Exposure Reconstruction and Risk Analysis for Six Semiconductor Workers with
Lymphohematopoietic Cancers
SUPPLEMENTARY MATERIALS
Table S.I. Occupational epidemiology studies identified by consensus panels or government agencies in determining whether
formaldehyde (FORM) is capable of causing leukemia. All outcome measures are for leukemia unless otherwise specified
(myeloid leukemia denoted ML, acute myeloid leukemia denoted AML, lyphohematopoietic cancers denoted LHP)
Reference
Ambroise et al.(1)
Andjelkovich et al.(2)
Beane Freeman et
al.(3)
Study population
181 men ever employed in a
municipal pest-control service
between 1979 and 1994, followed
1979-2000
3929 men who worked in an
automotive iron foundry and were
exposed to FORM, 1960-1989
25,619 workers in 10 FORM
producing or using facilities who
worked before 1966, followed
through 2004
Bertazzi et al.(4)
1332 men employed in a resin
manufacturing facility, 1959-1986
Blair et al.(5)
Study of 513 leukemia cases from
cancer registry and hospital
surveillance network and 1,087
population based controls, 19801983
4,631 white men who worked ≥ 1
year at a fiberglass manufacturing
Chiazze et al.(6)
FORM exposure metrics
Semi-quantitative expert rating for
job-exposure matrix
Exposed to formaldehyde
Risk estimate
SMR=4.42
(1 death)
95% CI
0.11-24.6
Any FORM exposure.
(highest exposures estimated for core
machine operation ≤ 2.6 ppm)
Job exposure matrix, professional
judgment of intensity and peak
Highest peak exposure (> 4 ppm vs.
>0 - <2 ppm )
Cumulative exposure ≥5.5 ppm-years
(vs > 0 - <1.5)
Highest peak exposure (> 4 ppm vs.
>0 - <2 ppm )
Cumulative exposure ≥5.5 ppm-years
(vs > 0 - <1.5)
Any FORM exposure.
(Air monitoring data had mean values
0.2-3.8 mg/m3 and maximum values
0.5-9.8 mg/m3, 1974-1979)
Low exposure intensity (expert
judgment)
High exposure intensity (expert
judgment)
SMR=0.43
(2 deaths)
0.05-1.57
RR= 1.42
(48 deaths)
RR=1.11
(29 deaths)
RRML =1.78
(19 deaths)
RRML=1.11
(29 deaths)
SMRLHP=1.73
(3 deaths)
0.92-2.18
ORAML = 0.9
(14 cases)
ORAML= 0
(0 cases)
0.5-1.6
Worked in fiberglass manufacturing
(Formaldehyde exposure assessment
SMR=0.24
(US rates, 1
0.01-1.36
0.70–1.74
0.87-3.64
0.70–1.74
NR
[0.36-5.06]
Reference
Coggon et al. 2014(7)
Edling et al.(8)
Hansen and Olsen(9)
Linos et al.(10)
Marsh et al.(11)
Study population
plant, followed 1951-1991
14,014 men working at 7 companies
that used or produced FORM. 3,991
men with high exposure, followed
1941-2012
521 men manufacturing abrasive
materials, followed 1958-1983
Diagnosed cancers among 2,041
men and 1,263 women who worked
at companies who manufactured or
used FORM, Denmark, 1970–1984
Case-control study of 578 men with
leukemia and 625 men with nonHodgkin’s lymphoma from cancer
registry and hospital surveillance
network and 1245 population-based
controls
32,110 fiberglass workers employed
≥ 1 year between 1945 and 1978 in
any of 10 facilities (US), followed
for mortality 1941-1992
FORM exposure metrics
used in case control study of
respiratory cancers; not further
described for leukemia)
Risk estimate
death)
95% CI
SMR=0.27
(SC rates, 1
death)
0.01-1.50
High exposure (> 2 ppm TWA)
SMRML = 0.93
(8 deaths)
ORML=0.96
(4 cases)
No leukemia
cases reported
SIRLY=2
(2 cases)
SPIR=0.8
(39 cases, men)
SPIR=1.0
(23 cases, men)
OR = 2.1
(4 cases and 4
controls
exposed)
ORAML=6.7
(3 cases and 4
controls
exposed)
SMRLHP=0.92
(US rates, 199
deaths)
0.40-1.82
High exposure ≥ 1 year
Exposure based on job title
(Exposures described as moderate,
0.1-1 mg/m3; or intermittent, heavy
with peaks up to 20-30 mg/m3.)
