Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Figures & data

Table 1.  Formaldehyde cohort studies.

Reference	Study population	Subjects (n)	Job/Exposure Category	Period of Employment	Period of Follow-up	Total Follow-Up (person-years)	Minimum Employment (years)	Mean Time-Weighted Average Exposure (ppm)	Peak Exposure (ppm)	Cumulative Number of Peaks ≥4.0 ppm
Harrington and Shannon, 1975	UK Pathologists and medical laboratory technicians	156 154	Pathologists Medical laboratory technicians	1955–1973 1963–1973	1955–1973 1963–1973	24,119.7 73,025.6
Walrath and Fraumeni, 1983	New York State embalmers	1,132	Embalmers (length of time from first license to death was used to approximate exposure)	1902–1980	1925–1980
Wong et al., 1983	United States Formaldehyde plant workers	2,026	White male chemical workers	1940–1977	1940–1977	32,514.3
Levine et al., 1984	Ontario, Canada undertakers	1,477	Undertakers exposed to formaldehyde	1928–1957	1950–1977	34,774
Walrath and Fraumeni, 1984	California embalmers	1,007	Embalmers (length of time from first license to death was used to approximate exposure)	1916–1978	1925–1980
Bertazzi et al., 1986, 1989	Italian male resin producers	1,332	Workers exposed to formaldehyde, exposed to other compounds or exposure unknown	1959–1980	1959–1986	5,731	≥1 month
Logue et al., 1986	US radiologists and pathologists	785 455	Radiologists Pathologists (based on entrance into professional society)	1962–1977	1962–1977
Stroup et al., 1986	US anatomists	2,317	Anatomists	1889–1969	1925–1979
Edling et al., 1987	Swedish abrasive manufacturing workers	521	Abrasives industry workers	1958–1981	1958–1981		≥5
Robinson et al., 1987	US plywood mill workers	2,283	Plywood mill workers	1945–1955	1945–1977	57,588	≥1
Stern et al., 1987	Minnesota and Wisconsin leather tannery workers	9,365	Tannery A Tannery B Department (finishing 0.5–7 ppm formaldehyde)	1940–1979	1940–1982
Matanoski et al., 1991	US pathologists	6,411	Pathologists	1912–1950	1925–1978
Hayes et al., 1990	US embalmers and funeral directors	4,046	Embalmers and funeral directors exposed to formaldehyde (measured average 0.98–3.99 ppm and peak 20 ppm)	NR	1975–1985
Hall et al., 1991	UK pathologists	3,872	Pathologists	1974–1987	1974–1987
Andjelkovich et al., 1995	US iron foundry workers	3,929	Iron foundry workers (formaldehyde exposed or unexposed)	1960–1987	1960–1989	83,064	≥6 months	Low 0.05 Medium 0.55 High 1.5
Dell and Teta, 1995	New Jersey workers at plastics manufacturing and R&D facility	5,932	Hourly and salaried employees	1946–1967	1946–1988		≥7 months
Hansen and Olsen, 1995	Denmark formaldehyde male workers	126,347	Working for company making or importing formaldehyde at least 10 years before diagnosis	1970–1984	1970–1984
Chiazze et al., 1997	South Carolina fiberglass workers	4,631	Cumulative exposure to formaldehyde	1951–1991	1951–1991	73,259
Stellman et al., 1998	US wood industry workers	45,399	Woord workers Wood dust exposed workers (asbestos and formaldehyde exposure)	1982–1988	1982–1988	2,101,145
Marsh et al., 2001	US fiberglass workers	32,110	Workers exposed to formaldehyde in ten fiberglass plants	1945–1978	1946–1992	209,726	≥1
Coggon et al., 2003	UK factory workers where formaldehyde was used or produced	14,014	Formaldehyde production workers	1941–1989	1941–2000			<0.1 0.1–0.5 0.6–2.0 >2.0
Pinkerton et al., 2004	Georgia and Pennsylvania garment workers	11,039	Garment workers	1955–1982	1955–1998		≥3 months
Ambroise et al., 2005	French pest-control workers	181	Pest-control workers (ever employed)	1979–2000	1979–2000	3107
Beane Freeman et al., 2009 (update of Hauptmann et al., 2003)	US workers at formaldehyde production or usage plants	25,619	Formaldehyde production workers (exposed or unexposed)	1934–1966	1934–2004	998,106			0 0.1–1.9 2.0–3.9≥4.0	Data not shown
Reference	Average intensity (ppm)	Cumulative exposure (ppm)	Duration of exposure or length of employment (years)	Time since first exposure (years)	Latency period (years)	Hire date or year of first exposure (year)	ICD code	Observed (total)	Expected (total)	Possible co-exposures discussed
Harrington and Shannon, 1975							ICD-8, 200–209 201 204–207	8/3 1/01/1	4.0/5.5 0.7/1.6 1.6/2.2
Walrath and Fraumeni, 1983					<35 ≥35		ICD-8, 200–209 200 201 202, 203 204–207	25 5 2 6 12	20.6 4.7 2.3 4.9 8.5	Embalming fluids that contain other chemicals (e.g., tissue moisturizers, antiseptic solutions, dyes, and deodorizers)
Wong et al., 1983			<5 5–9 10–14 15–19 20+		10 20	Before 1961 After 1961	ICD-8, 200–209 201 204–207	6 2 2	4.42 0.83 1.70	Formaldehyde, oxygenated hydrocarbons, benzene, asbestos, pigments
Levine et al., 1984							ICD-8, 200–209 204–207	8 4	6.5 2.5	Methanol, phenol, and dyes
Walrath and Fraumeni, 1984			<20 ≥20				ICD-8, 200–209 200 201 202, 203, 208, 209 204–207	19 3 0 4 12	15.6 3.1 2.5 3.0 6.9	Embalming fluids containing coloring and modifying agents, anticoagulants, surfactants, deodorants, and vehicles
Bertazzi et al., 1986, 1989							ICD-8, 200–209	3	1.11	Styrene, polystyrene
Logue et al., 1986						Before 1962 After 1962	ICD-7, 200–203, 205 204	Not reported	Not reported	Radiation
Stroup et al., 1986							ICD-8, 200–209 200 201 204–207 202–203, 208–209	18 2 0 10 6	14.6 2.9 1.9 6.8 3.0	Solvents, methyl alcohol, phenol, and biological agents
Edling et al., 1987							ICD-8, 200–202 203	2 2	1.0 0.5	Aluminum oxide, silicon carbide, clay, phenol, silica, total dust
Robinson et al., 1987			<20 ≥20		<20 ≥20		ICD-7, 200 201 204 202, 205	4 2 3 3	3.9 1.8 0.9 1.1	Wood dust, pentachlorophenol, carbon disulfide, and volatiles
Stern et al., 1987			<1 1–9 ≥10		≥15		ICD-7, 200–205 204 200–203, 205	8/14 4/6 4/8	12.3/19.4 5.2/8.0 7.0/11.4	Cu, Cr, Mn, Co, n-butyl acetate, MEK, MIK, toluene, xylene, acetone, dust, and butyl cellosolve
Matanoski et al., 1991							ICD-8, 200–209 201204–207	115 3 34 12 20 22 7 24 20 3 4	82.7 4.2 27.1 10.7 14.6 16.3 9.4 15.3 8.8 0.8 2.6	Phenol, methyl alcohol, glutaraldehyde, and biologic materials, and in the past were exposed to mercury, arsenic, and zinc
Hayes et al., 1990							ICD-8, 200–209 201 200, 202 200 203 202 204 205 206, 207 208 209	1104	0.83 6.93 2.63
Hall et al., 1991							ICD-8, 201 200–209 204–207	57 2 31	45.6 5.6 23.0	Other chemicals and infectious agents
Andjelkovich et al., 1995							ICD-8, 200–209 200 201 204–207	7 1 1 2	12.0 1.8 1.4 4.6	Silica, PAHs, nickel, and chromium
Dell and Teta, 1995			<5 5–9 10–19 ≥20		0 10 15		ICD-7, 200–205 200 204 204.4	23 3 11 8	13.63 2.39 5.56 4.30	Asbestos, carbon black, epichlorohydrin, formaldehyde, polyvinyl chloride (PVC), acrylonitrile, styrene, and numerous chemical additives, such, as plasticizers, emulsifiers, and antioxidants
Hansen and Olsen, 1995							ICD-7, 200, 202 201 204	32 12 39	27.2 12.2 47.0	Wood dust, other chemicals
Chiazze et al., 1997							ICD-7, 200–205 204	51	10.8 54.11	Respirable glass fibers, total particulate, asbestos, refractory ceramic fibers, respirable silica, total chrome, and arsenic
Stellman et al., 1998			<10 10–19 ≥20				ICD-9, 200–208 200, 202 203 204–208	28 11 4 12	NR	Wood dust and asbestos
Marsh et al., 2001							ICD-8, 200–209	199	NR	Fiberglass fibers, arsenic, asbestos, asphalt, epoxy, phenolics, silica, styrene, and urea
Coggon et al., 2003			<1 1–14 ≥15				ICD-9, 201 200, 202, 202.1, 202.8 203 204–208	6 31 15 31	8.5 31.7 17.5 34.1	Asbestos, styrene, ethylene oxide, epichlorhydrin, solvents, chromium, and cadmium
Pinkerton et al., 2004			<3 3–9 ≥10	<1010–19≥20		<19631963–1970≥1971	ICD-9, 200–208 200 201 204–208 202–203	59 5 2 24 28	60.8 5.9 3.6 22.0 28.9
Ambroise et al., 2005		Four quartiles of exposure					ICD-9, 204–208	1	0.23	Ethylene oxide, insecticides, and rodenticides (over 60 chemicals)
Beane Freeman et al., 2009 (update of Hauptmann et al., 2003)	0 >0–<0.5 0.5–<1.0 ≥1.0	0 >0–<1.5 1.5–<5.5 ≥5.5	Data not shown	0 >0–15 >15–25 >25–35 >35	0 >0–25 >25–42 >42		ICD-8, 200–209 200, 202 201 203 204–207 204 205	286 94 25 48 116 36 44	304.3 110.6 17.6 51.1 113.7 31.3 48.9	Antioxidants, asbestos, benzene, carbon black, dyesand pigments, hexamethylenetetramine, melamine, phenol,plasticizers, urea, and wood dust

