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 Study population FORM exposure metrics Ri 95% CI sk est im ate Ambroise et al.(1) 181 men ever employed in a Semi-quantitative expert rating for S 0.11-24.6 municipal pest-control service job-exposure matrix M between 1979 and 1994, followed Exposed to formaldehyde R= 1979-2000 4.4 2 (1 de ath ) Andjelkovich et al.(2) 3929 men who worked in an Any FORM exposure. S 0.05-1.57 automotive iron foundry and were (highest exposures estimated for core M exposed to FORM, 1960-1989 machine operation ≤ 2.6 ppm) R= 0.4 3 (2 de ath s) Beane Freeman et al. 25,619 workers in 10 FORM Job exposure matrix, professional (3) producing or using facilities who judgment of intensity and peak worked before 1966, followed Highest peak exposure (> 4 ppm vs. R 0.92-2.18 through 2004 >0 - <2 ppm ) R= 1.4 2 Reference Study population FORM exposure metrics Ri 95% CI sk est im ate (4 8 de ath s) Cumulative exposure ≥5.5 ppm-years R 0.70–1.74 (vs > 0 - <1.5) R= 1.1 1 (2 9 de ath s) Highest peak exposure (> 4 ppm vs. R 0.87-3.64 >0 - <2 ppm ) RM L =1. 78 (1 9 de ath s) Cumulative exposure ≥5.5 ppm-years R 0.70–1.74 (vs > 0 - <1.5) RM L= 1.1 Reference Study population FORM exposure metrics Ri 95% CI sk est im ate 1 (2 9 de ath s) Bertazzi et al.(4) 1332 men employed in a resin Any FORM exposure. S NR manufacturing facility, 1959-1986 (Air monitoring data had mean values M [0.36-5.06] 3 0.2-3.8 mg/m and maximum values RL 3 0.5-9.8 mg/m , 1974-1979) HP= 1.7 3 (3 de ath s) Blair et al.(5) Study of 513 leukemia cases from Low exposure intensity (expert O 0.5-1.6 cancer registry and hospital judgment) RA surveillance network and 1,087 ML population based controls, 1980- = 1983 0.9 (1 4 cas es) High exposure intensity (expert O judgment) RA ML Reference Study population FORM exposure metrics Ri 95% CI sk est im ate = 0 (0 cas es) Chiazze et al.(6) 4,631 white men who worked ≥ 1 Worked in fiberglass manufacturing S 0.01-1.36 year at a fiberglass manufacturing (Formaldehyde exposure assessment M plant, followed 1951-1991 used in case control study of R= respiratory cancers; not further 0.2 described for leukemia) 4 (U S rat es, 1 de ath ) S 0.01-1.50 M R= 0.2 7 (S C rat es, 1 de Reference Study population FORM exposure metrics Ri 95% CI sk est im ate ath )

Coggon et al. 2014(7) 14,014 men working at 7 companies High exposure (> 2 ppm TWA) S 0.40-1.82 that used or produced FORM. 3,991 M men with high exposure, followed RM 1941-2012 L = 0.9 3 (8 de ath s) High exposure ≥ 1 year O 0.24–3.82 RM L= 0.9 6 (4 cas es) Edling et al.(8) 521 men manufacturing abrasive Exposure based on job title No materials, followed 1958-1983 (Exposures described as moderate, leu 0.1-1 mg/m3; or intermittent, heavy ke with peaks up to 20-30 mg/m3.) mi a cas Reference Study population FORM exposure metrics Ri 95% CI sk est im ate es rep ort ed SI 0.2-7.2 RL Y= 2 (2 cas es) Hansen and Olsen(9) Diagnosed cancers among 2,041 Exposure based on job title SP 0-6-1.6 men and 1,263 women who worked IR at companies who manufactured or =0. used FORM, Denmark, 1970–1984 8 (3 9 cas es, me n) Exposed to formaldehyde only, based SP 0.6-1.4 on job title IR =1. 0 (2 3 cas Reference Study population FORM exposure metrics Ri 95% CI sk est im ate es, me n) Linos et al.(10) Case-control study of 578 men with Employed in funeral homes or O 0.4-10.0 leukemia and 625 men with non- crematories R Hodgkin’s lymphoma from cancer = registry and hospital surveillance 2.1 network and 1245 population-based (4 controls cas es an d 4 co ntr ols ex po se d) Employed in funeral homes or O 1.2-36.2 crematories RA ML =6. 7 (3 cas es an Reference Study population FORM exposure metrics Ri 95% CI sk est im ate d 4 co ntr ols ex po se d) Marsh et al.(11) 32,110 fiberglass workers employed Worked in fiberglass manufacturing S 0.80-1.06 ≥ 1 year between 1945 and 1978 in (FORM mean average concentration, M any of 10 facilities (US), followed 1946-1987, at all plants was 0.076 RL for mortality 1941-1992 ppm and mean cumulative exposure HP= 0.546 ppm-years.) 0.9 2 (U S rat es, 19 9 de ath s)

