Document RJZjqOyRy3xXRxVk6GJZdBYdX

EHPS 104(6)Linet http://ehpnet1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html Clinical Features of Hematopoietic Malignancies and Related Disorders among Benzene-exposed Workers in China Martha S. Linet,l Song-Nian Yin? Lois B. Travis,l Chin-Yang Li? Zhi-Nan Zhang? De-Gao Li? Nathaniel Rothman,l Gui-Lan Li? Wong-Ho Chow,l Jennifer Donaldson,l Mustafa Dosemeci,l Sholom Wacholder,l William J. Blot,l Richard B. Hayes,' and The Benzene Study Group* Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; *Institute of OccupationalMedicine, Chinese Academy of Preventive Medicine, Beijing, China; 3Section of Hematopathology,Mayo Clinic, Rochester, Minnesota; 4Division of Hematology, Peking Union Medical College Hospital, Beijing University School of Medicine, Chinese Academy of Medical Sciences, Beijing, China e Abstract Introduction e Methods e Results e Discussion Abstract Previous occupational cohort studies of benzene-exposed workers have for the most part used only death certificates to validate diagnoses of workers developing leukemia and other hematopoietic and lymphoproliferativemalignancies and related disorders (HLD). In a follow-up study of 74,828 benzene-exposed workers and a comparison group of 35,805 nonexposed workers from 12 cities in China, we sought to characterize clinicopathologicallyand to confirm diagnoses of all cases of HLD. Using medical records, laboratory hematology results, and histopathology, U.S. and Chinese expert hematopathologists,blinded to exposure status, carried out a detailed review using standardized evaluation forms. Key among the findings were a notable diversity of malignant and nonneoplastic hematopoietic and lymphoproliferativedisorders, documentationof excess myelodysplastic syndromes among benzene workers, and widespread dyspoiesis involving all hematopoietic cell lines. As sophisticated clinicopathologiccharacterizationand correspondingclassification schemes for HLD become increasingly widespread, it is recommended that future epidemiologicinvestigations of benzene workers incorporate similarly detailed morphologic evaluation. In extending follow-up of this cohort of young workers, we will continue to use all available clinical, laboratory hematology, and pathology data as well as cytogenetic and biochemical markers to characterizevarious HLD outcomes. These careful surveillancemechanisms should also provide additional insight into carcinogenic mechanisms of benzene and allow comparison of the molecular pathogenesis of HLD induced by benzene versus chemotherapy,radiation, or other exposure. -- Environ Health Perspect 104(Suppl6):1353-1364 (1996) Key words: hematopoietic malignancies, benzene, leukemia, acute myeloid leukemia, chronic myeloid leukemia, nonHodgkin's lymphoma, aplastic anemia, myelodysplastic syndromes, dyspoiesis *Includes Y-Z. Wang, T-R. Dai, and X-J. Chao of the Stations of Health and Anti-Infectious Diseases in Shanghai, Chengdu, and Chong Qing, China; Z-L. Jiang, W-U. Zhang, P-Z. Ye, Q-R. Kou, Y-H. Fan, 1 of 17 11/7/9710:33 AM EHPS 104(6) Linet http://ehpnet1 .niehs.nih.gov/docs/l996/Suppl(6)/linet.html X-C. Zhang, X-F. Lin, J-F. Meng, and J-S. Zho of the Institutes of Labor, Health and Occupational Disease in Tianjin, Sichuan, Heilongjiang, Shenyang, Jinzhou, Henan, Guangzhou, Jiang Xi, and Nanchang, China This paper was presented at Benzene '95: An International Conference on the Toxicity, Carcinogenesis, and Epidemiology of Benzene held 17-20June 1995 in Piscataway, New Jersey. Manuscript received 16 January 1996;manuscript accepted 14 June 1996. Address correspondenceto Dr. MS Linet, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6130 Executive Boulevard, MSC 7368, Bethesda, MD 20892-7368. Telephone: (301) 496-4153. Fax: (301) 402-0081. E-Mail: linetm@,epndce.nci.nih.gov Abbreviationsused: AML, acute myeloid leukemia; CAPM, Chinese Academy of Preventive Medicine; HLD, hematolymphoproliferativedisorders; NCI, National Cancer Institute; NOS, not otherwise specified. Introduction Benzene, a ubiquitous constituent of cigarette smoke, industrial solvents, automobile emissions, and a broad variety of other products, (1) is widely recognized to be etiologically linked with acute myeloid leukemia (2). Other hematopoietic and lymphoproliferativemalignant and related disorders (HLD) associated with benzene exposure include aplastic anemia (3,4) and possibly non-Hodgkin's lymphoma (9,chronic myeloid leukemia (6),multiple myeloma (7-9), chronic lymphocytic leukemia (lo), and various myelodysplastic syndromes (11,12). To evaluate further the quantitative relationship of acute myeloid leukemia (AML) with benzene exposure and to determine whether other types of HLD were linked with this chemical, the U.S.National Cancer Institute (NCI) and the Chinese Academy of Preventive Medicine (CAPM) collaborated in a large cohort study of benzene-exposed workers in China (13,14). Clinicopathologicfeatures of benzene-exposed workers developing acute myeloid leukemia (15-17), pancytopenia, and aplastic anemia (3) have been previously described in case series. Ascertainment of HLD among benzene workers in defined occupational cohorts, however, has been largely based on death certificates (18,19) in which information typically is limited only to overall diagnosis(es), often without specificationof subtype (20). Therefore, a major objective of the collaborativeNCI-CAPM cohort investigation was to obtain detailed clinical diagnostic information from all available medical record and laboratory sources to describe incident HLD cases (21). In an earlier report (22), we included descriptions of salient clinicopathologic features of HLD cases for which bone marrow, lymph node or related tumor tissue, peripheral blood smears, and pathology and laboratory hematology reports were available. The goal of the present paper is to provide a comprehensive overview of the sources and types of information available for all patients and to describe clinical features. In addition to individual case descriptions (22), we also present summary statistics for selected HLD subtypes. Methods A detailed description of the methods for identifying and following up subjects using written factory records can be found in earlier reports (13,21). The study population includes 74,828 benzene-exposed workers and a comparison group of 35,805 nonexposed workers, with 60%of the total person-years (P-Y) contributed by workers less than 30 years of age at study entry, and 47% of the exposed and 40% of the nonexposed P-Y contributed by women (13,21). For deceased subjects and all incident cases suspected as having HLD, cause of death or diagnostic information, respectively, was first sought from medical records, then other factory records or death certificates, followed only if necessary by contacts with treating physicians and next of kin. 2 of 17 11/7/9710:33 A M EHPS 104(6) Linet http://ehpnet1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html