Mortality From Lymphohematopoietic Malignancies

Among Workers in Formaldehyde Industries

Michael Hauptmann, Jay H. Lubin, Patricia A. Stewart, Richard B. Hayes,

Aaron Blair

Background: Many U.S. factory workers are exposed to

formaldehyde. Although increased risks for leukemia have

been found in medical workers and other professionals exposed to formaldehyde, studies in industrial workers, who

are thought to have higher exposures, have shown inconsistent associations. We extended follow-up of a cohort of industrial workers to evaluate the association between formaldehyde exposure and lymphohematopoietic cancers.

Methods: The cohort consisted of 25 619 workers (865 708

person-years) employed before January 1, 1966, at one of 10

U.S. industrial plants and followed through December 31,

1994. We analyzed formaldehyde exposure (peak exposure,

average exposure intensity, cumulative exposure, and duration of exposure) and mortality from lymphohematopoietic

malignancies using standardized mortality ratios and relative risks and 95% confidence intervals (CIs) based on Poisson regression. Statistical tests were two-sided. Results:

Among the cohort, there were 178 deaths from lymphohematopoietic malignancies. Relative risks for leukemia (69

deaths), particularly for myeloid leukemia (30 deaths), increased with formaldehyde exposure. Compared with workers exposed to low peak levels of formaldehyde (0.1–1.9

ppm), relative risks for myeloid leukemia were 2.43 (95% CI

 0.81 to 7.25) and 3.46 (95% CI  1.27 to 9.43) for workers

exposed to peak levels of 2.0–3.9 ppm and >4.0 ppm, respectively (Ptrend  .009). Compared with workers exposed

to low levels of average exposure intensity of formaldehyde

(0.1–0.4 ppm), workers exposed to 0.5–0.9 ppm and >1.0

ppm average intensity had relative risks of 1.15 (95% CI 

0.41 to 3.23) and 2.49 (95% CI  1.03 to 6.03), respectively

(Ptrend  .088). The relative risk for leukemia was not associated with cumulative exposure but was weakly associated

with duration of exposure. Relative risks for Hodgkin’s disease also increased with formaldehyde exposure. Conclusions: Exposure to formaldehyde may cause leukemia, particularly myeloid leukemia, in humans. However, results

from other investigations are mixed, suggesting caution in

drawing definitive conclusions. [J Natl Cancer Inst 2003;95:

1615–23]

Approximately 12 million tons of formaldehyde, a flammable and colorless gas, were produced worldwide in 1992

(1). Formaldehyde is used in the production of resins, molding compounds, photographic film, decorative laminates, and

plywood, and as a bactericide and a tissue preservative. The

U.S. National Institute of Occupational Safety and Health

estimated that, in 1981–1983, approximately 1.5 million workers

in the United States were exposed to formaldehyde (2). Occupational exposures occur mainly to formaldehyde gas. However,

formaldehyde-containing particulates can occur as products (i.e.,

paraform) or can be formed when formaldehyde gas adheres to

Affiliation of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and

Human Services, Bethesda, MD.

Correspondence to: Michael Hauptmann, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Bethesda,

MD 20892 (e-mail: hauptmann@nih.gov).

See “Notes” following “References.”

DOI: 10.1093/jnci/djg083

Journal of the National Cancer Institute, Vol. 95, No. 21, © Oxford University

Press 2003, all rights reserved.

Journal of the National Cancer Institute, Vol. 95, No. 21, November 5, 2003 ARTICLES 1615
carrier agents such as wood dust. Dermal exposure is possible

from formalin solutions or liquid resins (3).

Formaldehyde at a concentration of approximately 0.5–1 ppm

causes acute health effects, including irritation of the eye and upper

airway mucosa (3). Rats and mice that were exposed by inhalation

to formaldehyde gas at concentrations of greater than 5 ppm for 2

or more years developed squamous cell carcinomas of the nasal

cavity (4,5). However, formaldehyde can have effects away from

the site of exposure. Human leukocytes exposed to formaldehyde

developed DNA–protein cross-links in vitro and in vivo, which may

result in a loss of genetic material (6).

The International Agency for Research on Cancer found

sufficient evidence to declare that formaldehyde is carcinogenic

in animals but only limited evidence for carcinogenicity in

humans (3). However, formaldehyde exposure has been associated with cancer of the nasal sinuses and nasopharynx in some

studies of industrial workers (3). Although some studies have

reported an increased risk of leukemia (range of standardized

mortality ratios [SMRs]  1.1–3.0) among medical workers and

other professionals exposed to formaldehyde, the results of

studies among industrial workers are mixed (3). We previously

assessed mortality among the largest cohort of industrial workers exposed to formaldehyde (7). Here, we extended follow-up

of the cohort by 15 years, and assessed the relationship between

formaldehyde exposure and lymphohematopoietic malignancies.

SUBJECTS AND METHODS

Cohort Design and Follow-up

Details of the study design have been described previously

(7,8). In brief, the cohort consisted of 25 619 workers first

employed at one of 10 industrial plants before January 1, 1966

(878 workers of unknown sex or race/ethnicity and 64 workers

who started work after January 1, 1966, were excluded). In the

original follow-up (7), information for each worker regarding

birth date, race/ethnicity, sex, and each job held at a participating

plant was obtained from company records. Subjects were followed from the year of initial cohort identification (1934–1958,

depending on the plant) or first employment at a plant, whichever was later, through January 1, 1980. Data from the Social

Security Administration, Health Care Finance Administration,

Veterans Administration, credit bureaus, motor vehicle departments, and telephone directories were used to determine vital

status. Death certificates were obtained for 4349 individuals

through 1980 to determine the underlying cause of death. For the

866 subjects (3.4%) lost to follow-up, follow-up ended at the last

date known alive.

