We found a statistically significant association between death from lymphohematopoietic malignancies and peak exposure to formaldehyde in this large cohort of workers in formaldehyde industries followed through 2004 but no association with average intensity or cumulative exposure. For peak exposure, the cumulative risk estimates, calculated by extending follow-up by yearly increments for the highest exposure category, remained statistically significant throughout but decreased when extending the follow-up beyond 1980. Relative risks with average intensity were at or near their maxima when follow-up ended in the 1980s and declined with accrual of additional person-years and events. Other studies that have examined associations with all lymphohematopoietic malignancies have reported mostly small excesses of these cancers that were based on small numbers of subjects (11
). A cohort study of 11 039 garment workers was recently updated (19
) and found no excess of all lymphohematopoietic malignancies.
The overall associations of formaldehyde exposure with leukemia and myeloid leukemia in the NCI cohort have diminished with an additional 10 years of follow-up since our previous analysis (5
). For peak exposure and myeloid leukemia, the cumulative risk estimates were highest before 1980 but only achieved statistical significance in the early 1990s, after which they slowly declined. This pattern could reflect the increased precision of the relative risk estimates with accrual of additional person-years and myeloid leukemia cases or could reflect a relatively short induction–incubation time for myeloid leukemia because analyses by time since first exposure and first high peak both indicate highest risks within the first 25 years. Our analysis also revealed striking differences in the relative risk for lymphatic and myeloid leukemia for peak exposure, suggesting subtype specificity over the entire cohort follow-up, although this is difficult to reliably assess with mortality data.
Studies of pathologists, embalmers, and other professionals exposed to formaldehyde have provided evidence of increased risk of leukemia in these individuals (11
), with some suggesting an association between work in occupations with formaldehyde exposure and myeloid leukemia (11
). Studies of industrial workers exposed to formaldehyde are less consistent, with some showing positive associations with leukemia (19
) and others not (23
). Two cohorts of industrial workers have been recently updated. In a study of 11 039 garment workers in the United States, Pinkerton et al. (19
) found a statistically nonsignificant excess of myeloid leukemia that was greatest among workers exposed at earlier time periods, with 10 or more years of exposure and with 20 or more years since first exposure. However, quantitative estimates of peak, average intensity, or cumulative exposure were not developed. The mean TWA8 intensity of 0.15 ppm (range = 0.09–0.20 ppm) reported by Pinkerton et al. (19
) for a random sample of study workers in the early 1980s was probably higher than that in the past but considerably lower than in our study. In a study of 14 014 men in British chemical factories similar to those in our study, Coggon et al. (24
) showed no association with leukemia or any other lymphohematopoietic malignancy. The authors reported that 28% of workers had estimated exposures >2.0 ppm, suggesting higher exposure levels than those in our study. However, the exposure assessment was not calendar time specific. Because exposure levels have generally decreased over time in most factories, exposures for those working more recently would therefore be classified at higher levels than in our study (8
). Second, exposure in the Coggon study was evaluated as intensity in the highest exposed job ever held, whereas intensity of exposure in the NCI cohort was based on person–time–weighted average intensity across all jobs. These differences would create the appearance that levels in the British cohort were higher than those in the NCI cohort, when they likely were not. Finally, Marsh and Youk (29
) reanalyzed the data from an earlier report of the NCI cohort using different category cut points for average intensity, cumulative exposure, and exposure duration and showed a similar pattern of relative risks as observed by Hauptmann et al. (5
) for leukemia and myeloid leukemia. They examined the effect of duration of time worked in each highest peak category and of time since highest peak exposure within each category of peak and the effect of duration and time since first exposure within categories of average intensity of exposure. They found little evidence of associations within exposure categories, which is not unexpected given the limited power for conducting stratified analyses (eg, three categories of time by three categories of exposure based on 28 exposed cases for myeloid leukemia). They also demonstrated that standardized mortality ratios for peak exposure categories and all leukemia and myeloid leukemia increased from deficits in the lowest exposed (eg, 0.4–0.5) to excesses in the highest exposed (eg, 1.2–1.4) categories (29
). In our current update through 2004, standardized mortality ratios similarly increased from the lowest to the highest peak exposure categories; however, the standardized mortality ratios in the lowest exposed (referent) category did not statistically significantly differ from 1.0, with values of 0.87 for leukemia and 0.68 for myeloid leukemia.
