Document LpepvQb1YVG7vK0eD5M6dkwew

1... CASE-CONTROL ST.UDIES OF ACUTE MYELOID LEUKEMIA (AML) AND NON-HODGKIN'S LYMPHOMA (NHL) IN SHANGHAI Prepared jointly by Otto Wong, 5c.D., F.A.C.E. ChiefEpidemiologist, Applied Health Sciences, USA Adjunct Professor of Epidemiology, Tulane University Medical Center, USA Visiting Professor of Occuparional Epidemiology, Sbanghai Medical University, China Visiting Professor of Community Medicine, Chinese University orHong Kong. HongKong and FU Hua, M.B., Ph.D_ Deputy Dean, School of Public Health, Shanghai Medical University, China Professor ofPreventive Medicine & Epidemiology, Shanghai Medical University, China-- Senior Scientist. Applied Health Sciences, USA ,~, ' -- - June 12, 2000 MOC0004426Q INTRODUcnON In 1979-1981 the Institute of Occupational Medicine, Chinese Academy of Preventive Medicine (CAPM), carried out II national survey in China. in which more than SOO,OOO workers were identified to have been exposed 10 benzene (Yin tit aI., 1987a), The 95% range of benzene concentrations at worlcplaces was 0.06-844.74 mg/m' (0.02-266 ppm). Subsequently, 28,460 of these exposed workers from a variety of industries in 12 cities and 28,257 unexposed workers from the same cities were included in a historical cohort study (the: "CAPM" study). The results were reported in a oomber of pubUcations (Yin and Li, 19&6; Yin et aI., 1987b; Yin et aI., 19&9). A total or 2S leukemia deaths and 5 incidence cases were reported among the exposed workers, while 4 deaths among the UOClCPosed workers were attributed to leukemia. The standardized mortality ratio (SlR) of leukemia for the exposed workers in comparison to the unexposed wOIkers was 5.74 (p < 0.01). No exposure-response analysis was performed. but the authors reported actual benzene measurements from locations where leukemia deaths and cases were observed (Yin and Li, 1986; Yin et aI., 1987b; Yin et aL. 1989). Exposure levels reported were as high as 5,508 mg/m3 or 1,732 ppm. [n 1988, Li and Yin published a case-control study of leukemia and benzene exposure in four cities in China (Li et aI., 1988). The reported rda!ive risle was 3.4. No benzene exposure levels were available in the case-control study.' Since 1987, the US National Cancer Institute (NCI) has collaborated with CAPM in expanding and updating the C\linese benzene study. The previous study was expanded to include 74.828, benzene-exposed workers and 35,805 unexposed workers who were employed ror any length of time between 1972 and 1987 at 71:2. factone:; in 12 cities (the "CAPM-NCl" study). The genera.! methods and resources of the expanded study were dl:Scribed by Yin et at. (1994). In a second paper, all historical benzene exposurc assessment to characterize benzene exposure profiles ofthe cO'hort members was outlined (Dosemeci et aL, 1994). Based on comparisons between the exposed and unexposed workers, increased mortality risk ratios (RR) were reponed for a variety of cancers (Yin et aI., 1996). Some exposureresponse analyses in terms of cumulative exposure (ppm-years) far selected disease cal.egories were reported by Hayes et al. (199fi). in another paper. Hayes et aI. (1997) reported dose--relatcd inc;idence of hematologic neoplasms. For leukemia, the RR was 2.5 (95% Cl: 1,2-5.1). For acute non-lymphocytic leukemia (ANLL). \ht: RR was 3.0 (95% CI: 1.0-8.9). The RR for nOliHodgkin's lymphoma (NHL) was 3.0 (95% Cl: 0.9-10.5). The trend between A.NLL and cumulative exposure was close to, bul did not achievc, statistical significant:e (p 0.06). For NHL, the higbest risk (RR = 7.8) was observed among "chemlcal" workers, which included "organic. insecricide, and benzene production workers." ,6,lthough the Chinese benzene study was one of the largest studie.s in teons of number of exposed workers, some results were based on comparisons to small numbers of cases for di.ease andcategories of interest in the unexposed group. For example, there were only 4 ANLL cases 3 NEL cases among the t.I1le,lCposed workers. 10 the Chinese benzene study. results depended not only on the number of deaths in the exposed group but also all the number of deaths in the unexposed group. The small number of deaths in the unexposed group rendered the results unreliable. ';.-.Aooo _.. 0_ , - - - :-~ . -. 1 MOC000442B1 --------------- The exposed workers were employed in a variety ofindustrles. In the CAPM study, 64% of the exposed workers were either painters or paint production workers (Yin et a1., 19117b). In terms of exposures, only 5% were exposed to benzene only (Yin et aI., 19l!7a). The potential problem of concomitant exposures complicated the interpretation of the results in relation to benzene exposure (for example, the NHL increase in workers exposed to both bellZcne and insecticides). When compared to the unexposed worker:s, the exposed workers were reported to have increased risks ill a variety of diseases. More specifically, increased mortality rlskil among exposed male workers. when compared to unexposed male workers were reported for mnny spec16c eancer sites whien have not been