In this study, we extended the mortality follow-up through

December 31, 1994. All subjects alive on January 1, 1980, were

linked to the National Death Index Plus (http://www.cdc.gov/nchs/

r&d/ndi/ndi.htm). For deceased individuals, information was collected from death certificates to establish the underlying cause of

death. A total of 4137 new deaths were identified. The total number

of deaths for the cohort was therefore 8486. The remaining subjects

were assumed to be alive on December 31, 1994.

During this study, we did not contact study participants. Therefore, the institutional review board of the National Institutes of

Health (Bethesda, MD) determined that the study was exempt from

review. Approval was obtained from state institutional review

boards, where necessary, to obtain death certificates.

Exposure Assessment

The 10 industrial plants included in this study produced formaldehyde (three plants), formaldehyde resins (six plants), molding

compounds (six plants), molded plastic products (two plants), photographic film (two plants), and plywood (one plant). Exposure to

formaldehyde was estimated from work histories collected through

1980 on the basis of job titles, tasks, visits to the plants by study

industrial hygienists, discussions with workers and plant managers,

and monitoring data. Peak exposures were defined as short-term

exposures (generally 15 minutes) that exceeded the 8-hour, timeweighted average formaldehyde exposure intensity. Peak exposures

in the workplace occurred from routine (i.e., hourly, daily, or

weekly) or nonroutine high-exposure tasks or from working in

areas where nonroutine unusual upsets or events, such as spills,

occur. No measurements of peak exposure were available in this

study. Peak exposures were therefore estimated by an industrial

hygienist from knowledge of the job tasks and a comparison with

the 8-hour time-weighted average. The presence of particulates (i.e.,

solid formaldehyde such as paraform or trioxane), a formaldehydecontaining resin or molding compound particulate, or a particulate

onto which formaldehyde gas could be adsorbed, was assessed. The

routine use of respirators was determined. We identified exposures

to 11 other widely used chemicals in the plants (i.e., antioxidants,

asbestos, carbon black, dyes and pigments, hexamethylenetetramine, melamine, phenol, plasticizers, urea, wood dust, and benzene). We also identified workers employed as chemists or laboratory technicians. A comprehensive description of the exposure

assessment is given elsewhere (7,9,10). No information on formaldehyde exposure after 1980 was available.

Statistical Analysis

Subjects contributed person-years from the time of entry into the

cohort (1934–1966) through time of death or December 31, 1994,

whichever was earlier. For each job, the following was available:

8-hour time-weighted average formaldehyde exposure intensity (in

ppm), peak formaldehyde exposure category (unexposed, 0.1–1.9

ppm, 2.0–3.9 ppm, 4 ppm), frequency of peak exposure (none,

hourly, daily, weekly, monthly), presence of particulates (yes/no),

routine respirator use (yes/no), exposure to each of 11 other substances (yes/no), and working as a chemist or laboratory technician

(yes/no). On the basis of this information, the following exposure

variables were calculated as time-dependent variables: cumulative

formaldehyde exposure (in ppm-years), average formaldehyde exposure intensity (in ppm), and highest peak formaldehyde exposure

category. In addition, we calculated duration of formaldehyde exposure (in years) because this measure is widely used in occupational epidemiologic studies. However, the validity of exposure

duration requires the assumption that the exposure rate for all jobs

and over time be constant, which was not true in this, and most

similar, situations. We also calculated exposure to formaldehydecontaining particulates (ever/never), duration of exposure to each of

11 other substances (in years), and duration of working as a chemist

or laboratory technician (in years). Cut points for formaldehyde

exposure categories were approximately the 60th and 80th percentiles of the distribution of the respective exposure measure in

exposed subjects who died from cancer. These cut points ensured

that there were sufficient numbers of case subjects in the exposed

categories.

SMRs were calculated using sex-, race-/ethnicity-, age-, and

calendar year–specific U.S. mortality rates. For internal analy1616 ARTICLES Journal of the National Cancer Institute, Vol. 95, No. 21, November 5, 2003
ses, relative risks and 95% confidence intervals (CIs) were

estimated using log-linear Poisson regression models (11) stratified by calendar year (1930–1934, 1935–1939,..., 1990–

1994), age (0–14, 15–19, . . . , 75–79, 80), sex, and race/ethnicity (black/white) and adjusted for pay category (annual salary/

hourly wage/unknown). The low-exposure categories (i.e., 0.1–

1.9 ppm for peak exposure, 0.1–0.4 ppm for average exposure

intensity, 0.1–1.4 ppm-years for cumulative exposure, and 0.1–

4.9 years for duration of exposure) were used as the reference

categories to minimize the impact of any unmeasured confounding variables because unexposed workers may have differed

from exposed workers with respect to socioeconomic characteristics. However, workers in the low-exposure categories were

exposed to very low levels of formaldehyde and are thus an

appropriate referent group. Potential confounding was evaluated

for exposure to 11 other substances (listed above) and for

working as a chemist or laboratory technician. Tests of trend for

categorical variables were based on the likelihood ratio for the

slope of the corresponding continuous variable, with the exception of peak exposure, for which categorical ranks were used.

Heterogeneity among risk estimates was assessed by likelihood

ratio tests. Tests were two-sided at a 5% significance level.

EPICURE software (12) was used for the analysis.

All exposures were calculated using a 2-year lag interval to

account for latency, i.e., for the fact that formaldehyde exposures received within 2 years before death are unlikely to be

associated with the cause of death. We evaluated various lag

intervals from 2 to 20 years and did not find substantial differences in goodness of model fit from the 2-year lag interval (data

not shown).

