Document N2dpQmO10aOoK1jmnbKpO7nOE

:nous leukemia, Cancer Reid J: Granuiocytlc 'esentation of a systemic 808-1813, 1976 LE, Font RL: Ophthalmo. I of granulocytic sarcoma, 3:975. 1975 Thomas ED, Bryant J I . lemic transformation of irrow cells in vivo. Lancet Wang F, Hutton MM tic leukaemia developing nphoma. Br Med J 2:1329, d leukaemia. Lancet 1:519 Followup Study on the Mortality and the Development of Leukemia in 44 Pancytopenic Patients With Chronic Exposure to Benzene By Muzaffer Aksoy and Sakir Erdem \ A followup study of 2-17 yr was per- phils, the findings in peripheral blood, informed on 44 pancytopenic patients with cluding the levels of HbF and A, could not benzene exposure. They had been sub- be conslated with the outcome of benzene- jected to high concentrations of benzene ( I 50-650 ppm) i n adhesives for 4 mo to 15 yr. The benzene content of the ad- induced pancytopenia. On the other hand, in one patient a very low level of HbA, and a high level of HbF were already evi- hesives varied between 9% and BE%, (average 50%). Complete remission was seen in 23 patients and fatal outcome due to complications of pancytopenia was observed in 14 pancytopenic patients. I n 6 pancytopenic patients leukemia developed after a period of 6 mo to 6 yean. In a pa- tient with complete remission fatal myeloid metaplasia occurred. The mean age ond the duration of exposure of 21 patients with overall fatal outcome were significantly higher than those of 23 patients with complete remission. However, with dent during the pancytopenic period, whereas preleukemio developed 9 mo later. This observation suggests that low levels of HbA, with or without high levels of HbF during pancytopenia may be a sign of leukemia. Moreover, there was a clear relationship between the type- of bone marrow cellularity and the outcome of pancytopenic patients. The development of leukemia in 6 of 44 pancytopenic patients with chronic exposure to benzene is further evidence for the leukemogenic effect of benzene in man. the exception of mean values of neutro- A LTHOUGH there are numerous reports on the occurrence of pancytopenia associated with chronic exposure to benzene, only a few papers deal with the problem of the outcome and the development of leukemia among pancytopenic patients with chronic benzene poisoning.'.* Hunter reported ten fatal cases of a total of 89 pancytopenic patients with chronic exposure to this dromatic hydrocarbon.' In Germany 164 cases of benzene-induced aplastic Jnemia were encountered between 1913 and 1928; 27 of them were fatal! This corresponds to a mortality rate of 16.4%.Six of seven cases studied by Nilsby nere fatal.5 Contrary to this, in another report from Sweden only 2 cases of 60 were fatal.6 On the other hand, Vigliani and Forni studied 83 patients with benzene-induced hematotoxicity in the provinces of Milano and Pavia;' all of the 50 patients who were still alive at that writing had aplastic anemia, and 19 patients with acute leukemia and 14 with aplastic anemia in this series ended fatally. The discrepancies concerning mortality in cases of pancytopenia dssociated with chronic exposure to benzene are obvious. From the Seclion of Hematology, Internal Clinic of Istanbul Medical School, Capa. Istanbul. Turkey. Submitted Ocrober 19, 1977; accepted March 28. 1978 Supported by Grant 328 from The Scientijic and Technical Research Council of Turkey. Address for reprint requests: Dr. Muzaffer Aksoy, Biiyiikciflik sokak 1012 Ozler. ap. Tepikiye. Isianbul. Turkev. 1978 by Grune & Siration. Inc. 0006-4971 f 78~5202-0404%0l.00/0 Blood, Vol. 52, No. 2 (August), 1978 286 AKSOY AND ERDW Convincing data related to the outcome and the occurrence of leukemia in pancytopenic patients with chronic exposure to benzene were recently obtained in a long-term study among pancytopenic patients chronically exposed to this chemical in Istanbul. Prior to the period of 1955-1960, benzene was rarely used in Istanbul or in any other cities of Turkey. At that time, shoeworkers were preparing their adhesives by proceGiCg rubber in gasoline containing trace amounts of benzene.6As they discovered that adhesives