Note: NR = not reported. See Table 3 for ICD codes.

Table 2.  Formaldehyde case control studies.

Reference	Study Population	Job/Exposure Category	Period of Employment	Period of Follow-up	Total Follow-up (person-years)	Minimum Employment (years)	Mean Time-Weighted Average Exposure (ppm)	Peak Exposure (ppm)	Average Intensity (ppm)
Gerin et al., 1989	Canadian population in Montreal	Lifetime job histories obtained by interview and translated into level of exposureto formaldehyde	1979–1985	1979–1985					Low Medium High
Ott et al., 1989	US Union Carbide chemical manufacturing facilities	111 work areas, 21 specific chemicals and 52 chemical-activity groups	1940–1978	1940–1978		≥1 day
Linos et al., 1990	Iowa and Minnesota Funeral home workers	Funeral service and crematoria workers	NR	NR
Partanen et al., 1993	Finland Wood production workers	Wood workers (formaldehyde, solvents, wood dust)	1957–1982	1957–1982		≥1
Tatham et al., 1997	Atlanta, Connecticut, Iowa, Kansas, Miami, San Francisco, Detroit, and Seattle workers	Exposed to formaldehyde or other chemicals	1984–1988	1984–1988		≥1
Blair et al., 2001	Iowa and Minnesota Industrial workers	15 different industrial and occupational job categories (non-farming)	1980–1983	1980–1983		≥1
Wang et al., 2009b	Connecticut women	Exposure to organic solvents and formaldehyde	1996–2000	1996–2000
Hauptmann et al., 2009	US Embalmers	Never Embalming Ever Embalming	1932–1986	1960–1986	19,104		0 >0–0.10 >0.10–0.18 >0.18	0 >0–7.0 >7.0–9.3 >9.3	0 >0–1.4 >1.4–1.9 >1.9
Gerin et al., 1989		<10 ≥10		ICD-8, 200, 202 201	206 53	533
Reference	Cumulative Exposure (ppm)	Duration of Exposure or Length of Employment (years)	Number of Embalmings	ICD code	Cases (total)	Controls (total)	Possible Co-Exposures Discussed
Ott et al., 1989		0 <5 ≥5		Non-Hodgkin’s Multiple Myelpoma Leukema	2 1 3	NR	52 chemical groups (e.g., epoxides, halogenated compounds, fused cyclics, nitriles, vinylics)
Linos et al., 1990				Leukemia Non-Hodgkin’s	578 622	1245	NR
Partanen et al., 1993				ICD-7, 200–202 201 200, 202 204	5 1 4 2	152	Wood dust, pesticides, chlorophenols, phenol, terpenes, solvents (stains, lacquers, toluene, xylenes, benzene, styrene, butyl acetate, ethyl acetate, butanol, isopropanol, ethanol), aliphatic hydrocarbons (solvent naphtha, white spirits), ketones, glycol ethers, and engine exhaust
Tatham et al., 1997		<10 ≥10		ICD-8, 200, 202	1511	1659	Pesticides, herbicides, wood/saw dust, solvents, shoe/leather dust, meat packaging or processing, metal plating, cutting oils, chlorophenols, heterocyclic nitrogens, carbamates, organophosphates, phenoxy herbicides, chlorinated hydrocarbons, and pyrethroids
Blair et al., 2001	Low High	<10 ≥10		ICD-8, 204–207 205.0 205.1 204.0 204.1	64 14 8 0 30	137	Solvents, paints, metals, solder
Wang et al., 200b	Never Low Medium–High			ICD-9, 200–202	601	717	Organic solvents (benzene, chloroform, carbon tetrachloride, dichloromethane, methyl chloride, trichloroethylene)
Hauptmann et al., 2009	0 >0–4058 >4058–9253 >9253(ppm-h)	0 >0–20 >20–34 >34	0 >0–1422 >1422–3068 >3068	ICD-8, 200–209 200–204 205, 206, 208, 209 205	168 99 48 34	265	Isopropanol, ethylene glycol, methanol, phenol, glutaraldehyde, ionizing radiation, benzene, and cigarette smoking

Note: NR = not reported; AML = acute myeloid leukemia; CML = chronic myeloid leukemia; ALL = acute lymphoid leukemia; CLL = chronic lymphoid leukemia. See Table 3 for ICD codes.

Table 3.  International disease classification (ICD) codes.

ICD Code	Revision 7	Revision 8	Revision 9
	(200–207) Neoplasms of lymphatic and hematopoietic tissues	(200–209) Neoplasms of lymphatic and hematopoietic tissue	(200–208) Malignant neoplasms of lymphatic and hematopoietic tissue
200	Lymphosarcoma and reticulosarcoma	Lymphosarcoma and reticulum-cell sarcoma	Lymphosarcoma and reticulosarcoma and other specified malignant tumors of lymphatic tissue
201	Hodgkin’s disease	Hodgkin’s disease	Hodgkin’s disease
202	Other forms of lymphoma (reticulosis)	Other neoplasms of lymphoid tissue	Other malignant neoplasms of lymphoid and histiocytic tissue
203	Multiple myeloma	Multiple myeloma	Multiple myeloma and immunoproliferative neoplasms
204	Leukemia & aleukemia	Lymphatic leukemia	Lymphoid leukemia
204.0	Lymphatic leukemia	Acute lymphocytic leukemia	Acute lymphoid leukemia
204.1	Myeloid leukemia	Chronic lymphocytic leukemia	Chronic lymphoid leukemia
204.3	Acute leukemia	—	—
204.4	Other & unspecified leukemia	—	—
205	Mycosis fungoides	Myeloid leukemia	Myeloid leukemia
205.0	—	Acute myeloid leukemia	Acute myeloid leukemia
205.1	—	Chronic myeloid leukemia	Chronic myeloid leukemia
206	Lymphatic system	Monocytic leukemia	Monocytic leukemia
207	Hematopoietic system	Other and unspecified leukemia	Other specified leukemia
208	—	Polycythemia vera	Leukemia of unspecified cell type
209	—	Myelofibrosis	—
238.4	—	—	Polycythemia vera
289.83	—	—	Myelofibrosis
294	Polycythemia	—	—

Table 4a.  Association between formaldehyde and all lymphohematopoietic cancers (ICD 200–209).