Relative risk estimates were not adjusted for plant because

plant is highly correlated with exposure. However, we repeated

the analyses, selectively omitting one plant at a time, and found

relative risk estimates to be similar to those from the analysis

that included all plants (data not shown).

RESULTS

Demographic Description of the Cohort

The cohort included 25 619 subjects, 75% of whom entered

the cohort before 1960, and 865 708 person-years. The duration

of follow-up ranged from a few days to 58 years, with a median

duration of 35 years. Median ages at entry and end of follow-up

were 26 and 64 years, respectively. The majority of the cohort

were white men (81%) (Table 1). Less than 20% of the cohort

consisted of white women (12%), black men (7%), or black

women (1%) (Table 1).

Exposure to Formaldehyde

The median time-weighted average formaldehyde exposure

intensity for workers in jobs exposed to formaldehyde was 0.5

ppm (range  0.0–4.3 ppm), and 17% of all jobs and 3201

individuals had no exposure to formaldehyde. Of all jobs, 2.6%

had average exposure intensities of 2 ppm or higher, and 14.3%

had peak exposures of 4 ppm or higher. These exposures were

generally similar to or slightly higher than those in other studies

examining occupational exposures to formaldehyde (13). The

median duration in jobs with exposure to formaldehyde was 2

years (range  1 day to 46 years). Cumulative exposure to

formaldehyde ranged from zero to 107 ppm-years. Approximately 0.5% (n  133) of the individuals in the cohort ever

routinely used a respirator and, of these, only 24 individuals

used one routinely for 5 or more years.

Formaldehyde Exposure and Mortality

Among the 2099 cancer deaths in the cohort, there were 178

deaths from lymphohematopoietic malignancies: 17 among un--

exposed workers, and 161 among exposed workers (Table 2).

Compared with mortality among the U.S. population, mortality

from all causes, all cancers, and all lymphohematopoietic malignancies was statistically significantly lower among workers,

regardless of exposure status. For unexposed workers, the SMRs

for mortality from all causes, all cancers, and all lymphohematopoietic malignancies were 0.77 (95% CI  0.72 to 0.83), 0.65

(95% CI  0.56 to 0.75), and 0.62 (95% CI  0.39 to 1.00),

respectively. For exposed workers, the SMRs for mortality from

all causes, all cancers, and all lymphohematopoietic malignancies were 0.95 (95% CI  0.93 to 0.97), 0.90 (95% CI  0.86

to 0.94), and 0.80 (95% CI  0.69 to 0.94), respectively. In

exposed workers, there were statistically significantly fewer

deaths than expected from non-Hodgkin’s lymphoma (SMR

 0.61, 95% CI  0.46 to 0.83), whereas there were more

deaths than expected from Hodgkin’s disease (SMR  1.26,

95% CI  0.81 to 1.95), although the increase was not

statistically significant. Among unexposed workers, there

were statistically significantly fewer deaths than expected

from leukemia (SMR  0.38, 95% CI  0.14 to 1.00) and

more deaths than expected from multiple myeloma (SMR 

1.23, 95% CI  0.51 to 2.95), although the increase was not

statistically significant.

The relative risks for leukemia (69 deaths) increased by peak

and average level of exposure to formaldehyde, particularly for

myeloid leukemia (30 deaths). Compared with workers exposed

Table 1. Demographic characteristics of the cohort

Demographic

characteristic No. of subjects (%) Person-years (%)

Ethnicity and sex

Men

White 20 658 (81) 702 371 (81)

Black 1835 (7) 56 467 (7)

Women

White 3100 (12) 106 065 (12)

Black 26 (1) 805 (1)

Year of entry into cohort

Before 1945 3105 (12) 118 398 (14)

1946–1955 11 200 (44) 399 384 (46)

1956–1965 11 314 (44) 347 927 (40)

Age at entry, y

30 16 877 (66) 601 727 (70)

31–40 5122 (20) 170 793 (20)

41–50 2593 (10) 72 557 (8)

51–60 838 (3) 18 055 (2)

61 189 (1) 2577 (1)

Duration of follow-up, y

30 8273 (32) 172 723 (20)

31–35 5092 (20) 169 630 (20)

36–40 5109 (20) 195 628 (23)

41 7145 (28) 327 727 (38)

Vital status

Alive 16 267 (64) 633 576 (73)

Deceased 8486 (33) 228 050 (26)

Unknown 866 (3) 4081 (1)

Total 25 619 (100) 865 708 (100)

Percentages may not add up to 100 due to rounding.

Journal of the National Cancer Institute, Vol. 95, No. 21, November 5, 2003 ARTICLES 1617
to low levels of formaldehyde (0.1–1.9 ppm peak exposure or

0.1–0.4 ppm average exposure intensity), relative risks for myeloid leukemia were 2.43 (95% CI  0.81 to 7.25) and 3.46

(95% CI  1.27 to 9.43) for workers exposed to formaldehyde

at 2.0–3.9 ppm and 4.0 ppm peak exposure, respectively

(Ptrend  .009), and 1.15 (95% CI  0.41 to 3.23) and 2.49 (95%

CI  1.03 to 6.03) for workers exposed to formaldehyde at

0.5–0.9 ppm and 1.0 ppm average exposure intensity, respectively (Ptrend  .088) (Tables 3 and 4). When we excluded peak

exposures in jobs of short duration (1 year) or peaks that

occurred less often than daily, relative risks for all leukemia

associated with peak exposure were not substantially changed.

The association of duration of exposure with leukemia was

weak, and there was no association of cumulative exposure with

leukemia (Tables 5 and 6).