prepared with benzene were cheaper as well as extremely practical, they replaced their customary ad- hesives with these new products. Starting in 1961 cases of aplastic anemia and from about 1967 cases of leukemia due to chronic benzene poisoning began to occur. The details of blood changes in 34 pancytopenic patients with long-term exposure to benzene were published subsequently;9J0the overall mortality rate among these patients was 26.4%. By 1977 the number of pancytopenic patients we had studied increased to 46. - -In this paper we^ report the mortality r_ al t~e andl l l"" t"h-e -occurre~nc;ta: leukemia among 44 pa-akezs (two have been lost to followup) associated with chronic exposure to benzene. MATERIALS AND METHODS The series comprises 41 males and 3 females ages 15-57 yr (average 31). Of these 44,38 were initially admitted to the hematology department of Internal Clinic of Istanbul Medical School; after discharge they were followed by us for periods of 2-17 yr. Six patients were studied by US only in the outpatient department. Thirty-nine of our patients were described elsewhere9." The followup periods on the pancytopenic patients who recovered completely were 2-17 yr: > 10 yr in IO, 5-10 yr in 1 1 , and < 5 yr in 2 cases. Thirty-four patients were shoeworkers, two manufactured leather objects. two were car painters, one worked in a factory where benzene was used, one made benzene-containing glues, one was a radio technician, one was a whistlemaker, one was a handbag worker, and one was a furniture manufacturer. Thev h a w high concentratio- &l.SP,650 ppm) forperiods of 4 ~ G ( m e a n y&Thc --GlF-&posure to benzene varied from 15 min to 8 hr. Thirty of the patients were exposed to a high concentration of benzene for not less than 8 hr. The benzene content of the adhesives available during 1970-1972 was determined by gas chromatography in the laboratory of the Turkish department of labor (ISGUM), Ankara'* a: 9%-S8% (average 50%).The working conditions of most of the pancytopenic patients were hardly good; their working places were unhygienic and poorly ventilated. In the period of pancytopenia, the basic therapy for these patients consisted of supportive care with appropriate antibiotics for infections, fresh blood in plastic bags, and whole blood transfusions for thrombocytopenia and anemia. Furthermore, IO patients received only androgen, 10 corticosteroids and androgen together, 1I phytohemag lutinin, and 9 oral oxymetholone. The results of these treatments were partly described elsewhere.fW3 The hematologic methods were all standard. Blood counts in some patients were performed with a Coulter Counter model ZF. Platelet counts were determined with a phase-contrast micro- scope using the Brecher-Cronkite t e ~ h n i q u e . ' H~ bF was determined by the method of Singer et HbA, was estimated quantitatively by DEAE-cellulose chromatography and starch gel electrophore~is.'~~W'' ith these methods normal values for HbAz are 2%-3.2% for the former and l.5%-4% for the latter method. The concentration of benzene vapor in the air of the working environments of the patients was measured by a Drager Multigas detector (Model 21/23, Lubeck, Germany). The absorption spectra of benzene used for the preparation of adhesives was determined by using a Varian ultraviolet spectrophotometer Model 635 according to the technique described by Gillam and Stern." .._ . , . * . i l " . I o AKSOY A N D ERDEM id the occurrence of leukemia in .o benzene were recently obtained tients chronically exposed to this 55-1960, benzene was rarely used , At that time, shoewodcers Were bber in gasoline containing trace adhesives prepared with benzene hey replaced their customary ad961 cases of aplastic anemia and -onic benzene poisoning began to cytopenic patients with long-term :ntly;9.'0the overall mortality rate number of-pancytopenic patients and the occurrence of leukemia Jeen lost to fol~owup)associated fTHODS 57 yr (average 31). Of these 44, 38 were xnal Clinic of Istanbul Medical School: 2-17 yr. Six patients were studied by US r patients were described elsewhere.' I ' recovered completely were 2-17 yr: > 10 ty-four patients were shoeworkers, two :worked in a factory where benzene was dio technician, one was a whistlemaker. inufacturer. They had been subjected IO ds of 4 mo to 15 yr (mean 6.7 yr). The Thirty of the patients were exposed to ring 1970-1972 was determined by gas lrtment of labor (ISGUM), Ankara" as of the pancytopenic patients were hardl) ntilated. ' these patients consisted of supportive dood in plastic bags, and whole blood lore, 10 patients received only androgen. lutinin, and 9 oral oxymetholone. The y o . 