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Leukem ia in Shoe-W orkers Exposed Chronically to Benzene By Muzaffer Aksoy, akir Erdem, and G#{252}nca Din#{231}ol From 1967 to September 1973, 26 patients with acute leukemia or preleukemia were sean in Istanbul among 28,500 shoework- .rs exposed chronically to beniene. The incidence of leukemia among these work- crc was 13/100,000, which is a marked and statistically significant increase over that for leukemia in the general popula- tion and provides cogent evidence for the clinical impression of a leukemogenic effect of beniene in man. A LTHOUGH THERE HAVE BEEN numerous reports' of leukemia as- sociated with chronic benzene exposure since its original description by LeNoire et Claude,2 some doubt still exists as to the causal relationship be- tween benzene exposure and leukemia.3'4 This uncertainty results chiefly from `conflicting reports on the effect of benzene exposure in experimental animals and the lack of statistical data showing an increased incidence of leukemia among individuals known to have been exposed to benzene. In Istanbul, and to a lesser extent throughout Turkey, there have been a number of cases of chronic benzene poisoning in workers involved in the manu- facture of shoes and slippers. In this industry, benzene is used as a solvent. Of 34 patients with pancytopenia, six have been shown to have acute leukemia,1'9"#{176} and one myeloid metaplasia which followed aplastic anemia." The occurrence of acute leukemia in shoe workers exposed chronically to benzene was first noted in Istanbul in 1967; since then a number of cases have been observed. We have established an incidence of leukemia of 13 per 100,000 in shoe workers in Istanbul which is clearly greater than that of the general population. Here, we report these findings and discuss some clinical and hematologic observations in these patients. MATERIALS AND METHODS Official records of Istanbul indicate that there are 28,500 workers involved in the shoe, slipper, and handbag industry in which benzene is used as a solvent. 17 workers who had been exposed to benzene were admitted During the period from 1967 to 1973, with acute leukemia or preleukemia* to the Second internal Clinic at Istanbul Medical School (five patients have been previously de- In addition, nine other shoe workers with acute leukemia or preleukemia were seen in other hospitals in istanbul-five at the First Internal Clinic at Istanbul Medical *Another worker with acute lymphoblastic leukemia when exposed to benzene was not in- cluded because his occupation differed; paper, two cases of acute erythnoleukemia he was a furniture worker. Since submission of this due to benzene exposure were seen but are not included. From the Section of Hematology. Internal Clinic of istanbul Medical School, Capa. istanbul, Turkey. Submitted November 12. 1973; accepted June 27. /974. Supported by Grant No. TAG/I 72 from the Scientific and Technical Research Council of Turkey. Address for reprints: Muzaffer Aksoy. M.D.. internal Clinic of Istanbul Medical School, Capa. Istanbul. Turkey. 1974 by Grune & Stratton. inc. Blood, Vol. 44, No. 6 (December), 1974 837 838 AKSOY, ERDEM, AND DINCOL N 0 ION U `0 0 N If) C') N 0 C') N 0 It) C') 0 U `0.-N 0 0 U 0. 0 U C') <N a, N C') r- N ` .2 me we L 0 U a vs 1#{176}) 0N 2 XXI N XX N XXX 2: X I o ON0NOO'-P'-- If) `cc's OOOON'O NN 0 ooooac' 0' vs 000 `4) O C') 0' ij 0 C').-. U N <` N 8N vs C') mE C `0 N 0 It, .) `I U N<NW) .2. if) `- a. E`4, .?x' N 0 U <N ` ON :2 I owe P-. N N c's'c I 0X I N .- 0 r#{176}- 0 ` ` 0.-.-o `4) `4, if', 00N00C')' 0 E .v 3 A. A. 11 LI ) E 0 U N #{149}N NC') N 10 C') 0N U N<'OC')' a N .0010 `4, (`soc's.-. o XXX 0 XX+ oaooooa'c `4, F-00OOO0' i; . ow .C `C 2#{176} .c') A. 0 E Ic N 0a U `4, O XXX o'4' aoooooo.- 2: 0 0 0' U C') <F-P--C.) `weON `4) It) it) 1010 N XF-. I `4, ()o00C#{176}) C C, .s>.. 3 C tiLl `-d 1-I ip; #{238} C . #{149} w` .0 .u Ec o. LU .CC vo 2 lOG' .c.2 0 .0 . .0 ..2 #{149} . E0 >` V ` A. E - oE 2 .0 -co 2 .! 0. #{149} O.202.a' .0 0 #{1490} r .2 f 0 0 -#{149:.2}2 `a A.&c `t &j o` ,. %. 