This study was the first epidemiological investigation, to our knowledge, to relate cancer risk to duration of employment, work practices, and estimated formaldehyde exposure levels in the funeral industry. We observed an association between embalming and death from myeloid leukemia, with the greatest risk among those who practiced embalming for more than 20 years. Deaths from myeloid leukemia were also related to greater estimated formaldehyde exposure, which was based on exposure models. The association was specific to myeloid leukemia, with no evidence for an association with deaths from other lymphohematopoietic malignancies. Other studies have also found a greater than expected number of deaths from lymphohematopoietic malignancies in the funeral industry (3
), with the most consistent pattern being observed with cell-type groupings that include myeloid leukemia [(3
) and as reviewed by Zhang et al. (21
)]. Reports (6
) of mortality among pathologists and anatomists also indicated that these groups may have a higher number of deaths from lymphohematopoietic malignancies than expected, but studies among these professional groups also had not considered risks in relation to specific work practices (6
). Two recent assessments (14
) of formaldehyde and cancer risk in industrial workers also noted a potential relationship between formaldehyde and death from myeloid leukemia, although this relationship was not observed in another industrial study (22
). In our study, the findings for brain cancer are inconclusive, which is consistent with the literature on this topic. A meta-analysis (2
) found a statistically significant 50% excess of brain cancer deaths in studies among funeral industry professionals, pathologists, and anatomists; however, none of the large industrial cohort studies in the formaldehyde industry observed such an association (14
The biological mechanism of formaldehyde as a leukemogen has not been elucidated. Leukemia develops in pluripotent stem and progenitor cells in the bone marrow (21
). Formaldehyde reacts rapidly on contact with upper respiratory tract mucosa, and increased blood levels of formaldehyde have not been reported after the respiratory system has been exposed to formaldehyde (24
). Respiratory exposure to formaldehyde is related, however, to lymphocyte genotoxicity and damage to other peripheral blood cells (17
), potentially including circulating pluripotent cells in the blood vessels of the highly vascularized tissue of the nasal and olfactory mucosa (21
The associations with death from myeloid leukemia that we observed in our study were unlikely to have been the result of confounding exposures. Our analysis in one relatively homogeneous industry allowed us to compare causes of death of subjects who differed by exposure but were similar with respect to most other important factors. Embalming fluids and other embalming products contain numerous agents in addition to formaldehyde, including isopropanol, ethylene glycol, methanol, phenol, and glutaraldehyde; however, none of these have established leukemogenic properties. In contrast, ionizing radiation, exposure to benzene, and cigarette smoking have been related to risk for myeloid leukemia (25
). Although exposure to ionizing radiation may occur during the embalming of corpses containing radioactive isotopes (26
), the frequency of such embalmings and the resulting levels of radiation exposure are not likely to be sufficiently great to explain the observed association. Benzene is not used in embalming practice, and two surveys found that benzene could not be detected (18
) or was present in only trace amounts (ie, <0.1 ppm) (27
). Finally, smoking was not related to embalming practice or formaldehyde exposure in our study. We adjusted our analyses for tobacco use (ever or never), and almost identical results were found after adjustment for the number of cigarettes per day (data not shown). In addition, the similarity of the findings in this study to those in two industrial cohort studies (14
) is notable, in that embalmers and industrial workers share high levels of exposure to formaldehyde but have few other workplace exposures in common. We observed relatively similar associations between several exposure metrics and death from myeloid leukemia, including metrics that were not correlated with years of embalming practice or number of embalmings, for example, average formaldehyde intensity while embalming. These independent indicators provide support for the overall association of embalming practice and formaldehyde exposure with increased risk of myeloid leukemia.
Because of the absence of a known mechanism of formaldehyde carcinogenesis, we evaluated several exposure metrics that were derived directly from the questionnaire data (ie, ever embalming, duration of working in jobs with embalming, and number of embalmings) and others that relied on predictions derived from external measurements, and we observed relatively similar associations for myeloid leukemia. In formaldehyde industry–based studies, duration of work in jobs with exposure may not be the best estimate of delivered dose because of the many different jobs and tasks and because of assumptions of constant exposure levels across different jobs over time. In our study, however, the variability in exposure levels was likely to be lower than that in industry-based investigations because we studied only one type of job and therefore the number and type of sources and possible variations are more limited than those in other industries. Thus, duration may better approximate the delivered dose in the funeral industry than in most industry-wide studies. Myeloid leukemia was associated with higher model-derived peak exposure levels of formaldehyde but was not associated with frequency of such exposure, perhaps because of the uncertainty involved in predicting both level and frequency of peak exposures or because of the limited resolution of our peak prediction, with a range of predicted peak formaldehyde concentrations of 3.7–12.3 ppm.
This study has several limitations. Surrogate respondents (ie, next of kin and coworkers) may or may not accurately report exposure-related information, depending on the type of information and type of surrogate (28
). We addressed this concern by including multiple surrogates (next of kin and coworkers) for each study subject. Indeed, the high concordance rates between multiple respondents for the same subject with respect to the number of years worked in the funeral industry (93%) and the number of these years during which embalming was practiced (86%) increase confidence in the accuracy of these variables. Because we used surrogates for both case and control subjects, exposure misclassification was likely to be nondifferential, so that any resulting bias would be toward the null and thus would tend to underestimate risk. In addition, if any systematic positive bias were to occur, it would be expected to affect all cancer types equally. Therefore, the specificity of the association with myeloid leukemia but not with other leukemias was noteworthy.