For all exposed and nonexposed HLD cases, medical records from diagnostic and subsequent visits, hematology and histopathology reports, and peripheral blood smears, bone marrow, lymph node, and all other tumor tissue pathology slides were sought. Information from all sources was abstracted onto standardized forms by physician investigators blinded to benzene exposure status of the patients. Abstracted data included the date and medical record diagnosis of the hematopoietic disorder; peripheral blood counts prior to therapy (including hemoglobin, hematocrit, total white blood count, a white blood cell differential count, platelet count, reticulocyte count, and date the specimen was obtained); peripheral blood morphology; diagnostic report of bone marrow aspirate andor biopsy, lymph node or other lymphoproliferativetumor tissue and results of immunohistochemicalstains; selected physical examination findings (including lymph node palpation, liver and spleen evaluation, and other pertinent abnormalities); diagnostic X-ray interpretation (chest and abdominal radiographs and other pertinent evaluations); surgical reports at the time of diagnostic evaluation; and stage and classification scheme used to evaluate extent of lymphoproliferativedisorder. Although we searched for other laboratory data (including leukocyte alkaline phosphatase score, cytogenetic studies, serum and urine lysozyme, lactose dehydrogenase, and bilirubin), these data were rarely available in the medical records during the study period. All abstracted forms, medical records, and available hematopathologic laboratory slides were reviewed systematicallyby expert U.S. and Chinese hematopathologists, from Mayo Clinic, NCI, and the Division of Hematology of the Peking Union Medical College Hospital, Beijing University School of Medicine, who were blinded to the exposure status of the cases. Most reviewers were fluent in reading Chinese, the language in which the original records were written. Details of the hematologic evaluation have been described (22). Diagnoses were assigned after evaluation of all available clinical, laboratory, and pathologic data. Published criteria were used to classify acute myeloid (also called nonlymphocytic) leukemia (23-25), acute lymphoblastic leukemia (23), chronic myeloid leukemia (26), myelodysplastic syndromes (27), and non-Hodgkin's lymphoma (28). To summarize presenting symptoms and signs of disease and peripheral blood counts within HLD groups, we performed univariate analyses (calculating medians, means, standard deviations, etc.). We evaluated the distribution of survival times after diagnosis with product limit estimates (29). Survival was also examined according to age and exposure status, and tests of significancewere performed using log-rank (30). Results A total of 81 HLD were diagnosed among benzene-exposed workers and 13 among nonexposed workers during 1972 to 1987. Twenty-nine (36%) of the 81 exposed cases and 3 (23%) of the 13 nonexposed cases were women. Median age at diagnosis for all cases was 40 years for exposed and 48 for nonexposed. As shown in Table 1, categories of specific disease types with the largest numbers among the Chinese benzene workers were AML and non-Hodgkin's lymphoma, followed by aplastic anemia, chronic myeloid leukemia and myelodysplastic syndromes, and then acute lymphoblastic leukemia. It is noteworthy that tumors derived from B-lymphocytes were quite rare. Confirmation of approximately 80% of all HLD cases among both exposed and nonexposed workers was based on review of either tissue specimens or corresponding hematopathology reports. Eighty-eight percent of diagnoses were confirmed by evaluation of medical record data or hematopathology specirnensh-eports(Table 1). 3 of 17 11/7/9710:33 A M EHPS 104(6) Linet http://ehpnet1 .niehs.nih.gov/docs/1 996/Suppl(6)/linet.html Table 1. Nurrbers of hemrtopuetic and lyrrphopmliferativerralgnanciesand related disorders among benzene. expcsedChineseworkers ty bestsoulceofdiagncses. Diagnases Bpmed Review ofsldes or pathology Medical report NOrd Other Nonexpcsed Review ofsldes or pathology Medical report record Other All HLD 65(803%) All leukemias 35 Acute myeloid 21 Acute lyrrphoblastic 4 Acuteleukemia. NDS 3 Chronic rryeloid 7 Leukemia. NOS 0 All nonmrlgnant 16 blood disorders Aplasticanemia 7 Myelodysplasticsyndmme 7 Ag mnuIocyt06 is 2 All lyrrphqtic and histiocytic 14 Non-Hodgkin's lymphom 1 1 Other hbticcytic 2 Multiple rrydomr 1 6[7.4%) lO(l23%) 25 02 00 00 10(769%) 2(15.4%) 1(7.7%) 6 21 40 -3 -0 10 NOS. not otherw isespe: lied. Presenting symptoms abstracted from medical records of benzene-exposed patients with selected HLD are listed in Table 2, but small numbers limit comparisons with nonexposed cases, except for AML. For both the exposed and nonexposed patients with AML (data for latter not shown), the most common initial complaints were abnormal bleeding (including petechiae, purpura, or hemorrhage) and persistent fevers. These symptoms are similar to those associated with de novo AML (3 1). Table 2Nurrberand pelcentage(in parentheses) of expcsed workers with hemtopoieticand ~rrphoprolifemtivemlignanciesand reiatd disorders experiencing clinical prarentingsymptom andsgns ty type ofsymptomand type ofdisorder? Diagnosticc a t qoty Acutemyeloid Chronic rryeloid Acute lyrrphoblastic Myelodysplasia Aplasticanemia Non-Hodgkin's lymphoma Bleeding 12p7.1) 2tw 2l86.7) 4t57.l) 7(774 1 (7.1) Fever. nght swmts. chilb 12(57.l) 3(4W 1 (33) 5(71.4) - 5(35.7] Wtigue. mrlaise. wmk. anomia. mr Inutrition 8 (38.1) . 1 wtw9 4 (44.4) 4tm Weight Icss -o m -- 3(21.4) Lv mhdenomtlw 9(42$ 3(4W 2 (66.7) 3t-429 1 2 (857) SDlenorrslalv ~~~~ 3(143) 5t71.4) 2(86.7) l(1-4.3) 6(42$ "Differences i n numbersof expcsed ptientsshown in Tables 1and 2rellect incorrpleteinfometion i n medicalrccordsaboutsynptorrsandsigns. Hemtt 51: 511 2 (E 3It 2(; 5(: Peripheral blood cell counts at diagnosis are shown for exposed patients with six types of HLD and for nonexposed cases with acute myeloid leukemia and non-Hodgkin's lymphoma in Figures 1 through 4. For most HLD diagrammed in Figures 1 and 2, median hemoglobin concentrations and platelet counts were low at diagnosis, as expected. Consistent patterns were more difficult to identify for total white blood cell and absolute lymphocyte counts (Figures 3 and 4). For AML, median total white blood cell counts (10,000 versus 25,000 X 10% 1) and absolute lymphocyte count (1300 versus 4000 X 103/P1) were notably lower for benzene-exposed patients than for nonexposed cases (Figure 3). However, the median total white blood counts of benzene-exposed workers developing most other HLD conditions did not appear to differ from those described for most idiopathic cases reported in the literature (31). Benzene exposure appeared to exert a variable effect on absolute lymphocyte counts, which were low for acute and chronic myeloid leukemia cases but within the normal range for aplastic anemia, myelodysplastic syndromes and non-Hodgkin's lymphoma patients (Figure 4). 