8 E E. C C< ;- ;:++<X LEUKEMIA IN SHOE-WORKERS 839 School,'3 three at the Therapeutics Clinic at Cerrahpasa Medical School,'4 and one at the Internal Clinic at that school.15 The working conditions in the industry are not good; their shops usually are small, not hygienic, and poorly ventilated; the concentration of benzene was found to reach a maximum of 210-650 parts per million when adhesives containing ben- zene were in use (Measured by Drager Gasspurgerat/Multi-Gas Detector Mod. 21/23, Lubeck, Germany). RESULTS Clinical and hematologic data on 12 patients with acute leukemia or pre- leukemia are presented in Table 1. In Table 2, the types of leukemia and their frequency among the 26 patients diagnosed in Istanbul from 1967 to 1973 are compared with those previously reported by Gougel et al.'6 in 23 workers who developed acute leukemia or preleukemia after exposure to benzene. Acute myeloblastic leukemia which was seen in 14 of the 26 workers in our series was the most common diagnosis. The duration of exposure to benzene varied from ito 15 yr with a mean of 9.7 yr; the average age at the time of diagnosis was 34.2 with a range of 16-58 yr. During the 7-yr period of the study, 26 patients with acute leukemia or pre- leukemia were observed among a group of 28,500 workers at risk. Thus, there was an incidence of 13 per 100,000. This incidence was significantly greater (p > 0.02) than the overall incidence of leukemia in the general population which was 6/l00,000.' The peak incidence of leukemia, 19.7 cases/lOO,000, occured in the period between 1971 and 1973. CLINICAL FEATURES One of the new patients (case 12) and five of the overall groups of 26 pre- sented with pancytopenia. Fever of moderate or severe degree was present in all. With one exception (case ii), there were severe hemorrhagic manifestations, such as purpura, ecchymoses, epistaxis, hematuria, etc. Splenomegaly was present in three and lymphadenopathy in one. The diagnosis of preleukemia was made in three patients (10,11,12). In one patient there was an initial period of pancytopenia after which splenomegaly developed. The intial bone marrow was aplastic, but subsequent bone marrows were hyperplastic with megaloblastoid erythropoiesis and erythroid hyper- plasia; giant erythroid precursors varied from 38%-72%. Although serum folate Table 2. The Types of Acute Leukemia in 26 Shoe-Workers With Chronic Exposure to Benzene and in 23 Workers Exposed Chronically to Benzene Studied by Goguel et al.16 Types of Acute Leukemia Acute myeloblastic leukemia Preleukemia Acute erythroleukemia Acute lymphoblastic leukemia Acute monocytic leukemia Acute promyelocytic leukemia Unidentified Total Pr. sent Study Number of Cases Percentage 14 53.9 4 15.4 3 11.5 3 11.5 1 3.8 1 3.8 26 Study of 0 oguel et al Number of Cases Percentage 11 47.8 5 21,7 2 8.7 2 8.7 1 4.3 2 8.7 23 840 AKSOY, ERDEM, AND DINOL levels were low, he failed to respond to treatment with folic acid. In view of this, we felt that the patient had either preleukemia or acute erythroid leukemia. A second patient (case I I ) had hypochromic microcytic anemia with a normal serum iron. The morphologic consistent with heterozygous hemoglobins. Genetic studies findings, indices, and hemoglobin analysis were a or fi thalassemia with normal levels of A2 and F confirmed this assumption. The patient also had a persistent pseudo-Pelger-Huet anomaly and erythroid elements in the periph- eral blood. Myeloblasts were present in the peripheral blood during the final stages of his illness; at that time, erythroid elements comprised 74 of the nucleated cells in the bone marrow, and there were 20 proerythroblasts. There were no frank signs of increased hemolysis. We considered this patient as hay- ing preleukemia or acute erythroleukemia. The third patient (case 12) had pancytopenia prior to the onset of preleukemia. At that time, his bone marrow was hyperplastic. A year later when the patient had recovered from pancyto- penia he was again exposed to benzene, and a severe anemia, leukopenia, and recurrent pulmonary infections ensued. The bone marrow continued to be hy- perplastic and was consistent with but not diagnostic of leukemia. However, prior to his death, he developed a peripheral blood picture more consistent with leukemia, there being l5 myeloblasts. in three patients,8 the diagnosis of acute erythroleukemia was made. These patients had 16-29 nucleated red cells/l00 white cells in the peripheral blood and 49-95#{176}',, erythroid elements in a hyperplastic bone marrow. In one of these patients, proerythroblasts comprised 59 of bone marrow nucleated cells. Megaloblastic changes were also observed in these patients. One of these pa- tients (case 8) was thought to have a significant amount of ineffective eryth- ropoiesis as well as early red cell destruction; he had striking reticulocytosis, increased osmotic fragility, and increased fecal urobilinogen, as well as a de- crease in serum haptoglobin. DISCUSSION A number of physical and chemical agents have been