Document Eqy5pBkYR7XYezdXgKZwerqZj

f PPLLAAININTITFIFF'SF'S^ EXHCEUT Hematotoxicity and Carcinogenicity of Benzene by Muzaffer Aksoy* The hematotoxicity of benzene exposure has been well known for a century. Benzene causes leukocflopenia. thrombocytopenia pancytopenia. etc. The clinical and hematologic picture of aplastic anemia resulting from benzene exposure is not different from classical aplastic anemia; in some cases. mild bilirubinemia. changes in osmotic fragility. increase in lactic dehydrogenase and fecal urobilinogen. and occasionally some neurological abnormalities are found. Electromicroscopic tindings in some cases of aplastic anemia with benzene esposure were similar to those observed by light microscopy. Benzene hepatitis-aplastic anemia syndrome was observed in a technician with benzene exposure. Ten months after occurrence of hepatitis H.a severe aplastic anemia developed. The first epidemiologic study proving the leukemogenicity of benzene was performed hetween 1967 and 19i3 to 1974 among shoe workers in Istanbul. The incidence of leukemia was 13.59 per IOU.Ou0. which is a significant inhease over that of leukemia in the general population. Following the prohibition and discontinuation of the use of benzene in Istanbul. there was a striking decrease in the number of leukemic shoe workers in Istanbul. In 23.7% of our series. consisting of 59 leukemic patients with benzene exposure. there was a preceding pancytopenic period. Furthermore. a familial connection was found in 10.2% of them. The 89.8% of our series showed the findings of acute leukemia. The possible factors that may determine the types of leukemia in benzene toxicity are discussed. The possible role of benzene exposure is presented in the development of maliKnant lymphoma, multiple myeloma. and lung cancer. Introduction The hematotosicity of chronic benzene poisoning has been well known for nearly a century. The effects of benzene include leukocytopenia. thrombocytopenia, anemia, t 1.ansitoi.y leukocytosis. lymphopenia. rarely lymphocytosis. very rarely pseudo-Pelger Huet anomaly changes in the leukocyte osmotic resistance. decreased phagocytic function of granulocytes. reduced glucogen content and inhibited activity of peroxidase of neutrophils, an increase in the acid phosphatase and p-glucoronidase activity of the neutrophils. and a decrease of alkaline phosphatase, tnyeloperoxidase and lipid content of the neutrophils (11. in addition, in chronic benzene toxicity a decrease of the E, and E rosetts (T cells) was noted (1). Furthermore. ;in increase of leukoagglutinins was demonstrated in the s e n of some workers exposed chronically to benzene. ( 11. An increase of eosinophils. basophils. and monocytes in chronic benzene toxicity is a matter of discussion (1).This problem, particularly concerning monocytes. deserves further investigation with modern techniques. In chronic benzene tosicity, some other qualitative abnormalities. such as the presence of giant platelets. has been found (1). `The Scientific and Technical Research Council of Turkey. Researcn I!>.~titutleor Basic Sciences. Del~irtmenutt' Bioloq. Gebze. E;uc;ieli. Turkey. According to Craveri. the hemoi-rhapic effects of chronic benzene toxicity are not solely due to thrombocytopenia but are also due to increased fibrinolytic activity (2). Aplastic Anemia or Pancytopenia Resulting from Chronic Benzene Exposure The clinical and hematolosc picture of benzene-induced aplastic anemia which is characterized by pancytopenia. is not different from that of classical aplastic anemia idiopathic or because of different chemicals or other agents (1). In some cases of benzene-induced aplastic anemia, there are characteristics that are absent when this hematologic disorder is caused by other agents. such as mild bilirubinemia. changes in osmotic fragility. shortened erythrocyte survival time. increased serum lactic dehydrogenase activity, increased fecal urobilinogen, and mild reticulocytosis (1).These findings are the result of a hemolytic component in aplastic anemia due to chronic benzene exposure. A4dditionally,in some cases of benzene-mediated aplastic anemia. absolute and relative lymphocytosis are absent (1).In other words, in addition to aplastic anemia resulting from other causes, absolute lymphopenia is present in this hematologic disorder due to chronic benzene exposure. 