Partanen et al.(12) Case-control study of 12 cases of Exposed to formaldehyde O 0.25-7.91 leukemia, 4 cases of Hodgkin’s R= disease and 8 cases of NHL and 152 7.4 matched referents, Finish 0 Reference Study population FORM exposure metrics Ri 95% CI sk est im ate woodworking industry (2 cas es) Meyers et al.(13) 11,039 garment at 3 facilities; Exposed, based on job assignments S 0.73-1.44 worked ≥ 3 months before 1983 and (Personal exposures in early 1980s M followed 1955-1998 had GM = 0.15 ppm, GSD = 1.90) R= 0.67-2.05 1.0 4

S M RA ML =1. 22 Stellman et al.(14) 45,319 men participating in the Self-reported exposure, and not R 0.54-1.71 American Cancer Society Cancer woodworker R= Prevention study in wood-related 0.9 occupations and/or with exposure to Woodworker exposed to FORM 6 1.44-23.25 wood dust; 387 reported exposure to (1 FORM, followed 1982-1988 2 de ath s)

R R= 5.7 Reference Study population FORM exposure metrics Ri 95% CI sk est im ate 9 (2 de ath s) Stern et al.(15) 9,365 workers in one of two leather Tannery A S 0.19-1.80 tanneries, employed 1940-1980, M followed through 1982 R= 0.7 0 (M N rat es, 4 de ath s) Tannery B S 0.28-1.64 M R= 0.7 5 (W I rat es, 6 Reference Study population FORM exposure metrics Ri 95% CI sk est im ate de ath s) Worked in Finishing Department. S 0.5-2.58 (This area had highest FORM M exposures. The mean of 5 samples was R= 2.45 ppm, range 0.5-7 ppm). 1.2 5 (7 de ath s) 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 Study population TCE Risk estimate 95% CI exposure metrics Anttila et al.(17) 1,698 men and 1,391 women Exposed SIR=1.81 0.78-3.56 biologically monitored for TCE in (8 cases) Finland, followed 1967-1992 Urine levels < SIR=2.01 0.65-4.69 100 mol/L (5 cases) Urine levels ≥ SIR=1.40 0.17-5.04 100 mol/L (2 cases) Axelson et al.(18) 1,670 male workers in Sweden Ever exposed SIR=1.56 0.51-3.64 exposed to TCE, followed 1958-1987. (5 cases) Exposed < 2 SIR=1.47 0.04-8.19 years (1 case) Exposed ≥ 2 SIR=1.50 0.41-3.85 years (4 cases) Blair et al.(19) 14,457 aircraft maintenance civilian Exposed based RR=2.0 0.9-4.6 employees at the Hill Air Force Base on job titles (28 deaths) 1952-1956, followed through 1990. (compared to workers with no chemical exposures) Low, RR=1.5 0.5-4.3 intermittent (15 deaths) exposure among males relative to workers (Professional Reference Study population TCE Risk estimate 95% CI exposure metrics judgment) Low, RR=1.8 0.6-5.2 continuous (12 deaths) exposure among males (Professional judgment) Frequent peaks RR=1.5 0.5-4.4 in exposure (9 deaths) among males (Professional judgment) Boice et al.(20) 2,267 workers exposed to TCE among Judged to have SMR=1.19 0.65-1.99 77,965 workers employed ≥ 1 year potential (14 deaths) after 1960 at Lockheed Martin aircraft routine manufacturing factories, followed to exposure 1996. Potential SMR=1.62 0.82-3.22 routine or (14 deaths) intermittent exposure for ≥5 years relative to 0 years Boice et al.(21) 8,372 workers employed ≥ 6 months Judged to have SMR=0.21 0.01-1.18 after 1948 at the Santa Susana Field job titles with (1 death) Laboratory (Rocketdyne), followed to any potential 1999. for exposure Reference Study population TCE Risk estimate 95% CI exposure metrics (22) Greenland et al. Nested case-control study of 1,821 Any exposure ORLY=0.76 0.24–2.42 white male decedents formerly compared to (# cases not specified) employed at a transformer no exposure manufacturing plant before 1984, 1969-1984. Workers deceased from cancer were matched with workers deceased from other causes Hansen et al.