Measures	Hauptmann et al., 2009					Beane Freeman et al., 2009					Andjelkovich et al., 1995
	Embalmers case-control					NCI cohort (1934–2004)					Iron foundry workers
	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI
Unexposed/Exposed	Never embalming	24	OR	1.00	—	Unexposed	33	SMR	0.86	0.61–1.21	Unexposed	8	SMR	0.89	0.38–1.76
	Ever embalming	144	OR	1.40	0.80-2.60	Exposed	286	SMR	0.94	0.84–1.06	Exposed	7	SMR	0.59	0.23–1.21
Peak Exposure	0 ppm	24	OR	1.00	—	0 ppm	33	RR	1.07	0.70–1.62
	>0–<2.0 ppm	48	OR	1.60	0.80–3.20	>0–<2.0 ppm	103	RR	1.00	—
	2.0–<4.0 ppm	55	OR	1.60	0.90–3.10	2.0–<4.0 ppm	75	RR	1.17	0.86–1.59
	≥4.0 ppm	41	OR	1.20	0.60–2.30	≥4.0 ppm	108	RR	1.37	1.03–1.81
	ptrend = .302 (exposed)					ptrend = .02 (exposed)
	ptrend = .555 (exposed and unexposed)					ptrend = .04 (exposed and unexposed)
Average Intensity	0 ppm	24	OR	1.00	—	0 ppm	33	RR	0.99	0.66–1.48
	0.1–0.4 ppm	53	OR	1.60	0.90–3.20	>0–<0.5 ppm	164	RR	1.00	—
	0.5–0.9 ppm	47	OR	1.40	0.70–2.70	0.5–<1.0 ppm	67	RR	1.29	0.97–1.73
	≥1.0 ppm	44	OR	1.30	0.70–2.50	≥1.0 ppm	55	RR	1.07	0.78–1.47
	ptrend = .443 (exposed)					ptrend > .5 (exposed)
	ptrend = .591 (exposed and unexposed)					ptrend > .5 (exposed and unexposed)
Cumulative Exposure	0 ppm-yr	24	OR	1.00	—	0 ppm-yr	33	RR	0.89	0.59–1.34
	>0–<1.5 ppm-yr	40	OR	1.30	0.60–2.50	>0–<1.5 ppm-yr	168	RR	1.00	—
	>1.5–<5.5 ppm-yr	49	OR	1.40	0.80–2.80	>1.5–<5.5 ppm-yr	49	RR	0.77	0.56–1.07
	≥5.5 ppm-yr	55	OR	1.60	0.80–3.00	≥5.5 ppm-yr	69	RR	1.07	0.8–1.42
	ptrend = .753 (exposed)					ptrend = .25 (exposed)
	ptrend = .422 (exposed and unexposed)					ptrend = .25 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm						No association. Results not shown.
Exposure/Employment Duration	0 yrs	24	OR	1.00	—	No association. Results not shown.
	>0–20 yrs	28	OR	0.80	0.40–1.80
	>20–34 yrs	50	OR	1.50	0.80–2.80
	>34 yrs	66	OR	1.80	1.00–3.40
	ptrend = .131 (exposed)
	ptrend = .058 (exposed and unexposed)
Number of Embalmings	0	24	OR	1.00	—
	>0–1422	29	OR	0.90	0.60–1.80
	>1422–3068	62	OR	1.90	1.00–3.60
	>3068	53	OR	1.50	0.80–2.90
	ptrend = .477 (exposed)
	ptrend = .844 (exposed and unexposed)
8-Hour Time-Weighted Average Intensity	0	24	OR	1.00	—
	>0–0.10	47	OR	1.30	0.70–2.60
	>0.10–0.18	52	OR	1.60	0.80–3.10
	>0.18	45	OR	1.40	0.70–2.80
	ptrend = .635 (exposed)
	ptrend = .855 (exposed and unexposed)
Time Since First Exposure						0 yrs	30	RR	0.67	0.31-1.46
						>0-15 yrs	21	RR	1.00	-
						>15-25 yrs	46	RR	1.30	0.68-2.49
						>25-35 yrs	59	RR	0.82	0.40-1.70
						>35 yrs	163	RR	0.67	0.32-1.41
Time Since First Exposure ≥4 ppm						0 yrs	211	RR	0.57	0.36-0.88
						>0-25 yrs	28	RR	1.00	-
						>25-42 yrs	45	RR	0.69	0.41-1.17
						>42 yrs	35	RR	0.61	0.34-1.09

Table 4b.  Other cohorts.

Reference	Obs	Estimate		95% CI
Wong et al., 1983	6	SMR	1.36	0.50–2.95
Levine et al., 1984	8	SMR	1.24	—
Hayes et al., 1990	115	PMR	1.39	1.15–1.67
Hall et al., 1991	9 (M)	SMR	1.42	0.65–2.69
Hall et al., 1991	1 (F)	SMR	1.75	0.04–9.77
Matanoski et al., 1991	57	SMR	1.25	0.95–1.62
Bertazzi et al., 1986, 1989	3	SMR	1.73	0.36–5.06
Stellman et al., 1998*	28	RR	1.22	0.84–1.77
Marsh et al., 2001	199	SMR	0.90	0.78–1.04
Pinkerton et al., 2004*	59	SMR	0.97	0.74–1.26

*ICD-8 200–208.

Table 5a.  Association between formaldehyde and cancers of lymphoid origin (ICD 200–204).

Measures	Hauptmann et al., 2009					Beane Freeman et al., 2009
	Embalmers case-control					NCI cohort (1934-2004)
	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI
Unexposed/Exposed	Never embalming	18	OR	1.00	—
	Ever embalming	81	OR	1.10	0.50-2.10
Peak Exposure	0 ppm	18	OR	1.00	—	0 ppm	26	RR	1.17	0.72–1.89
	>0–7.0 ppm	29	OR	1.20	0.60–2.70	>0–<2.0 ppm	73	RR	1.00	—
	>7.0–9.3 ppm	37	OR	1.50	0.70–3.20	2.0–<4.0 ppm	56	RR	1.27	0.89–1.82
	>9.3 ppm	15	OR	0.60	0.20–1.30	≥4.0 ppm	74	RR	1.35	0.97–1.89
	ptrend = .111 (exposed)					ptrend = .06 (exposed)
	ptrend = .523 (exposed and unexposed)					ptrend = .10 (exposed and unexposed)
Average Intensity	0 ppm	18	OR	1.00	—	0 ppm	26	RR	1.08	0.68–1.71
	>0–1.4 ppm	34	OR	1.40	0.60–2.90	>0–<0.5 ppm	116	RR	1.00	—
	>1.4–1.9 ppm	26	OR	1.00	0.50–2.20	0.5–<1.0 ppm	49	RR	1.36	0.97–1.9
	>1.9 ppm	21	OR	0.90	0.40–1.90	≥1.0 ppm	38	RR	1.05	0.72–1.53
	ptrend = .287 (exposed)					ptrend > .5 (exposed)
	ptrend = .598 (exposed and unexposed)					ptrend > .5 (exposed and unexposed)
Cumulative Exposure	0 ppm-h	18	OR	1.00	—	0 ppm-yr	26	RR	0.94	0.59–1.49
	>0–4058 ppm-h	23	OR	0.90	0.40–2.00	>0–<1.5 ppm-yr	123	RR	1.00	—
	>4058–9253 ppm-h	33	OR	1.30	0.60–2.80	>1.5–<5.5 ppm-yr	30	RR	0.65	0.44–0.98
	>9253 ppm-h	25	OR	1.00	0.40–2.00	≥5.5 ppm-yr	50	RR	1.06	0.75–1.49
	ptrend = .912 (exposed)					ptrend > .5 (exposed)
	ptrend = .965 (exposed and unexposed)					ptrend > .5 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm						No association. Results not shown.
Duration of Exposure/Employment	0 yrs	18	OR	1.00	—	No association. Results not shown.
	>0–20 yrs	16	OR	0.70	0.30–1.60
	>20–34 yrs	32	OR	1.20	0.60–2.60
	>34 yrs	33	OR	1.20	0.60–2.50
	ptrend = .360 (exposed)
	ptrend = .449 (exposed and unexposed)
Number of Embalmings	0	18	OR	1.00	—
	>0–1422	17	OR	0.70	0.30–1.60
	>1422–3068	37	OR	1.50	0.70–3.00
	>3068	27	OR	1.00	0.50–2.20
	ptrend = .963 (exposed)
	ptrend = .865 (exposed and unexposed)
8-Hour Time-Weighted Average Intensity	0	18	OR	1.00	—
	>0–0.10	32	OR	1.20	0.60–2.60
	>0.10–0.18	25	OR	1.00	0.50–2.10
	>0.18	24	OR	1.00	0.50–2.10
	ptrend = .766 (exposed)
	ptrend = .605 (exposed and unexposed)

Table 5b.  Other cohorts

Reference	Obs	Estimate		95% CI
Dell and Teta, 1995*	23	SMR	1.69	1.07–2.53
Chiazze et al., 1997*	5	SMR	0.46	0.15–1.08

Note: *ICD-7 200–205.