13 :ounts in some patients were performed determined with a phase-contrast micros determined by the method of Singer cellulose chromatography and starch alues for HbA, are 2%-3.2% for the ntration of benzene vapor in the air of by a Drager Multigas detector (Model :ene used for the preparation of adhesl`c. iotometer Model 635 according to t h t BENZENE EXPOSURE A N D LEUKEMIA 287 Table 1. RelationshipAmong Age, Duration of Exposure, and Outcome, Including Development of Leukemia, in 44 Pancytopenic Patients Associated With Chronic Exposure to Benzene c Pancytopenia, complete remission pancytopenia, fatal outcome Pancytopenia, leukemia developed Pancytopenia. myeloid metaplasia developed No. of Patients/ Percentage 23/52.3% 14/3 1.8% 6/13.6% 1/2.3% A* 1 (rr) 26.87 f 9.50 37.0 f 9.81 35.0 f 7.46 Duration of Exposure (mo) 65.43 f 42.30 93.0 f 41.49 94.67 f 60.17 Pancytopenia. overall fatal outcome Meon f SD. 2 1/47.7% 36.0 f 8.98 93.62 f 45.0 RESULTS The absorption spectra of benzene available in Turkey showed that despite the absence of benzo(a)pyrene,* the well-known carcinogenic agent, it contained some impurities such as toluene and naphtalen and also possibly xylene, phenathren, and chrysen. Relationship among, age, durarion of exposure, and outcome including dewloprnent of leukemia. These are given in Table l . Complete remission was obtained in 23 patients? (52.3%). Fatal outcome due to the complications of pancytopenia, such as infection or bleedings, occurred in 14 patients (31.8%); 7 pancytopenic patients died in the first year following diagnosis, 6 in the second, and only one died after 5 yr of survival. In 6 pancytopenic patients (13.6%) leukemia developed after a period of 6 mo to 6 yr. In most of these patients clinical and hematologic findings of pancytopenia improved considerably or even disappeared, but in spite of such improvement leukemia occurred. In 5 patients leukemia developed during the course of pancytopenia, in 1 patient 6 yr after complete recovery. Five patients were not reexposed to benzene following diagnosis of aplastic anemia. One patient died from myeloid metaplasia 9 yr after recovery." The mean age of the pancytopenic patients who recovered completely was 26.87 yr, 37.0 for the pancytopenic patients with fatal outcome and 35.0 for those in whom leukemia developed. Furthermore, the mean age of 21 pancytopenic patients who died (36.0 yr) was significantly higher ( p < 0.01, 1 = 3.2681) than that of 23 pancytopenic patients with complete remission (26.87 yr). On the ~ *We will not discuss the possibility of this carginogen in the development of leukemia in our pancytopenic patients because of the absence of benzo(a)pyrene in benzene available in Turkey. On the other hand, at present it is extremely difficult to interpret the possible role of other impurities in the development of leukemia in our pancytopenic patients. +In I of these 23 patients with complete recovery, carcinoma of the rectum developed. The relationship between this malignancy and chronic exposure to benzene is open to discussion. ./,,,,..m, n,,lF""",,*l",,,,I,,,,,,,,,",",,.,,,.... 288 AKSOY AND m t M Table 2. Relationship Between Data Concerning Pancytopenia and Outcome, Including Development of leukemia, in 44 PatientsWith Chronic Exposure to Benzene (Mean rt SD) -_ Hb (d4 With CR (n = 23) 6.33 f 2.04 With Fatal ---+IOutcome = 14) 5.19 f 1.19 Leukemia Developed (n = 6) 5.75 f 1.09 With Overall Fatal Outcome (n = 21) - 5.33 f 1.14 PCV 0.21 ~ 0 . 0 7 0.17 f 0 . 