4 o f 17 11/7/97 10:33 AM EHPS 104(6) Linet A 7300 D http://ehpnet 1.niehs.nih.gov/docs/ 1996/Suppl(6)/linet.html B i EF Figure 2. Platelet counts at diagnosis of patients with six hematopoietic and lymphoproliferative malignancies and related disordersby type of HLD and exposure status. A 309 0 I I ~~ Exposed In1211 Noncxpsed(n=4] - -= I - .....rI.n.... I -I I I 0 0 DE . I 0I I0 I II hposd b=81 Noncxposed(n=O] II ExposedIn= 41 Nonexposed (n= 11 0 II Expscd In= 141 NoncrposedIn= 31 Figure 3. Total white blood cell counts of patients with six hematopoietic and lymphoproliferative malignancies and related disorders by type of HLD and exposure status. 5 of 17 11/7/97 10:33 AM EHPS 104(6) Linet A http://ehpnet1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html B E x p s e d l c 19 Nonexposed(cQ1 D Ex posed l s=71 Nonexpased (E01 E k p o s d b=81 Nonexposedln=ll F k p o s d b = 5 ) NonexposedlcO) Exposed (1)=41 Nonexpased(E11 Exposedlt 13 Nonexposed(n=2] Figure 4. Absolute lymphocyte counts of patients with six hematopoieticand lymphoproliferativemalignancies and related disorders by type of HLD and exposure status. Among subjects with available pathology material or records, morphologic features in the peripheral blood and/or bone marrow of benzene-exposed workers with AML commonly included anemia, thrombocytopenia, increased bone marrow cellularity, and dyspoiesis (data not shown). Basophilia was evident in some patients with AML. The most common subtypes for cases with adequate information to determine French-American-Britishclassificationwere AML-M2 and AML-M3, but one patient was believed to have either a myelomonocytic or monocytic leukemia and another possibly megakaryoblastic leukemia (the latter classified as acute leukemia not otherwise specified (NOS) because pertinent immunohistochemical stains of bone marrow were not performed). Several other patients were also classified as acute leukemiaNOS because of unavailability of additional immunohistochemicalstains. Nevertheless, some AMLs and acute leukemiasNOS demonstrated dysplastic changes in peripheral blood and bone marrow. Myelodysplasticsyndromes, evident among seven patients based on review of histopathologictissue or reports, included refractory anemia, refractory anemia with excess blasts, and chronic myelomonocytic leukemia, with subclassificationnot possible in three cases. Overall, findings for benzene-exposed workers with myelodysplastic syndromes included bone marrow hypocellularity and marked dyserythropoieticfeatures such as multinuclearity, megaloblastoid changes, impaired hemoglobinization,abnormal nuclear shape, and dimorphic morphology of red cells. Of benzene-exposed patients with chronic myeloid leukemia, most also demonstrated dyserythropoiesisand dysgranulopoiesis,as described earlier (22). Based on available tissue and/or pathology reports, we were often unable to update diagnoses of non-Hodgkin's lymphoma (assigned during 1972-87)to reflect recent advances in disease classification, since immunohistochemicalstains and other appropriate tests had not been performed. Frequently we could only maintain the original diagnoses. In benzene-exposed subjects, diagnoses included diffuse, cleaved, mixed-cell lymphoma or lymphosarcoma(four cases of each); gastric lymphoma, T-cell non-Hodgkin's lymphoma, malignant lymphoma NOS (two each); and poorly differentiated non-Hodgkin's lymphoma (one case). Among nonexposed workers, diagnoses of gastric lymphoma, diffuse, cleaved, mixed lymphoma, and lymphosarcomawere each apparent in one patient. Assigned diagnoses reflected the evolution of classification schemes over several decades as well as differences in 6 of 17 11/7/9710:34A M EHPS 104(6) Linet http://ehpnet1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html levels of expertise among pathologists in hospitals throughout China. Sixty-five (80%)of benzene-exposed patients with HLD died during the study period, including 39 of 42 with leukemia, 17 of 21 with lymphocytichistiocytic disorders, and 9 of 18 with nonmalignant hematopoietic conditions. Similarly, all but one of the 13 nonexposed HLD cases died. Overall, benzene-exposed HLD patients had somewhat, though not significantly, shorter age-adjusted relative survival (median 0.8 year) than nonexposed patients with these disorders (median 1.O year); survival did not vary by age (older versus younger than the median) among exposed HLD patients (median 0.7 year for both age groups), but among nonexposed cases, younger persons survived substantially longer (median 2.4 years) than older subjects (median 0.4 year). Older benzene-exposed workers with AML demonstrated no difference in survival by exposure status (median 0.1 year for benzene-exposed and for nonexposed), but younger exposed patients had notably shorter survival (median 0.2 years) than nonexposed cases (median 1.O year), although none of these differences are statistically significant. There were too few nonexposed workers with non-Hodgkin's lymphoma and related tumors to evaluate survival, but exposed older and younger workers with these neoplasms had similar survival (median approximately 1.O year for both age groups). For subjects with all nonmalignant hematopoietic disorders (all were exposed), younger workers survived substantially longer (median 9.6 years) than older subjects (median 3.3 years). Discussion In one of the largest cohort studies of benzene-exposed workers ever carried out, we sought to validate and characterize clinicopathologically all cases of HLD among the exposed study population and the nonexposed comparison group. Key among the findings was a notable diversity of malignant and nonneoplastic hematopoietic and lymphoproliferativedisorders, documentation of excess myelodysplastic syndromes among benzene workers, and widespread dyspoiesis involving all hematopoietic cell lines among numerous patients. Overall, survival of patients diagnosed with HLD was poor but slightly (nonsignificantly) shorter among benzene-exposed compared with nonexposed patients, though somewhat (nonsignificantly)longer among younger than older patients. Survival differences must be interpreted cautiously, however, because of small numbers and multiple comparisons. 7 of 17 11/7/9710:34A M EHPS 104(6) Linet http://ehpnet1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html Chmicalmf;lcblrhg Thwpe. 1974G'a 383276 OOnBecotauflle..e1t9a7l..61139383(n BDnd et al.. 1985c35) Bond et al.. 1986W ) k8.17 l a 594 407P94 24,571 Pwetal..198603 wbng. 1937(5) 94,524 133986 O'BergetaI.. 19871383 2.489390 (males] 463933tfmales) Rimkyet al., 1988@SI691,181 Onetal.. 1989(40 hksoad m- comlcmdy of HLDfrom Rimky et al.. 1988 27,415 (est) 51.366 Nesa case- comlsudy of HLD Foxand Colier. 