Table 6a.  Association between formaldehyde and leukemia (ICD 204–207).

Measures	Beane Freeman et al., 2009					Pinkerton et al., 2004					Stern et al., 1987
	NCI cohort (1934–2004)					US garment workers					Leather tannery workers
	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI
Unexposed/exposed	Unexposed	7	SMR	0.48	0.23–1.01	Exposed	24	SMR	1.09	0.70–1.62
	Exposed	116	SMR	1.02	0.85–1.22
Peak exposure	0 ppm	7	RR	0.59	0.25–1.36
	>0–<2.0 ppm	41	RR	1.00	—
	2.0–<4.0 ppm	27	RR	0.98	0.60–1.62
	≥4.0 ppm	48	RR	1.42	0.92–2.18
	ptrend = .12 (exposed)
	ptrend = .02 (exposed and unexposed)
Average intensity	0 ppm	7	RR	0.54	0.24–1.22
	>0–<0.5 ppm	67	RR	1.00	—
	0.5–<1.0 ppm	25	RR	1.13	0.71–1.79
	≥1.0 ppm	24	RR	1.10	0.68–1.78
	ptrend > .5 (exposed)
	ptrend = .5 (exposed and unexposed)
Cumulative exposure	0 ppm-yr	7	RR	0.53	0.23–1.21
	>0–<1.5 ppm-yr	63	RR	1.00	—
	>1.5–<5.5 ppm-yr	24	RR	0.96	0.60–1.56
	≥5.5 ppm-yr	29	RR	1.11	0.70–1.74
	ptrend = .12 (exposed)
	ptrend = .08 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm	No association. Results not shown.
Duration of exposure/employment	No association. Results not shown.					<3 yrs	7	SMR	0.96	—	<1 yr	2	SMR	0.45	0.05–1.68
						3–9 yrs	5	SMR	0.72	—	1–9 yrs	2	SMR	1.00	0.11–3.61
						10+ yrs	12	SMR	1.53	—	10+ yrs	6	SMR	1.70	0.63–3.73
						ptrend > .05
Time since first exposure	0 yrs	5	RR	0.28	0.06-1.32	<10 yrs	2	SMR	0.68	—
	>0-15 yrs	6	RR	1.00	-	<10–19 yrs	3	SMR	0.65	—
	>15-25 yrs	22	RR	2.13	0.64-7.15	20+ yrs	19	SMR	1.31	—
	>25-35 yrs	26	RR	0.94	0.25-3.51	ptrend > .05
	>35 yrs	64	RR	0.53	0.14-2.09
Year of first exposure						<1963	19	SMR	1.23	—
						1963–1970	4	SMR	0.81	—
						≥1971	1	SMR	0.56	—
						ptrend > .05
Time Since First Exposure ≥4 ppm	0 yrs	75	RR	0.34	0.18-0.67
	>0-25 yrs	14	RR	1.00	-
	>25-42 yrs	16	RR	0.37	0.16-0.83
	>42 yrs	18	RR	0.51	0.22-1.19

Table 6b.  Other cohorts.

Reference	ICD code	Obs	Estimate		95% CI
Harrington and Shannon, 1975 (pathologists)	204–207	1	SMR	0.63	0.02–3.48
Harrington and Shannon, 1975 (technicians)	204–207	1	SMR	0.45	0.01–2.53
Walrath and Fraumeni, 1983	204–207	12	PMR^†	1.40	na
Wong et al., 1983	204–207	2	SMR^†	1.18	0.13–4.26
Levine et al., 1984	204–207	4	SMR^‡	1.60	0.44–4.10
Walrath and Fraumeni, 1984	204–207	12	PMR^†	1.50	p < .05
Logue et al., 1986 (radiologists)	204^¶	na	SMR	1.55	na
Logue et al., 1986 (pathologists)	204^¶	na	SMR	1.06	na
Stroup et al., 1986	204–207	10	SMR	1.50	0.70–2.70
Robinson et al., 1987	204^¶	1	SMR^¶	0.59	0.01–3.28
Stern et al., 1987 (Plant A)	204^¶	4	SMR^†	0.70	0.19–1.80
Stern et al., 1987 (Plant B)	204^¶	6	SMR^†	0.75	0.28–1.64
Stern et al., 1987 (Finishing Department)	204^¶	7	SMR^†	1.25	0.50–2.58
Ott et al., 1989*	Non-lymphocytic	2	OR	2.6	na
Ott et al., 1989*	Lymphocytic	1	OR	2.60	na
Linos et al., 1990*	na	4	OR	2.10	0.40–10.00
Hall et al., 1991	204–207	4	SMR	2.63	0.41–3.89
Matanoski et al., 1991	na	31	SMR	1.35	0.92–1.92
Partanen et al., 1993	204^¶	2	OR	1.40	0.25–7.91
Andjelkovich et al., 1995	204–207	2	SMR^†	0.43	0.05–1.57
Dell and Teta, 1995	204^¶	8	SMR^†	2.65	1.15–5.24
Hansen and Olsen, 1995	204^¶	39	SPIR	0.80	0.60–1.60
Chiazze et al., 1997	204^¶	1	SMR	0.24	0.006–1.36
Stellman et al., 1998	na	12	RR	0.96	0.54–1.71
Blair et al., 2001*	na	64	OR^‡	0.98	0.70–1.36
Coggon et al., 2003	204–208	31	SMR	0.91	0.62–1.29
Ambroise et al., 2005	204–208	1	SMR	4.42	0.11–24.64

Note: na = not available.

*Case-control study.

†SMR or PMR values divided by 100.

‡Risk estimate not provided in original citation, value calculated by Bachand et al. (2010).

¶ICD-7.

Table 7a.  Association between formaldehyde and lymphatic leukemia (ICD 204).

Measures	Beane Freeman et al., 2009					Blair et al., 2001
	NCI cohort (1934–2004)					US industrial workers
	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI
						Acute
Unexposed/Exposed	Unexposed	1	SMR	0.26	0.04–1.82	Low	0	OR	—	—
	Exposed	36	SMR	1.15	0.83–1.59	High	0	OR	—	—
						Chronic
						Low	29	OR	1.20	0.70–1.80
						High	1	OR	0.60	0.10–5.30
Peak Exposure	0 ppm	1	RR	0.27	0.03–2.13
	>0–<2.0 ppm	14	RR	1.00	—
	2.0–<4.0 ppm	8	RR	0.81	0.33–1.96
	≥4.0 ppm	14	RR	1.15	0.54–2.47
	ptrend > 0.5 (exposed)
	ptrend = 0.3 (exposed and unexposed)
Average Intensity	0 ppm	1	RR	0.26	0.03–2.01
	>0–<0.5 ppm	22	RR	1.00	—
	0.5–<1.0 ppm	7	RR	0.92	0.39–2.16
	≥1.0 ppm	6	RR	1.61	0.76–3.39
	ptrend > 0.5 (exposed)
	ptrend > 0.5 (exposed and unexposed)
Cumulative Exposure	0 ppm-yr	1	RR	0.24	0.03–1.88
	>0–<1.5 ppm-yr	21	RR	1.00	—
	>1.5–<5.5 ppm-yr	5	RR	0.57	0.21–1.54
	≥5.5 ppm-yr	10	RR	1.02	0.47–2.21
	ptrend = 0.46 (exposed)
	ptrend = 0.41 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm	No association. Results not shown.
Duration of Employment	No association. Results not shown.