demonstrated 10 be related to be.nzene exposure. in other studies; including lung cancer, liver cancer, stomach cancer, intestinaJ cancer, esophageal cancer, and nasopharyngeal cancer. For e"ample, no study has ever demonstrated an association between. benzene exposure: and nasopharyngeal cancer. These observatiot\s raised potential concerns regarding the comparability of the unexposed workers, potentia! under-ascertainment of cancer among the unexposed worker.;. and confounding c:xposufes (or other risk factors) in the exposed group (Yin et al" \989). Olle of the areas of uncertainty in Ihe Chinese belUene study involved the exposure estimates. Comparing the assumptions used in the development of estimates and the expOSUfe estimates themselves to a.ctual data reported identified a number of inconsistencies andlor inadequacy of exposure categories. For e:x:ample, the actual average exposure of spny painters (fullday exposure) at a factory in Shanghai in 19651969 was 331 mglm) (104 ppm), whereas the estimate developed by Dosemel:i et al. (1994) for spray painters in the sa.me time period was 22.1 ppm. Thc:re are other similar cxlUl1pl~s. It app!:ared that the cKposurc c:sumates were consistently lower than the actual exposure data. Dosemeci et aJ. (1994) recognized that Uttle confidenet: could be attached to the estimates: only 2% of the t:Stimates for the lime interval 19491959 lind only 6% of the estimates prior to 1975 were rated in the "high confidence" CalegolJ' by Dosemeci et aI. Exposure-response analyses based all these exposure estimates shou.ld be intm-prc:ted with extTcme CIlution. A detailed critique of the exposure assessment developed byDosemeci et aI. has been published by Wong (1999). Bath CAPM and NCI have made substantial etforts in studying the relation between I;lenzeoe expo5Ule Bnd malignancies. Unfortunately, because of the problems discussed above, the results of Ihe CAPM-NCI study arc diffiGult to interpret. Nevertheless., be(;!luse of the large ornumber of Chinese workers who are or have been exposed to relatively high levels benzene (compared to, for example, levels ilt refineries in the US), China represents a unique opportunity for investigating the carcinogenic effects o{benzene. In this proposal, we will outline an epidemiologic investigation to assess the relation betwet:n exposure to benzene and the risk of developing acute myeloid leukemia (MU.).or nonHodgkin'. lymphoma (NHI.) in China. Mare specifically, the investigation will consist of hospital-based case-control studies of male and female patients diagnosed with AML or NHL in Shanghai. 1 MOC00044282 PROPOSAL Objectives The objectives of th~ proposed hospital-bued case-control studies of A1vIT.. and NHL in Shanghai are as follows: 1. To determine the risk of developing AML or NHL (and major subtypes) among workers exposed to benzene in.Shanghai. 2. To quantifY the exposure-response relations between exposure to benzene and AML Of NHL among these workers. J. 'To determine other risk factors (e.g. occupational exposures oilier than benzene) of AMI. or NHL among these workers. Rtllsons ror cboosmg Shanghai Shangbai is the largest city in China.. with a population of 1J to 14 million. A wide .. variety of industries are located within the metropolitan area.. and benzene is and has bcen used in many industries in Shanghai. The reasons fur choosing Shllllghai as the location for our investigation arc summariud below. 1. The largest data contributor in rhe CAPM-NCI tohon study. 2. One ofthe sites ofthe CAl'M case-comrol study. 3. Site aithe CAPM-NCI clinical investigation. 4. Large popUlation (13-14 milUon). 5. Major medical establishments (universities, hospitals, tumor registry). 6. Experienced local il)vestigato!1;. 7. A wide variety ofil1oustries ill the area. 8. A wide range ofbelW:l1e exposure levels. 9. Documented employmenl histories from employers througb the Shanghai Center for Disease Control {CDC). 10. Availability of historical measurements ofben.J:ene e:<:posure at workplaces. 3 MOC000442B3 Identificllti~n of A]'.1LINBL CllSes and matched controls All cancer cases diagnosed in Shanghai are reported to the Shanghai Tumor Registry. Thus, the Shanghai Tumor Registry will be our primary data soun::e for AML and NHl. cases. Other sources will consist of Shanghai Medical University nffiliated hospitals (including Ihe Hua Shan Hospital), other major hospitals in Shanghai, and members of the Shanghai Hematology Association. The final selection of panicipating hospitals or other iJellllh care facilities Wlli be: determined by the Shanghai Medical University. Both male and female patients will be eliJ51ole. The diagnoses of aU identffied cases of A1vfL and NHL will be verified. In addition, SUbtypes of AML and NHL will also be made. COlltrols wiJl be selected from other patients at the: same hospitals or health care facilities. Patients with other Iymphohcmatopoietic cancers or blood disorders will be excluded from selection. Matching variables win include gender. age and year of diagnosis. It is estimated that the study will consist