Under the assumption that formaldehyde exposure is causally linked with myeloid leukemia death, one might have expected stronger associations for the formaldehyde exposure metrics than for duration of embalming. However, the uncertainty in estimating the lifetime formaldehyde exposure may have attenuated estimated risks, despite the prediction model that explained a large fraction of the variation in measured formaldehyde concentrations during embalmings that were performed at various times and by following various protocols. In this context, trend tests that were based on categories were less influenced by extreme values of exposure metrics than those that were based on continuous values, which was the method that we selected a priori. For example, category-specific associations between exposure and death from myeloid leukemia (eg, 8-hour time-weighted average intensity) were statistically significant if ordinal scores (1, 2, 3, and 4) were used as a continuous variable (P for trend = .021) but not if continuous exposure was used (P for trend = .396) () (trend tests that were based on ordinal scores gave P = .012 for number of embalmings and P = .023 for cumulative formaldehyde exposure; data not shown). The observation that associations between formaldehyde exposure metrics and myeloid leukemia were generally similar to those for duration of embalming or number of embalmings supports the possibility that formaldehyde may be involved in the greater than expected number of deaths from myeloid leukemia among embalmers.
A major limitation of our study is the relatively small number of deaths from myeloid leukemia, although the numbers of case subjects with myeloid leukemia were roughly similar in our study (n = 34) and in the largest industrial cohort (n = 48) (15
). To address small numbers for myeloid leukemia, we carried out additional analyses that combined never and low-frequency embalmers as a referent group and found results that were similar to those in the main analysis. There were also considerable missing exposure data requiring imputation and, when subjects whose work history was more than 30% incomplete were excluded, the strength of the associations decreased. However, because the missing data did not differ substantially between case and control subjects, we believe this decrease can be attributed to smaller numbers of subjects and to chance. The strongest associations were with ever embalming and number of years of embalming, the variables in which we have the most confidence.
Our study also has some unique strengths compared with other studies of formaldehyde exposure (14
). In industrial cohort studies (15
), exposure is usually assessed for thousands of different job types, and every subject is assigned the same exposure for a given period and job. These studies often rely on aggregated information for plants and departments to estimate job-specific exposure levels and so measurement data, particularly historical data, are limited. In contrast, we studied only one exposed job type (embalming) and individual exposure levels were estimated by use of study subject–specific information from questionnaires combined with statistical models that were based on high-quality measurement data.
This study adds supporting and complementary data to other epidemiological evidence of an association between formaldehyde exposure and risk of myeloid leukemia. When we compared this study in the funeral industry with the National Cancer Institute cohort study of formaldehyde industries (15
), we found that funeral home workers who embalm tended to have longer duration of formaldehyde exposure and higher cumulative levels of formaldehyde exposure but lower 8-hour time-weighted average intensity. Peak exposure levels of greater than 4 ppm, the lower bound of the highest exposure category in the analysis of the industrial cohort study, appear to be more common among embalmers (ie, 77% of control subjects) than among industrial workers (ie, 25% of workers). Our study assessed work in the funeral industry approximately through the early 1980s and so the work patterns and estimated exposure levels of deceased control subjects may not be entirely representative of current practice in the funeral industry. However, the average estimated formaldehyde intensity while embalming among control subjects (1.7 ppm, SD = 0.7 ppm; ) was generally consistent with levels that were reported previously (17
) in limited surveys of funeral homes, which tend to show average exposure levels in the range of 1 ppm.
The absolute impact of exposure to formaldehyde on death from myeloid leukemia in the general population is difficult to assess on the basis of data in this study, which are not population based. However, if formaldehyde exposure is causally related to myeloid leukemia, then from the best linear approximation of the exposure–response relationship in this study, US-wide formaldehyde exposure at an equivalence of a decade of employment in an embalming job would roughly increase the age-adjusted mortality from myeloid leukemia in the United States (ie, 3.4 deaths per 100 000 person-years ) by approximately 36% (ie, by 1.2 more deaths from myeloid leukemia per 100 000 person-years). Within the limits of this quantitative exposure assessment, the number of additional deaths from myeloid leukemia associated with an additional average formaldehyde intensity of 1 ppm would be 1.7 per 100 000 person-years. Because of the case–control design of this study and the limitations discussed above, these exposure estimates should be used with caution in quantitative risk estimation.
In summary, this is the first study, to our knowledge, to specifically relate number of years of embalming practice and related formaldehyde exposures in the funeral industry to mortality from myeloid leukemia. No associations were observed with other lymphohematopoietic malignancies, and associations with brain cancer were unclear. Further studies of leukemia risk in relation to specific embalming practices and exposures, as well as similar specific exposure studies in other professional groups that are exposed to formaldehyde and that have an increased risk of leukemia (ie, anatomists and pathologists), should help to clarify our understanding of cancer risks related to formaldehyde. This study adds to the accumulating evidence from studies of industrial workers that increased exposure to formaldehyde is associated with increased risk of myeloid leukemia.