Increased relative risks for all leukemia by peak and average

intensity of formaldehyde exposure were similar within categories of age, pay, exposure to formaldehyde-containing particulates, and employment as a chemist or laboratory technician

(data not shown).

Table 3. Relative risks for mortality from lymphohematopoietic malignancies by peak exposure to formaldehyde

Cause of death (ICD†)

Relative risk (95% confidence interval)‡

Ptrend§ Ptrend

No. of deaths

Peak exposure, ppm¶

0 0.1–1.9 2.0–3.9 4.0

Lymphohematopoietic malignancies (200–209) 1.08 (0.60 to 1.94) 1.00 (Referent) 1.71 (1.14 to 2.58) 1.87 (1.27 to 2.75) .002 .002

17 48 49 64

Non-Hodgkin’s lymphoma (200, 202) 1.12 (0.38 to 3.31) 1.00 (Referent) 1.39 (0.67 to 2.91) 1.23 (0.59 to 2.55) .604 .536

5 15 14 15

Hodgkin’s disease (201) 0.51 (0.06 to 4.52) 1.00 (Referent) 3.45 (0.98 to 12.16) 3.35 (0.97 to 11.59) .014 .042

157 8

Multiple myeloma (203) 2.10 (0.66 to 6.75) 1.00 (Referent) 1.48 (0.56 to 3.92) 1.67 (0.68 to 4.12) .669 .355

5 9 8 11

Leukemia (204–207) 0.78 (0.25 to 2.43) 1.00 (Referent) 2.04 (1.04 to 4.01) 2.46 (1.31 to 4.62) .001 .004

4 16 20 29

Lymphatic leukemia (204) 0.00 (0.00 to 2.24) 1.00 (Referent) 1.51 (0.48 to 4.74) 1.39 (0.46 to 4.17) .279 .559

066 7

Myeloid leukemia (205) 0.67 (0.12 to 3.61) 1.00 (Referent) 2.43 (0.81 to 7.25) 3.46 (1.27 to 9.43) .003 .009

2 6 8 14

Other/unspecified leukemia (207) 1.92 (0.33 to 11.33) 1.00 (Referent) 2.33 (0.63 to 8.66) 2.47 (0.69 to 8.87) .277 .154

246 7

No. of person-years 135 396 335 923 194 468 199 921

Analyses were not feasible for polycythemia vera (ICD 208, one death) and myelofibrosis (ICD 209, five deaths) due to small numbers. No association with

formaldehyde exposure was observed for other diseases of blood cells in the bone marrow, including seven deaths from anemia of which four were aplastic, one

was hypochromic with iron loading, one was specified as other, and one was unspecified, and three deaths from agranulocytosis.

†Codes of the International Classification of Diseases (ICD), 8th revision.

‡Relative risks were derived from Poisson regression stratified for calendar year, age (both in 5-year intervals), sex, and race/ethnicity (black/white), and adjusted

for pay category (salary/wage). Cut points for formaldehyde exposure categories were approximately the 60th and 80th percentiles of the distribution of the respective

exposure measure in exposed subjects who died from cancer. These cut points ensured that there were sufficient numbers of cases in the exposed categories.

§Two-sided likelihood ratio test (1 degree of freedom) of zero slope for continuous formaldehyde exposure among unexposed and exposed person-years;

parentheses indicate negative slope estimate.

Two-sided likelihood ratio test (1 degree of freedom) of zero slope for continuous formaldehyde exposure among exposed person-years only; parentheses indicate

negative slope estimate.

¶Exposure was calculated using a 2-year lag interval.

Table 2. Number of observed deaths and standardized mortality ratios (SMRs) with 95% confidence intervals (CIs)

Cause of death (ICD codes†)

No. of observed deaths SMR (95% CI)

Unexposed Exposed Unexposed Exposed

All causes (001–999) 827 7659 0.77 (0.72 to 0.83) 0.95 (0.93 to 0.97)

All cancer (140–209) 183 1916 0.65 (0.56 to 0.75) 0.90 (0.86 to 0.94)

All solid malignant neoplasms (140–199) 166 1755 0.65 (0.56 to 0.76) 0.91 (0.87 to 0.96)

Lymphohematopoietic malignancies (200–209) 17 161 0.62 (0.39 to 1.00) 0.80 (0.69 to 0.94)

Non-Hodgkin’s lymphoma (200, 202) 5 44 0.52 (0.22 to 1.25) 0.61 (0.46 to 0.83)

Hodgkin’s disease (201) 1 20 0.37 (0.05 to 2.65) 1.26 (0.81 to 1.95)

Multiple myeloma (203) 5 28 1.23 (0.51 to 2.95) 0.88 (0.61 to 1.28)

Leukemia (204–207) 4 65 0.38 (0.14 to 1.00) 0.85 (0.67 to 1.09)

Benign neoplasms (210–239) 1 26 0.26 (0.04 to 1.87) 1.12 (0.76 to 1.64)

Circulatory system diseases (390–458) 371 3474 0.68 (0.62 to 0.76) 0.88 (0.85 to 0.91)

Respiratory diseases (460–519) 43 501 0.50 (0.37 to 0.67) 0.81 (0.74 to 0.89)

No. of person-years 135 396 730 312

Exposure status was calculated by using a 2-year lag interval.

†Codes of the International Classification of Diseases (ICD), 8th revision.