0 4 0.21 f0.03 0.18 &0.04 WBC x lo'/liter 2.47 =t0.85 2.06 f 0.85 2.18 f 1.08 2.11 *0.88 Neutrophils x lO'/liter Platelets x 1 iter 1.51 =t0.73 87 f 56 0.76 f 0.26 56 f 49 1.28 f 0.89 64 f 44 0.96 f0.58 61 &446 other hand, the duration of exposure was 65.43 mo in the pancytopenic patients who recovered completely and was 93.0 and 94.67 mo respectively, in those who died from complications of pancytopenia and in those in whom leukemia developed. Furthermore, the duration of exposure was significantly shorter ( p < 0.05, t = 2.2194) in 23 pancytopenic patients who recovered completely (65.43 mo) than in 21 pancytopenic patients with overall fatal outcome (93.62 mo). Although the concentration of benzene in all working places was not less than 150 ppm, 8 of 14 pancytopenic individuals with fatal outcome were subject to comparatively shorter daily exposure. Furthermore, all pancytopenic patients in whom leukemia developed were heavily exposed to benzene during long working hours. Although in one of these patients the duration of exposure was only 6 mo, his daily exposure was over 8 hr at a benzene concentration of 150 ppm. Relationship between data concerning pancytopenia and the outcome, including development of leukemia. This is shown in Table 2. Relationship between types of bone marrow cellularity and outcome, including development of leukemia. Of 42* pancytopenic patients, 2 I had hypocellular bone marrow. This was observed in 17 of these patients 1-6 mo after appearance of the first signs or symptoms attributable to pancytopenia, and 6--12 mo in 3 patients; only in 1 was it as long as 2 yr. Of these 21 pancytopenic patients with hypocellular bone marrow, 1 I died from complications of aplastic anemia, and in 5 patients leukemia developed later. Contrary to this, only 1 of 13 pancytopenic patients with normocellular bone marrow died. The normoplastic bone marrow was found in 10 of 13 pancytopenic patients 1-6 mo after appearance of the first clinical manifestations; in the remaining 3 this finding was observed in a symptomless period during a survey o f workers using benzene- containing materials. On the other hand, 4 of 8 pancytopenic patients with hypercellular bone marrow recovered completely, and 2 died from complications o f pancytopenia: in 1 of these 2 leukemia developed 1 yr later, and in the other the occurrence of myeloid metaplasia 9 yr after complete recovery was the cause of death. In 7 of these 8 pancytopenic patients a hyperplastic bone marrow was found 1-6 mo following the appearance of the first signs or symptoms attributable to pancytopenia; in 1 this period was 2 yr. 'In two pancytopenic patients bone marrow puncture was not performed. I AKSOY AND ERDEM ng Pancytopenia and Outcome, atients With Chronic Exposure :SD) 0e1 DLeevuekloempeiad FMatahl OOuvtceoramlle 1) (n = 6) (n = 21) .19 5.75 f 1.09 5.33 f 1.14 .04 0.21 k 0.03 0.18 k0.04 .85 2.18f 1.08 2.11 k0.88 .26 1.28 f 0.89 0.96 f 0.58 9 64 f 44 61 k 4 6 I .43 mo in the pancytopenic pa0 and 94.67 mo respectively, in rtopenia and in those in whom 3n of exposure was significantly nic patients w h o recovered comtients with overall fatal outcome working places was not less than h fatal outcome were subject to 'more, all pancytopenic patients vposed to benzene during long its the duration of exposure was at a benzene concentration of penia and the outcome, including le 2. dlularity and outcome, including c patients, 2 I had hypocellular : patients 1-6 mo after appearto pancytopenia, and 6-12 mo f these 21 pancytopenic patients mplications of aplastic anemia. zontrary to this, only I of 13 narrow died. The normoplastlc c patients 1 - 6 mo after appear:maining 3 this finding was ob'ey of workers using benzene' 8 pancytopenic patients with ly, and 2 died from complica1 developed 1 yr later, and in i 9 yr after complete recover) iic patients a hyperplastic bone ance of the first signs or sympd was 2 yr. ot performed. i 1 1 1 BENZENE EXPOSURE AND LEUKEMIA 289 Table 3. Relationship Between levels of HbF and Outcome, Including Development of leukemia, in 32 Pancytopenic Patients With Chronic Exposure to Benzene - -No.of Fetal Hb(%) Pancytopenia Patients (Mean f SD) Complete remission 22 1.33 f 4.79 Fatal outcome Leukemia developed 