(23) 803 workers in Denmark with Men. No cases SIR=3.5 0.6-4.4 personal air or urine measurements of among (8 cases) TCE, followed 1968-1996. women. Men with SIR= 3.9 1.1-10 mean (4 cases) individual exposure < 19 mg/m3 Men with SIR=3.2 1.1-10 mean (4 cases) individual exposure ≥ 19 mg/m3 Hardell et al.(24) 105 cases with NHL matched with Self-reported OR=1.0 Referent 335 controls, admitted to hospital work and 1974-1978, Sweden leisure history; No exposure Exposed OR=7.2 1.3-42 (4 ca/4 co exposed) Miligi et al.(25) 1,135 cases of NHL admitted to Professional hospitals matched with 1,246 judgment of population controls, 1991-1993, Italy probability and intensity of Reference Study population TCE Risk estimate 95% CI exposure metrics exposure from questionnaire data Very low or OR=0.8 0.5-1.3 low (35 cases) (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 OR=1.2 0.7-2.0 high (35 cases) (Medium and high were judged to result from working in a place with poor or no control measures, respectively.) (26) Morgan et al. 4,733 workers exposed to TCE among Potentially SMRLY=0.96 0.20-2.81 Reference Study population TCE Risk estimate 95% CI exposure metrics 20,508 workers employed ≥ 6 months exposed > 6 (3 deaths) at a Hughes aircraft manufacturing months site, 1950-1985, followed to 1985. Job exposure matrix, semi- quantitative score, professional judgment Peak: medium RR=1.31 0.28-6.08 and high vs (2 exposed) low and no exposure (peak defined as highest TCE exposure rating) Cumulative RR=2.25 0.46-11.09 low (2 exposed) Cumulative RR=0.81 0.10-6.49 high (1 exposed) (27) Nordström et al. 121 cases with Hairy Cell Leukemia Self-reported ORHCL=1.5 0.7-3.3 from cancer registry were matched exposure for ≥ (9 cases and 26 controls exposed) with 484 population controls , 1987- 1 day, with a 1 1992, Sweden year induction period versus no exposure Persson and 199 cases with NHL from hospital and Self-reported OR=1.2 0.5-2.4 Fredrikson(28) cancer registry matched with 479 work and (16 cases and 32 controls exposed) controls diagnosed between 1964- leisure 1986, Sweden exposure for ≥ Reference Study population TCE Risk estimate 95% CI exposure metrics 1 year 5-45 years before diagnosis versus no exposure Raaschou- 40,049 blue-collar workers employed Men SIR=1.2 0.98-1.52 Nielsen et al.(29) ≥ 3 months in one of 347 Danish (83 cases) companies with documented TCE use, Women SIR=1.4 0.73-2.34 1968-1997 (13 cases) Workers SIR=1.5 1.2-2.0 employed (65 cases) before 1980 and ≥ 1 year employment (mean concentration of trichloroethyle ne in Danish work environments was 318 mg/m3 for measurements taken in the 1960s and 75 mg/m3 for measurements taken in the 1980s Reference Study population TCE Risk estimate 95% CI exposure metrics Radican et al.(30) 14,457 civilian employees at the Hill Semi- Air Force Base 1992-1956, followed quantitative to 2000 score of frequency, intensity, and duration using professional judgment Any exposure HR=1.56 0.72-3.35 among males (37 deaths) Low, HR=1.50 0.67-3.34 intermittent (25 deaths) exposures among males Low, HR=1.74 0.76-3.97 continuous (20 deaths) exposures among males Infrequent HR=1.90 0.69-5.24 peak (7 deaths) exposures among males Frequent peak HR=1.57 0.67-3.69 exposures (16 deaths) among males Ritz(31) 3,814 white men employed ≥ 3 Job exposure months and first hired at the Fernald matrix, uranium-processing facility 1951- professional 1972, followed to 1989. judgment of exposure Reference Study population TCE Risk estimate 95% CI exposure metrics intensity