1618 ARTICLES Journal of the National Cancer Institute, Vol. 95, No. 21, November 5, 2003
We found evidence of an association between Hodgkin’s

disease (21 deaths) and exposure to formaldehyde. Compared

with workers exposed to low levels of formaldehyde (0.1–1.9

ppm peak exposure or 0.1–0.4 ppm average exposure intensity),

relative risks for Hodgkin’s disease were 3.45 (95% CI  0.98

to 12.16) and 3.35 (95% CI  0.97 to 11.59) among workers

Table 4. Relative risks for mortality from lymphohematopoietic malignancies by average intensity of exposure to formaldehyde

Cause of death (ICD)

Relative risk (95% confidence interval)†

Ptrend‡ Ptrend§

No. of deaths

Average intensity, ppm

0 0.1–0.4 0.5–0.9 1.0

Lymphohematopoietic malignancies (200–209) 0.91 (0.52 to 1.59) 1.00 (Referent) 1.63 (1.11 to 2.37) 1.50 (1.01 to 2.24) .050 .062

17 81 42 38

Non-Hodgkin’s lymphoma (200, 202) 1.02 (0.36 to 2.86) 1.00 (Referent) 1.33 (0.65 to 2.71) 0.98 (0.43 to 2.20) .690 .607

5 25 11 8

Hodgkin’s disease (201) 0.46 (0.05 to 3.93) 1.00 (Referent) 4.70 (1.61 to 13.77) 3.12 (0.91 to 10.74) .022 .031

17 8 5

Multiple myeloma (203) 1.88 (0.62 to 5.65) 1.00 (Referent) 1.50 (0.60 to 3.74) 1.42 (0.56 to 3.58) (.855) (.801)

5 14 7 7

Leukemia (204–207) 0.56 (0.19 to 1.66) 1.00 (Referent) 1.52 (0.83 to 2.79) 1.68 (0.91 to 3.08) .193 .242

4 32 16 17

Lymphatic leukemia (204) 0.00 (0.00 to 2.02) 1.00 (Referent) 1.56 (0.52 to 4.65) 1.43 (0.47 to 4.34) .495 .632

09 5 5

Myeloid leukemia (205) 0.41 (0.08 to 1.95) 1.00 (Referent) 1.15 (0.41 to 3.23) 2.49 (1.03 to 6.03) .086 .088

2 14 5 9

Other/unspecified leukemia (207) 1.27 (0.25 to 6.40) 1.00 (Referent) 1.69 (0.56 to 5.12) 0.98 (0.26 to 3.71) (.697) (.710)

29 5 3

No. of person-years 135 396 454 927 139 628 135 757

Codes of the International Classification of Diseases (ICD), 8th revision.

†Relative risks were derived from Poisson regression stratified for calendar year, age (both in 5-year intervals), sex, and race/ethnicity (black/white), and adjusted

for pay category (salary/wage). Cut points for formaldehyde exposure categories were approximately the 60th and 80th percentiles of the distribution of the respective

exposure measure in exposed subjects who died from cancer. These cut points ensured that there were sufficient numbers of cases in the exposed categories.

‡Two-sided likelihood ratio test (1 degree of freedom) of zero slope for continuous formaldehyde exposure among unexposed and exposed person-years;

parentheses indicate negative slope estimate.

§Two-sided likelihood ratio test (1 degree of freedom) of zero slope for continuous formaldehyde exposure among exposed person-years only; parentheses indicate

negative slope estimate.

Exposure was calculated using a 2-year lag interval.

Table 5. Relative risks for mortality from lymphohematopoietic malignancies by cumulative exposure to formaldehyde

Cause of death (ICD)

Relative risk (95% confidence intervals)†

Ptrend‡ Ptrend§

No. of deaths

Cumulative exposure, ppm-years

0 0.1–1.4 1.5–5.4 5.5

Lymphohematopoietic malignancies (200–209) 0.74 (0.42 to 1.30) 1.00 (Referent) 0.79 (0.52 to 1.21) 1.03 (0.70 to 1.52) .157 .202

17 94 29 38

Non-Hodgkin’s lymphoma (200, 202) 0.82 (0.29 to 2.34) 1.00 (Referent) 0.53 (0.22 to 1.31) 0.92 (0.45 to 1.88) .968 .969

5 27 6 11

Hodgkin’s disease (201) 0.29 (0.04 to 2.34) 1.00 (Referent) 1.35 (0.45 to 3.99) 1.17 (0.31 to 4.46) .037 .045

1 12 5 3

Multiple myeloma (203) 1.49 (0.50 to 4.46) 1.00 (Referent) 0.62 (0.21 to 1.85) 1.03 (0.42 to 2.52) (.877) (.899)

5 17 4 7

Leukemia (204–207) 0.48 (0.16 to 1.42) 1.00 (Referent) 0.90 (0.47 to 1.73) 1.14 (0.63 to 2.07) .183 .235

4 35 13 17

Lymphatic leukemia (204) 0.00 (0.00 to 1.67) 1.00 (Referent) 0.72 (0.20 to 2.63) 1.20 (0.43 to 3.33) .406 .476

0 10 3 6

Myeloid leukemia (205) 0.32 (0.07 to 1.51) 1.00 (Referent) 0.57 (0.19 to 1.73) 1.02 (0.40 to 2.55) .123 .157

2 17 4 7

Other/unspecified leukemia (207) 1.37 (0.26 to 7.20) 1.00 (Referent) 1.60 (0.51 to 5.01) 1.28 (0.38 to 4.36) (.740) (.783)

285 4

No. of person-years 135 396 494 579 135 240 100 493

Codes of the International Classification of Diseases (ICD), 8th revision.