5 5.28 f 2.42 4 17.85 rt 20.81 Myeloid metaplasia developed 1 14.0 Overall fatal outcome 10 11.18 rt 13.67 T ~ pOancytopenic patients with high fetal Hb level (brothers), one with fatal outcome and the other with 'complete remission, were not included in this table because both were also @-thalassemic heterozygotes. They were described elsewhere Relationship between levels of HbF and A , and outcome, including development Ieukernia. This is shown in Table 3. Because different methods were used in determining HbA,, the mean level of HbA, is not included in Table 3. In 22 plncytopenic patients who recovered completely, the mean level of H b F was 33",,. This value was a little lower in 5 pancytopenic patients with fatal outcome (5.28%), but this difference is statistically insignificant. On the other hand, in -t pancytopenic patients in whom leukemia developed the percentage rate \\,I\ comparatively higher (17.85'/), due mainly to a high percentage of HbF (dx",) found in 1 patient. The level of HbA, was slightly or moderately deiredsed in 5 of 22 pancytopenic patients with complete remission (1.5%-1.950/,). On the other hand, HbA, was slightly decreased only in 1 of 5 pancytopenic piltients with fatal outcome. Furthermore, in 3 of 4 pancytopenic patients in N horn leukemia developed HbA, was decreased. In one of these pancytopenic pJtients in whom later preleukemia developed the levels of HbF and A, were 4X' ,, and 0.67'(,, respectively. I n another pancytopenic patient in whom acute t.r)throleukemia developed, HbF and A, levels were 15% and 1.8%, respect i ~ e l y In a third pancytopenic patient the levels of H b F and A, were 6.4:; ,ind 2.6'4, respectively; when preleukemia developed 6 y r after recovery these mounts were 11.5'/, and 1.6'?/,,respectively. DISCUSSION Pancytopenia similar to that of aplastic or hypoplastic anemia is the classic ~ flinding of human benzene hematotoxicity. As Goldstein rightly pointed o u t , the great variation in the cellularity of the bone marrow tissue, ranging lrom hypercellularity to acellularity, is the cause of hesitation of some investlgators to call all such disease aplastic anemia.' In our series the overall mort.rlity was 47.7'>;, slightly more favorable than mortality rates obtained in series of xquired aplastic anemia of various etiologies.2k23On the other hand, there \\J\ a wide variation in the range of mortality of the pancytopenic patients u I t h chronic exposure to benzene according to the cellularity of the bone illmow. Of 21 pancytopenic patients with hypocellular bone marrow, 16 died tither from the complications of aplastic anemia or from leukemia. I n contrast, tml! 1 of 13 pancytopenic patients with normoplastic bone marrow showed fatal k U I c o m e. rhere was a certain relationship among some clinical findings such as age, a 290 AKSOY AND ERDEM duration of exposure, and outcome of pancytopenic patients with chronic exposure to benzene. The mean age of the pancytopenic patients with corn. plete remission was significantly less than in those with overall fatal outcome, 26.87 and 36 yr, respectively. Similarl*the mean duration of exposure was significantly shorter in the pancytopenic patients who recovered completely than those with overall fatal outcome, 65.43 and 93.62 mo, respectively. Despite this, in one of the patients in whom preleukemia developed the duration of exposure was very short, only 4 mo, but this patient was heavily exposed to benzene during this short period. Individual susceptibility and genetic predisposition are also very important factors in the occurrence of chronic benzene poisoning, including the develop- ment of leukemia.2c26Unlike the age and duration of exposure, with the excep- tion of mean values of neutrophils the findings of peripheral blood could not be correlated with the outcome of benzene-induced pancytopenia. There was no relationship between the levels of HbF and A, and the outcome of the pancytopenic patients. Increased levels of HbF with or without decreased levels of HbA, were found in pancytopenic patients both with complete remis- sion and with fatal outcome, but very high levels of