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CASE-CONTROL STUDIES OF ACUTE MYELOID LEUKEMIA (AML) AND NON-HODGKIN'S LYMPHOMA (NHL) IN SHANGHAI
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Otto Wong. Sc.D . F.A.C.E. Chief Epidemiologist, Applied Health Sciences, USA Adjunct Professor of Epidemiology, Tulane University Medical Center, USA Visiting Professor of Occupational Epidemiology, Shanghai Medical University, China Visiting Professor of Community Medicine, Chinese University of Hong Kong. Hong Kong
and
FU Hua. M.B., Ph.D. Deputy Dean, School of Public Health. Shanghai Medical University, China Professor of Preventive Medicine & Epidemiology, Shanghai Medical University. China
Senior Scientist, Applied Health Sciences, USA
June 12, 2000 Washington, DC
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Benzene studies: chronology
Pre-1970s
Case reports: clinical description, but no risk estimates Aksoy: shoe makers in Turkey
1978 1986
Ott: Dow Chemical workers in Michigan Bond: Update of the Dow study
1983
Decoufh~: Conoco plant in Baltimore (a former refinery)
1987
Wong: 7 chemical plants in the US
1980s & 1990s Cohort studies of petroleum workers in the US and UK
1995
Wong & Raabe: Meta-analysis by cell type (n=208,0001
1977 1981,1987 1994 1995
Infante: Pliofilm workers in Ohio Rinsky: First update of the Pliofilm study (totalleukemial Paxton: Second update of the Pliofilm study (total leukemia) Wong: Second update of the Pliofilm study (AML, exposure-response)
2000
Wong and Raabe: Meta-analysis of NHL In = 308.000)
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Studies of Chinese workers
Original epidemiologic study by the Chinese Academy of Preventive Medicine (CAPM)
Yin et al.. 1986; Epidemiologic study [in Chinese] Yin et al . 1987; Exposure survey Yin et al.. 1987; Epidemiologic cohort study (28.460 exposed workers) Li and Yin. 1988; Case-control study of leukemia Yin et al.. 1989; Epidemiologic cohort study
Expanded epidemiologic study by CAPM and US NCI
Yin et al.. 1994; General methods and resources of epidemiologic study Dosemeci et al.. 1994; Exposure assessment Yin et al.. 1996; Overall epidemiologic results (74.828 exposed workers) Hayes et al.. 1997; Dose-response analyses in epidemiologic study
Clinical investigations by CAPM and US NCI
Travis et al.. 1994; Clinical discussion of 82 cases Rothman et al.. 1996; Hematotoxicity of 44 exposed workers Rothman et al.. 1998; Benzene metabolites of 38 exposed workers
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Studies of Chinese workers
Study attribute Number of workers: exposed
unexposed Follow-up period Person-years: exposed
unexposed Number offacHities: benzene
control
Major industries with benzene exposure (exposed group)
Industries with no benzene
exposure(unexposedJlrou~)
Exposure assessment
Number of deaths: e<posed un . .posed
Major diseases analyzed
Major findings reporied
Comparison of the CAPM and CAPM-NCI'tudy attributes
Original CAPM study 28460 28257
1972-1981 178556 199201
233 exposed factories
83 unexposed factories Painting, paint producing, rubber, glue, shoemaking, leather, & organic synthesis.
Machine production, textile, & cloth factories. Exposure levels of leukemia cases were
reported. No overall exposure assessment was done.
474 277 Leukemia (all cell types), No exposure-response an.lyses done,
Increased risk ofl.ukemi. (primarily ANLL),
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Expanded CAPM-NCI study 74828 35805
1972-1987 782497 419523
672 exposed factories 40 unexposed factories + 69 unexposed units Food, textile, leather products, wood and furniture, paper products, stationery, printing, agricultural
chemical, organic chemical, other chemical, pharmaceutical, rubber and plastic, petroleum
products, glass products, metallurgy, fabricated metal, electrical equipment. transportation equipment, precision machinery, other manufacturing, & construction. Not reported,
An overa11 exposure assessment was done for the
entire cohort.