†Relative risks were derived from Poisson regression stratified for calendar year, age (both in 5-year intervals), sex, and race/ethnicity (black/white), and adjusted

for pay category (salary/wage). Cut points for formaldehyde exposure categories were approximately the 60th and 80th percentiles of the distribution of the respective

exposure measure in exposed subjects who died from cancer. These cut points ensured that there were sufficient numbers of cases in the exposed categories.

‡Two-sided likelihood ratio test (1 degree of freedom) of zero slope for continuous formaldehyde exposure among unexposed and exposed person-years;

parentheses indicate negative slope estimate.

§Two-sided likelihood ratio test (1 degree of freedom) of zero slope for continuous formaldehyde exposure among exposed person-years only; parentheses indicate

negative slope estimate.

Exposure was calculated using a 2-year lag interval.

Journal of the National Cancer Institute, Vol. 95, No. 21, November 5, 2003 ARTICLES 1619
exposed to formaldehyde at 2.0–3.9 ppm and 4.0 ppm peak

exposure, respectively (Ptrend  .042), and 4.70 (95% CI  1.61

to 13.77) and 3.12 (95% CI  0.91 to 10.74) for workers

exposed at 0.5–0.9 ppm and 1.0 ppm average exposure intensity, respectively (Ptrend  .031) (Tables 3 and 4). A trend was

also observed for cumulative exposure (Ptrend  .045) (Table 5).

Neither non-Hodgkin’s lymphoma nor multiple myeloma was

associated with any of the formaldehyde exposure measures

(Tables 3–6).

Because information on exposure ended in 1980, exposure

may have been underestimated for some subjects who were

exposed after 1980. However, the underestimate would be small

because only 3.7% of all person-years were contributed by

workers aged 65 years or younger and in exposed jobs in 1980.

When those person-years were excluded from the analysis, the

results did not change.

Potential Confounding by Exposure to Substances Other

Than Formaldehyde

Forty-seven percent of the cohort members were ever exposed in the workplace to at least one of the following substances: antioxidants (22%), asbestos (14%), carbon black

(11%), dyes and pigments (16%), hexamethylenetetramine

(15%), melamine (28%), phenol (14%), plasticizers (20%), urea

(27%), wood dust (10%), and benzene (2%). Of those ever

exposed to benzene, there were six deaths from lymphohematopoietic malignancies, including one from myeloid leukemia.

Only 8% of the cohort ever worked as chemists or laboratory

technicians, and only 2% worked in such jobs for 5 or more

years. Duration of exposure to dyes and pigments, melamine,

and plasticizers was associated with all leukemia mortality (data

not shown). Working as a chemist or laboratory technician was

also associated with leukemia mortality (data not shown). The

small numbers precluded a detailed evaluation of associations

with benzene.

Relative risk estimates for myeloid leukemia, all leukemias,

and all lymphohematopoietic malignancies did not change substantially, compared with the unadjusted analysis, when analyses

were adjusted for duration of exposure to each of the 10 other

substances and for working as a chemist or laboratory technician. We also repeated all analyses excluding the 586 subjects

exposed to benzene and found no substantial differences between those results and the results of the analysis including all

subjects.

Peak exposure and average exposure intensity were not evaluated in the previous analysis of this cohort (7). We evaluated

the earlier data for associations with these exposure measures by

limiting the analysis to follow-up through 1980, and found that

relative risks for leukemia (25 deaths) and the exposure categories shown in Tables 3 and 4 for peak exposure were 1.00, 1.00,

1.68, and 1.49 (Ptrend  .423) and for average intensity were

0.89, 1.00, 1.50, and 1.35 (Ptrend  .863). Increased relative risks

for medium- and high-exposure categories show that there was

some indication of an association in the earlier follow-up.

DISCUSSION

We observed an association between mortality from leukemia, particularly for myeloid leukemia, and several indices of

potential exposure to formaldehyde among industrial workers.

Table 6. Relative risks for mortality from lymphohematopoietic malignancies by duration of exposure to formaldehyde

Cause of death (ICD*)

Relative risk (95% confidence interval)†

Ptrend‡ Ptrend§

No. of deaths

Duration of exposure, y

0 0.1–4.9 5.0–14.9 15.0

Lymphohematopoietic malignancies (200–209) 0.75 (0.42 to 1.31) 1.00 (Referent) 0.74 (0.47 to 1.18) 1.07 (0.73 to 1.55) .905 (.752)

17 90 24 47

Non-Hodgkin’s lymphoma (200, 202) 0.86 (0.29 to 2.49) 1.00 (Referent) 0.56 (0.21 to 1.49) 0.98 (0.49 to 1.96) (.613) (.512)

5 25 5 14

Hodgkin’s disease (201) 0.23 (0.03 to 1.85) 1.00 (Referent) 0.77 (0.24 to 2.45) 0.59 (0.12 to 2.93) (.799) (.422)

1 14 4 2

Multiple myeloma (203) 1.44 (0.48 to 4.35) 1.00 (Referent) 0.36 (0.08 to 1.57) 1.05 (0.45 to 2.43) (.706) .980

5 17 2 9

Leukemia (204–207) 0.55 (0.18 to 1.66) 1.00 (Referent) 1.16 (0.59 to 2.26) 1.39 (0.78 to 2.49) .214 .465

4 30 13 22

Lymphatic leukemia (204) 0.00 (0.00 to 2.51) 1.00 (Referent) 1.87 (0.58 to 6.05) 1.62 (0.55 to 4.74) .498 .684

075 7

Myeloid leukemia (205) 0.34 (0.07 to 1.67) 1.00 (Referent) 0.49 (0.14 to 1.73) 1.35 (0.56 to 3.24) .423 .911

2 15 3 10

Other/unspecified leukemia (207) 1.36 (0.25 to 7.23) 1.00 (Referent) 1.49 (0.44 to 5.09) 1.30 (0.41 to 4.13) .402 .292

284 5

No. of person-years 135 396 498 167 134 963 97 182

Codes of the International Classification of Diseases (ICD), 8th revision.

