Formaldehyde Exposure and Mortality Risks From Acute Myeloid Leukemia and Other Lymphohematopoietic Malignancies in the US National Cancer Institute Cohort Study of Workers in Formaldehyde Industries

Formaldehyde is environmentally and biologically ubiquitous. Major occupational exposure sources include manufacturing of construction materials, plastics, and garments. Cigarette smoking, consumer products including personal care products and some medications, and ambient air pollution are common nonoccupational sources.1,2 Formaldehyde is also produced endogenously and is an essential intermediate in the biosynthesis of purines, thymidine, and various amino acids.3 Thus, formaldehyde is present in small quantities in all body tissues. Exogenous formaldehyde is rapidly metabolized at the site of entry (typically the upper respiratory tract). There is consistent evidence that exogenous formaldehyde cannot reach distant organs including the bone marrow.4–7 Cancer risks associated with formaldehyde exposure have been investigated in occupational cohort and community-based case–control studies. The occupational cohort studies generally provide higher-quality evidence than population-based case–control studies—primarily due to better exposure data and a greater potential for higher and more sustained levels of formaldehyde exposure.8 In 2009, the International Agency for Research on Cancer Working Group concluded that “There is sufficient evidence in humans for the carcinogenicity of formaldehyde. Formaldehyde causes cancer of the nasopharynx and leukaemia.”9(p430) Baan et al summarized the findings of the Working Group meeting and reported that “The Working Group concluded that, overall, there is sufficient evidence for leukaemia, particularly myeloid leukaemia.”10(p1144) Despite the clear language regarding causation, the Volume 100F monograph reported that the consensus was based on the small majority of the working group who held the view that the evidence for leukemia was sufficient while a minority of the working group found the evidence for leukemia to be limited. Subsequently, the National Institute of Environmental Health Sciences National Toxicology Program changed the classification of formaldehyde from “anticipated to be carcinogenic in humans” as listed in the Second Report on Carcinogens (RoC) to “known to be a human carcinogen” in the 12th RoC.11 (Each revision of the RoC is cumulative and includes previous substances as well as newly reviewed substances. The 13th RoC, released in October 2014, contains 243 substance profiles.) The change in classification from anticipated carcinogen to known carcinogen was based on “consistent findings of increased risks of nasopharyngeal cancer, sinonasal cancer, and lymphohematopoietic cancer, specifically myeloid leukemia among individuals with higher measures of exposure to formaldehyde (exposure level or duration), which cannot be explained by chance, bias, or confounding. The evidence for nasopharyngeal cancer is somewhat stronger than that for myeloid leukemia.”11 Findings from one large cohort mortality study of workers from 10 US plants producing or using formaldehyde 12 have been especially influential in the designation by the International Agency for Research on Cancer9 and the National Institute of Environmental Health Sciences National Toxicology Program13 of formaldehyde as leukemogenic. This study was begun by the US National Cancer Institute (NCI) in the 1980s in collaboration with the Formaldehyde Institute, and the first results were published in 1986.14 Sequential analyses of updated mortality for the NCI cohort12,15 reported associations of “peak” exposures with myeloid leukemia (ML) and Hodgkin lymphoma (HL), but not with cumulative, average, or frequency of “peak” exposures. Null or very weak associations were observed with cumulative or “peak” exposures and the other specific lymphohematopoietic malignancies (LHMs) including lymphatic leukemia (LL), non-Hodgkin lymphoma (NHL), and multiple myeloma. Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) were not reported separately in the NCI analyses but were combined as ML. Although both AML and CML arise in myeloid stem cells, the risk factors associated with AML and CML differ. Most individuals diagnosed with CML have a gene mutation in the leukemia cells called the Philadelphia chromosome, describing the translocation between chromosomes 22 and 9. The translocation leads to the development of the Bcr-Abl oncogene, and this gene instructs the bone marrow to produce Bcr-Abl tyrosine kinase, leading to the development of CML.16,17 In addition, the known risk factors for AML—tobacco smoking, exposure to benzene, chemotherapy, or radiation treatment—are not recognized risk factors for CML.17 High-dose radiation, such as that experienced by survivors of atomic bombs or nuclear reactor accidents, is the only recognized environmental risk factor for CML.17 These recognized differences in histopathology and in the risk factors for AML and CML raise the question of whether the reported association between formaldehyde exposure and combined MLs reflects an underlying association between formaldehyde exposure and the more plausible specific type of leukemia, AML. We obtained the data included in the most recent update of the NCI cohort12 via a Technology Transfer Agreement. Our objectives were to replicate the updated findings reported by Beane Freeman et al12 and to conduct additional analysis of associations of specific LHM, and especially AML, with peak exposure, using an alternative, more standard definition of peak.