Table 7b.  Other cohorts.

Reference	ICD Code	Obs	Estimate		95% CI
Hayes et al., 1990	204	7	PMR *	0.7	0.29–1.53
Pinkerton et al., 2004	204	3	SMR	0.60	0.12–1.75

Note: na = not available, *PMR divided by 100.

Table 8a.  Association between formaldehyde and cancers of non-lymphoid origin (ICD 205, 206, 208, 209).

Measures	Hauptmann et al., 2009*					Beane Freeman et al., 2009
	Embalmers case-control					NCI cohort (1934–2004)
	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI
Unexposed/Exposed	Never embalming	4	OR	1.00	—
	Ever embalming	44	OR	3.00	1.00-9.50
Peak Exposure	<500 embalmings	9	OR	1.00	—	0 ppm	5	RR	1.01	0.34-2.98
	≤7.0 ppm	10	OR	1.60	0.60–4.50	>0–<2.0 ppm	15	RR	1.00	—
	>7.0–9.3 ppm	12	OR	1.40	0.50–3.70	2.0–<4.0 ppm	11	RR	1.19	0.54–2.62
	>9.3 ppm	17	OR	2.30	0.90–5.60	≥4.0 ppm	21	RR	1.80	0.91–3.57
						ptrend = .09 (exposed)
						ptrend = .09 (exposed and unexposed)
Average Intensity	<500 embalmings	9	OR	1.00	—	0 ppm	5	RR	0.89	0.32–2.5
	≤1.4 ppm	13	OR	1.70	0.70–4.50	>0–<0.5 ppm	25	RR	1.00	—
	>1.4–1.9 ppm	12	OR	1.70	0.70–4.60	0.5–<1.0 ppm	11	RR	1.40	0.68–2.86
	>1.9 ppm	14	OR	1.80	0.70–4.70	≥1.0 ppm	11	RR	1.51	0.72–3.16
						ptrend > .5 (exposed)
						ptrend > .5 (exposed and unexposed)
Cumulative Exposure	<500 embalmings	9	OR	1.00	—	0 ppm-yr	5	RR	0.69	0.25–1.95
	≤4058 ppm-h	5	OR	1.10	0.30–3.80	>0–<1.5 ppm-yr	30	RR	1.00	—
	>4058–9253 ppm-h	12	OR	1.40	0.50–3.70	>1.5–<5.5 ppm-yr	7	RR	0.61	0.26–1.41
	>9253 ppm-h	22	OR	2.40	1.00–5.80	≥5.5 ppm-yr	10	RR	0.86	0.41–1.81
						ptrend > .5 (exposed)
						ptrend > .5 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm						No association. Results not shown.
Duration of Exposue/Employment	<500 embalmings	9	OR	1.00	—	No association. Results not shown.
	≤20 yrs	2	OR	0.30	0.10–1.70
	>20–34 yrs	16	OR	2.00	0.80–5.00
	>34 yrs	21	OR	2.60	1.00–6.40
Number of Embalmings	<500 embalmings	9	OR	1.00	—
	≥500–1422	3	OR	0.60	0.20–2.60
	>1422–3068	15	OR	1.80	0.70–4.60
	>3068	21	OR	2.30	1.00–5.70
8-Hour Time-Weighted Average Intensity	<500 embalmings	9	OR	1.00	—
	≤0.10 ppm	9	OR	1.30	0.50–3.60
	>0.10–0.18 ppm	16	OR	2.10	0.80–5.30
	>0.18 ppm	14	OR	1.90	0.70–4.80

Note: *Results from analyses using those who never embalmed as a referent group (with one myeloid leukemia case) were highly unstable. Results presented here are from analyses using individuals with <500 embalmings as the referent group (see Table 4 in Hauptmann et al., 2009).

Table 8b.  Other cohorts.

Reference	Code	Obs	Estimate		95% CI
Pinkerton et al., 2004	206–208	6	SMR	0.92	0.34–2.00
Hayes et al., 1990	206, 207	20	PMR	2.28	1.39–3.52
Hayes et al., 1990	208	3	PMR	3.90	0.80–11.38
Hayes et al., 1990	209	4	PMR	2.62	0.42–3.91

Table 9a.  Association between formaldehyde and myeloid leukemia (ICD 205).

Measures	Hauptmann et al., 2009* (ICD 205)					Hauptmann et al., 2009* (ICD 205.0)					Beane Freeman et al., 2009					Pinkerton et al., 2004					Blair et al., 2001
	Embalmers case-control					Embalmers case-control					NCI Cohort (1934–2004)					US garment workers					US industrial workers
	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI
Unexposed/Exposed	Never embalming	1	OR	1.00	—						Unexposed	4	SMR	0.65	0.25–1.74						Acute
	Ever embalming	33	OR	11.20	1.3-95.6						Exposed	44	SMR	0.90	0.67–1.21	Exposed	15	SMR	1.44	0.80–2.37	Low	14	OR	0.9	0.50–1.60
																					High	0	OR	—	—
																Acute	9	SMR	1.34	0.61–2.54
																Chronic	4	SMR	1.39	0.38–3.56	Chronic
																Other/unspecified	1	SMR	2.15	0.05–11.94	Low	7	OR	1.3	0.60–3.10
																					High	1	OR	2.9	0.30–24.50
Peak Exposure	<500 embalmings	5	OR	1.00	—	<500 embalmings	3	OR	1.00	—	0 ppm	4	RR	0.82	0.25–2.67
	>0–7.0 ppm	9	OR	2.90	0.9–9.8	>0–7.0 ppm	4	OR	1.80	0.4–9.3	>0–<2.0 ppm	14	RR	1.00	—
	>7.0–9.3 ppm	9	OR	2.00	0.6–6.6	>7.0–9.3 ppm	5	OR	2.10	0.5–9.2	2.0–<4.0 ppm	11	RR	1.30	0.58–2.92
	>9.3 ppm	11	OR	2.90	0.9–9.5	>9.3 ppm	7	OR	2.90	0.7–12.5	≥ 4.0 ppm	19	RR	1.78	0.87–3.64
											ptrend = .13 (exposed)
											ptrend = .07 (exposed and unexposed)
Average Intensity	<500 embalmings	5	OR	1.00	—	<500 embalmings	3	OR	1.00	—	0 ppm	4	RR	0.70	0.23–2.16
	>0–1.4 ppm	10	OR	2.60	0.8–8.7	>0–1.4 ppm	6	OR	2.50	0.6–10.9	>0–<0.5 ppm	24	RR	1.00	—
	>1.4–1.9 ppm	10	OR	2.80	0.8–9.1	>1.4–1.9 ppm	5	OR	2.00	0.4–9.4	0.5–<1.0 ppm	9	RR	1.21	0.56–2.62
	>1.9 ppm	9	OR	2.30	0.7–7.5	>1.9 ppm	6	OR	2.30	0.5–10.3	≥ 1.0 ppm	11	RR	1.61	0.76–3.39
											ptrend = .43 (exposed)
											ptrend = .40 (exposed and unexposed)
Cumulative exposure	<500 embalmings	5	OR	1.00	—	<500 embalmings	3	OR	1.00	—	0 ppm-yr	4	RR	0.61	0.2–1.91
	>0–4058 ppm-h	5	OR	2.10	0.5–8.1	>0–4058 ppm-h	2	OR	1.30	0.2–9.4	>0–<1.5 ppm-yr	26	RR	1.00	—
	>4058–9253 ppm-h	10	OR	2.20	0.7–7.1	>4058–9253 ppm-h	6	OR	1.90	0.4–8.2	>1.5–<5.5 ppm-yr	8	RR	0.82	0.36–1.83
	>9253 ppm-h	14	OR	3.10	1.0–9.6	>9253 ppm-h	9	OR	3.20	0.8–13.1	≥ 5.5 ppm–yr	10	RR	1.02	0.48–2.16
											ptrend > .5 (exposed)
											ptrend = .44 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm											No association. Results not shown.
Duration of exposure/employment	<500 embalmings	5	OR	1.00	—	<500 embalmings	3	OR	1.00	—						<3 yrs	3	SMR	0.83	—
	>0–20 yrs	2	OR	0.50	0.1–2.9	>0–20 yrs	1	OR	0.40	0.04–4.9	No association. Results not shown.					3–9 yrs	4	SMR	1.26	—
	>20–34 yrs	13	OR	3.20	1.0–10.1	>20–34 yrs	8	OR	2.90	0.7–12.2						10+ yrs	8	SMR	2.19	—
	>34 yrs	14	OR	3.90	1.2–12.5	>34 yrs	8	OR	3.10	0.7–13.7						ptrend > .05
Time since first exposure																<10 yrs	1	SMR	0.90	—
																<10–19 yrs	1	SMR	0.40	—
																20+ yrs	13	SMR	1.91	^†
																ptrend > .05
Number of embalmings	<500 embalmings	5	OR	1.00	—	0	3	OR	1.00	—
	>0–1422	3	OR	1.20	0.30–5.50	>0–1422	0	OR	0.00	0.0–1.8
	>1422–3068	12	OR	2.90	0.90–9.10	>1422–3068	8	OR	2.90	0.7–12.0
	>3068	14	OR	3.00	1.00–9.20	>3068	9	OR	2.90	0.7–11.6
8-Hour time-weighted average intensity	<500 embalmings	5	OR	1.00	—	0	3	OR	1.00	—
	>0–0.10	8	OR	2.40	0.70–8.20	>0–0.10	3	OR	1.40	0.3–7.8
	>0.10–0.18	10	OR	2.60	0.80–8.70	>0.10–0.18	7	OR	2.60	0.6–11.4
	>0.18	11	OR	2.60	0.80–8.30	>0.18	7	OR	2.60	0.6–11.3