†Relative risks were derived from Poisson regression stratified for calendar year, age (both in 5-year intervals), sex, and race/ethnicity (black/white), and adjusted

for pay category (salary/wage). Cut points for formaldehyde exposure categories were approximately the 60th and 80th percentiles of the distribution of the respective

exposure measure in exposed subjects who died from cancer. These cut points ensured that there were sufficient numbers of cases in the exposed categories.

‡Two-sided likelihood ratio test (1 degree of freedom) of zero slope for continuous formaldehyde exposure among unexposed and exposed person-years;

parentheses indicate negative slope estimate.

§Two-sided likelihood ratio test (1 degree of freedom) of zero slope for continuous formaldehyde exposure among exposed person-years only; parentheses indicate

negative slope estimate.

Exposure was calculated using a 2-year lag interval.

1620 ARTICLES Journal of the National Cancer Institute, Vol. 95, No. 21, November 5, 2003
On the basis of our results and those previously reporting more

leukemia than expected among professional workers exposed to

formaldehyde (14), it appears that formaldehyde may cause

leukemia in humans. The association found between Hodgkin’s

disease and formaldehyde exposure is more difficult to interpret

because it has not been observed previously.

Increased SMRs and relative risks for lymphohematopoietic

malignancies have been reported in several studies of professionals exposed to formaldehyde (14–19) and occasionally

among industrial workers (14,20). In several of these studies, the

excess of leukemia was mainly due to myeloid leukemia (16–

19), a finding that also emerged from our data.

Our findings can be compared with recent results from extended follow-ups of two other cohort studies of formaldehydeexposed workers. Among 14 014 men employed in the British

formaldehyde industry, there were fewer deaths than expected

from leukemia overall (31 deaths observed versus 34.1 deaths

expected) and among workers in high-exposure jobs (eight

deaths observed versus 11.3 deaths expected) (21). The study by

Coggon et al. (21) was similar to ours in that it included

quantitative estimates of formaldehyde exposure from production of urea and melamine formaldehyde resins, but it differed

from ours in that peak exposure and average exposure intensity

were not evaluated and in that our study had more than twice the

number of deaths from leukemia. In a National Institute for

Occupational Safety and Health cohort study of 11 039 textile

workers with potential exposure to formaldehyde, researchers

found an increase in leukemia mortality with longer duration of

employment, i.e., SMRs (number of deaths)  0.96 (seven),

0.72 (five), and 1.53 (12) for 3, 3–9, and 10 years, respectively (22). The increase in SMR with duration of employment

was similar to the increasing relative risks associated with duration of exposure in our study.

Experimental evidence regarding the effects of formaldehyde

at sites other than the upper respiratory tract is inconsistent.

Some biologic evidence suggests that carcinogenic effects of

formaldehyde at non–upper respiratory tract sites would be

unlikely. For example, nearly the total inhaled dose of formaldehyde is deposited in the upper respiratory tract after long-term

inhalation in rats (23), blood levels of formaldehyde did not

change after inhalation exposure to formaldehyde in rats or

humans (24), and, after rats inhaled radioactively labeled formaldehyde, substantial concentrations of radioactivity were localized in bone marrow DNA, but there was no indication that

inhaled formaldehyde formed adducts or cross-links with bone

marrow macromolecules (25).

However, other experimental evidence supports the epidemiologic findings by suggesting that formaldehyde is associated

with toxicity at sites remote from the respiratory tract. For

example, increased frequencies of micronuclei (26–28), sister

chromatid exchanges (28–31), chromosomal aberrations (28,32),

and DNA–protein cross-links (6,30) have been found in peripheral lymphocytes of humans exposed to formaldehyde. Other

studies (33–37) found some of these anomalies. Although there

is a clear link between chromosomal aberrations and cancer (38),

the relationships between micronuclei or sister chromatid exchanges and health risks are not well documented (39). In rats,

long-term inhalation of formaldehyde vapor at low concentrations of 0.6 and 1.8 ppm was associated with dose-related bone

marrow cytotoxicity, including chromosomal aberrations and

aneuploidy (40), although short-term exposure to formaldehyde

at high concentrations of 15 ppm was not (41). A statistically

significant dose-related increase in leukemia incidence was observed in Sprague-Dawley rats administered 10–1500 ppm

formaldehyde in drinking water for 2 years (42), but not in

Wistar rats (43,44). It appears that formaldehyde-induced mutagenesis involves mainly small-scale chromosomal rearrangements rather than point mutations (45). Small-scale chromosomal rearrangements are reminiscent of karyotypic anomalies

found in the hematopoietic stem cells of many patients with

lymphohematopoietic malignancies (46). Hematopoietic stem

cells are found in the bone marrow and in the peripheral blood.

In peripheral blood, they could be exposed to the potentially

toxic effects of formaldehyde, although the clinical significance

of such exposures in leukemogenesis is unclear.

In this study, leukemia was associated with peak exposure to

formaldehyde and, to a lesser degree, average exposure intensity

and duration of exposure, but not with cumulative exposure.