1976144) k;90B67 Andjekovichetal.. l977(4 b8.418 r=13570 Dekelland h m n , 19810 wbtf et al.. 1981(533 441.96 (WMunia-tl 28.729 (NWMmbnl 134397 (Funbrd 110S7 (Msabripd 82.012 (F &rid) Nesa case- comlstldyof leukemias b33 B 15 1962-71 1915154:1973 1947-80 :wb CML-2;AML-1; "EL- 1; ACUTE, MS1; LEU(, NOS12 A II LEU(-10 AMol-1; C L L l 1940-90 1338-78:1982 A II LEU(30 "EL-4 1971:1982 1946E:1977 All LEN-7 All LEK7 1%6M A II LEU(-169M. 22F 1940-78 1940-78 All LEU(64 NLL-39;LL- 18 15690 196472 196472 1968-74 196473 1940-76 1940-78 196473 iwm;iw5 A ML-1;ALL-1; CML-1 All LEU(-16 AML-7; CML-8; NLL-2;ALL4 CLL-11; LL-3; LEM.MS7 All LEU(28 MDL-3; NLI.6: LL-8; LEUK, M S 4 All LEN-78 pap. &UP W Munion-68 WMmbrcO F mbw8 MSlXied-10 Fd~ied-1 NLL-27;LL-31; OM L U 1 4 All LEN31 LS13; Hal0 LY-2 LY-11 LY-5: HD3 E l l 1M. 16F: HDIOSY. 15F LY-48; H M NHL-52 LY-14 LY-16: H a l0; OM LYM9 LY-5; HD2 OM LYMlO OM HD55 All L E N 68 0 8 10 1 OM HD18 MM2 OM18 AA-1; WFlBl OM7;WFO2 OM 18; O E D 7 MM7 MMlO: WFlBl LYMard MM: 76 6 11 15 7 hamC b l hc 8 of 17 11/7/9710:34 A M EHPS 104(6)Linet C h & m y etai., 1994156) G m m n et al.. 193615a kmrdinellietal.. 198719 Rimky et ai., 1987Is1 69,213 31.612 SoMan a d b e . 1993(59) e2.410 http://ehpnet1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html 1954-73 196673 19j2-75:1930 1962-R:1%3 1940-66:1%1 1%-94 LL-15 LL-11 All LEK-7 WEL2; OTH LBJIC1 AML-6; MDL-1; MYEL-1;CML-1 All LEN4 HD2 LYM3 MM5 MM4; OTH HD2 Lance Death c Deathc SNedis cam Death c Deathc hmpk reccrd path01 Death c Rimrsand relatedW r s Gmerberg. 197216@ k670 Lbydetal.. 1977161) .L-2.804 Greene et al.. 197916i9 *a7 PqanLHilletal.. 1990(1 kl.361 &M~etal.. 1996I64) k1.901 Paintersardp a h t m a r u m r n g Chianeetal.. 193OW ~226 blghrd, 198016.q 1Q ,754 Morganetal.. 1981[69) e1624 Whwarnetal.. 19B(A4 k2.aoO Mamaki etai.. 1996 i7l 257222 Deathsdung 1564-86 Deaths dung 11M8 k t h s dung 1948-77 19@-66:1978 Deaths dung 1SWl 1949-6323 Deathsdung 1970-76 196671 194676 197679 1975-79 ALL LEUC4 A LL LEUICPl ALLLEUICIG AMMDLG; MYEL-1 ALL LEUIC9 him NGA LEUIC4; M T g W LEN-4 ALL LEUICZ LL- 13 ALL LEUICPO ALL LEUK-2 ALL LEUIC44 Ls3: cal NHL-7; H17 NHL-11 NHL-6 NHL-6 LYM3 Ls15: HD7; OTH LYM9 MMlO WFIB1 WFIB3 Deathc Death C Death c Deathc Death c Death c Deathc Swdis Regist Death c pcpulal Cancel Dealh c Abbrwiaicns: LS, ~ o s a c o m aN;HL.ncn4bdW-h tp-phana;LY, t)Trphoma. not otherwisespecifieda Ilrrphosarcomap b s r e t i a r l w m ; HI, Hxlgkm'sdkase;All LBJ ELL,chmk lirrphocytiC klkemia;ALL, a m i)qhoblastic klkemia;CML. chmc myeloil kukemia;AML, acute myebkl leukemia;AWL. acute mocytk leukemia;AMWL HLD: A4. aplasticanemia;M,perniciousanemia;MYFIB. myelofbrosh: NLL.nontpphaytic leukemia: LL. Iy-~-#~ocyticleukemia;OBIU.diseaseof bbcd-fmnig organs: LBJK ard histocyticnecptasms;OTHHD.all H L O m p t klkemia:ACUTE IUS. acute kukemia.notohmise spcifed: WM, Mitemaks: NWM,nonMig maks;M. males; F.fema of OperafhQ Rinters. Eraaphkal.ard Media Personnel. %=5.994Wrs. snce p m h p x s not fmvided. bErer errp b@ drhg ysarsm left of mlm(:)andf o l h d up Ilrou! Compared with other cohort studies of benzene-exposed workers or workers in major occupational categories included in the current series (4,5,7,18,19,32-71), the present investigation is one of very few using all available sources in addition to death certificates to review HLD diagnoses (Table 3). If one considers only the key studies of benzene workers (3,5,7,8,16-19)there is an impression that only two hematopoietic disorders (AML and aplastic anemia) are indisputably associated with benzene exposure. Despite the limited and generally qualitative nature of data demonstrating a link between benzene exposure and HLD outcomes, Table 3 reveals that the specific industries included in the present investigation are characterized by mortality outcomes that include a wide range of HLD (32-71). Relatively few studies have attempted to evaluate quantitatively the relationship between benzene or other specific solvents and HLD (5,8,14,18,51,54,56)and none of these evaluated HLD other than the leukemias. Thus, the absence of clinical, hematologic, and/or pathologic data in conjunction with few detailed investigations of specific benzene measures in relation to various HLD types has limited the 9of 17 11/7/9710:34A M EHPS 104(6) Linet http://ehpnet1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html opportunity to draw inferences with regard to hematopoietic cell lines targeted by benzene. Fatal aplastic anemia was first reported among benzene-exposed workers nearly 100 years ago (72), while leukemia was initially linked with benzene exposure in 1928 (73). During the subsequent half century, important series of leukemia cases were described among benzene-exposed printers in rotogravure plants and shoemakers in cottage shoe factories in Milan and Pavia, Italy (15,74,75), exposed workers in small shoe and handbag factories in Istanbul, Turkey (3,16,17,76), and hospitalized patients reporting prior occupational exposure to benzene (77). Case-control studies have also linked benzene exposure (primarily occupational) with leukemia (1 0,78,79). These clinical series, case-control studies, and two important cohort investigations (18,19,80) were considered to provide sufficient evidence to link benzene with leukemia, particularly AML, in humans (2). Subsequent cohort investigations of benzene-exposed workers within chemical manufacturing, petroleum refinery, or other industries in the United States, the United Kingdom, Italy, and China have confirmed the benzene-leukemia association (Table 3) (81,82).Although acute myeloid leukemia, not otherwise characterized,has been the type of malignancy most consistently associated with benzene exposure, other unusual variants of acute myeloid leukemia, particularly erythroleukemiaand to a lesser extent acute myelomonocytic leukemia, appear to occur disproportionately in some studies of benzene-related leukemia (15,83-85). While chronic myeloid leukemia has been mentioned in clinical reports (86,87), the only previous cohort investigation in which this leukemia type was noted was the first cohort study by Yin et al. in China (6). Lymphopoietic malignancies (including chronic lymphocytic leukemia, acute lymphoblastic leukemia, malignant lymphoma, and multiple myeloma) have only infrequently been directly associated with benzene exposure. More commonly, reports indirectly suggest a possible link. For example, two case-control investigations imply that benzene may be related to increased risk of chronic lymphocytic leukemia (10,78), a neoplasm observed in excess in cohort and nested case-control studies of rubber industry workers (43,51,54,56) and long-term petroleum industry workers (88-90). Hodgkin's disease has been observed in a few cohorts of rubber industry workers (43,47,58). Reports of benzene-related acute lymphoblastic leukemia have been limited to occasional case descriptions (73), while speculation (9,85), but few analytic investigations, has linked benzene with multiple myeloma (7,8,85) or non-Hodgkin's lymphoma (5,91-93). Explanations