Table 9b.  Other cohorts

Reference	Obs	Estimate		95% CI
Stroup et al., 1986	5	SMR	8.8	—
Hayes et al., 1990	24	PMR^‡	1.57	1.01–2.34
Linos et al., 1990 (acute)	3	OR	6.70	1.20–36.20

*Results from analyses using those who never embalmed as the referent group (with one myeloid leukemia case) were highly unstable. Results presented here are from analyses using individuals with <500 embalmings as the referent group. (See Table 4 in Hauptman et al., 2009).

^†95% CI does not include 1.0.

^‡PMR divided by 100.

Table 10a.  Association between formaldehyde and other unspecified leukemia (ICD-8 207).

Measures	Beane Freeman et al., 2009
	NCI Cohort (1934-2004)
	Category	Obs	Estimate		95% CI
Peak Exposure	0 ppm	2	RR	0.61	0.13–2.85
	>0–<2.0 ppm	13	RR	1.00	—
	2.0–<4.0 ppm	8	RR	0.86	0.35–2.12
	≥4.0 ppm	13	RR	1.15	0.53–2.53
	ptrend > .5 (exposed)
	ptrend = .5 (exposed and unexposed)
Average Intensity	0 ppm	2	RR	0.58	0.13–2.62
	>0–<0.5 ppm	21	RR	1.00	—
	0.5–<1.0 ppm	7	RR	0.98	0.42–2.33
	≥1.0 ppm	6	RR	0.84	0.33–2.12
	ptrend > .5 (exposed)
	ptrend > .5 (exposed and unexposed)
Cumulative Exposure	0 ppm-yr	2	RR	0.77	0.16–3.59
	>0–<1.5 ppm-yr	15	RR	1.00	—
	>1.5–<5.5 ppm-yr	10	RR	1.65	0.73–3.73
	≥5.5 ppm-yr	9	RR	1.44	0.61–3.36
	ptrend = .15 (exposed)
	ptrend = .13 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm	No association. Results not shown.
Duration of Employment	No association. Results not shown.

Table 10b.  Other cohorts

Reference	Code	Obs	Estimate		95% CI
Hayes et al., 1990	206, 207	20	PMR	2.28	1.39–3.52

Table 11a.  Association between formaldehyde and Hodgkin’s lymphoma (ICD 201).

Measures	Beane Freeman et al., 2009					Andjelkovich et al., 1995
	NCI cohort (1934–2004)					Iron foundry workers
	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI
Unexposed/Exposed	Unexposed	2	SMR	0.70	0.17–2.80	Unexposed	0	SMR	0.00	0.00–4.12
	Exposed	25	SMR	1.42	0.96–2.10	Exposed	1	SMR	0.72	0.01–4.00
Peak Exposure	0 ppm	2	RR	0.67	0.12–3.60
	>0–<2.0 ppm	6	RR	1.00	—
	2.0–<4.0 ppm	8	RR	3.30	1.04–10.50
	≥4.0 ppm	11	RR	3.96	1.31–12.02
	ptrend = .01 (exposed)
	ptrend = .004 (exposed and unexposed)
Average Intensity	0 ppm	2	RR	0.53	0.11–2.66
	>0–<0.5 ppm	10	RR	1.00	—-
	0.5–<1.0 ppm	9	RR	3.62	1.41–9.31
	≥1.0 ppm	6	RR	2.48	0.84–7.32
	ptrend = .05 (exposed)
	ptrend = .03 (exposed and unexposed)
Cumulative Exposure	0 ppm-yr	2	RR	0.42	0.09–2.05
	>0–<1.5 ppm-yr	14	RR	1.00	—
	>1.5–<5.5 ppm-yr	7	RR	1.71	0.66–4.38
	≥5.5 ppm-yr	4	RR	1.30	0.4–4.19
	ptrend = .08 (exposed)
	ptrend = .06 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm	No association. Results not shown.
Duration of Employment	No association. Results not shown.

Table 11b.  Other cohorts

Reference	Obs	Estimate		95% CI
Wong et al., 1983	2	SMR	2.40	0.27–8.66
Robinson et al., 1987	2	SMR	3.33	0.59–10.49
Gerin et al., 1989	8	OR	0.50	0.20–1.40
Hayes et al., 1990	3	PMR	0.72	0.15–2.10
Hall et al., 1991	1	SMR	1.31	0.03–7.33
Matanoski et al., 1991	2	SMR	0.36	0.04–1.31
Hansen and Olsen, 1995	12	SPIR	1.00	0.50–1.70
Coggon et al., 2003	6	SMR	0.70	0.26–1.53
Pinkerton et al., 2004	2	SMR	0.55	0.07–1.98
Hauptmann et al., 2009	8	OR	0.50	0.10–2.60

Table 12a.  Association between formaldehyde and non-Hodgkin’s lymphoma (ICD 200, 202).

	Beane Freeman et al., 2009					Wang et al., 2009b					Gerin et al., 1989
	NCI cohort (1934–2004)					Connecticut women (1996–2000)					Montreal workers (1979–1985)
Measures	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI	Category	Obs	Estimate		95% CI
Unexposed/Exposed	Unexposed	12	SMR	0.86	0.49–1.52	Never	398	OR	1.00	—
	Exposed	94	SMR	0.85	0.70–1.05	Ever	203	OR	1.30	1.00–1.70
Peak Exposure	0 ppm	12	RR	1.06	0.53–2.14
	>0–<2.0 ppm	39	RR	1.00	—
	2.0–<4.0 ppm	27	RR	1.08	0.65–1.78
	≥4.0 ppm	28	RR	0.91	0.55–1.49
	ptrend > .5 (exposed)
	ptrend > .5 (exposed and unexposed)
Average Intensity	0 ppm	12	RR	1.08	0.55–2.12	Never	398	OR	1.00	—
	>0–<0.5 ppm	59	RR	1.00	—	Low	129	OR	1.40	1.00–1.80
	0.5–<1.0 ppm	22	RR	1.20	0.73–1.96	Medium–High	74	OR	1.20	0.80–1.70
	≥1.0 ppm	13	RR	0.71	0.39–1.32	ptrend = .21
	ptrend > .5 (exposed)
	ptrend = .45 (exposed and unexposed)
Cumulative Exposure	0 ppm-yr	12	RR	0.94	0.46–1.86						Short	13	OR	0.70	0.30–1.60
	>0–<1.5 ppm-yr	60	RR	1.00	-						Long—low	15	OR	1.10	0.50–2.20
	>1.5–<5.5 ppm-yr	13	RR	0.58	0.31–1.06						Long—medium	14	OR	1.00	0.50–2.10
	≥5.5 ppm-yr	21	RR	0.91	0.54–1.52						Long—high	5	OR	0.50	0.10–1.70
	ptrend > .5 (exposed)
	ptrend = .42 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm	No association. Results not shown.
Duration of Employment	No association. Results not shown.

