national cancer advisory board formaldehyde exposure and
TRANSCRIPT
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National Cancer Advisory Board
Formaldehyde Exposure and Risk of Nasopharyngeal Cancer
and Leukemia
Laura Beane Freeman, Ph.D.
Occupational and Environmental Epidemiology BranchDivision of Cancer Epidemiology and Genetics
December 2, 2009
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Formaldehyde: An Important Chemical• Ubiquitous in the atmosphere and life forms
• >5% of yearly U.S. GDP
• 2.1 million U.S. workers exposed (1995)– Fixatives and disinfectants– Wood products, resins, molded plastics, crease-resistant
fabrics, paper products
• Environmental exposures– Off-gassing from home furnishings, automobile engines,
cigarette smoke, incomplete fuel combustion
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U.S. Occupational Standard
0.75 ppm for 8-hr time weighted average
2.0 ppm for short-term exposure limit
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Background: Evidence for Carcinogenicity
• Genotoxic
• Causes DNA-protein cross-links at site of contact
• Inhaled formaldehyde causes nasal tumors in rats
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Formaldehyde Research: 3 Exposure Scenarios
• NCI Cohort of Industrial Workers
• Study of Funeral Industry Workers
• Molecular Epidemiology Study
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Formaldehyde and Nasopharyngeal Cancer
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NCI Cohort of Industrial Workers
Blair, et al. JNCI 1986
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NCI Industrial Cohort Study• Mortality study of 25,619 workers in 10 plants
– Employed prior to 1966– Work histories through 1980
• Time-dependent exposure metrics
• 13,951 deaths as of 2004
• 42 years of median follow-up
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NCI Industrial Cohort Study:Nasopharyngeal Cancer
• 8 exposed cases – All cases in highest peak exposure category:
• RR=1.83, p-trend=0.044
Hauptmann, et al., Amer J Epidemiol, 2004
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Formaldehyde and Leukemia
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Relative Risks by Peak Formaldehyde Exposure (ppm)
0 >0-<2.0 2.0-<4.0 >4.0
RR
1.07
0.59
0.27
0.82
RR
1.0
1.0
1.0
1.0
RR
1.17
0.98
0.81
1.30
RR
1.37*
1.42
1.15
1.78
p-trend*0.02
>0.50
>0.50
0.13
Lymphohemato.
Leukemia
Lymphatic leukemia
Myeloid leukemia
Beane Freeman, et al., JNCI. 2009; 101: 751-761.
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RR for Medium and High Peak Formaldehyde Exposure Categories
0 .0 0
0 .2 5
0 .5 0
1 9 6 0 1 9 7 0 1 9 8 0 1 9 9 0 2 0 0 00 .1
1
1 0
Rel
ativ
e ris
k
C a le n d a r y e a r o f e n d o f fo l lo w - u p
M Y L
Exposure-response trend p-values
Myeloid Leukemia
RR for Peak Medium
High
Last known formaldehyde exposure
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0.00
0.25
0.50
1960 1970 1980 1990 20000.1
1
10
Rel
ativ
e ris
k
Calendar year of end of follow-up
MYL
0.00
0.25
0.50
1960 1970 1980 1990 20000.1
1
10
Rel
ativ
e ris
k
LYL
Calendar year of end of follow-up
RR for Medium and High Peak Formaldehyde Exposure Categories
RR for Peak Medium
High
Myeloid Leukemia Lymphatic Leukemia
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Study of Funeral Industry Workers
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Study of Funeral Industry Workers
• 6,808 deaths among 13,994 inactive/deceased funeral directors/embalmers
• Identified through professional associations and licensing boards
• 268 deaths from lymphohematopoietic malignancies, 34 from myeloid leukemia
• 286 controls: deaths due to natural causes, matched by study source, sex, dates of birth and death
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Study of Funeral Industry Workers:Exposure Assessment
• 1,278 interviews with next of kin and co-workers
• Work history, including embalming characteristics
• Exposure study– 25 embalmings under controlled conditions
• Ventilation• Solution strength• Type of case (intact or autopsy)
– Continuous measurement of formaldehyde concentration in breathing zone
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Study of Funeral Industry Workers: Results
• 3-fold increased risk of myeloid leukemia for– Longest duration of embalming – Most embalmings performed– Highest cumulative exposure
• First study to relate cancer risk to work practices in funeral industry
Hauptmann, et al. JNCI, 2009
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Molecular Epidemiology Study
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Molecular Epidemiology Study
• Is formaldehyde-->leukemia plausible?