Exposure based on job title
Exposed to formaldehyde only, based
on job title
Employed in funeral homes or
crematories
Employed in funeral homes or
crematories
Worked in fiberglass manufacturing
(FORM mean average concentration,
1946-1987, at all plants was 0.076
ppm and mean cumulative exposure
0.546 ppm-years.)
0.24–3.82
0.2-7.2
0-6-1.6
0.6-1.4
0.4-10.0
1.2-36.2
0.80-1.06
Reference
Partanen et al.(12)
Meyers et al.(13)
Stellman et al.
Stern et al.(15)
(14)
Study population
Case-control study of 12 cases of
leukemia, 4 cases of Hodgkin’s
disease and 8 cases of NHL and 152
matched referents, Finish
woodworking industry
11,039 garment at 3 facilities;
worked ≥ 3 months before 1983 and
followed 1955-1998
45,319 men participating in the
American Cancer Society Cancer
Prevention study in wood-related
occupations and/or with exposure to
wood dust; 387 reported exposure to
FORM, followed 1982-1988
9,365 workers in one of two leather
tanneries, employed 1940-1980,
followed through 1982
FORM exposure metrics
Exposed to formaldehyde
Risk estimate
OR=7.40
(2 cases)
95% CI
0.25-7.91
Exposed, based on job assignments
(Personal exposures in early 1980s
had GM = 0.15 ppm, GSD = 1.90)
Self-reported exposure, and not
woodworker
SMR=1.04
0.73-1.44
SMRAML=1.22
RR=0.96
(12 deaths)
0.67-2.05
0.54-1.71
Woodworker exposed to FORM
RR=5.79
(2 deaths)
1.44-23.25
Tannery A
SMR=0.70
(MN rates, 4
deaths)
SMR=0.75
(WI rates, 6
deaths)
SMR=1.25
(7 deaths)
0.19-1.80
Tannery B
Worked in Finishing Department.
(This area had highest FORM
exposures. The mean of 5 samples was
2.45 ppm, range 0.5-7 ppm).
0.28-1.64
0.5-2.58
Table S.II. Occupational epidemiology studies identified by consensus panels or government agencies in determining whether
trichloroethylene (TCE) is capable of causing non-Hodgkin’s lymphoma (NHL). All outcome measures are for NHL unless
otherwise specified (all lymphomas denoted by LY, hairy cell leukemia denoted by HCL, all lyphohematopoietic cancers
denoted LHP, leukemia denoted by LK).
Reference
Anttila et al.(17)
Axelson et al.(18)
Blair et al.(19)
Boice et al.(20)
Boice et al.(21)
Study population
1,698 men and 1,391 women
biologically monitored for TCE in
Finland, followed 1967-1992
1,670 male workers in Sweden
exposed to TCE, followed 1958-1987.
14,457 aircraft maintenance civilian
employees at the Hill Air Force Base
1952-1956, followed through 1990.
2,267 workers exposed to TCE among
77,965 workers employed ≥ 1 year
after 1960 at Lockheed Martin aircraft
manufacturing factories, followed to
1996.