011the other hand, althouqh there are no symptoms and findings relating to the nervous system in aplastic anemia. idiopathic or because of different agents. in some cases of aplastic anemia resulting from chronic exposure to benzene. there are some findings relating to the nervous system (.A. Xlthouph as early as 1967 Ti-uhaut has indicated in his reports on benzene the possibility of longteim effects of this chemical agent on the nervous system such as polyneuritis of the lower extremities. there are very few reports on this subject (3.4).Baslo and Aksoy performed neurolopal. electromyographical. and motor conduction velocity examinations in sis patients it-ith aplastic anemia and two patients n-ith preleukemia caused by chronic esposure to benzene (3).In addition. sensory conduction velocities were measured in three patients. Seurological abnormalities such as global atrophy and decreased sensory vibration of lower extremities (in one case), distal latency lengthening of median nerve (in I me case), decrease in the sensory conduction velocities of the lower estremities (in one case) were found (3). 'There \vas ;t certain relationship between the presence I ~f neui*olopical abnormalities and the period of the ex- ~)osul*e. The findings of bone marrow examination in chronic twnzene toxicity are extremely variable. The picture imges from complete aplasia to highly hyperplastic bone imiri*oiv.I n some patients. the bone marrow is fully acellular in the terminal stage (1).According to Mallory et al. the effects of benzene on the bone marrow will vary with the individual and are independent of the length of esImui-e(5).More than one type of foci can be encountered in the bone marrow. Using 'H-methylthymidine autoradiography. Moeschlin and Speck studied the bone marrow of animals poisoned by benzene and found that the results v;ii*ieri from animal to animal: 1 very hypoplastic. 6 !iypoplastic, 5 normocellular. and 4 hypercellular (6).No i.oi*relation \ i x s found between cellularity of the bone t i i m a~nd~duration of exposure to benzene. .A follow-up study was performed in 44pancflopenic patients with chronic benzene toxicity (7). Only 21 patients h a d hypocellulai- bone marrow. It was normocellular in 13 patients and hypercellular in 8. Contrary to the findings of peripheral blood, there was a relationship between the types of cellularity of the bone marrow and the outcome. including the development of leukemia. Out of 21 patients with hjpocellular bone marrow, 11died (52.4%). and in 5 patients 123.85%l)eukemia developed later. Cont r a y to this. only 1out of 13(7.7%)pancytopenic patients with normocellular bone marrow died. On the other hand, 1out of S patients with h-ypercellular bone marrow recov- tAred completely (50%).Two died from the complications 01' aplastic anemia. In 1of the remaining 2 , leukemia de- veloped and in the second 8 years after complete recoveiy, the occurrence of myeloid metaplasia was the cause of death. Ultrastructural studies in 4 patients with aplastic anemia and leukocytopenia were performed by Erbengi and Xksoy (8).Electronmicroscopic findings were in accorclmce with the changes in the bone marrow observed by light microscopy. Additionally. there was an increase in plasma cells with maturation arrest in the later phases of the erythroid series. Ultrastructural studies : Id some light on phagocytic activity of the reticulum c i. This study showed a hyperactivation in the bone n 'ow 0; one