for the diversity of HLD within the present study include additional workplace and possibly residential exposure to other solvents and chemicals as well as differences in genetic or other susceptibility factors between populations. Population-based cancer registration data have shown that Asians are characterized by low incidence of chronic B-cell malignancies, including chronic lymphocytic leukemia, multiple myeloma, and subtypes of non-Hodgkin's lymphoma of B-cell origin (94). While the types of HLD among benzene-exposed workers in our survey were compared with those among a nonexposed comparison group, there were no specific features that distinguished HLD associated with benzene exposure from those among nonexposed subjects, with the possible exception of dyspoietic findings. Aksoy (84) has noted that some case series of benzene-related HLD include a substantial proportion of individuals with preleukemia (3,76). Yet, reports of preleukemia among benzene-exposed workers only rarely include descriptions of dyspoietic features such as megaloblastoid dyserythropoiesis (17). There have also been reports of benzene-exposed workers with varying degrees of pancytopenia, among whom a few have been observed to develop aplastic anemia, then a preleukemic phase, followed by a transfonnation to overt acute myeloid leukemia (3,85). Honda and colleagues (95) and Cowles et al. (96) recently reported excess myelodysplastic syndromes and myelofibrosis during 1985 to 89 in conjunction with a deficit in leukemia during the same period among workers at a petroleum manufacturing and refining plant, where excesses of leukemia (as well as myelofibrosis though based on only two cases) had been observed during 1940to 84 (97-99). Changes in diagnostic or reporting practices were postulated to explain the apparent shifts from leukemia to myelodysplastic syndromes and myelofibrosis (95). Additional deceased workers employed in this factory had myelofibrosis or preleukemia reported as contributing causes rather than underlying causes of death (the latter coded as the official cause of death) (95). Two workers from the same facility whose cause of death was specified as "neoplasm of uncertain behavior" were also found to have myeloproliferative disease listed elsewhere on death certificates (95). One other study of petroleum refinery workers has also reported excess deaths from myelofibrosis (100). Recent modifications to rules for coding death certificates, revisions in the 10 of 17 11/7/9710:34AM EHPS 104(6) Linet http://ehpnet1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html International Classificationof Diseases classification schemes, failure to recognize these rare disorders, and other problems may have affected ascertainmentof these and possibly other specific HLD types. Aksoy (84) and others (101) have pointed out that defined criteria often were not used for myelodysplastic syndromes until an internationallyrecognized classification scheme was published in the early 1980s (27). With one recent exception (102), population-based incidence data for the myelodysplastic syndromeshave not been published, nor have these disorders been evaluated systematically in cohorts of benzene-exposed workers. In small case-control studies (12,103) and a case series (1l), however, myelodysplastic syndromes have been linked with prior exposure to gasoline or diesel exhaust within the United Kingdom (12), to pesticides or chemicals within the United States (103), and to organic solvents within Italy (11). These hematopoietic disorders also develop after treatment with alkylating agents or may precede transformation to overt AML in chemotherapy-treated patients developing secondary leukemia (104). Characteristic hematotoxic effects of benzene have been described for several decades, although specific mechanisms of action are still being elucidated. The most common reported abnormalitiesare peripheral pancytopenias, although anemia, leukopenia, and thrombocytopeniaindividually have been noted (105). As early as 1941, Goldwater (106) observed that an absolute lymphocytopenia was a relatively frequent and early manifestation of benzene hematotoxicity. Recently, we observed a decreased absolute lymphocyte count among healthy workers with moderate-to-high exposures to benzene compared with nonexposed controls in Shanghai (107). Though the finding of benzene-associated lymphocytopeniahas been confirmed by some (1OS), others have failed to find this result (109,110). However, administration of benzene to rats, mice, and rabbits has been shown to produce a dose-dependent decrease in the number of lymphocytes, which may precede the drop in levels of other blood cells (111). Similarly, lymphocytes are extremely sensitive to ionizing radiation, another known leukemogen (112). Unfortunately, few workers within the present study underwent systematic evaluation prior to onset of symptoms associated with HLD. Also, no patient with AML had been previously diagnosed with aplastic anemia, nor did any of those diagnosed with myelodysplastic syndromes subsequently develop acute myeloid leukemia. It should be noted, however, that several patients died of complicationsrelated to myelodysplastic syndromes. As we pointed out earlier (22), we observed considerable overlap in hematologic features present within several AMLs within our survey and those described for leukemias secondary to alkylating agents or radiotherapy (104). These findings included dysmyelopoieticchanges (113,114) and the common occurrence of anemia, thrombocytopenia, and increased bone marrow cellularity. While some of these features have been observed in previous descriptions of benzene-related AML, we were the first to report dyspoiesis among benzene workers with a variety of HLD (22). We also observed basophilia among several patients with acute myeloid leukemia, although this finding has not been considered to be characteristic of chronic benzene toxicity (84,108). Treatment-relatedleukemias are distinct clinicopathologicentities based on morphologic and cytogenetic abnormalities (104,115). Although cytogenetic studies were not performed as part of the routine diagnostic evaluation of HLD cases arising among Chinese benzene-exposed workers, morphologic and hematologic similarities between our cases and treatment-relatedAMLs suggest possible similarities in pathogenesis, perhaps involving damage to marrow stem cells and/or extra-medullary mediators of carcinogenesis. Similarly, a recent clinicopathologic description of AML following exposure to organic solvents revealed comparable types of abnormalities (116). The major limitation of our study is the historical nature inherent within retrospective cohort investigations. Particularly for workers within early years of the study period, incomplete characterization of HLD diagnoses at initial presentation was common. Ideally, work-up of patients with newly diagnosed HLD should include