8,372 workers employed ≥ 6 months
TCE exposure metrics
Exposed
Risk estimate
SIR=1.81
(8 cases)
SIR=2.01
Urine levels < 100 mol/L
(5 cases)
SIR=1.40
Urine levels ≥ 100 mol/L
(2 cases)
Ever exposed
SIR=1.56
(5 cases)
Exposed < 2 years
SIR=1.47
(1 case)
Exposed ≥ 2 years
SIR=1.50
(4 cases)
Exposed based on job titles (compared RR=2.0
to workers with no chemical exposures) (28 deaths)
Low, intermittent exposure among
RR=1.5
males relative to workers (Professional (15 deaths)
judgment)
Low, continuous exposure among
RR=1.8
males (Professional judgment)
(12 deaths)
Frequent peaks in exposure among
RR=1.5
males (Professional judgment)
(9 deaths)
Judged to have potential routine
SMR=1.19
exposure
(14 deaths)
Potential routine or intermittent
SMR=1.62
exposure for ≥5 years relative to 0
(14 deaths)
years
Judged to have job titles with any
SMR=0.21
95% CI
0.78-3.56
0.65-4.69
0.17-5.04
0.51-3.64
0.04-8.19
0.41-3.85
0.9-4.6
0.5-4.3
0.6-5.2
0.5-4.4
0.65-1.99
0.82-3.22
0.01-1.18
Reference
Greenland et al.(22)
Hansen et al.(23)
Hardell et al.(24)
Study population
after 1948 at the Santa Susana Field
Laboratory (Rocketdyne), followed to
1999.
Nested case-control study of 1,821
white male decedents formerly
employed at a transformer
manufacturing plant before 1984,
1969-1984. Workers deceased from
cancer were matched with workers
deceased from other causes
803 workers in Denmark with
personal air or urine measurements of
TCE, followed 1968-1996.
105 cases with NHL matched with
335 controls, admitted to hospital
1974-1978, Sweden
TCE exposure metrics
potential for exposure
1,135 cases of NHL admitted to
hospitals matched with 1,246
population controls, 1991-1993, Italy
95% CI
Any exposure compared to no exposure ORLY=0.76
(# cases not
specified)
0.24–2.42
Men. No cases among women.
SIR=3.5
(8 cases)
SIR= 3.9
(4 cases)
SIR=3.2
(4 cases)
OR=1.0
0.6-4.4
OR=7.2
(4 ca/4 co
exposed)
1.3-42
OR=0.8
(35 cases)
0.5-1.3
OR=1.2
0.7-2.0
Men with mean individual exposure
< 19 mg/m3
Men with mean individual exposure
≥ 19 mg/m3
Self-reported work and leisure history;
No exposure
Exposed
Miligi et al.(25)
Risk estimate
(1 death)
Professional judgment of probability
and intensity of exposure from
questionnaire data
Very low or low
(Very low was judged equal to upper
end of range for general public, while
low was judged to be similar to
working environment with control
measures.)
Medium or high
1.1-10
1.1-10
Referent
Reference
Study population
Morgan et al.(26)
4,733 workers exposed to TCE among
20,508 workers employed ≥ 6 months
at a Hughes aircraft manufacturing
site, 1950-1985, followed to 1985.
Nordström et al.(27)
Persson and
Fredrikson(28)
RaaschouNielsen et al.(29)
121 cases with Hairy Cell Leukemia
from cancer registry were matched
with 484 population controls , 19871992, Sweden
199 cases with NHL from hospital and
cancer registry matched with 479
controls diagnosed between 19641986, Sweden
40,049 blue-collar workers employed
≥ 3 months in one of 347 Danish
companies with documented TCE use,
1968-1997
TCE exposure metrics
(Medium and high were judged to
result from working in a place with
poor or no control measures,
respectively.)