1369
598
Lymphohematopoietic malignancies & other hematologic disorders, Exposure-response analyses on selected diseases. Increased risk of aillymphohematopoietic malignancies, malignant lymphoma, leukemia (particularly ANLL), agranUlocytosis, aplastic aOl,mia, & myeiodvslllastic syndrome,
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Studies of Chinese workers
CAPM-NCI study (1972-1987) (Yin et aI., 1996) Major findings:
Diagnosis
Lymphohematopoietic cancers Non-Hodgkin's Lymphoma Multiple myeloma All leukemias AML CML ALL
Exposed workers
63 17 1 42 23 9 5
Unexposed workers 13 3 1 9 4 2 1
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Relative
Risk
2.6
3.5
0.4
2.6
3.1
2.6
2.8
--
-
95% CI
1.5-5.0 1.2-14.9 0.1-10.7 1.3-5.7 1.2-10.7 0.7-16.9 0.5-54.5
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" Studies of Chinese workers CAPM-NCI study (1972-1987) (Hayes et aI., 1997)
Overall analyses:
Cancer
AML NHL
.
Cases in exposed workers
21 16
----
Cases in
Relative Risk
unexposed workers
4 3.0
--
3
- - -------
____ L______
3.0
95%CI
1.0-8.9 0.9-10.5
Exposure-response analyses:
Diagnosis
Non-Hodgkin's Lymphoma Number Relative Risk 95% CI
Acute Myeloid Leukemia Number Relative Risk 95% CI
Unexposed
<40
40-99
100+ p-value
workers ppm-years ppm-years ppm-years trend
3 619 1.0 3.3 1.1 3.5 0.02
-- 0.8-13.1 0.1-11.1 0.9-13.2
4 5 5 11
1.0 1.9 4.3 3.6 0.06
-- 0.5-7.0
1.1-16.0 _, 1.10-11.6 ---
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Comparison of leukemia results in studies of workers exposed to benzene
Study variable
Author, year Cohort:
exposed workers follow-up person-years comparison group
RR (n): leukemia AML
Bz measurements: range & high levels
Industries or occupations
Potential concomitant exposures
Pliofilm US
Wong 1995
1,212 1950-1987
40,345 general population
3.60 (14) 5.03 (6) 1974 mean: 8-260 ppm max: 355 ppm Pliofilm (rubber hydrochloride) manufacturing
A few cases previously worked in tire building
CAPM-NCI China
Yin 1996
74,828 1972-1987
782,497 35,805 unexposed
workers 2.6 (42) 3.1 (23) 1979-1981 95%: 0.02-266 ppm 1.3% > 314 ppm Paint, varnish, shoe, insecticide, chemical, rubber, pharmaceutical, .printing, plastic Other solvents, other chemicals, insecticides, drugs, etc. -
Petroleum US&UK
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Wona & Raabe 1995
250,000+ 1937-1995 5,000,000+ general population
1.02 (498) 0.96 (148)
1973-1982 89% < 1 ppm 10%: 1-10 ppm Refining (majority), distribution, &
pipeline
Other petroleum products
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,. Benzene exposure and leukemia: Summary
Exposure to benzene increases the risk of AML.
Question: What is the threshold for benzene-related AML? Based on US (NIOSH) data: 200-500 ppm-years (or 4 to 12 ppm for a 40-year work life)
(Wong, Occup Environ Med, 1995)
Based on Chinese data: 40 ppm-years? Exposure levels underestimated (see critique by Wong. Regul Taxical Pharmacal, 2000)
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Benzene exposure and NHL
Cohort studies of chemical workers exposed to benzene in the US
Author (year) Cohort Benzene levels
Observed deaths
Expected deaths
SMR
(95% CIl
Wong 1987
7676 TWA> 50 ppm peaks > 100 ppm
7
5.12
1.37
(0.55-2.82)
Rinsky 1987; Wong 1998
1165 TWA up to 260 ppm. peaks up to 680 ppm
Ott 1976; Bond 1986
594 TWA> 25 ppm peaks up to 937 ppm
Decoufle 1982 259 not reported
3
3.28
0.91
(0.19-2.66)
2
1.70
1.17
(0.14-4.221
0 not 0 reported
Total
9694
12 10.10
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1.18 (0.60-2.051
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NHL in a multi-national cohort of more than 308.000 petroleum workers by country and by industrial division
country
Division
US Refinery
Observed deaths
317
Expected deaths
330.79
SMR 0.96
95%CI 0.86-1.07
Non-US
Refinery
91
81.41
1.12
0.90-1.37
Global Distribution
64
99.38
0.64 0.50-0.82
Global
Crude Oil
34
50.10
0.68
0.47-0.95
Global
ALL
506
561.68
0.90 0.82-0.98
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---
