Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: the National Cancer Institute Cohort

Abstract

Background: Formaldehyde exposure is associated with leukemia in some epidemiological studies. In the National Cancer Institute's formaldehyde cohort, previously followed through December 31, 1979, and updated through December 31, 1994, formaldehyde exposure was associated with an increased risk for leukemia, particularly myeloid leukemia, that increased with peak and average intensity of exposure.

Methods: We extended follow-up through December 31, 2004 (median follow-up = 42 years), for 25 619 workers employed at one of 10 formaldehyde-using or formaldehyde-producing plants before 1966. We used Poisson regression to calculate relative risk (RR) estimates and 95% confidence intervals (CIs) to examine associations between quantitative formaldehyde exposure estimates (peak exposure, average intensity and cumulative exposure) and death from lymphohematopoietic malignancies. All statistical tests were two-sided and considered to be significant at P = .05.

Results: When follow-up ended in 2004, there were statistically significant increased risks for the highest vs lowest peak formaldehyde exposure category (> or =4 parts per million [ppm] vs >0 to <2.0 ppm) and all lymphohematopoietic malignancies (RR = 1.37; 95% CI = 1.03 to 1.81, P trend = .02) and Hodgkin lymphoma (RR = 3.96; 95% CI = 1.31 to 12.02, P trend = .01). Statistically nonsignificant associations were observed for multiple myeloma (RR = 2.04; 95% CI = 1.01 to 4.12, P trend > .50), all leukemia (RR = 1.42; 95% CI = 0.92 to 2.18, P trend = .12), and myeloid leukemia (RR = 1.78; 95% CI = 0.87 to 3.64, P trend = .13). There was little evidence of association for any lymphohematopoietic malignancy with average intensity or cumulative exposure at the end of follow-up in 2004. However, disease associations varied over time. For peak exposure, the highest formaldehyde-related risks for myeloid leukemia occurred before 1980, but trend tests attained statistical significance in 1990 only. After the mid-1990s, the formaldehyde-related risk of myeloid leukemia declined.

Conclusions: Evaluation of risks over time suggests a possible link between formaldehyde exposure and lymphohematopoietic malignancies, particularly myeloid leukemia but also perhaps Hodgkin lymphoma and multiple myeloma. Observed patterns could be due to chance but are also consistent with a causal association within the relatively short induction-incubation periods characteristic of leukemogenesis. Further epidemiological study and exploration of potential molecular mechanisms are warranted.

Figure 1

Association between peak formaldehyde exposure and the risk of lymphohematopoietic malignancy. Relative risks for medium-peak (2.0 to <4.0 ppm) and high-peak (≥4.0 ppm) formaldehyde exposure categories compared with the low exposed category (>0 to <2.0 ppm) for lymphohematopoietic malignancies are shown by year of end of follow-up, 1965–2004. Values plotted at 0.1 represent RR = 0 due to no cases in the exposure category; values plotted at 20 represent RR = infinity due to no cases in the referent category. The small graphs above the relative risk plots represent the exposure–response trend P values based on two-sided likelihood ratio tests (1 df) of zero slope for continuous formaldehyde exposure among exposed person-years only. The points represent the relative risk estimates based on the cumulative number of cases and person-years accrued from the start of the study to that point in time and for 2004 are equivalent to the relative risk estimates presented in Table 2. HLP = lymphohematopoietic malignancies, NHL = non-Hodgkin lymphoma, HDG = Hodgkin lymphoma, MM = multiple myeloma, LEU = leukemia, LYL = lymphatic leukemia, MYL = myeloid leukemia; RR = relative risk.

Figure 2

Association between average intensity of formaldehyde exposure and the risk of lymphohematopoietic malignancy. Relative risks for medium (0.5–<1.0 ppm) and high (≥1.0 ppm) average-intensity formaldehyde exposure categories compared with the low exposed category (>0–<0.5 ppm) for lymphohematopoietic malignancies by year of end of follow-up, 1965–2004. Values plotted at 0.1 represent RR = 0 due to no cases in the exposure category. The small graphs above the relative risk plots represent the exposure–response trend P values based on two-sided likelihood ratio tests (1 df) of zero slope for continuous formaldehyde exposure among exposed person-years only. The points represent the relative risk estimates based on the cumulative number of cases and person-years accrued from the start of the study to that point in time and for 2004 are equivalent to the relative risk estimates presented in Table 3. HLP = lymphohematopoietic malignancies, NHL = non-Hodgkin lymphoma, HDG = Hodgkin lymphoma, MM = multiple myeloma, LEU = leukemia, LYL = lymphatic leukemia, MYL = myeloid leukemia; RR = relative risk.