Potentially exposed > 6 months
Job exposure matrix, semi-quantitative
score, professional judgment
Peak: medium and high vs low and no
exposure (peak defined as highest TCE
exposure rating)
Cumulative low
Risk estimate
(35 cases)
95% CI
SMRLY=0.96
(3 deaths)
0.20-2.81
RR=1.31
(2 exposed)
0.28-6.08
RR=2.25
(2 exposed)
Cumulative high
RR=0.81
(1 exposed)
Self-reported exposure for ≥ 1 day,
ORHCL=1.5
with a 1 year induction period versus
(9 cases and
no exposure
26 controls
exposed)
Self-reported work and leisure
OR=1.2
exposure for ≥ 1 year 5-45 years before (16 cases and
diagnosis versus no exposure
32 controls
exposed)
Men
SIR=1.2
(83 cases)
Women
SIR=1.4
(13 cases)
Workers employed before 1980 and ≥ 1 SIR=1.5
year employment (mean concentration (65 cases)
of trichloroethylene in Danish work
environments was 318 mg/m3 for
measurements taken in the
0.46-11.09
0.10-6.49
0.7-3.3
0.5-2.4
0.98-1.52
0.73-2.34
1.2-2.0
Reference
Study population
Radican et al.(30)
14,457 civilian employees at the Hill
Air Force Base 1992-1956, followed
to 2000
TCE exposure metrics
1960s and 75 mg/m3 for measurements
taken in the 1980s
Semi-quantitative score of frequency,
intensity, and duration using
professional judgment
Any exposure among males
Low, intermittent exposures among
males
Low, continuous exposures among
males
Infrequent peak exposures among
males
Frequent peak exposures among males
Ritz(31)
Seidler et al.(32)
3,814 white men employed ≥ 3
months and first hired at the Fernald
uranium-processing facility 19511972, followed to 1989.
710 cases with malignant lymphoma
from hospital registries were matched
with population-based controls, years
not identified
Job exposure matrix, professional
judgment of exposure intensity
Low exposure intensity for > 2 years,
no lag
Moderate exposure intensity for > 2
years, no lag
Semi-quantitative scale of intensity and
frequency of exposure, Professional
judgment
No exposure
>0 - ≤ 4.4 ppm-yrs (Professional
judgment)
>4.4 - ≤35 ppm-yrs (Professional
judgment)
>35 ppm-yrs (Professional judgment)
Risk estimate
95% CI
HR=1.56
(37 deaths)
HR=1.50
(25 deaths)
HR=1.74
(20 deaths)
HR=1.90
(7 deaths)
HR=1.57
(16 deaths)
0.72-3.35
RRLH=1.35
(18 cases)
RRLY=0.98
(1 case)
0.68-2.69
OR = 1.0
ORLY =0.7
(40 ca/55 co
Exposed)
ORLY =0.7
(32 ca/44 co)
ORLY=2.1
Referent
0.4–1.1
0.67-3.34
0.76-3.97
0.69-5.24
0.67-3.69
0.13-7.41
0.5–1.2
1.0–4.8
Reference
Study population
TCE exposure metrics
Subset of 554 cases of B-NHL
lymphoma compared to populationbased controls
No exposure
>0 - ≤ 4.4 ppm-yrs (Professional
judgment)
>4.4 - ≤35 ppm-yrs (Professional
judgment)
>35 ppm-yrs (Professional judgment)
Wang et al.(33)
601 cases of NHL from cancer
registry matched with 717 populationbased controls, 1996-2000,
Connecticut
Job-exposure matrix, semi-quantitative
score
Working at job with exposure relative
to never exposed
Low exposure intensity relative to no
exposure
Medium-high exposure intensity
relative to no exposure
Zhao et al.(34)
6,044 men employed 1950-1979 and
worked for ≥ 2 years at any
Rocketdyne/Rockwell facility,
followed 1950-2001.
Semi-quantitative score, professional
judgment
Medium exposure versus low exposure
High exposure versus low exposure
Subcohort of 5,049 followed for
cancer incidence, 1988-2000
Medium exposure versus low exposure
High exposure versus low exposure
Risk estimate
(21 ca/9 co)
OR=1.0
ORB-NHL=0.7
(32 ca/55 co
exposed)
ORB-NHL=0.8
(27 ca/44 co
exposed)
ORB-NHL=2.3
(17 ca/9 co
exposed)
95% CI
OR=1.2
(77 ca/79 co
exposed)
OR=1.1
(64 ca/71 co
exposed)
OR=2.2
(13 ca/8 co
exposed)
0.9-1.8
RRNHL+LK=1.5
(27 deaths)
RRNHL+LK=1.3
(6 deaths)
RRNHL+LK=0.9
(16 incident
cancers)
RRNHL+LK=0.2
0.86-2.57
Referent
0.5–2.0
0.5–1.3
1.0–5.3
0.8-1.6
0.9-5.4
0.52-3.23
0.47-1.65
0.03-1.46
Reference
Study population
TCE exposure metrics
Risk estimate
(1 incident
cancer)
95% CI
REFERENCES
1. Ambroise D, Moulin JJ, Squinazi F, Protois JC, Fontana JM, Wild P. Cancer mortality
among municipal pest-control workers. Int Arch Occup Environ Health. 2005; 78: 387393.
