exposure. In a few cases there may be a long latency period between the end of work with benzene and the onset of leukemia I In a recent patient that we recently observed in our Institute (C. A., female, 66 I 1: TABLE 4 "BENEFIT CASES" OF BENZENE HEMOPATHY IN THE PROVINCES OF MILANO (1960-1967) AND PAVIA(1960-1965) I"Benefit Cases" of Benzene Hemopathy ICases Living +: Anemia 50 Deaths Aplastic anemia Acute leukemia Erythroleukemia I14 18 33 1 years old), who had suffered from a typical benzene anemia in 1957, there was a period of 14 years with almost normal blood counts before the onset of acute erythroleukemia in 1972: the patient died five months after leukemia had been diagnosed. TABLE 5 shows the length of exposure and the latency period of the cases seen in Milano and Pavia. Among the cases of benzene leukemia, at least 20 cases of erythroleukemia have been reported in the literature. Of the eleven cases of benzene leukemia seen at our Institute in Milan from 1942 until now. seven were myeloblastic; one erythremic, and three. erythroleukemic. Because of the rarity of this disease, the number of these cases seems to be significant. In the French and American reports, and especially in the summarivng reports by Browning and Goguel et aI..l3 cases of chronic myeloid and chronic lymphocytic leukemias have been attributed to benzene, together with the mow numerous cases of acute leukemia (TABLE 6). This is neither our experiemx ~ nor the experience of the Institute of Occupational Health of the University of . Pavia, where only acute or subacute myeloid leukemia occurred at the same time as cases of pancytopenia among workers heavily exposed to benzene vapors. Also. the four cases of leukemia seen by Aksoy and coworkers among 3 I TABLE 5 CASESOF BENZENE LEUKEMIA OBSERVED AT THE CLINICA DEL LAVOROOF MILANO, 1942-1975 * r .'a$ Cases reported by Vigliani & Saira. 1964 lo Type Of Leukemia Years from Start Duration of of Exposure to Exposure (yr) Onset of Leukemia 1. M.D. 2. R.F. 3. T.S. I 4. M.A. 5. M.A., 50 yrs. 6. L A . AML AML AML AML AML AML 99 55 88 11 23 19 20 33 i Cases Seen Between 1965 and 1974 I I . Z.G. 8. S.M. AML AEL 22 24 77 9. B.M. AEL 35 i 10. C.A. 11. DF.S. AEL AE 3 19 7 12 * AMLracute myeloblastic leukemia: AELzacute erythroleukemia: AE=acute erythremia. 1 I cases of hyporegenerative anemia in workers using benzene-containing glues in i the manufacture of shoes and slippers, were acute: 3 myeloblastic (one occurred 3 years after recovery from aplastic anemia) and one monocytic. Aksoy's cases were exposed to 210 ppm benzene when adhesives containing benzene were being used. There is therefore ample reason to believe that acute leukemias developing concurrently with cases of anemia, or as a terminal stage of an aplastic anemia i in workers exposed to benzene, are really cases of occupational cancer. Many cases have low white-cell counts or show only a moderate leucocytosis, with a small percentage of immature cells .in the circulating blood, except in the terminal stage. I Saita and myself calculated that for workers heavily exposed to benzene in the rotogravure and shoe industries of the Provinces of Milano and Pavia, the .risk of acute leukemia was at least 20 times higher than for the general populaI tion. I b TABLE 6 CASES OF LEUKEMIA IN SUBJECTS WITH CHRONIC BENZENE EXPOSURE, IDENTIFIED IN THE PARIS REGION FROM 1950 TO 1965 b Identified Cases I (37 Males. 