immunohistochemical stains on histopathologic specimens in addition to cytogenetic,immunophenotypic,and other studies. Currently, we are initiating extended follow-up of this cohort, and efforts are being made to implement up-to-date evaluation of all HLD. Nevertheless, our study of benzene-exposed workers is one of the first occupational investigations in which HLD outcomes for a large proportion (close to 90%) of cases have been validated through standardizedreview of medical records or diagnostic pathology-related data. As routine clinicopathologic characterization of individual patients and classification schemes for all categories of 1 1 of 17 11/7/9710:34AM EHPS 104(6) Linet http://ehpnet1.niehs.nih.gov/docs/1996/Suppl(6)/linet.html HLD have become increasingly sophisticated, it is hoped that future epidemiologic investigations of benzene workers will incorporatethe approach for outcome assessment that we have described. In the extended follow-up of this cohort, we will continue to utilize all available clinical, laboratory hematologic, and pathologic data as well as cytogenetic and biochemical markers to characterize HLD outcomes. Workers diagnosed with aplastic and myelodysplastic syndromes will also continue to be followed after diagnosis for evolution of these conditions to acute myeloid leukemia. We are also considering a prospective evaluation of workers diagnosed with benzene poisoning by means of various biochemical and molecular markers that might be associated with the subsequent development of HLD. It is hoped that these studies might eventually lead to identification of patients who are particularly susceptible to benzene toxicity and carcinogenesis, and, conversely, description of molecularhiochemical profiles that correlate with resistance to these end points. These facets of our investigations are designed to provide further clarification of underlying molecular mechanisms of leukemogenesis and development of HLD, with possible implications for other hematopoietic carcinogens such as ionizing radiation and chemotherapeuticagents. References 1. Wallace LA. Major sources of benzene exposure. Environ Health Perspect 82:165-169 (1989). 2. IARC. Benzene. In: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Some Industrial Chemicals and Dyestuffs. Vol29. Ly0n:Intemational Agency for Research on Cancer, 1982;93-148. 3. Aksoy M, Erdem S. Follow-up study on the mortality and the development of leukemia in 44 pancytopenic patients with chronic exposure to benzene. Blood 52:285-292 (1978). 4. Paci E, Buiatti E, Seniori Costantini AS, Miligi L, Pucci N, Scarpelli A, Petrioli G, Simonato L, Winkelmann R, Kaldor JM. Aplastic anemia, leukemia and other cancer mortality in a cohort of shoe workers exposed to benzene. Scand J Work Environ Health 15:313-318 (1989). 5 . Wong 0.An industry-wide mortality study of chemical workers occupationally exposed to benzene. 11: Dose response analyses. Br J Ind Med 44:382-395 (1987). 6. Yin SN, Li GL, Tain FD, Fu, ZI. Jin C, Chen YJ, Luo, SJ, Ye, P Z, Zhang JZ, Wang GC, Zhang XC, Wu HN, Zhong, QC. A retrospective cohort study of leukemia and other cancers in benzene workers. Environ Health Perspect 22:207-221 (1989). 7. Decoufle P, Blattner WA, Blair A. Mortality among chemical workers exposed to benzene and other agents. Environ Res 30:16-25 (1983). 8. Rinsky F U ,Smith AB, Hornung R, Filloon TG, Young RJ, Okun AH, Landrigan PJ. Benzene and leukemia. N Engl J Med 316:1044-1050 (1987). 9. Goldstein B. Is exposure to benzene a cause of human multiple myeloma? Ann. NY Acad Sci 609:225-234 (1990). 10. Linos A, Kyle R, OFallon WM, Kurland LT. A case-control study of occupational exposures and leukemia. Int J Epidemiol9:131-135 (1980). 11. Vineis P, Avanzi GC, Giovinazzo B, Ponzio G, Cambrin GR, Ciccone G. Cytogenetics and occupational exposure to solvents: a pilot study on leukemias and myelodysplastic disorders. Tumori 76:350-352 (1990). 12. Farrow A, Jacobs A, West RR. Myelodysplasia, chemical exposure, and other environmental factors. Leukemia 3:33-35 (1989). 13. Yin SN, Hayes RB, Linet MS, Li GL, Dosemeci J, Travis LB, Li CY, Zhang ZN,Li DG, Chow WH, Wacholder S, Zhang WU, Dai TR, Wang YZ, Jiang ZL, Zho JS, Meng JF, Lin XF, Zhang XC, Fan YH, Kou QR, Ye PZ, Chao XJ, Blot WJ. A cohort study of cancer among benzene-exposed workers in China. Am J Ind Med, 29:227-235 (1996). 14. Hayes RB, Yin SN, Linet MS, Dosemeci M, Wacholder S, Li CY, Zhang ZN,Li DG, Chow WH, Travis LB, Wang YZ, Rothman N, Jiang ZL, Dai TR, Zhang WU, Chao XJ, Ye PZ, Kou, QR, Zhang XC, Lin XF, Meng JF, Deng,CY, Zho JS, Blot WJ. Mortality among benzene-exposed workers in China. Environ Health Perspect 104:OOO-000 (1 996). 15. Forni A, Moreo L. Chromosome studies in a case of benzene-induced erythroleukaemia. Eur J Cancer 5:459-463 (1969). 16. Aksoy M, Dincol K, Erdem S, Dincol G. Acute leukemia due to chronic exposure to benzene. Am J Med 52:160-166 12 of 17 11/7/97 10:34 AM EHPS 104(6) Linet http://ehpnet1 .niehs.nih.gov/docs/l996/Suppl(6)/linet.html (1972). 17. Aksoy M, Erdem S, Dincol G. Leukemia in shoe-workers exposed chronically to benzene. Blood 44937-841 (1974) 18. Ott MG, Townsend JC, Fishbeck WA, Langner RA. Mortality among individuals occupationally exposed to benzene. Arch Environ Health 33:3-10 (1978). 19. Rinsky RA, Young RJ, Smith AB. Leukemia in benzene workers. Am J Ind Med 2:217-245 (1981). 20. Percy C, Stanek E, Gloeckler L. Accuracy of cancer death certificates and its effect on cancer mortality statistics. Am J Public Health 71:242-250 (1981). 21, Yin SN, Linet MS, Hayes RB, Li GL, Dosemeci M, Wang YZ, Chow WH, Jiang ZL, Wacholder S, Zhang WU, Dai TR, Chao XJ, Zhang XC, Ye PY, Kou QR, Meng JF,Zho JS, Lin XF, Ding CY, Kneller R, Blot WJ. Cohort study among workers exposed to benzene in China. I. General methods and resources. Am J Ind Med 26:383-400 (1994). 22. Travis LB, Li CY, Zhang ZN,Li DG, Yin SN, Chow WH, Li GL, Dosemeci M, Blot W, Fraumeni JF Jr, Hayes RBLhet, MS. Hematopoietic malignancies and related disorders among benzene-exposed workers in China. Leuk Lymph 14:91-102 (1994). 23. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the acute leukaemias, French-American-British(FAB) Co-operative Group. Br J Haematol33:45 1-458 (1976). 24. Bennett JM. Correspondence: A variant form of hypergranular promyelocytic leukaemia (M3). Br J Haematol 44:169-170 (1980). 25. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French-American-BritishCo-operative Group. Ann Intern Med 1031460-462 (1985). 26. Spiers ASD, Bain BJ, Turner JE. The peripheral blood in chronic granulocytic leukaemia: study of 50 untreated Philadelphia-positivecases. Scand J Haematol 18:25-38 (1977). 27. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol51 :189-199 (1982). 28. National Cancer Institute-Sponsored Study of Classifications of Non-Hodgkin's Lymphomas: Summary and Description of a Working Formulation for Clinical Usage Cancer 49:2112-2135 (1982). 29. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481 (1958). 30. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170 (1966). 3 1. Champlin R, Golde DW. The leukemias. In: Harrison's Principles of Internal Medicine, 1lth ed. (Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JB, Martin MA, Fauci AS, eds). New York:McGraw-Hill 1987;1541-1550. 32. Thorpe JJ. Epidemiologic survey of leukemia in persons potentially exposed to benzene. J Occup Med 16:375-382 (I 974). 33. Ott MG, Holder BB, Langner RR. Determinants of mortality in an industrial population. J Occup Med 18:171- 177 (1976). 34. Pel1 S, OBerg MT, Karrh BW. Cancer epidemiologic surveillance in the DuPont Company. J Occup Med 20:725-240 (1978). 35. Bond GG, Shellenberger RJ, Fishbeck WA, Cartmill JB, Lasich BJ, Wymer KT, Cook RR. Mortality among a large cohort of chemical manufacturing employees. J Natl Cancer Inst 752359-869 (1985). 36. Bond GG, McLaren EA, Baldwin CL, Cook RR. An update of mortality among chemical workers exposed to benzene and other agents. Br J Ind Med 43:685-691 (1986). 37. Pifer JW, H e m e T, Friedlander BR, McDonough JR. Mortality study of men employed at a large chemical plant, 1972 through 1982. J Occup Med 28:438-444 (1986). 38. O'Berg MT, Burke CA, Chen JL, Walrath J, Pel S, Gallie CR. Cancer incidence and mortality in the duPont company: an update. J Occup Med 29:245-252 (1987). 39. Rinsky RA, Ott G, Ward E, Greenberg H, Halperin W, Leet T. Study of mortality among chemical workers in the 13 of 17 11/7/97 10:34AM EHPS 104(6) Linet http://ehpnet1.niehs.nih.gov/docs/1996/Suppl(6)/linet.html Kanawha Valley of West Virginia. Am J Ind Med 13:429-438 (1988). 40. Ott MG, Teta MJ, Greenberg HL. Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment. Am J Ind Med 16:631-643(1989). 41. Olsen GW, Hearn S, Cook RR, Currier JF,Allen S. Mortality of Louisiana chemical workers. J Occup Med 3 1:32-34 (1989). 42. McMichael AJ, Spirtas R, Kupper LL. An epidemiologic study of mortality within a cohort of rubber workers, 1964-72.J Occup Med 16:458-464 (1974). 43. McMichael AJ, Spirtas R, Kupper LL, Gamble JF.Solvent exposure and leukemia among rubber workers: an epidemiologic study. J Occup Med 17:234-239 (1975). 44. Fox AJ, Collier, PF. A survey of occupational cancer in the rubber and cable-making industries: analysis of deaths occurring in 1972-74.Br J Ind Med 33:249-264 (1976). 45. Monson RR, Nakano KK. Mortality among rubber workers. I: White male union employees in Akron, Ohio. Am J Epidemiol 103:284-296 (1976). 46. Andjelkovich D, Taulbee J, Symons M. Mortality experience of a cohort of rubber workers 1964-73.J Occup Med 18~387-394(1976). 47. Andjelkovich D, Taulbee J, Symons M, Williams T. Mortality of rubber workers with reference to work experience. J Occup Med 19:397-405 (1977). 48. Monson RR, Fine LJ. Cancer mortality and morbidity among rubber workers. J Natl Cancer Inst 61:1047-1053 (1978). 49. Delzell E, Monson RR. Mortality among rubber workers. 111: Cause-specificmortality, 1940-1978. J Occup Med 231677-684(1981). 50. Delzell E, Monson RR. Mortality among rubber workers. IV: General mortality patterns. J Occup Med 23:850-856 (1981). 51. Wolf PH, Andjelkovich D, Smith A, Tyroler H. A case-control study of leukemia in the U.S. rubber industry. J Occup Med 23:103-108 (1981). 52. Parkes HG, Veys CA, Waterhouse JAH, Peters A. Cancer mortality in the British rubber industry. Br J Ind Med 39~209-220(1982). 53. Norseth T, Andersen A, Giltvedt J. Cancer incidence in the rubber industry in Norway. Scand J Work Environ Health 9(Suppl2):69-71. 54. Arp E.W, Wolf PH, Checkoway H. Lymphocytic leukemia and exposures to benzene and other solvents in the rubber industry. J Occup Med 25:598-602 (1983). 55. Holmberg B, Westerholm P, Maasing R, Kestrup L, Gumaelius K, Holmlund L, Englund A. Retrospective cohort study of two plants in the Swedish rubber industry. Scand J Work Environ Health 9(Suppl. 2):59-68 (1983). 56. Checkoway H, Wilcosky T, Wolf P, Tyroler H. An evaluation of the associations of leukemia and rubber industry solvent exposures.Am J Ind Med 5:239-249 (1984). 57. Gustavsson P, Hogstedt C, Holmberg B. Mortality and incidence of cancer among Swedish rubber workers, 1952-1981. Scan J Work Environ Health 12538-544, 1986. 58. Bernardinelli L, De Marco R, Tinelli C. Cancer mortality in an Italian rubber factory. Br J Ind Med 44:187-191 (1987). 59. Sorahan T, Pope D. Mortality study of workers employed at a plant manufacturing chemicals for the rubber industry: 1955-86.Br J Ind Med 50:998-1002 (1993). 60. Greenberg M. A proportional mortality study of a group of newspaper workers. Br J Ind Med 29: 15-20 (1972). 61. Lloyd JW, Decoufle P, Salvin LG. Unusual mortality experience of printing pressmen. J Occup Med 19543-550 (1977). 62. Greene MH, Hoover RN, Eck RL, Fraumeni JF Jr. Cancer mortality among printing plant workers. Environ Res 20:66-73 (1979). 63. Paganini-Hill A, Glazer E, Henderson BE, Ross RK.Cause-specific mortality among newspaper web pressmen. J Occup Med 22542-544 (1980). 14 of 17 11/7/97 10:34 AM EHPS 104(6) Linet http://ehpnet1.niehs.nih.gov/docs/1996/Suppl(6)/linet.html 64. Zoloth SR, Michaels DM, Villalbi JR, Lacher M. Patterns of mortality among commercial pressmen. J Natl Cancer Inst 76: 1047-1051 (1986). 65. Leon DA. Mortality in the British printing industry: a historical cohort study of trade union members in Manchester. Occup Environ Med 51:79-86 (1994). 66. Chiazze L Jr, Ference LD, Wolf PH. Mortality among automobile assembly workers. I. Spray painters. J Occup Med 22520-526 (1980). 67. Englund A. Cancer incidence among painters and some allied trades. J Toxicol Environ Health 6:1267-1273(1980). 68. Engholm G, Englund A. Cancer incidence and mortality among Swedish painters. In: Advances in Modem Environmental Toxicology. Vol 11: Occupational Health Hazards of Solvents (Englund A, Rmgen K, Mehlman MA, eds). Princeton, NJ:Princeton Scientific Publishers, 1982;173-185. 69. Morgan RW, Kaplan SD, Gaffey WR. A general mortality study of production workers in the paint and coatings manufacturing industry. A preliminary report. J Occup Med 23:13-21 (1981). 70. Whorton MD, Schulman J, Larson SR, Stubbs HA, Austin D. Feasibility of identifying high-risk occupations through tumor registries. J Occup Med 25:657-660 (1983). 71. Matanoski GM, Stockwell HG, Diamond EL, Haring-Sweeney M, Joffe RD, Mele LM, Johnson ML. A cohort mortality study of painters and allied tradesmen. Scand J Work Environ Health 12:16-21 (1 986). 72. Santesson GG.Uber Chronishce Vergiftungen mit Steinkohlen Benzin vier Todesfalle. Arch Hyg 31:336-376 (1897). 73. Delore P, Borgomano J. Leucemie aique au cours de intoxication benzenique. Sur origine toxique de certaines leucemies aigues et leurs relations avec le anemies graves. J Med Lyon 9:227-233 (1928). 74. Penatti F, Vigliani E. Sub problema della mielopatic aplastifiche, pseudo aplastichemiche de benzols. Rass Med Ind 9~345-361(1938). 