2. Andjelkovich DA, Janszen DB, Brown MH, Richardson B, Miller FJ. Mortality of iron
foundry workers: IV. Analysis of a subcohort exposed to formaldehyde. J Occup Environ
Med. 1995; 37: 826-837.
3. Beane Freeman LE, Blair A, Lubin JH, Stewart PA, Hayes RB, Hoover RN, et al.
Mortality from lymphohematopoietic malignancies among workers in formaldehyde
industries: the National Cancer Institute cohort. J Natl Cancer Inst 2009; 101:751–761.
4. Bertazzi PA, Pesatori A, Guercilena S, Consonni D, Zocchetti. C. Rischio cancerogeno
per i producttori di resine esposti a formaldeide: estensione del follow up. xposure to
formaldehyde and cancer mortality in a cohort of workers producing resins. Med Lav
1989; 80: 111-122.
5. Blair A, Zheng T, Linos A, Stewart PA, Zhang YW, Cantor KP. Occupation and
leukemia: A population-based case-control study in Iowa and Minnestoa. Am J Ind Med.
2001; 40: 3-14.
6. Chiazze L, Watkins DK, Fryar C. Historical cohort mortality study of a continuous
filament fiberglass manufacturing plant: I. White men. J Occup Enviorn Med. 1997; 39:
432-441.
7. Coggon D, Ntani G, Harris EC, Palmer KT. Upper airway cancer, myeloid leukemia, and
other cancers in a cohort of British chemical workers exposed to formaldehyde. Am J
Epidemiol 2014; 179: 1301-1311.
8. Edling C, Järvholm B, Andersson L, Axelson O. Mortality and cancer incidence among
workers in an abrasive manufacturing facility. Br J Ind Med. 1987; 44: 57-59.
9. Hansen J, Olsen JH. Formaldehyde and cancer morbidity among male employees in
Denmark. Cancer Causes Control. 1996; 6: 354-360.
10. Linos A, Blair A, Cantor KP, Burmeister L, VanLier S, Gibson RW, Schuman L, Everett
G. Leukemia and non-Hodgkin’s lymphoma among embalmers and funeral directors. J
Natl Cancer Inst. 1990; 82: 66.
11. Marsh GM, Youk AO, Stone RA, Buchanich JM, Gula MJ, Smith TJ, Quinn MM.
Historical cohort study of US man-made vitreous fiber production workers: I. 1992
fiberglass cohort follow-up: Initial findings. J Occup Envion Med. 2001: 43: 741-756.
12. Partanen T, Kauppinen T, Hernberg S, Nickels J, Luukkonen R, Hakulinen T, Pukkala E.
Formaldehyde exposure and respiratory cancer among woodworkers – an update. Scand J
Work Environ Health. 1990; 16: 394-400.
13. Meyers AR, Pinkerton LE, Hein MJ. Cohort mortality study of garment industry workers
exposed to formaldehyde: update and internal comparisons. Am J Ind Med. 2013; 56:
1027-1039.
14. Stellman SD, Demers PA, Colin D, Boffetta P. Cancer morality and wood dust exposure
among participants in the American Cancer Society Cancer Prevention Study – II (CPSII). Am J Ind Med. 1998; 34: 229-237.
15. Stern FB, Beaumont JJ, Halperin WE, Murthy LI, Hills BW, Fajen JM. Mortality of
chrome leather tannery workers and chemical exposures in tanneries. Scand J Work
Environ Health. 1987; 13: 108-117.
16. West RR, Stafford DA, Farrow A, Jacobs A. Occupational and environmental exposures
and myelodysplasia: a case-control study. Leuk Res. 1995; 19: 127-139.
17. Antilla A, Pukkala E, Sallmén M, Hernberg S, Hemminki K. Cancer incidence among
Finnish workers exposed to halogenated hydrocarbons. J Occup Environ Med. 1995; 37:
797-806.