case and a depression in the erythroid elemc in aecond patient. These different findings may g- ne pression that the effect of benzene on the bo1 ;1r may change from patient to patient, Benrene-Hepatitis-Aplastic I .emia Syndrome The occurrence of aplastic anemia in chronic benzene toxicity may be accelerated by the occurrence of viral hepatitis. Recently we have observed a severe case of aplastic anemia associated with chronic benzene toxicity 10 months after t h e appearance of hepatitis B. The propositus was a 32-year-old technician working in a petroleum plant (1). X sample of the product disclosed 2.2%benzene. Two years ago he had hepatitis B for a duration of 1 month. A t that time he was not anemic and there was no leukocytopenia or hemorrhagic diathesis. ,Approximately 10 months later the signs of aplastic anemia appeared. He had severe pancytopenia. The bone inarrow was very hypocellular, and the findings were consistent with the diagnosis of severe aplastic anemia. The tests for hepatitis B-virus antigens determined by ELISA showed that anti-HBs, anti-HBe, and anti-HBc were positive. The clinical and hematologc picture of the patient was similar to those of chloramphenicol-hepatitisaplastic anemia syndrome first described by Hodgkinson (9). Following the failure of oxymetholon therapy, a trial with anti-lymphocytic serum, the patient's clinical and hematological picture improved considerably. He is in remission a t the present. We call this syndrome "benzene-hepatitis-aplasticanemia syndrome"(I ) . Benzene and Malignancies Benzene is a suspected leukemogenic and carcinogenic agent since the first description of a case of leukemia by Le Noire and Claude in 189`7(10).Recently, Maltoni and Scarnato showed in rats and mice that oral intake of high doses of benzene causes malignancies in several tissues (11).Any agent toxic to pluropotent stem cells can cause an alteration in two important capabilities of the colony forming cells (12):self-renewal and differentiation to produce a variety of lineage restricted progenitor cells, in other words, the long-term maintenance of self-renewal and differentiation. Any block or disturbance in these capabilities will cause either aplastic anemia (ablock in selfrenewal) o r leukemia (a block in differentiation). Therefore, benzene as a toxic agent for stem cells, may cause aplastic anemia or leukemia. Although there were numerous case reports showing the possible role of benzene in the development of'ieukemia, the first epidemiologic study on this problem appeared in 1974 (13).From 1967 to September 1973.26 patients with leukemia or pre-leukemia were seen among H E.cIATOTO.YI CI TI. .LV D C.4 RCISOGE.VI CI TY 0F BESZE.VE !!Id Table 1. Annual number of leukemic shoe workers in Istanbul between 1967 and 1918. Year 19617 1968 1Yti9 1970 19171 1972 1973 1Y74 1973 lYTG 1977 1978 No. of leukemic shoe workers 1 1 3 1 ti J- I 1 3 0 0 0 25,500 shoe-slipper and handbag workers chronically esposed to benzene in Istanbul. A t that time, the concentration of benzene was found to reach a maximum of 210 to GO ppm during working hours in workplaces. The content of benzene in adhesives and thinners was between 9C7c anJ88clc (7.15).Of these leukemic workers. 17 were investigated at the Second Internal Clinic of Istanbul Nedical School. The remaining 9 leukemic workers were studied in other hospitals in Istanbul. As explained in this study, another worker with acute Iumphoblasticleukemia resulting from benzene exposure was not included in this series because his profession was different. In 1974.the number of the leukemic shoe workers in Istanbul increased to 31 (15).Thus the incidence of leukemia among them was 13.59 per 100.000,which is a markedly and statistically significant increase over that of leukemia in general population. 