HbF and very low levels of HbAz are encountered only in leukemic states, unless the presence of a &thalassemic gene or a gene for hereditary persistence of fetal Hb is eliminated. In one of our patients, a very low level of HbA2 and a high level of HbF had been found already during the preceding pancytopenic stage, whereas leukemia developed 9 mo later. As we pointed out previously,'." this observation suggests that very low levels of HbA2 with or without high levels of HbF during the pancytopenic state may be a sign of leukemia. In cytogenetic studies performed by Erdogan and Aksoy, in 10 of 44 pancy- topenic patients, 6 with complete remission, 2 with fatal outcome, and 2 in whom leukemia developed later, there was no relationship between cytogenetic findings and outcome, including the development of leukemia following ben- zene-induced pancytopenia.27b28 The development of leukemia in 6 of 44 pancytopenic patients with chronic exposure to benzene should be stressed here. Similarly, Harnberg et ob- served a case of leukemia during a 9-yr followup of 147 individuals occupa- tionally exposed to high levels of benzene; 107 showed certain degrees of hematologic abnormalities. Furthermore, Vigliani and Forni7 in Italy found 19 cases of leukemia among 83 pancytopenic workers exposed chronically to benzene. In addition, during a followup period of 9 yr the present authors and their associates encountered one case of acute leukemia among 217 apparently healthy workers with chronic exposure to 51 of them showed hema- tologic abnormalities. -c The development of leukemia in 6 of 44 pan2top:nkpatjents BsfuLiher- I evidence for the leukemogenic effect of benzene in man. Moreover, studies on the incidence of leukemia among s h o e w m Etaniul during 1967-1975 show a rate of 13/ 100,000, a statistically significant increase over- that within the general p o p u l a t i ~ n . ~ *Fu~r~th*e~rm' ore, the decline of the annual number of leukemic shoeworkers in Istanbul following the substitition for and prohibi- tion of benzene after 1969 is further confirming evidence for the leukemogenic effect of benzene in man.8326 AKSOY A N D ERDEM ancytopenic patients with chronic :pancytopenic patients with corn. 1 those with overall fatal outcome, e mean duration of exposure was jatients who recovered -xxnplete\j and 93.62 mo, respectively. Despite ikemia developed the duration of lis patient was heavily exposed to isposition are also very important poisoning, including the developation of exposure, with the excep. igs of peripheral blood could not h c e d pancytopenia. s of HbF and A2 and the outcome of HbF with or without decreased atients both with complete remisvels of HbF and very low levels states, unless the presence of a 'sistence of fetal Hb is eliminated. 'A2and a high level of H b F had ftopenic stage, whereas leukemia )usly,'*" this observation suggests t high levels of HbF during the '1 and Aksoy, in 10 of 44 pancy2 with fatal outcome, and 2 in -elationship between cytogenetic ent of leukemia following ben- cytopenic patients with chronic Similarly, Harnberg et al.29obup of 147 individuals occupa07 showed certain degrees of mi and Forni' in Italy found vorkers exposed chronically to if 9 yr the present authors and ukemia among 217 apparentlq e;87350I of them showed hema- ncytopenic patients is further in man. Moreover, studies on n Istanbul during 1967-1975 'ant increase over that within d i n e of the annual number :substitition for and prohibividence for the leukemogenic ~ E N Z E ~E~XPEOSURE A N D LEUKEMIA 29 1 REFERENCES I Browning E: Toxicity and Metabolism of -,ndustrialSolvents. Amsterdam. Elsevier, 1965, pp 41* 49 Goldstein BD: Hematotoxicity in man, S, Goldstein BD (eds): A Critical I,,,luation of Benzene Toxicity. New York, .,mcr,can Petroleum Inst, 1977, pp 135, 138 1. Hunter FT: Chronic exposure to benzene ,kn,ol). [I. The clinical effects. J Indust Hyg rorlcol 21:331, 1939 4. Engelhardt EW: Arch Gewerbepathol 1 4 7 ~ 1. 931 (cited by Savilahti M: Mehr als 100 \crglftungsfalledurch Benzol in einer SchuhIJbrik. Arch Gewerbepathol Gewerbehyg 15: 1.17. 