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Source: Wong and Raabe. Journal of Occupational and Environmental Medicine. 2000
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Case-control studies of non-Hodgkin's lymphoma and benzene exposure
Authors (year)
Schumacher and Delzell (1988)
Ott et al. (1989)
Location North Carolina. US West Virginia. US
No. of Exposure Odds ratios (confidence Interval) cases as stated
501 Benzene 0.77 (95% CI 0.56-1.07) for whites
0.94 (95% CI 0.47-1.87) for blacks
52 Benzene 1.0 (95% CI not reported)
,
Scherr et al. (1992)
Boston. US
303 Benzene 1.2 (95% CI 0.5-2.6)
Blair et al. (1993)
Siemiatycki et al. (1991)
Iowa and Minnesota. US
Montreal, Canada
622 Benzene 1.1 (95% CI 0.9-1.4)
215 Benzene 0.7 (90% CI 0.5-1.0) for any exposure O.B (90% CI 0.41.7) for substantial exposure
Franceschi et al. (1989) Northeast Italy
208 Benzene & 1.14 (95% CI 0.572.28) solvents
Cartwright et a!. (1988) Yorkshire, UK & Bernard at (1984)
158 Benzene 0.49 (95% CI 0.212.00)
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Source: Wong and Raabe, Journal of Occupational and Environmental Medicine, 2000
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Chinese Academy of Preventive Medicine-US National Cancer Institute CAPM-NCI study (Hayes et al . 19971
Occupation
Mean exposure Person-years NHL cases Relative risk
All occupations
22.5 ppm
698,000
16
3.0
Coatings/paints
21.5 ppm
350,000
4
1.6
Rubber
53.5 ppm
34,000
1
4.0
Chemical
24.8 ppm
88,000
5
7.8
Shoe
21.8 ppm
68,000
1
1.6
Other/mixed
17.4 ppm
158,000
5
4.1
- - - ----
"Chemical" included "organic, insecticide, & benzene production" (Dosemeci et a!., 1994).
Numerous studies have found an association between agricultural chemicals and NHL.
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Comparison of NHL results
Study
Country
NHL cases
Cohort studies of US US benzene workers
12
Cohort studies of petroleum workers
US, UK, Canada, Australia, Finland, Italy
506
Case-control studies US, Canada, Italy, UK
2059
Cohort study of workers in different industries
China
16
Risk ratios
Meta-SMR= 1.18
Meta-SMR =0.90
Range of RR: 0.49-1.2 i
. RR =3.0 overall
RR = 7.8 "chemical"
RR =4.1 "mixed"
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Benzene exposure and NHL: Summary
Does exposure to benzene increase the risk of NHL? Why are the results from the Chinese study not consistent with other studies?
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Occupational Epidemiologic Studies in China
Difficulties in conducting historical cohort studies in China: No systematic follow-up similar to that in the US (e.g., SSA, NOI). Follow-up depends on a variety of sources (employers, families, co-workers, treating
physicians), which may vary in quality and reporting completeness. Unavailability of detailed national mortality rates of AMUNHL for comparison. Comparison may have to rely on ad hoc "unexposed" workers. Rates derived from ad hoc comparison groups are unstable. Since rates of AML and NHL are low in China, cohorts (exposed and unexposed) have
to be extremely large.
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PROPOSAL
Hospital-based case-control studies of AML and NHL in Shanghai
Objectives:
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 or NHL among these workers.
3. To determine other risk factors (e.g., occupational exposures other than benzene) of AML or NHL among these workers.
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Reasons for choosing Shanghai
1. The largest data contributor in the CAPM-NCI cohort study. 2. One of the sites of the CAPM case-control study. 3. Site for the CAPM-NCI clinical investigation. 4. Large population (13-14 million). 5. Major medical establishments (universities, hospitals, tumor registry). 6. Experienced local investigators. 7. A variety of industries in the area. 8. A wide range of benzene exposure levels. 9. Documented employment histories from employers through Shanghai CDC. 10. Availability of historical measurements of benzene exposure at workplaces.