6 per 1OO.OOO. In Turkey, according to the official Year Book of Health Statistics. the incidence of leukemia is between 2.25 and 2.80 per 100.000 (16). As can be seen from Table 1, the peak incidence among shoe workers in Istanbul occurred between 19il and 1973 (17). It was 21.7 per 1OO.OOO.The number of leukemic shoe workers in Istanbul started to decrease after the prohibition and discontinuation of the use of benzene since 1969 (17). The number of new leukemic shoe workers has decreased in 1974 to 1973 to the level of 1969 to 1970,and none were recorded in subsequent 3 years. But between 1979 and 1987, we observed 22 new cases of leukemia associated with chronic exposure to benzene. Only 3ofthem were shoe workers living in Istanbul. The decline in the annual occurrence of leukemia in the series of shoe workers in Istanbul may be attributed to the prohibition ancl gradual discontinuation of benzene in this city stairing in 1969. On the utheihancl. the reappearance of leukemia after 1979 in Istanbul and other Turkish cities may be attributed either t o the variation in the interval between the occurrence of leukemia antl esposure or the continued use of inateriais containing benzene (17 ) . The evidence for the use of bepzene in Istanbul antl other cities of Turkey following the prohibition of this chemical is shown in the following study (18).To illusti-ate the etiologic role of drugs and chemicals in the clevelopment of aplastic anemia. we andlyzed 108 cases of aplastic anemia among 3175 hematologic patients during ZL 10-year period (1973-1982)in the hematology section of the Istanbul Medical School (18). In 25 (23.1'7)of the cases, benzene was responsible for the development of aplastic anemia. On the other hand, a recent study pel*formed in the period between 1983 and 1985 in Istanbul ;tnd Izmit showed that despite the considerable decrease in the content of benzene in most of the materials. they n-ere still above permissible limits (19).Duiing the study mentioned above we have encountered 2 cases of acute leukemia in a modern tire cord fabric in Izmit (19). XpIwosimately 350 workers were employed. The working conditions were good and properly ventilated. The concentration of benzene in one part of the plant was 110 ppm. and in one solvent used in the ausillaiy repair shop t h e benzene content was nearly 5%. The incidence of leukemia was 60.6per 100,000in a period of G years. Development of Leukemia in Pancytopenic Patients with Chronic Benzene Toxicity In our series comprising 59 leukemic patients with benzene exposure. a preceding pancytopenic period was present in 14 leukemic patients (23.7%)(20).The interval between the onset of the preceding pancytopenic period ancl that of leukemia varied between 6 months and 6 years. Furthermore, in a follow-up study in 44pancytopenic patients with chronic benzene toxicity,,leukemia developed in 6 (13.65%)and myeloid metaplasia in 1 (2.8%)(3. Familial Connection and Individual Susceptibility A s can be seen from Table 2, in 6 leukemic patients associated with chronic benzene exposure. in our series. a 'lhble 2. Genetic relationship between eight leukemic patients with chronic expoeure to benzene or colchicine and saccharin. Case no. Age Duration of exposure years Occupation Type of leukemia 1 43 2 24 3 36 4 48 -3 36 ti" 65 1 43 sb 77 6 4 7 3 15 35 4 10-20 tablets dailv Shoe worker Shoe worker Shoe worker Painter Shoe worker Shoe worker Owner of a wallpaper and printing shop Stationer AML AM L AML .iML Erythroblastic leukemia Unidentifled type of leukemia Chronic lymphoid leukemia Chronic lymphoid leukemid "This case was not included in our series of leukemia because he was not studied before his death. bUsedcolchicine and saccharin. Genetic relationship Paternal uncle of case 2 Nephew of case 1 Maternal cousin of case 4 Maternal cousin of case 3 Son of case ti Father of case 5 Son of case 8 Father of case 7 .. . . '5 .If. AKSOY amilial connection was established (1,15,21).