1956) i Nilsby I: Kronisk benzolf6rgiftning inom ,k<,~ndustienN. ord Med 42:1225, 1949 (cited h, Savilahti M: Mehr ais I 0 0 Vergiftungsfalle <lurch Benzol in einer Schuhfabrik. Arch c,c~erbepathoGl ewerbehyg 15:147. 1956) 6 Helmer J: Et 60-tal fall av kronisk benzol- :;,rglfining vid gummifabrik. Nord Med 21: 1944 (cited by Savilahti M: Mehr als 100 \ crplftungsfalle durch Benzol in einer Schuh3,Ihrik. Arch Gewerbepathol Gewerbehyg 15: i4.. 1956) _I Vigliani EC, Forni A: Benzene and leu- rcmia Environ Res 11:122, 1976 x Aksoy M: Leukemia in workers due to ~icupationalexposure to benzene. New Istan?uI Contr Clin Sci 12:3. 1977 Y Aksoy M , Erdem $: Some problems of hcmoglobin pattern in different thalassemic \ \ ndromes showing the heterogeneity of beta:h.ilsrsemia genes. Ann N Y Acad Sci 165:13, I YhY IO. Aksoy M, DinCol K, Erdem S, AkgUn T. Ihqol G: Details of blood changes in 32 pa'isnts with pancytopenia associated with long:crm exposure to benzene. Br J lndust Med 29: '(1. I972 1 1 . Aksoy M, Erdem S, Schroeder WA, h w n a n THJ: Hemoglobins A2 and F in hronic benzene poisoning, in Aksoy M (ed): Inkrnational Istanbul Symposium on Abnor31JI Hemoglobins and Thalassemia. Istanbul, TRTAK, 1975, p 197 12. Report on the Solvents Analyzed in the I Ahoratories of the Turkish Department of I .her (1SGUM). Presented at the Meeting 'of hemagglutinins in aplastic anemia of various etiology. Med Bull Istanbul 356, 1970 14. Brechg_G, Cronkite EP: Morphology and enumeration of human platelets. J Appl Physiol 3:365. 1950 15. Singer K, Chernoff At, Singer L: Studies on abnormal hemoglobins. 1. Their demonstratation in sickle cell anemia and other hematologic disorders by means of alkali denaturation. Blood 6:413, 1951 16. Huisman THJ, Dozy AM: Quantitative determination of the minor hemoglobin component HbA2 by DEAE-cellulose chromatography. Anal Chem 2:400, 1961 17. Aksoy M, Erdem $: A simple method for the quantitation of haemoglobin A2 by starch gel electrophoresis. Clin Chim Acta 12:696, I965 18. Gillam AE. Stern ES: An Introduction to Electronic Absorption Spectroscopy in Organic Chemistry. London, Arnold, 1962, p 131 19. Aksoy M, Erdem S, DinCol G: Two rare complications of Jlronic benzene poisoning: Myeloid metaplasia and paroxysmal nocturnal hemoglobinuria. Report of two cases. Blut 30: 255, 1975 20. Scott JL, Cartwright GE, Wintrobe M M : Acquired aplastic anemia. An analysis of thirtynine cases and review of the pertinent literature. Medicine (Baltimore) 38:119, 1959 21. Vincent PC, D e Gruchy GC: Complications and treatment of acquired aplastic anaemia. Br J Haematol 13:977, 1966 22. Wintrobe MM, Lee GR, Boggs DR, Bithell TC, Athens JW, Foerster J: Clinical Hematology (ed 7). Philadelphia, Lea & Febiger, 1974, p 1764 23. Davis S, Rubin AD: Treatment and prognosis in aplastic anaemia. Lancet 1:871, 1972 24. Aksoy M, Erdem S, Erdokan G , Dinsol G : Acute leukaemia in two generations following chronic exposure to benzene. Hum Hered 2470, 1974 25. Aksoy M, Erdem 5,Erdogan G, DinCol K: Combination of genetic factors and chronic exposure to benzene in the aetiology of leukaemia. Hum Hered 26:149, 1976 26. Aksoy M, Erdem S, DinCol G: Types of leukaemia in chronic benzene poisoning. A '.he Committee for Benzene Problems in Turkey, study in thirty-four patients. Acta Haematol \nkara. 1972 (unpublished) 55:65, 1976 1 3 Aksoy M , DinCol K, Erdem $. AkgUn T: I h c results obtained from a triple treatment 'IIh androgens, corticosteroids and phyto- 27. Erdogan G, Aksoy M: Cytogenetic studies in thirteen patients with pancytopenia and leukaemia associated with long-term expo- :.* I 292 AKSOY AND ERDEM --sure to benzene. New Istanbul Contr Clin Sci J: Prognostic aspects of benzene poisoning. 10:230, 1973 ,Br J lndust Med 23:204, 1966 30. Aksoy M, DinFol K , Akgun T , Erdem S, 'I: Cytogenetic nic exposure to 'rican Division, DinCol G: Haematological effects of chronic benzene poisoning in 217 workers. Br J Indust Med 28:296. 1971 I hira Meeting 01 ISH, London, August 24-28, 31. Aksoy M, Erdem S, DinCol G: Leu. I 1975 (Abstr) kemia in shoe-workers exposed chronically to 29. Harnberg S, Savilahti K, Ahlman K , Asp benzene. Blood44:837, 1974