75. Vigliani EC, Saita G. Benzene and leukemia. N Engl J Med 271372-876 (1964). 76. Aksoy M, Erdcem S, Dincol G. Types of leukemia in chronic benzene poisoning. A study in thirty-four patients. Acta Haematol55:65-72 (1976). 77. Goguel A, Cavigneaux A, Bernard J. Benzene leukemias in the Paris region from 1950to 1965.Nouv Rev Fr Hematol 7:465-480 (1967). 78. Girard R, Revol L. La fiequence d'une exposition benzenique au cours des hemopathies graves. Nouv Rev Fr Hematol 10:477-484 (1970). 79. Brandt L, Nilsson PG, Mitelman F. Occupational exposure to petroleum products in men with acute non-lymphocytic leukemia. Br Med J 1 3 3 - 5 5 4 (1978). 80. Infante PF, Wagoner JK, Rinsky RA, Young RJ. Leukaemia in benzene workers. Lancet 2:76-77 (1977). 81. Austin H, Delzell E, Cole P. Benzene and leukemia. A review of the literature and a risk assessment. Am J Epidemiol 1271419-439 (1988). 82. Swaen GMH, Meijjers JMM. Risk assessment of leukaemia and occupational exposure to benzene. Br J Ind Med 46:826-8830 (1989). 83. Vigliani EC, Forni A. Benzene and leukemia. Environ Res 11:122-127(1976). 84. Aksoy M. Benzene Carcinogenicity. Boca Raton, F1orida:CRC Press, 1988;65-I 12. 85. Goldstein BD. Benzene toxicity. State of the Art Reviews. J Occup Med 3541-554 (1988). 86. Tareef EM, KontchaloskayaNM, Zorina LA. Benzene leukemias. Acta Unio Int Contra Cancrum 19:751-755 (1963). 87. Browning E. Benzene. In: Toxicity and Metabolism of Industrial Solvents. Amsterdam:Elsevier, 1965;3-65. 88. Wong 0,Raabe GK. Critical review of cancer epidemiology in petroleum industry employees, with a quantitative meta-analysis by cancer site. Am J Ind Med 15:283-310 (1989). 89. Wongsrichanalai C,Delzell E, Cole P. Mortality fiom leukemia and other diseases among workers at a petroleum 15 of 17 11/7/97 10:34 AM EHPS 104(6) Linet http://ehpnet 1 .niehs.nih.gov/docs/1996/Suppl(6)/linet.html refinery. J Occup Med 31:106-111(1989). 90.Bertazzi PA, Pesatori AC, Zocchetti C, Latocca R. Mortality study of cancer risk among oil refinery workers. Int Arc Occup Environ Health 61:261-270(1 989). 91.Young N.Benzene and lymphoma. Am J Ind Med 15:495-498(1989). 92.La Vecchia C, Negri E, D'Avanzo B, Franceschi S. Occupation and lymphoid neoplasms. Br J Cancer 60:385-388 (1989). 93.Blair A, Linos A, Stewart PA, Burmeister LF, Gibson R, Everett G, Schuman L, Cantor Kp. Evaluation of risks for non-Hodgkin's lymphoma by occupation and industry exposures from a case-control study. Am J Ind Med 23:301-312 (1993). 94.Parkin DM, Muir CS, Whelan SL, Gao YT, Ferlay J, Powell J. Cancer Incidence in Five Continents. Vol6.IARC Scientific Publications No. 120.Ly0n:International Agency for Research on Cancer, 1992. 95.Honda Y, Delzell E, Cole P. An updated study of mortality among workers at a petroleum manufacturing plant. J Occup Med 37:194-200(1995). 96.Cowles SR, Bennett JM, Ross CE. Medical surveillance for leukemia at a petrochemical manufacturing complex: four year summary.J Occup Med 33:808-812(1991). 97.McCraw DS, Joyner RE, Cole P. Excess leukemia in a refinery population. J Occup Med 27:220-222(1985). 98.Wongsrichanalai C, Delzell E, Cole P. Mortality from leukemia and other diseases among workers at a petroleum refinery. J Occup Med 31 :106-11 1 (1 989). 99.Austin H, Cole P, McCraw DS. A case-control study of leukemia at an oil refinery. J Occup Med 28:1169-1173(1986). 100.Kaplan SD. Update of a mortality study of workers in petroleum refineries. J Occup Med 28514-516 (1986). 101.Wintrobe MM, Lee GR, Boggs D, Bethell TC, Foerster J, Athens JW, Lukens JN. Clinical Hematology. 9th ed. Philade1phia:Lea & Febiger, 1981;700-705. 102.Cartwright RA,Alexander FE, McKinney PA. Leukaemia and Lymphoma. An Atlas of Distribution within Areas of England and Wales 1984-1988.London:Leukaemia Research Fund, 1990. 103.Michels SD, McKenna RW, Arthur DC, Brunning RD. Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases. Blood 65:1364-1372(1985). 104.Pedersen-Biergaard J. Rowley JD. The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may deveiop in different ways and may contribute differently to malignant transformation. Blood 83:2780-2786 (1994). 105.Goldstein BD. Hematotoxicity in humans. J Toxicol Environ Health (Supp1)2:69-147(1977). 106.Goldwater LJ. Disturbances in the blood following exposure to benzol. J Lab Clin Med 26:957-973(1941). 107.Rothman N,Li GL, Dosemeci M, Bechtold W, Marti GE, Wang YZ, Linet M, Xi LQ, Lu W, Smith MT. Titenko-HollandN, Zhang LP, Blot W, Yin SN, Hayes RB. Hematotoxicity among Chinese workers heavily exposed to benzene. Am J Ind Med 29:236-246(1996). 108. Aksoy M, Dincol K, Akgun T, Erdem S, Dincol G. Haematological effects of chronic benzene poisoning in 217 workers. Br J Ind Med 28:296-302(1971). 109.Hamilton-Paterson JL,Browning E. Toxic effects in women exposed to industrial rubber solutions. Br Med J 1:349-352 (1944). 110.Hernberg S,Savilahti,M. Ahlman K, Asp S. Prognostic aspects of benzene poisoning. Br J Ind Med 23:204-209(1966). 1 1 1. Irons RD,Wierda D, Pfeifer RW. The immunotoxicity of benzene and its metabolites. In: Advances in Modem Environmental toxicology, Carcinogenicity and Toxicity of Benzene. Vol4 (Mehlman MA, ed). Princeton, NJ:Scientific Publishers, 1983;37-48. 112.Pizzarello DJ, Witcofski RL. Response to total body radiation. In: Medical Radiation Biology. 2nd Ed. (Pizzarello DJ, Witcofski RL eds). Philade1phia:Lea and Febiger, 1982;134-145. 113.Pedersen-Bjergaard J, Philip P, Pedersen NT, Hou-Jensen K, Svegaard A, Jensen G, Nissen NI. Acute nonlymphocytic 16 of 17 11/7/9710:34 AM EHPS 104(6) Linet http://ehpnet 1.niehs.nih.gov/docs/1996/Suppl(6)/linet.html leukemia, preleukemia, and acute myeloproliferativesyndrome secondary to treatment of other malignant diseases. 11: Bone marrow cytology, cytogenetics, results of HLA typing, response to antileukemic chemotherapy and survival in a total series of 55 patients. Cancer 54:452-462 (1 984). 114. Brusamolino E, Papa G, Valagussa P, Mandelli F, Bemasconi C, Marmont A, Bonadonna G. Tura S,Bosi A, Mango G. Treatment-relatedleukemia in Hodgkin's disease: a multi-institution study on 75 cases. Hematol Oncol5:83-98 (1987). 115. Le Beau MM, Albain KS, Larson RA, Vardiman JW, Davis EM, Blough RR, Golomb HM, Rowley JD. Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7. J Clin Oncol4:325-345 (1986). 116. Fagioli F, Cuneo A, Piva N, Carli MG, Revati R, Balboni M, Tomasi P, Cariani D, Scapolik G, Castoldi G . Distinct cytogenetic and clinicopathologic features in acute myeloid leukemia after occupational exposure to pesticides and organic solvents. Cancer 70:77-85 (1992). < _~-~--.xxII__. . " " - , ~ - - ~ ~ ~ ~ , x _ - _ _ . .--xx^____ ~ ~ . ~ -~x-x.-."- [Table of Contents] Last Update: Febuary 13,1997 ----. x_I ___;_-x_ "I_Ix__ ,,,,, , ,", , ,,__xx___I _ _,~__x ,,,,, ~, ,.,,,, ,.__xx _.III^I^Ixx^-x IX X I * I X . ~ [EHIS Home1[Search EHP] Comment on article [Tech Assistance] [SubscriptionOptions1[ ingle COPY Order Form] 17 of 17 11/7/97 10:34 AM