18. Axelson O, Seldén A, Andersson K, Hogstedt C. Updated and expanded Swedish cohort
study on trichloroethylene and cancer risk. J Occup Environ Med. 1994; 36: 556-562.
19. Blair A, Harge P, Stewart PA, McAdams M, Lubin JH. Morality and cancer incidence of
aircraft maintenance workers exposed to trichloroethylene and other organic solvents and
chemicals: extended follow-up. Occup Environ Med. 1998; 55: 161-171.
20. Boice JD, Marano DE, Fryzek JP, Sadler CJ, McLaughlin JK. Mortality among aircraft
manufacturing workers. Occup Environ Med. 1999; 56: 581-597.
21. Boice JD, Marano DE, Cohen SS, Mumma MT, Blot WJ, Brill AB, et al. Mortality
among Rocketdyne workers who tested rocket engines, 1948-1999. J Occup Environ
Med. 2006; 48: 1070-1092.
22. Greenland S, Slavan A, Wegman DH, Hallock MF, Smith TJ. A case-control study of
cancer mortality at a transformer-assembly facility. Int Arch Occup Environ Health.
1994; 66: 49-54.
23. Hansen J, Raaschou-Nielsen O, Christensen JM, Johansen I, McLaughlin JK, Lipworth
L, et al. Cancer incidence among Danish workers exposed to trichloroethylene. J Occup
Environ Med. 2001; 43: 133-139.
24. Hardell L, Eriksson M, Degerman A. Exposure to phenoxyacetic acids, clorophenols, or
organic solvents in relation to histopathology, stage and anatomic localization of nonHodgkin’s lymphoma. Cancer Res. 1994; 54: 2386-2389.
25. Miligi L, Costantini AS, Benvenuti A, Kriebel D, Bolejack V, Tumino R, et al.
Occupational exposure to solvents and the risk of lymphomas. Epidemiology. 2006; 17:
552-561.
26. Morgan RW, Kelsh MA, Zhao K, Heringer S. Morality of aerospace workers exposed to
trichloroethylene. Epidemiology. 1998; 9: 424-431.
27. Nordström M, Hardell L, Magnuson A, Hagberg H, Rask-Andersen A. Occupational
exposures, animal exposure and smoking as risk factors for hairy cell leukaemia
evaluated in a case-control study. Br J Cancer . 1996; 77: 2048-2052.
28. Persson B, Fredrikson M. Some risk factors for non-Hodgkin’s lymphoma. Int J Occup
Med Environ Health. 1999; 12: 135-142.
29. Raaschou-Nielsen O, Hansen J, McLaughlin JK, Kolstad H, Christensen JM, Tarone RE,
Olsen JH. Cancer risk among workers at Danish companies using trichloroethylene: a
cohort study. Am J Epidemiol. 2003; 158:1182-1192.
30. Radican L, Blair A, Stewart P, Wartenberg D. Mortality of aircraft maintenance workers
exposed to trichloroethylene and other hydrocarbons and chemicals: Extended follow-up.
J Occup Environ Med. 2008; 50: 1306-1319.
31. Ritz B. Cancer mortality among workers exposed to chemicals during uranium
processing. J Occup Envrion Med. 1999; 41: 556-566.
32. Seidler A, Möhner M, Berger J, Mester B, Deeg E, Eisner G, et al. Solvent exposure and
malignant lymphoma: a population-based case-control study in Germany. J. Occup. Med.
Toxicol. 2007; 2:2
33. Wang R, Zhang Y, Lan Q, Holford TR, Leaderer B, Hoar Zahm, S, et al. Occupational
exposure to solvents and risk of non-Hodgkin’s lymphoma in Connecticut women. Am J
Epidemiol. 2008; 169: 176-185.
34. Zhao Y, Krishnadasn A, Kennedy N, Morgenstern H, Ritz B. Estimated effects of
solvents and mineral oils on cancer incidence and morality in a cohort of aerospace
workers. Am J Ind Med. 2005; 48: 249-258.