Table 12b.  Other cohorts

Reference	Obs	Estimate		95% CI
Edling et al., 1987	2	SPIR *	2.00	0.50–7.20
Ott et al., 1989^†	2	OR	2.00	—
Hayes et al., 1990	34	PMR	1.26	0.87–1.76
Linos et al., 1990^†	6	OR	3.2	0.80–13.40
Partanen et al., 1993^†	4	OR	4.24	0.68–26.60
Hansen and Olsen, 1995	32	SPIR	0.90	0.60–1.20
Tatham et al., 1997^†	93	OR	1.20	0.86–1.50
Stellman et al., 1998	11	RR	0.92	0.50–1.68
Coggon et al., 2003	31	SMR	0.98	0.67–1.39
Hauptmann et al., 2009	NR	OR	0.90	0.40–2.10

Notes *Standardized proportionate incidence ratio.

^†Case-control study.

Table 13a.  Association between formaldehyde and multiple myeloma (ICD 203).

	Beane Freeman et al., 2009
	NCI cohort (1934-2004)
Measures	Category	Obs	Estimate		95% CI
Unexposed/eEposed	Unexposed	11	SMR	1.78	0.99–3.22
	Exposed	48	SMR	0.94	0.71–1.25
Peak Exposure	0 ppm	11	RR	2.74	1.18–6.37
	>0–<2.0 ppm	14	RR	1.00	—
	2.0–<4.0 ppm	13	RR	1.65	0.76–3.61
	≥4.0 ppm	21	RR	2.04	1.01–4.12
	ptrend = .08 (exposed)
	ptrend > .5 (exposed and unexposed)
Average Intensity	0 ppm	11	RR	2.18	1.01–4.70
	>0–<0.5 ppm	25	RR	1.00	—
	0.5–<1.0 ppm	11	RR	1.40	0.68–2.86
	≥1.0 ppm	12	RR	1.49	0.73–3.04
	ptrend > .5 (exposed)
	ptrend > .5 (exposed and unexposed)
Cumulative Exposure	0 ppm-yr	11	RR	1.79	0.83–3.89
	>0–<1.5 ppm-yr	28	RR	1.00	—
	>1.5–<5.5 ppm-yr	5	RR	0.46	0.18–1.20
	≥5.5 ppm-yr	15	RR	1.28	0.67–2.44
	ptrend > .5 (exposed)
	ptrend > .5 (exposed and unexposed)
Cumulative number of peaks ≥4.0 ppm	No association. Results not shown.
Duration of Employment	No association. Results not shown.

Table 13b.  Other cohorts.

Reference	Obs	Estimate		95% CI
Edling et al., 1987	2	SPIR *	4.00	0.50–14.40
Ott et al., 1989^†	1	OR	1.00	—
Hayes et al., 1990	20	PMR	1.37	0.84–2.12
Dell and Teta, 1995	5	SMR	2.62	0.85–6.11
Stellman et al., 1998	4	RR	0.74	0.27–2.02
Coggon et al., 2003	15	SMR	0.86	0.48–1.41
Hauptmann et al., 2009	NR	OR	1.40	0.50–5.60

Notes: *Standardized proportionate incidence ratio.

^†Case-control study.

Figure 1.  Relative risks of leukemia in the NCI industrial worker cohort compared to study subjects in the low-exposure category for (a) peak, (b) average, and (c) cumulative formaldehyde exposure. The “no exposure” category is comprised of workers from facilities that were presumably unexposed. The only statistically significant trends were for peak exposure when the “no exposure” workers were included in the analyses; all other trend tests including or excluding the “no exposure” workers were null.

Table 14.  Formaldehyde animal hematotoxicity studies.

Study	Species	Sex	Exposure		Outcomes
			Concentration	Duration	RBC, Hct, Hb	WBC
Inhalation studies
Monticello et al., 1989	Monkey, rhesus	Male	0, 6 ppm	6 h/d, 5 d/wk, 6 wk	NS	NS
Appelman et al., 1988	Rat, Wistar	Male	0, 0.1, 1, 10 ppm	6 h/d, 5 d/wk, 13 or 52 wk	NS	NS
Holmstrom et al., 1989	Rat, Sprague-Dawley	Female	0, 12.6 ppm	6 h/d, 5 d/wk, 22 mo	NS	NS
Kerns et al., 1983	Rat, Fischer 344	Female, Male	0, 2.0, 5.6, 14.3 ppm	6 h/d, 5 d/wk, 24 mo with follow-up till 30 mo	NS	NS
As above	Mouse, B6C3F1	Female, Male	As above	As above	NS	NS
Dean et al., 1984	Mouse, B6C3F1	Female	0, 15 ppm	6 h/d, 5 d/wk, 3 wk	NS	↓ monocytes Other cell types NS
Kamata et al., 1997	Rat, Fischer 344	Male	0, 0.3, 2, 15 ppm	6 h/d, 5 d/wk, 28 mo	NS	NS
Woutersen et al., 1987	Rat, Wistar	Female, Male	0, 1, 10, 20 ppm	6 h/d, 5 d/wk, 13 wk	NS	NS
Ingestion Studies
Vargova et al., 1993	Rat, Wistar	Male	0, 20, 40, and 80 mg/kg bw/d	5 d/wk, 4 wk; gastric intubation	↑ at 40, 80 mg/kg/d	↑ monocytes ↓ lymphocytes
Til et al., 1989	Rat, Wistar	Female	0, 1.8, 21, 109 mg/kg bw/d	Daily, 24 mo, drinking water	NS	NS
As above	Rat, Wistar	Male	0, 1.2, 15 or 82 mg/kg bw/d	Daily, 24 mo, drinking water	NS	NS
Til et al., 1988	Rat, Wistar	Female, Male	5, 25 and 125 mg/kg bw/d	Daily, 4 wk	NS	NS
Johannsen et al., 1986	Rat, Sprague-Dawley	Female, Male	0, 50, 100, 150 mg/kg/d	Daily, 3 mo	NS	NS
As above	Dog, Beagle	Female, Male	0, 50, 75, 100 mg/kg/d	Daily, 3 mo	NS	NS
Tobe et al., 1989	Rat, Wistar	Female, Male	0, 200, 1000, 5000 ppm (0, 10, 50, 300 mg/kg bw/d)	Daily, 24 mo, drinking water	↓, not concentration dependent	Assessed, NR

Note. WBC = white blood cell count in peripheral blood; RBC = red blood cell count in peripheral blood; Hct = hematocrit; Hb = hemoglobin concentration in blood; NS = not statistically significant; ↓ = statistically significant decrease; ↑ = statistically significant increase; mg/kg bw/d = milligram per kilogram body weight per day; ppm = parts per million; wk = week(s); mo = month(s).

Table 15.  Formaldehyde animal carcinogenicity studies.