of sao AMI.. patients, 500 NHL patients and 1,500 controls. The study subjects will be enrolled On 11 prospective basis. and it is estimated that it will take 3 to .II years to reach the required study size. ' [nrormation on ri,k ractors Demographic data, lifestyle information, medical histories and employment histories will be obtained from medical records and through tne use of iI questionnaire. A questionnaire (in Chinese) has been tested in a sample .of AMI.. and other patients at the Shanghai Medical University Hospital during a reasibility trip to Shanghai in 1993 by Qtto Wong Bnd Fu Hua. It is anticipated that only a few minor modifications will be necessary in finalizing the questionnaire. . for study subjects identified to have \vorked at. factories with potential benzene use, copies of employment records will be obtained from the employers through Shanghai CDC. orMeasuremenis exposures to benzene and other chemiCals at these factories and other relevant documents (such as raw materials used, work practice and engineering controls) will be obtained from the employers as well as from Shanghai CDC. 'Exposure estimates specific to job tille, department, factory and 'calendar year will be developed. Based on employment histories a.nd exposure estimates, an individualized 6cposure profile Wlli be developed ror each exposed study :lUbject. These individual exposure profiles will be used in the epidemiologic analyses. Epidemiologi.c analyses "I:Both stratified analyses (the ManteI-Haenszel procedure) and multivariate analyses (Iogislic regression) Wlli be used in assessing the relation between exposure to benzene and the orrisk of developing AML or NHL. Exposure variables will include type of industry, type 4 MOC000442B4 ., occupation, length of exposure, calendar year, cumulative exposure, truncated exposure., and peak t:>:posure. These analyses will determine: whether there is an increased risk of AMI.. orNHL among workers exposed to benzene in Shanghai. If th~e is an increa.sed risk, the exposureresponse analysis will determine the level of exposure associa.ted with the increas~d risk. Similar analyses will be conducll:d to assess the relations between other I;onc:omitant exposures and the risk of developing AMI. or NHL. Lifestyle factors will also be investigated. Confounding factors will be controlled for ill the analyses on benzene exposure. Data atcess and collaboratiDn Cooperation amI data access have been obtained from: Shanghai Medical Ullivcrsily (and all affiliated hospitals) Shanghai Tumor Registry Shanghai Hematology Association Shanghai Municipal Cenler for Disease Control and Prevention {CDC} A joinl research agreement between Shanghai MediCal University and Applied Health Sciences has been signed, lind a copy has been filed with the Office of International Exchange Programs at the Shanghai Medical University. , Research team The Principal Investigators of the case-control studies of AMI. and NHL Will be Professors OUo Wong and Fu HUB. Professor Wong has 28 years of experience in occupatiollal research and has conducted more than 200 epidemiologic studies investigating occupational and envirorunental cancers. Professor Fu is th~ D'eputy Dean of the School of Public Health, Shanghai Medical University. and has full access to a. variety of health data ill Sbanghai. Principal' Tnvcstigatol] Otlp Wong. Sc.D., F.A.C.E, ChiefEpidemiologist, Applied Health Sciences, San Mateo, California Adjunct Professor ofEpidemiology, Tulane University. New Orleans Visiting Professor of Occupational Epidemiology, Shanghai Medical University, China Visiting Prafes.or of Cornmullity Medicine, Chinese Universily efHong Kong, HailS Kong Visitillg Professor of Epidemiolo&y, NDMC School ofPublic Health. Taipei, Taiwan Associate Editor, AIllIt:1/sofEpidemi%gy 5 ... ... __ - --~--------.,--~---- , .- ... MOcoo044285 Professor ofPreventive Medicine and Epidemiology, Shanghai ~{edtcal University. China Deputy Dean, School ofPublic Health, Shanghai Medical University, China Senior SeienLisl, Applied Health Sciences, San Matep. California (2 years at'the International Agency for Research on Cancer, Lyon. France) Co-Investigators; LIN Guowei, M.D, M,Sc,(U Penn) Profi:SSOf ofMedicine and Clinical Epidemiology, Shanghai Medical University, China Chairman, Shanghai Hematology Association Chairman, Chinese Clinical Epidemiology Association .. ~Qnd Taetle M,D, Chief ofHematology, University of Arizona Medical Center, Tucsol1' Professor ofMedic:ine, Pathology and Oncology, University of Arizona, Tucson Director, Bone Marrow Transplantation Labol'1ltory, University of Arizona Medical Center' Author ofchaptet "Tumor Steam Cells" in Harrison's Principles of11,lernaiMuiicine Editoria.l Board. Journal ofNatiollal Cancer lJ1.1titute LU Wei. M.D., MP,HWmea Swed~nl D9'uty Director General. Shanghai Municipal Cent.er for Disease Control and Prevention ~tjmated scbedule ;'.: ; It is estimated that the pro'posed case-control studies of AMI.. and NHL will take' . approximately 5 years [0 complete, 6 ., - ..., '-,--'-'- ._-- --'-- MOC000442B6