Multiple measures of exposure can complicate the interpretation

of results when the measure that best characterizes delivered

dose is unknown, as with formaldehyde. The initial interpretation of the results focused on whether any of the measures of

formaldehyde exposure was associated with leukemia. By using

four exposure measures rather than only one, we substantially

reduced the risk of an overall false-negative finding. Although

using four measures increased the chance of a false-positive

result for a single exposure measure, we limited the possibility

of a false-positive error for each measure by evaluating several

aspects of a potential exposure–response relationship (i.e., increasing relative risks with categories of exposure, statistically

significantly elevated relative risks, and statistically significant

trends). We then interpreted the pattern of the exposure measures for which an association was or was not found. Observing

generally weaker or no associations for duration of exposure

than for metrics of intensity, e.g., average exposure intensity or

peak exposure, was not surprising because duration as a measure

of exposure assumes a constant exposure rate for all jobs and

over time, which does not hold in this study. Therefore, the use

of duration of exposure to evaluate associations results in substantial exposure misclassification. However, the absence of an

association between cumulative exposure and leukemia given

the associations with the other three exposure measures was

unexpected.

Risk estimates could be confounded by other occupational

exposures. However, our findings of the association between

formaldehyde exposure and leukemia are not explained by exposure to 11 other agents used in these industrial plants or by

working as a chemist or laboratory technician. We were concerned about benzene, a known risk factor for leukemia, and

found no difference in the results when all workers exposed to

benzene were excluded from the analyses. Although tobacco

exposure has been weakly linked with leukemia (47), it is

unlikely to explain our findings because there was no consistent

increase in tobacco-related diseases, including lung cancer,

among the cohort. Information on smoking from medical records

for a sample of 63 workers with cancer and 316 age-matched

control subjects from two plants revealed no major differences

in smoking prevalence by level of exposure to formaldehyde (8).

Analyses were not adjusted for plant for two reasons. First, we

directly addressed confounding by factors potentially associated

with plant by adjusting for 11 potentially confounding substances. Second, adjusting for plant may potentially result in

Journal of the National Cancer Institute, Vol. 95, No. 21, November 5, 2003 ARTICLES 1621
overadjustment. However, to address the potential effect of

unmeasured confounders associated with plant, we performed

analyses adjusted for plant and separately by plant type (resins,

four plants; plywood, one plant; film, two plants; formaldehyde

and resins, three plants). Although some of these analyses were

based on small numbers and, as a consequence, estimates had

large variances, associations for leukemia and Hodgkin’s disease

found in the adjusted analyses were similar to those in the

analyses that did not adjust for plant.

One potential limitation of our study was exposure misclassification. The detailed approach to developing quantitative estimates of time-weighted average exposure intensity by using

monitoring data provided by the companies, monitoring in each

plant by study investigators (13), having study industrial hygienists visit the plants, and discussing exposure with plant managers

and long-time workers (9) should have minimized misclassification of average and cumulative exposure and of duration of

exposure. The assessment of peak exposure could have been

more susceptible to misclassification because peak levels were

estimated from time-weighted average exposure and job tasks.

However, any exposure misclassification should be nondifferential with respect to disease status in a cohort study, in which

exposure is assessed before disease outcome, and this nondifferential exposure misclassification would attenuate exposure–

response patterns. Moreover, associations with peak exposure

changed little when peak exposures in jobs of short duration (1

year) and when peak exposures that occurred less often than

daily were excluded from the analyses. Therefore, exposure

misclassification is unlikely to be responsible for the positive

findings in our study.

A second potential limitation was the lack of information on

exposures during the recent follow-up (1980–1994), which

could cause an underestimation of exposure for individuals

working after 1980. However, the impact would be minimal

because only a small proportion of individuals was likely exposed after 1980 (3.7% of all person-years) and, for those

workers, levels of exposure were probably considerably lower

after 1980 than in earlier years. Although the accuracy of death

certificates for lymphohematopoietic malignancies is generally

high, classification of subtypes of leukemia and lymphoma from

death certificates is less accurate than classification from hospital records (48). However, in this study, any disease misclassification should be nondifferential with respect to formaldehyde

exposure. In our follow-up, individuals not identified as deceased by the National Death Index Plus were assumed to be

alive. Although a violation of this assumption could result in

some underascertainment of deaths, underascertainment is unlikely to be related to formaldehyde exposure and, therefore,

should not have biased the results.

Our study has several major strengths, including its large size

(up to 60 years of follow-up and 178 deaths from lymphohematopoietic malignancies) and the extensive assessment of formaldehyde exposure by using several measures (peak, average,

cumulative, and duration of exposure). Because these measures

were only moderately correlated (10), they classify workers

differently and provide relatively independent assessments of

exposure–response. Duration of exposure to formaldehyde was

poorly correlated with peak exposure or average intensity [Pearson correlation coefficients were 0.3 and 0.0, respectively (10)],

which may explain its lack of association with leukemia. In

addition, we did not rely on external comparisons (i.e., SMRs),

which are subject to a healthy worker bias (49), but instead

focused on internal analyses that compared similar individuals.

In summary, the increased risk for leukemia mortality, particularly myeloid leukemia, from peak and average exposure to

formaldehyde could not be explained by obvious biases or

confounding. The exposure–response gradient observed and the

consistency with other epidemiologic studies of workers in occupations with formaldehyde exposure and some experimental

studies suggest a causal association between formaldehyde exposure and leukemia. However, lack of an association in a recent

follow-up of a similar but smaller industrial cohort in Great

Britain (21) introduces uncertainty regarding the relationship.

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NOTES

Funded by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

We thank Drs. Elizabeth Fontham, David Savitz, Michael Thun, and Robert

Hoover for review and helpful suggestions. We shared the manuscript with

participating companies and unions and appreciate their comments.

Manuscript received April 4, 2003; revised August 29, 2003; accepted

September 11, 2003.

Journal of the National Cancer Institute, Vol. 95, No. 21, November 5, 2003 ARTICLES 1623