Low exposure RRLH=1.35 0.68-2.69 intensity for > (18 cases) 2 years, no lag

Moderate RRLY=0.98 0.13-7.41 exposure (1 case) intensity for > 2 years, no lag Seidler et al.(32) 710 cases with malignant lymphoma Semi- from hospital registries were matched quantitative with population-based controls, years scale of not identified intensity and frequency of exposure, Professional judgment No exposure OR = 1.0 Referent

>0 - ≤ 4.4 ORLY =0.7 0.4–1.1 ppm-yrs (40 ca/55 co (Professional Exposed) judgment)

>4.4 - ≤35 ORLY =0.7 0.5–1.2 ppm-yrs (32 ca/44 co) (Professional judgment)

>35 ppm-yrs ORLY=2.1 1.0–4.8 (Professional (21 ca/9 co) judgment) Subset of 554 cases of B-NHL No exposure OR=1.0 Referent

lymphoma compared to population- >0 - ≤ 4.4 ORB-NHL=0.7 0.5–2.0 Reference Study population TCE Risk estimate 95% CI exposure metrics based controls ppm-yrs (32 ca/55 co exposed) (Professional judgment)

>4.4 - ≤35 ORB-NHL=0.8 0.5–1.3 ppm-yrs (27 ca/44 co exposed) (Professional judgment)

>35 ppm-yrs ORB-NHL=2.3 1.0–5.3 (Professional (17 ca/9 co exposed) judgment) Wang et al.(33) 601 cases of NHL from cancer Job-exposure registry matched with 717 population- matrix, semi- based controls, 1996-2000, quantitative Connecticut score Working at job OR=1.2 0.9-1.8 with exposure (77 ca/79 co exposed) relative to never exposed Low exposure OR=1.1 0.8-1.6 intensity (64 ca/71 co exposed) relative to no exposure Medium-high OR=2.2 0.9-5.4 exposure (13 ca/8 co exposed) intensity relative to no exposure Zhao et al.(34) 6,044 men employed 1950-1979 and Semi- worked for ≥ 2 years at any quantitative Rocketdyne/Rockwell facility, score, RRNHL+LK=1.5 0.86-2.57 Reference Study population TCE Risk estimate 95% CI exposure metrics followed 1950-2001. professional (27 deaths) judgment Medium exposure versus low exposure

High exposure RRNHL+LK=1.3 0.52-3.23 versus low (6 deaths) exposure

Subcohort of 5,049 followed for Medium RRNHL+LK=0.9 0.47-1.65 cancer incidence, 1988-2000 exposure (16 incident cancers) versus low exposure

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