thought to be impli- cated as etiologic factors in leukemia. Among these, however, ionizing radia- tion is the only one which has been shown conclusively to have a leukemogenic effect. These conclusions are based on the high incidence of leukemia among Japanese exposed at Hiroshima'8"9 and the British patients treated with x-rays for ankylosing spondylitis.2#{176} There is a strong inferential evidence, however, to suggest that benzene may have a role in the induction of leukemia. The inci- dence of leukemia among workers chronically exposed to benzene, described herein, provide further proof for an etiologic role for benzene in leukemia. The incidence of leukemia of 13/100,000 in the exposed shoe workers was sig- nificantly greater than that seen in the general population. It is of interest that, in the patients in this study, all had acute leukemia. In this respect, our experience is similar to that reported by Vigliani and Saita.2"22 We observed, as have others, that the morphologic type of leukemia among those exposed to benzene is variable, but acute myeloblastic leukemia is the most common. The frequency of various morphologic types in our patients was also similar to that reported by Goguel'6 in patients exposed to benzene. LEUKEMIA IN SHOE-WORKERS 841 In the present study, the incidence of leukemia during the first 4 yr was some- what lower than it was in the last 3. Only nine cases were diagnosed between 1967 and 1971, whereas 17 cases were seen in the last 3 yr. The latter would have given an incidence of 19.7/100,000. For this reason, we searched for ad- ditional possible leukemogenic factors but were unable to detect any other than benzene. REFERENCES I. Browning E: Toxicity and Metabolism of Industrial Solvents. Amsterdam, Elsevier, 1966, p41, 49 2. Le Noire, Claude: attribu#{233} a l'intoxication M#{233}m Soc Hop Paris Sur un cas de purpura par Ic benz#{234}ne. Bull 14:1251 (cited from Browning) 3. Eckardt RE: Industrial Carcinogens. In- dustrial Monographs in Industrial Medicine. No 4, New York, Grune & Stratton, 1959, p 8 4. Gallo RC: On the etiology of human acute leukemia. Med Clin North Am 57:343, 1973 5. Aksoy M, Dincol K, AkgUn T, Erdem S. Dincol G: Haematological effects of chronic benzene poisoning in 217 workers. Br J Ind Med 26:296, 1971 6. Aksoy M, Dincol K, Erdem 5, AkgLln T, Dincol G: Details of blood changes in 32 pa- tients with pancytopenia associated with long- term exposure to benzene. Br J Ind Med 29: 56, 1972 7. Aksoy M, Dincol K, Erdem 5, Din#{231}olG: Acute leukemia due to chronic benzene. Am J Med 52:160, 1972 exposure to 8. Aksoy hemoglobin M, Erdem 5: Some problems of pattern in different thalassemic syndromes showing the heterogeneity of beta- thalassemia genes. Ann NY Acad Sci 165:13, 1969 9. Inceman 5, Tangtln Y: Impaired platelet/ collagen reaction in a case of acute myeloblastic leukemia due to chronic benzene intoxication. Bull Turk Med Soc 35:4 17, l969 10. Aksoy M, Erdem 5, Erdogan G, Dincol G: Acute leukemia in two generations following chronic exposure to benzene. Hum Hered (in press) II. Aksoy M, Erdem 5, Din#{231}ol G: Myeloid metaplasia seven years following the recovery from aplastic anemia due to chronic benzene exposure (Abstract). New Istanbul Contrib Clin Sci, 1974 12. Topuzoglu I: The report on the produc- tion and the use of benzene problems in Tur- key. Presented at the Meeting of the Com- mittee for Benzene Problems in Turkey. ISGUM, Ankara, 1972 13. TangUn Y, Inceman S: Personal com- munication 14. Akgontll G, Berkerda B: Personal com- munication 15. Ulutin ON: Personal communication 16. Goguel A, Cavigneaux leucemies benzeniques. Bull 1967 A, Bernard J: Les Inst Nat Sante 421, 17. Gunz FW: Problems in leukemia etiol- ogy. Plenary Sessions Scientific Contributions. XIII International Congress of Hematology. Munich, August 2-8, 1970, p 48 18. Brill AB, Tomonoga M, Heyseel RM: Leukemia in man following exposure to ioniz- ing irradiation: Summary of findings in Hiroshima and Nagasaki and comparison with other human experience. Ann Intern Med 56: 590, 1962 19. Bizzozero OJ Jr, Johnson KG, Ciocco A: Radiation-related leukemia in Hiroshima and Nagasaki, 1946-1964. 1. Distribution, inci- dence, and appearance time. N Engl J Med 274:1095, 1966 20. Court-Brown WM, Abbatt JD: The in- cidence of leukemia in ankylosing spondylitis treated with x-rays. Lancet 1:1283, 1955 21. Vigliani EC, Saita toblastique de benzol. 1943 G: Leuc#{233}mie h#{233}mocy- Med Lavoro 34:182, 22. Vigliani EC, Saita G: Benzene kemia. N Engl J Med 27 1:872, 1964 and leu-