7 Females) I Acute leukemia I Chronic myeloid leukemia Chronic lymphocytic leukemia 44 23 13 8 From Goguel et al." --* 148 Annals New York Academy of Sciences If there seems to be little doubt about acute or subacute leukemia being induced by benzene. the occurrence of chronic benzene leukemias is not so convincingly demonstrated in all cases. Many were isolated cases, and a consistent exposure to benzene is not always well documented. However, several cases of chronic leukemia seem to have been heavily exposed to benzene, and there is no a priori reason for not accepting them as benzene-induced leukemia simply on the grounds that we have never seen such cases. Unfortunately, almost no statistical data demonstrating a higher incidence of chronic leukemia among workers exposed to benzene are available at present. In this respect, a recent study by Girard and Rev0115 is worth mentioning. They made a re- spective statistical study of severe hemopathies seen in Lyon hospitals a found a history of exposure to benzene and/ or its homologues in the preceding ten years in a significantly higher proportion of patients with acute leukemia, chronic lymphocytic leukemia, and aplastic anemia, but not with chronic myeloid leukemia and other blood disorders, than among control patients with diseases not related to the hemopoietic system. The study by Girard and Revol also raises the problem of whether th homologs of benzene might be leukemogenic. At present. there are no other data in support of this hypothesis; since the replacement of benzene with toluene as a solvent in the rotogravure industry in 1964, we have seen no new cases of aplastic anemia nor of leukemia due to toluene exposure. Furthermore, toluene- exposed workers do not show the chromosome aberrations frequently seen in workers exposed to benzene. Another interesting study comes from Japan. Ishimaru and coworkers 16 examined 303 cases of leukemia that occurred among adult survivors of the atomic bomb explosions of Hiroshima and Nagasaki and compared them with 303 matched controls exposed to the same amount of ionizing radiations from the bomb. They found that the risk of leukemia was approximately 2.5 tima higher among those with a history of probable exposure to benzene or its derivatives and to medical x rays. The relative risk, however. was 2.9 for acute and 1.8 for chronic leukemia, and was definitely higher among those who had been engaged in these occupations for at least five years. The conclusion of this study was that there is an increased risk of leukemia only in those occupations in which there is frequent exposure to benzene or to x rays. In order to have a better insight into the possibility of benzene being respon- sible for the occurrence of chronic types of leukemia, it would be highly de- sirable that a precise evaluation of the existence and severity of the exposure to benzene vapors be made in every case of leukemia. whatever type it may be, and that pathological and epidemiological studies be carried out on the incidence of chronic leukemia among workers exposed to concentrations of benzene above or below the threshold limit value. or exposed only occasionally to this solvent, compared with nonexposed controls. The problem is important. inasmuch as the gasoline presently used for motor vehicles often contains a percentage of benzene that may be as much as 6-8 % . From the vast literahre accumulating over the last forty years. the conclusion can be drawn that clinical as well as epidemiological data are indicative of a strong leukemogenic action of benzene in man. the leukemia being mostly acute and myeloblastic in type, occurring directly or following aplastic change in the bone marrow, and that the probability exists that benzene might also induce chronic types of leukemia. .2 INSI The bles v tmne .e cablt 465: F I.OO0. istitute me mar, :ries, mo pa' asts. S 1 whicf. k e n ai 1 elobla 5 elobla akemia A. Fc benzer This >hemblii `e lininr id feve, `00 wit :s,ooo. imaturt iphebit c myc -onths. 