Study	Species	Sex	Exposure		Tumor rate vs. control (%)	Background tumor rate
			Concentration	Duration	Hematopoietic malignancies	Mean (range)
Inhalation studies
Albert et al., 1982	Rat, Sprague-Dawley	Male	0, 14.7 ppm	6 h/d, 5 d/wk, 19.4 mo	NR (Authors performed complete necropsy and histological sections taken from organs with gross pathological alterations)
As above	As above	Male	As above	As above	NS
Kerns et al., 1983	Rat, Fischer 344	Female	0, 2.0, 5.6, 14.3 ppm	6 h/d, 5 d/wk, 24 mo with follow-up till 30 mo	NS
As above	As above	Male	As above	As above	NS
As above	Mouse, B6C3F1	Female	As above	As above	NS
As above	As above	Male	As above	As above	NS
DeVoney et al., 2006 poster, 2010 poster abstract (analysis of Battelle Columbus Laboratories [1981])^*	Rat, Fischer 344	Female	0, 2.0, 5.6, 14.3 ppm	6 h/d, 5 d/wk, 24 mo with follow-up till 30 mo	Leukemia; 24% vs. 15% (14.3 ppm) (no statistical test identified)	Leukemia; 37.3% (24%–54%)^†
As above	As above	Male	As above	As above	NS
As above	Mouse, B6C3F1	Female	As above	As above	Lymphoma; 28% vs. 18% (14.3 ppm) (no statistical test identified)	Lymphoma; 19.9% (6%–44%)^†
As above	As above	Male	As above	As above	NS
Woutersen, 2007^* (analysis of Battelle Columbus Laboratories [1981])	Rat, Fischer 344	Female	0, 2.0, 5.6, 14.3 ppm	6 h/d, 5 d/wk, 24 mo with follow-up till 30 mo	NS
As above	As above	Male	As above	As above	NS
As above	Mouse, B6C3F1	Female	As above	6 h/d, 5 d/wk, 24 mo with follow-up till 27 mo	Lymphoma; considered data immediately after 24-month exposure: 17%, 16%, 9%, 29% (0, 2.0, 5.6, 14.3 ppm, respectively);considered data 3 months after 24-month exposure: 50%, 20%, 15%, 45% (0, 2.0, 5.6, 14.3 ppm, respectively)	Lymphoma; 19.9% (6%–44%)^†
As above	As above	Male	As above	As above	NS
Sellakumar et al., 1985(extended analysis of the study by Albert et al. [1982]).	Rat, Sprague-Dawley	Male	0, 14.8 ppm (with or without ~10 ppm HCl)	6 h/d, 5 d/wk, >28 mo	NS
Kamata et al., 1997	Rat, Fischer 344	Male	0, 0.3, 2, and 15 ppm	6 h/d, 5 d/wk, 28 mo	NR (No hematological changes were found. Also, the authors examined femur, mesenteric lymph nodes, many other organs, and “any other gross lesions”
Feron et al., 1988	Rat, Wistar	Male	0, 10, 20 ppm	6 h/d, 5 d/wk, (4, 8 or 13 wk); follow-up >28 mo	NR (Animals were autopsied and examined for gross pathological changes. The authors found no gross pathological changes)
Ingestion studies
Til et al., 1989	Rat, Wistar	Female	0, 1.8, 21, 109 mg/kg bw/d (0, 20, 260, 1900 ppm)	Daily, 24 mo, drinking water	NS
As above	Rat, Wistar	Male	0, 1.2, 15, 82 mg/kg bw/d (0, 20, 260, 1900 ppm)	As above	NS
Soffritti et al., 1989	Rat, Sprague-Dawley	Female	Experiment 1: 0, 10, 50, 100, 500, 1000, 1500 (rats were 7 weeks old at start) Experiment 2: 0, 2500 ppm (rats were 25 week old breeder and their offspring)	Daily, 24 mo, drinking water with lifetime follow-up >36 mo	All hematopoietic malignancies Experiment 1: 14% vs. 3% Experiment 2: Breeders: 11.1% vs. 5% Offspring: 0% vs. 6.1%	Up to 19% in males and 14% in males and females combined^‡
As above	Rat, Sprague-Dawley	Male	As above	As above	All hematopoietic malignancies Experiment 1: 22% vs. 4%) Experiment 2: Breeders: 11.1% vs. 0% Offspring: 11.1% vs. 5.1%	Up to 19% in males and 14% in males and females combined^‡
Tobe et al., 1989	Rat, Wistar	Female	0, 200, 1000, 5000 ppm	Daily, 24 mo, drinking water	NR (No hematological changes were found. Also, authors examined lymph nodes and several other organs and “tumorous tissues”)
As above	As above	Male	As above	As above	As above
Takahashi et al., 1986	Rat, Wistar	Male	0, 5000 ppm	Daily, 32 wk after 8 wk exposure to N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), drinking water	NR (Animals were necropsied and “no malignant tumors found outside the gastroduodenal tract”)

Note. NR = not reported; NS = not statistically significant; NA = not applicable/available; mg/kg bw/d = milligram per kilogram body weight per day; ppm = parts per million; wk = week(s); mo = month(s).

*To adjust for early deaths, Woutersen (2007) used the Peto mortality prevalence trend test, and DeVoney (2006 poster, 2010 poster abstract) “adjusted for early deaths and time to tumor observation.” It should be noted that these two references are a conference presentation and a conference poster, respectively, and are not peer-reviewed publications.

^†Data from Haseman et al. (1998); background tumor rates from NTP studies data based on spontaneous tumor rates in approximately 1000 animals.

^‡Data from the review by Feron et al. (1990) of background leukemia incidence in rats from the same colony used in the study by Soffritti et al. (1989).

Table 16.  Human hematotoxicity studies.

Study	Exposure (ppm)	Number of persons (exposed, control)	% change in WBC count between groups or % of subjects with decreased hematology parameters	Peripheral blood changes			Other findings
				Total WBC	Platelets	Hb
Yang et al., 2007*	0.018–0.036	239, 200	WBCs: 14% (E) vs. 4% (C) Platelets: 11% (E) vs. 1% (C) RBCs: 32% (E) vs. 21.5% (C)	↓↓	↓↓	↓↓
Kuo et al., 1997	ND–0.054 (personal samples) 0.006–0.237(area samples)	50, 71	NA	↓	NS	NS	Statistically significant (−0.33, p < .05) inverse relationship between FA and WBC counts, but not 11 other hematology parameters
Cheng et al., 2004*	0.2–0.76	72, 150	WBCs: 14% in E vs. 5% in C	↓	NA	NA
Lyapina et al., 2004	0.52–1.049 (mean, 0.71)	29, 21	NA	NS	NS	NR	Statistically significant inverse relationship between duration of exposure to formaldehyde and RBC counts and Hct
Xu et al., 2007*	0.36–5.56	10, 10	−11.4	NS	NS	NS
Ye et al., 2005	0.8 (8-h TWA), 1.38 (max) in workers; vs. 0.009 (mean), 0.012 (max) in controls	36, 6	NA	NA	NA	NA	Workers vs. students in dorms. Statistically significantly increased B lymphocytes. Statistically significantly decreased CD3 and CD8 but not CD4 T lymphocytes in peripheral blood
As above	0.09 (5-h TWA), 0.24 (max); vs. 0.009 (mean), 0.012 (max) in controls	18, 6	NA	NA	NA	NA	Waiters vs. students in dorms. No change in B or T lymphocytes counts in peripheral blood
Zhang et al., 2010b	0.63–2.51 (mean, 1.28)	43, 51	−13.5	↓↓	↓	NS	Decreased RBC; increased MCV (statistically significant)
Qian et al., 1988*	2.44 (estimated)	55, 41	−13.3	↓↓↓	NA	NA	Increase in immunoglobulins (Ig) IgM and IgA, and eosinophils (no statistical significance reported)
Feng et al., 1996*	0.57–15.61	104, 68	NA	NS	NA	NS
Srivastava et al., 1992	NR	6, 0	Increased blood lymphocyte counts in 3 of 6 subjects	NA	NA	Decrease	Decreased Hb in 4 of 6 subjects
Tang et al., 2003*	NR	110, 120	−17.1	NS	NA	NA	Decreased WBC count with increasing work years (no statistical significance reported)
Tong et al., 2007*	NR	65, 70	−18	↓↓↓	↓↓↓	NS	WBC and platelet counts decreased with increasing work years (no statistical significance reported)

Note. E = exposed group; C = control group; NR = not reported; NS = not statistically significant; NA = not applicable/available; WBC = white blood cell count in peripheral blood; RBC = red blood cell count in peripheral blood; Hct = hematocrit; Hb = hemoglobin content of RBCs; ↓ = statistically significant decrease (p < .05); ↓↓ = statistically significant decrease (p < .01); ↓↓↓ = statistically significant decrease (p < .001).

* As cited in Tang et al. (2009). These studies are in Chinese and are not available on PubMed.

Table 17.  Comparison of formaldehyde hematotoxicity to known leukemogens.

	Benzene	Cyclophosphamide	Radiation	Formaldehyde
Pancytopenia in animals	Yes	Yes	Yes	No
Hematopoietic malignancies in animals	Yes	Yes	Yes	No
Pancytopenia in humans	Yes	Yes	Yes	More research needed

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