*Two were .I] uncle and his nephew. and 2 were cousins (15). The Lither of the fifth leukemic patient. a 65-year-old shoe imker with a long history of benzene exposure, died in ( hospital with the diagnosis of myelosclerosis, but re.valuation of the case report showed that this patient had cute leukemia of an unidentified type (15).The father of he seventh patient with chronic benzene exposure also iutl the same hematologic malignancy associated with the ise of colchicine and/or saccharin (21).These 6 leukemic )atients among the f r s t - and second-degree relatives con.tituted 10.2% of the leukemic patients with chronic exm u r e to benzene.' In these 6 patients including case 7, he development of leukemia possibly resulted from .imultaneous presence of genetic determinants. in addiion to benzene as an estraneous or environmental facor. This suggestion is in accordance with the view that takemia may be caused by the combination of various inrinsic atid esttinsic factors (22).On the other hand. famly susceptibility in the development of various disorders !Ichronic benzene tosicity suggested by numerous invesigatora were evident in our studies concerning benzene osicity (1,17 ) . r-rpes of Leukemia in Chronic Benzene I'oxicity It is evident from the literature that there is a signifi:ant difference in the distribution of leukemia types :aused by benzene exposure (1,15,20,23)I.n one group, icute types of leukemia, mostly myeloblastic or erythroh s t i c . predominate. and in the other chronic leukemia. ,nyeloitland lymphoid take the most important place. Al:hough in our seiies. acute leukemia was 89.8%, the per:entage of chronic types comprising myeloid. lymphoid, m d hairy cell leukemia was 10.2% (PO).Considering these !'acts we have tried to explain the possible factors that may determine the types of leukemia in chronic benzene toxicity (23). One factor may be the differences in the content of benzene in the material used. The benzene content of the adhesives and thinners used by workers with acute leukemia in our series was very high (H,15,f723).In contrast, it was very low (2.8%) in a worker n i t h chronic lymphoid ieukemia (231.Second, the adhesives and thinners that were used by nearly all the workers with acute leukemia contained only benzene (15,15,23).Contrary to this, the solvent used by a worker with chronic lymphoid leukemia had a low level of benzene and a high percentage of toluene (23).Third, the great majority of the individuals with acute leukemia in the series was exposed to high concentration of benzene ranging between 150 and 210 ppm during all working hours (13,1523)C.ontrary to this, .3 out of 6 patients with chronic leukemia, 2 u i t h chronic myeloid. 2 with chronic 1-ymphoid,and one with hairy cell *Cases ti and 8 were not included in this series because one (case 6) AXS studied in another hospital w d the second (case8) was not exposed o benzene (15.21). leukemia were exposed to benzene intennictentl* 1 for a short time during the daily work. Fourth. th .Able -d e of genetic factors may help to esplain the h p - ment of different types of leukemia. As can be tYom Table 2, G patients in 3 families had acute type- .ul; mia. I n the fourth family. despite ctiffei-ent I- eo factors such as chronic benzene esposure anc ise . colchicine and/or saccharin, the same type 01 iemia. namely chronic lymphoid, developed at tlif rit apes (21). Benzene, Malignant Lymphoma, Multiple Myeloma, and Lung Cancer There are a few investigations that suggest a possible role of benzene in the etiology of maiignant lymphoma, multiple myeloma, and lung cancer. In 1961. Wirtschafter and Bichell showed that tissue responses coulcl be observed in lvmphnodes. spleen, thymus. and bone marrow of the rat after a single injection of benzene (24). Recently, Irons et al. showed that the effects of benzene administration in mice on lymphocyte function are at the doses of the compound that produce little Qrno measurable differences