• Formaldehyde is highly reactive
• Almost completely deposited in the upper respiratory tract
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Molecular Epidemiology Study of Formaldehyde in Guangdong, China*
Designed to evaluate whether formaldehyde can cause toxic effects on the bone marrow
43 workers in two plastic dish manufacturing plants currently exposed to formaldehyde (1-2 ppm)
51 healthy age- and sex-matched unexposed controls in three control factories
*Study initiated and designed by Drs. Lan and Rothman
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0
500
1000
1500
2000
2500
3000
3500
4000
4500
Granulocytes Platelets*100 MonocytesLymphocytes
Cel
ls/µ
l
Controls <1 ppm 1-10 ppm >10 ppm
p < 0.0001
p = 0.018
p = 0.018p = 0.023
0
500
1000
1500
2000
2500
3000
3500
4000
GranulocytesPlatelets*100 Monocytes
CFU_GM*10-3Lymphocytes
Cel
ls/u
l
Controls Exposedp = 0.02
p = 0.01 p = 0.0002
p = 0.07p = 0.09
Comparison of Benzene and Formaldehyde Exposures and Peripheral Blood Cells
Benzene Formaldehyde
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Hematopoietic progenitor cells from peripheral blood were cultured to measure chromosomal abnormalities relevant for myeloid leukemia
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0
5
10
15
20
Monosomy 7
Mon
osom
y 7
(%)
Controls (n=12)Exposed (n=10)
**
0
0.5
1
1.5
2
Trisomy 8
Tris
omy
8 (%
)
*
p < 0.05
p < 0.01
Formaldehyde Exposure and Leukemia-specific Chromosome Aberrations in Cultured Myeloid Progenitor
Cells (CFU_GM)
Controls Exposed
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Molecular Epidemiology Study: Results•Among formaldehyde-exposed workers we observed:
– Decrease in all cells derived from myeloid lineage progenitor cells
– Elevation of leukemia-specific chromosome changes in myeloid progenitor cells
•Suggests formaldehyde may cause toxic effects in bone marrow of exposed workers
•Findings support biologic plausibility of leukemia association
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Impact of Research Findings
• WHO-IARC review in 2004– Sufficient evidence for nasopharyngeal cancer– Strong, but not sufficient evidence for leukemia
• WHO-IARC review in 2009– Sufficient evidence for leukemia, particularly myeloid– Reaffirmed status for nasopharyngeal cancer
• National Toxicology Program Report on Carcinogens 2009– Outside Expert Panel– Sufficient evidence for nasopharyngeal cancer and myeloid leukemia
• EPA ongoing– Updating risk assessment of formaldehyde
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Formaldehyde Exposure and Risk of Nasopharyngeal Cancer and Leukemia
• Long-term investment recent results with leukemia
• Emerging molecular epidemiologic techniquescan address important issues (plausibility)
• Combination of strategies useful
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Collaborators
Cohort and Case-control StudiesNCI:Aaron Blair, Joseph F. Fraumeni, Jr., Michael Hauptmann, Richard Hayes, Robert Hoover, Jay Lubin, Trish Stewart
Harvard University:Robert Herrick
University of Cincinnati:Richard Hornung
Molecular Epidemiology StudyNCI:Qing Lan, Nat Rothman, Min Shen, Richard Hayes, Blanche Alter, Aaron Blair, Joseph F. Fraumeni Jr.
Guangdong National Poisoning Control Center (China):Xiaojian Tang
Utrecht University (Netherlands):Roel Vermeulen, Boris Reiss
UC Berkeley:Martyn Smith, Luoping Zhang, Stephen Rappaport