In its evaluation of the carcinogenicity of formaldehyde, the IARC Working Group concluded that based on available data, it was not possible to identify the mechanism by which formaldehyde may induce leukemia. Although the relevance of cytogenetic damage in mature peripheral lymphocytes to leukemogenesis is unknown (3
), the Working Group did note that agents known to cause leukemia in humans also cause chromosomal aberrations in peripheral blood cells of humans. Multiple published studies of humans exposed to inhaled formaldehyde have shown higher rates of chromosomal aberration in peripheral blood lymphocytes in exposed individuals compared with controls (30
), although the difference was statistically significant only in a subset of these studies (31
). One study showed an inverse association of chromosomal aberrations with exposure (42
Excess risks for Hodgkin lymphoma and multiple myeloma also contribute to the association with lymphohematopoietic malignancies overall. Although based on only 27 deaths, the association with Hodgkin lymphoma in our study was strong and includes a statistically significant exposure–response trend for both peak and average exposure. Cumulative risk estimates were greatest in the 1970s, but remained elevated through 2004. Although recent updates of studies of industrial workers by Coggon et al. and Pinkerton et al. showed standardized mortality ratios for Hodgkin lymphoma of 0.70 (95% CI = 0.26 to 1.53) and 0.55 (95% CI = 0.07 to 1.98), respectively (19
), the strength of the association observed between formaldehyde and Hodgkin lymphoma shown here warrants further study. There are no well-established chemical causes of this disease (43
), although there is some evidence that employment in woodworking occupations may increase risk (44
); the strongest evidence for an etiologic factor for Hodgkin lymphoma may be immune response to childhood infections (43
). In our analysis, controlling for wood dust or other industrial coexposures did not substantively change the association.
Multiple myeloma showed evidence of exposure–response trends for peak exposure within the exposed categories, but the greatest risks occurred among the unexposed. The epidemiological literature regarding formaldehyde and multiple myeloma is limited; Hayes et al. (16
) reported a small, non-statistically significant excess among embalmers, but the Pinkerton study found no excess (24
A limitation of our study is that exposure assessment ceased in 1980. In primary analyses, we assumed that zero exposure occurred after 1980, which may have increased exposure misclassification. Only 11% of the cohort was exposed to formaldehyde in 1980. If exposure continued until age 65, we would have underestimated exposure for 6% of the person-years. Estimated exposure levels in our cohort decreased before 1980 and likely continued to decline for the small numbers exposed after 1980. This pattern of decreasing levels over time is supported by measurement data from OSHA (46
) and a study in the wood panel industry (47
). Thus, it is unlikely that many workers in the cohort would have had substantial exposures after 1980. When we censored workers still exposed in 1980, risks increased for myeloid leukemia, which may reflect exposure misclassification resulting from assuming zero post-1980 exposure. When we assumed that exposure continued at the same level among the exposed in 1980 until age 65 years, results did not substantively change for any site.
Although exceptional efforts were made to develop high-quality exposure assessments, misclassification undoubtedly occurred. As with all studies, estimation of exposures from limited measurement data is difficult and complex. Although validation was not possible, effects of misclassification may be gauged by comparing full-shift exposure estimates with the monitoring data. A sample of 21 jobs showed a correlation coefficient of 0.50 (8
). In a prospective study such as this where information on exposure is assembled independently from, and before, determination of mortality, exposure misclassification would be nondifferential, which would bias relative risks toward the null (48
We used cause of death information provided by NDI Plus. Although agreement between underlying cause of death on death certificates and hospital diagnoses is generally high, certain types or sites of cancer are underreported on death certificates, including lymphocytic and myeloid leukemia (49
). Any misclassification should be nondifferential with respect to exposure. Additionally, we may have underascertained cases because we considered an individual alive if NDI Plus did not identify the subject as deceased. Any resulting underascertainment should have also been nondifferential with respect to exposure. Thus, both possibilities for misclassification would bias our results toward the null.
The large size, extended follow-up, and quantitative exposure assessment are major strengths of this study. Despite inherent limitations, the detailed occupational exposure assessment allowed the development of formaldehyde exposure indices not possible in other investigations. Unlike other analyses of cohort studies (19
), we used an internal comparison group to calculate relative risks as opposed to using the general population to calculate standardized mortality ratios. This was a distinct advantage as it reduces the bias that accompanies comparisons between occupational groups and an external referent (50
), reduces confounding by unknown factors, and is the most appropriate approach for analyses with quantitative exposure assessments (48
). Unexposed and exposed groups may have differed on characteristics such as socioeconomic status; therefore, as in the previous analyses of this cohort (5
), we used the lowest exposure category as the referent to minimize the impact of unmeasured confounding. We calculated standardized mortality ratios to allow comparison of our results with other studies. Patterns of relative standardized mortality ratios, found by dividing the exposure category–specific standardized mortality ratios by the standardized mortality ratio in the referent (low exposed) category, mirrored those of the relative risk estimates.
The IARC Working Group determined there was “strong, but not sufficient evidence for a causal association between leukemia and occupational exposure to formaldehyde” (3
). In the current follow-up, the overall risk of myeloid leukemia has declined from our previous report, but remains somewhat elevated. Although that time trend may suggest that the previous excess risk estimates were due to chance, the pattern is consistent with a possible causal association, with the largest risks occurring closer in time to relevant exposure. The wavelike pattern of the relative risks over time resembles that seen for known leukemogenic agents (51
). In addition, the excess risk of lymphohematopoietic malignancies related to peak formaldehyde exposure is partially due to increased risks of multiple myeloma and Hodgkin lymphoma, which were also seen in the earlier follow-up. These associations are more difficult to interpret since, unlike leukemia, they have not been linked to formaldehyde exposure in other epidemiological studies. It is our opinion that the overall pattern of risks seen in this extended follow-up of formaldehyde workers, although not definitive, warrants continued concern. Further studies are needed to evaluate risks of leukemia and lymphatic tumors in other formaldehyde-exposed populations and to assess the biological plausibility of a causal association.