in the number of circulating cells (25).I n 1974. we described 6 cases of Hodgkin's disease with chronic exposure to benzene (26). Despite the lack of statistical data, we suggested that chronic exposure to benzene might play a role in the development of Hodgkin's disease. IIn the last few years we have studied 7 more cases of different t-ypes of malignant lymphoma with benzene exposure (1.17.19).In 1979. Vianna and Polan performed a comparative study on the mortality rates of different types of malignant 1-mphomaamong workers exposed to benzene (27).According to the investigators. their results are consistent with the possibility that chronic esposure to benzene might be important in the e t i o l o a of malie;nant lymphoma. A recent study of Norseth e t al. is also in favor of this assumption (28).Furthermore, there are several studies showing a high mortality rate from different types of malignant lymphoma among pathologists. chemists, and persons handling chemicals containing benzene (29). Multiple Myeloma As early as 1970, Torres et al. reported 2 cases of multiple myeloma with chronic benzene exposure (30).In 1980and 1984, we described 4 cases of multiple myeloma with chronic benzene exposure (31.52).Only one of these p a t i e n t s had a short period of pancytopenia with hvypoplastic bone marrow. The mean exposure time to benzene was longer than that of cases of leukemia and malignant lymphoma: 18years in the former and 10.5 in the latter (1). In an epidemiu.dgic assessment study of Rinsky et al. in 1987, there was a statistically significant increase in deaths from leukemia and multiple myeloma t.13). HEJIATOTOXICITI'.~.L'D C.4RCISOGESICITI'OF B E S Z E S E "1,- Lung Cancer In 1976, we considered 5 individuals with lung cancer associated uith chronic benzene exposure and suggested that there is a causal relationship between this chemical and lung cancer (344).In our series of malignancies resulting from chronic exposure to benzene, there are 7 cases of lung cancer (1,171. Only 3 showed mild hematologic findings of chronic benzene toxicity. Because benzene available in Turkey did not contain benzo[alpyrene determined by ultraviolet spectrophotometry, lung cancer in these 7 patients cannot be attributed to this carcinogenic agent (1.7).Benzene is mainly absorbed via the lungs, and about 40% of the absorbed portion is exhaled unchanged (.15).After 24 hr. a small percentage of benzene can still he detected in the expired air (35).Therefore, a carcinogenic effect of benzene in the lung is possible. Because our patients were also smokers, a contributory role of Ymoking in the development of lung cancer is possible. REFERENCES Xksoy, M. Benzene hematotoxicity and benzene carcinogenicity.In: Benzene Carcinogenicity (M. Aksoy, Ed.) CRC Press Boca Raton, FL, 1988. p p 59-151. Craveii. A. La fibrinolisi. le piastiine. le fibrinogene a atritests cmocoayulativi ne1 benwlismoclinico. Med. Lav. 53:722-727 (1962). Basla A.,and Aksoy, M. Newlogical abnormalities in chronic ben. zene poisoning. A study in six patients with aplastic anemia and two with preleukemia Environ. Res 2T 457-465 (1982). Truhaut. R. As rapporteur of the rep0i.t of the meeting of experts on the safe use of benzene and solvents contilingbenzene. In: Ben- zene: Uses. Toxic Effects and Substitutes. International Labor Of- tier. Geneva, 1968. pp. 1-24. hfallorv. T. B.. Gall. E. X.. and Bicklev. W. J. Chronic esposure to benzene. J. Ind. Hgg. Toxicol. 11: 355-39d (1939). Moeschlin. S,and Speck. B. Experimental studies on the mecha- nismof action of benzene on the bone marrow (radiographicstudies using 'H-tymidinel Acta Hernatol. 38:104-111 (1967). Xksoy, M.,ant1 Lrdem. 3. A follow-up study on the moitality and the development of leukernid in 44 pancytopenic patients usociiited with long-term exposure to benzene. Blood 52: 35-292 (1978). Erbengi, T., and Aksoy, M. Electron microscopic studies of the hone maimw in four patients with chiunic benzene poisoning. In: .ibstl-dct and Symposia. International Society of HaematioloKy, Euiupean and African Division. Fourth Meeting, Istanbul. September 5-9. 