967. r r\ thr0ld This ca udies ir From olvent c itter spr For c Vigliani: Leukemia and Benzene Exposure 149 r SYNOPSIS OF THE CASES OF BENZENE LEUKEMIA SEEN A T THE INSTITUTE OF OCCUPATIONAL HEALTH OF MILAN FROM 1964 TO 1974 f Case 7: Z.G.. Female. Age 36 Years The patient worked from 1942 to 1964 as a finisher of electric cables. The cables were covered with a rubber muff. which she c!e:xd by ixnring a benzene-containing solvent on cotton wool and rubbing the external surface of the cable muff. September 1964: severe anemia: RBC 2.1 million. November 1965: RBC 1.9 million. WBC 4800 with normal differential count. platelets 90,000. Dry tap on several sternal punctures. Upon first admission to our Institute in December 1965, RBC 2.0 million, WBC 3200. platelets . I 20,000; bone marrow very poor. with rare normoblasts and some cells of the myeloid series. mostly myeloblasts and promyeloblasts. In March 1966 the spleen became palpable: WBC 3000 with 3% myelocytes. l % myeloblasts. 2% normoblasts. She was discharged and readmitted in May 1966. with WBC 3000. I O % of which were myeloblasts. and platelets. 48.000. In the following months, the spleen and liver became enlarged. WBC from 2600 to 24.000, with 15-18% myeloblasts. Upon a fourth admission to our Institute, WBC 10,000 with 20% myeloblasts. Exitus at home on April 7. 1967. Diagnosis: Acute myeloblastic leukemia superimposed on benzene aplastic anemia. (This case was described by A. Forni and L. Moreo. in 1967, in a paper, Cytogenetic studies in a case of benzene leukemia. Europ. J. Cancer 3: 251.) Case 8: S.M.. Female. Age 37 Years This patient worked from 1959 to 1966 in a small beauty-case factory. assembling the cases with a glue diluted with benzene, which was spread over the lining with the finger. In 1965 metrorrhages, in July 1966, weakness, pallor, and fever. Admitted to our Institute September 1, 1966; RBC 3.0 million. WBC 4500 with 14% metamyelocytes, 26% myelocytes, 10% erythroblasts, platelets 125,000. Bone marrow rich in elements of both series, especially of the more immature forms, often atypical. October 1966, severe metrorrhagia, thrombophebitis, fever; RBC 2.0 million. WBC 30,000 with 19% metamyelocytes, 2% myelocytes, 6 % myeloblasts; 27 erythroblasts/lOO WBC. In the next months, fever, hemorrhages, spleen and liver enlargement. Exitus February 16. 1967. Postmortem revealed massive infiltration of spleen and liver, with erythroid and myeloid elements. Diagnosis: Subacute benzene erythroleukemia. (This case was published by A. Forni & L. Moreo in 1969: Chromosome studies in a case of benzene-induced erythroleukemia. Europ. J. Cancer 5: 459.) Case 9: B.M., Male. Age 31 Years From 1959 to 1961. shoemaker; he weakened the tip of the shoe with a solvent containing 40% benzene and then heated it to give the final shape. After spring 1962. pallor. weakness. and anemia. Admission to a hospital in I.For cases 1-6. seen between 1942 and 1964. see Ref. 10. 150 Annals New York Academy of Sciences \NwPavia in October 1962; diagnosis, anemia with hyperactive normoblastic bopc marrow. Admitted to our Institute in May 1963: RBC 2.98 million, 5400, platelets 130,000; 44 erythroblasts/ 100 WBC. Sternal biopsy: boac marrow hyperactive, with 90% erythroblasts. In the following weeks, appear. ance of some myeloblasts in the circulating blood, with reduction in the per- centage of erythroblasts. Discharged September 1963, readmitted November 1963, with RBC 3 million, WBC 3700, with 1% myeloblasts and 3% e- blasts; platelets, 42,000, Discharged and readmitted March 6, 1965; RBC 3 3 million, WBC 53,000, mostly myeloblasts, platelets 45,000. In the followin8 , days, white cells increased to 215,000 and the spleen was enlarged. Follo- therapy, WBC fell to 12000, RBC to 2.2 million. May 12, 1965: WBC 20,800 with 3% myeloblasts and 78 % blasts with hystiomonocytoid appearance. Exih May 14, 1965. Postmortem: myeloid erythroleukemic hyperplasia of the bpc .imarrow, enlarged spleen with multiple infarctions, myeloid metaplasia in lung and stomach, hemorrhagic pneumonia. Diagnosis : Subacute b e e m erythroleukemia. I 6. Pi r.:..: Case 10: C . A . ,Female, Age 66 Years 1972 she was treated at home for anemia. Admission to our Institute in Sep tember 1972: RBC 2.4 million, WBC 3600. platelets 16,000. NO immaftvO elements in circulating blood. Dry tap on 3 sternal punctures. In the f o l l o ~ months appearance in the circulating blood of erythroblasts and proerythm ij, :i,Ab Case II: D.F.S.,Male, Age 55 Years From 1958 to 1965 he worked as a shoemaker close to workers using adhesives and glues containing benzene (percentage not stated). Operated for perianal abscess and final f i m l a in 1961, 1964, and 1969, when a hyporegenbhr tive anemia was found: RBC 2.6 million. WBC 5500. with bone marrow plasia. Admitted to our Institute in January 1970: Hb 38%. RBC 2.0 WBC 1200. platelets 35.000. No immature cells in circulating blood, slightly enlarged. in February WBC 8500 with 4 erythroblasts/ 100 Sternal puncture: dry t'ap. March 12. WBC 22.000. with 70% erythro 18% granulocytes, 6% lymphocytes. 1% monocytes. Exitus a few days at home. Diagnosis: Acute erythremia, superimposed on aplastic anemia to benzene. a Vigliani: Leukemia and Benzene Exposure 151 blastic bc Ilion, u' REFERENCES )psy: bc 1. ONKI KITE^ E. P. 1961. Evidence for radiation and chemicals as leukemogenic 'ks, aPPe agents. Arch. Envir. Health 3: 297. in t h e F 2. DELORE, P. & c. BORC~OMASO1.928. Leucgmie aigue au c o w s de !'intoxication Novem. benzknique: sur I'origine toxique de certaines leudniies aipues et leur rela- % erytt tions avec tes a n h i e s graves. J . Med. Lyon 9: 227. ;; RBC 3. LIGNACG, . 0.E. 1932. Die Benzolleukamie bei Menschen und Weissen Mau- :follou sen. 111 Zweite Benzol-versuchsreihe-von 54 Mause gehen 8 an Leukimie Follou d e r Lymphoblastoma infiltrans aleucaemicum zugrunde- fruhere Tierbenzolversuche. Krankheitsforsch. 9: 426. BC 20.1 4 IARC Monographs o n 1'2 Evaluation of Cancerogenic Risk of Chemicals in ce. Ex Man. 1974. Vol. 7: ::.? IARC. Lyon. France. f the bc 5. VIGLUNI, E. C. 1938. Sulla clinica delle intossicazioni d a solventi della serie isia in aromatica. Bericht. \.I11 Intern. Kongr. Unfallmed. Berufskrankh. Frankfurt 2 benzr 6. a.M. :825. Thierne. Lei;zig. c.PENATI, F. & E , \.IGLr,sI. Germany. 1938. SUI problema delle mielopatie aplastiche. pseudoaplastiche e 1ec;cmiche da benzolo. Rassegna Med. indust. 9(5-6): 345. SAITA, G. 1915. Mielmi aplastica e successiva mielosi leucemica leucopenica, provocate d i benzoyi. \led. Lavoro 36: 143. BROWNING, E. 1965. I-. Tsxicity and Metabolism of Industrial Solvents : 3-65. Elsevir. Amrrerdam. :-l %etherlands. TAREEFFE,. sf..3 . 51. ~ ~ O N T C H A L O V S K A Y&A L. A . ZORINA.1963. Benzene leukemias. .Acta. L-c. I-.:. Cancer. 19: 751-755. ~ L I A N EI ., C 6; G ..:s, . 1964. Benzene and leukemia. New Engl. 1. Med. 271: 872-8-6. FORNI,A. & E C . \-bL-..w. 1974. Chemical leukemogenesis in man. Ser. Haemat. \- 2 f: 2 i :-::I VIGLIANI,E. C 19-2 l z J k e m i a . Occupational chemical factors. h o c . XI Inter. Con% Cancer Fl$:ccnce, Italy. In press. GOGUEL,A.. .+. C*\K-.L---X& J. BERNARD. 1967. Les Leuckmies benzeniques de la regicr ::+>irz2 $-:re 1950 et 1965 (Etude de 50 observations). NOW. Rev. Frar_; Ze-;: -: --:. AKSOY,M.. I; D:\:: 1. 5 ERDEM& G . DINCOL. 1972. Acute leukemia due to chronic ey?:c-:z I; : c z z n e . Amer. J. Med. 52: 160. GIRARD,R. j ; :m.11-370. La frtquence d'une exposition benzenique aux c o w s des z c r G a~e s . ~Nouv.~ Rev.~FranG. Hemat. 1 0 477. ~ M A R U T, . :k c t T. TOMIYASUT, . TSUCHIMOTO, T . HOSHINO& M. ICHIMARL :-: f:c=zzitional factors in the epidemiology of leukemia in Hiroshima ZL X - n Amer. J. Epidem. 93: 157-165.