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Information on risk factors
Demographic. lifestyle. medical histories and occupational information will be obtained from medical records and by questionnaire.
For those identified to have been exposed to benzene, detailed benzene exposure histories will be obtained from employers through Shanghai CDC.
Exposure levels and other relevant information (such as engineering controls) will be obtained from employers and Shanghai CDC (limited data before 1970).
Based on employment histories and exposure data, an exposure profile will be developed for each exposed study subject.
In addition to benzene, attempts will be made to obtain information on a number of selected other occupational exposures.
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Feasibility investigations
First feasibility investigation (October and November, 1998) Procedure for access to patient records was developed. Number of AML and NHL patients per year estimated. A test sample of 6 AML cases and 24 patient controls was selected. The questionnaire used in the Montreal study (by Siemiatycki) was translated and tested in the sample. Suggestions were made for future revision. Exposure data at Shanghai CDC was reviewed.
Second feasibility investigation (August, 19991 Visits to factories confirmed high exposure levels at some work sites. Review of exposure data at Shanghai CDC.
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Data Access
Cooperation and data access have been obtained from: Shanghai Medical University (and all affiliated hospitals) Shanghai Tumor Registry Shanghai Hematology Association Shanghai Municipal Center for Disease Control and Prevention (SCDCI
A joint research agreement between Shanghai Medical University and Applied Health Sciences has been signed, and a copy has been filed with the Office of International Exchange Programs at SMU.
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Principal Investigators
Otto Wong. Sc.D., F.A.C.E.
Chief Epidemiologist. Applied Health Sciences. San Mateo. California Adjunct Professor of Epidemiology, Tulane University, New Orleans Visiting Professor of Occupational Epidemiology. Shanghai Medical University. China Visiting Professor of Community Medicine. Chinese University of Hong Kong. Hong Kong Visiting Professor of Epidemiology. National Defense Medical Center. Taiwan Associate Editor, Annals of Epidemiology
FU Hua. M.B . Ph.D.
Professor of Preventive Medicine and Epidemiology. Shanghai Medical University, China Deputy Dean, School of Public Health, Shanghai Medical University, China Senior Scientist, Applied Health Sciences, San Mateo, California (2 years at the International Agency for Research on Cancer, lyon, Fran(;e)
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Co-Investigators
LIN Guowei. M.D" M.Sc.(U Penn)
Professor of Medicine and Clinical Epidemiology, Shanghai Medical University, China Chairman, Shanghai Hematology Association Chairman, Chinese Clinical Epidemiology Association
Raymond Taetle, M.D.
Chief of Hematology, University of Arizona Medical Center, Tucson Professor of Medicine, Pathology and Oncology, University of Arizona, Tucson Director, Bone Marrow Transplantation Laboratory, University of Arizona Medical Center Author of chapter "Tumor Steam Cells" in Harrison's Principles of Internal Medicine Editorial Board, Journal of National Cancer Institute
LU Wei, M.D., M.P.H.(Umea, Sweden)
Deputy Director General, Shanghai Municipal Center for Disease Control and Prevention
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Other Investigators (subject to availability)
YE Xibiao, M.B., M.Sc.
Assistant Professor of Preventive Medicine and Epidemiology, Shanghai Medical University (Likely to be at IARC for two years, depending on funding)
Edward IIgren, M.D., D.Phii. (Oxford) Consulting Pathologist, Philadelphia Formerly Research Pathologist at Green College, Oxford University
Roy Rando, Sc.D., C.I.H. Associate Professor of Environmental Health Sciences, Tulane University
Shau-Nong Chang. Ph.D . C.I.H. Associate Professor of Environmental Health Sciences, Tulane University
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Summary
Optimal study design: hospital-based case-control studies in Shanghai.
Study size: 500 AML cases, 500 NHL cases and 1500 controls. AML or NHL cases can be enrolled over 3 to 4 years (approximately 150 cases per
year) on prospective basis.
The investigation will take approximately 5 years to complete.
Occupational exposure information from 1970s onward will be relatively complete.
Occupational exposure information prior to 1970 will likely be limited.
Study subject cooperation will be high, given that data collection will be non-invasive.
Data access has been obtained from all major organizations.
Joint research agreement between Shanghai Medical University and Applied Health Sciences has been signed. and a copy has been filed with the Office of International Exchange Programs at SMU.
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