1977, p. 232. De Ctuchv. G. C. Drug-Induced Blood Disorders. Blackwell. Oxford. 1975. 1,. 46. Le Noire, M. M.. and Claude Sur un case de purpura atribue a I'intoxica-par le benzene Bull. Mern. Soc. Med. Hop.Paris 14: c.c..1251-1260 (1897). Xaltoni. and Scarnato. First espeiimental demonstration of the carcinogenic effects of benzene. Long-term bioassays on Spt-ague-Dawley i-ats by o t d actministi-atition . Med Lav. 70: 352-257 i1979). 12. Dexter. T.M..Heyworth. C. M., and Whetton. A. D. The role of haemopoietic cell growth factor (interleukin 3) in the development of haemopoietic cells. In: Growth Factor in Biology and Medicine. Ciba Foundation Symposium,Vol. 116((D. Evered. J. Nugent, and J. Ivhelm, Eds.), Pitman, London, 1985. pp. 129-142. 1% .iksoy. 11.. Erdem. 5.. aiitl Dicnol. ti. Leukemia in s h o e - n w t h i . ~ c\posetl cnlvnic;iily to benzene. Blood 44: 837-841 ( 19741. 11. Tolx~zoiluI.. The report on the piwluctiun antl the use of t h c i w t i . zene problems in Turkey. Presented at the meeting u t the ( f m i iiiittee for Benzene Pivblems iii Turkey rTuikwh and unpubli>hetl). .lilkard. 1972. 15. .\ksoy. 11..Eidem. 5..anti Dincol. C. T)l)esut'leukemia in chnitiic Iienzene poisotiint.. A du(ly 111 iut.ty-ti)ut.patients. Actit Haeniatt ,I. .X: 65-72 ( 1976). 11;. Health Statistics. YearbooK ufsurkey. 1973-1974. Publishetl l i i Ministry ot' Health and Social Welfare. The Prime Miiii3ti.y P m r . inp Office. .iiikaix. 1977. 17. .iksoy. 11. !vlali~manciedsue to occup;iticiiiul trsposut~t o beiizctic.. A n . J. Ind. bled. 7 ::395-402-(1983). 18. Aksoy. .\I.. Erdem. 3.. DinCol. G.. Bitkiorlu. I., and Kutlar. .i. Aplastic anemia due to chemicals atid i l l y i p . X dud? of 108 ~ i i i . tients. S e x ,Trans. Dis. (suppl) ll(4): 847-350 (1984). 19. Aksoy, M., Ozeris, S, Sabuncu. H., and Yanardak, R. Esposure to benzene in Turkey between 1983and 1985: a haematoloflcal study on 231 workers Br. J. Ind. Med. 44:785-787 (1987). 10. Aksoy, M.The types of leukemia in 59 patients with chronic ben- zene toxicity. In preparation. 21. Aksov, M. Simultaneouspresenceof genetic factorsand some chem- icals in the development of chronic lymphoid leukemia in a father and son. In press E. Cunz. F. W. Problems in leukemia etiology, In: Plenary Sessions Scientific Contributions XI11 International Congress of Hematol- ogy, Munich. August 2-8.1970, Lehmann Verlag. Munich. 1970.pp. 18-57. 23. Aksoy, M. Chronic lymphoid leukaemia and hairy cell leukaemia due to chronic exposure to benzene: report of three cases Br. J. Haernatol. 66:209-211 (1987). 24. Wiitschtrfter. Z.T.. antl Bichell. M. C. Reticuloendothelial twponsca to benzene. Xirh. Envirun. Health 9: 1HO-183 (19;l). 25. Irons. R. D.. Wierda. D.. and Pfeifer. R. W. The inlmunotoslclt!. of benzene and its metabolites. 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Different types of malignancies due to occupational es- posure to benzene: a review of recent observations in Turkey. Envirun. Res 23: 181-190 (1980). 31. Xksoy. M.,Erdem. $.. Dincol. G.. Kular. A.. Bakioilu. I.. ritid Hepyuksel. T. Clinical observations showing the tule some factors in the etiology of multiple myeloma. A study in seven pitielit>. Acta Haematol. 71: 116-120 (1984. 3.Rinsky. R.X.. Smith, A. B.. Hoi-nuny, R.. Fillwn. T. C.. Youtic. R. J.. Okun. A. H.. and Landrigen. P. J. Benzene and leukemia. An epidemiologic risk assessment. N. End. J. Med. 316: 1044-1U.3) (1987). 34. Akaoy. M. Benzene, malignant Ivmphoma and lung cancer. Presented at the International Workshop on Toxicology of Benzene. Paris. November 9-11. 1976. :S.Shenvood. R. J.. and Cater. F. W. G. The me&uiwnent ofoccupc- tional esposure to benzene vapour. Ann. Occup. Hyg. 18: 125- llti ( 1970).