Formaldehyde and leukemia: epidemiology, potential mechanisms, and implications for risk assessment

Abstract

Formaldehyde is widely used in the United States and other countries. Occupational and environmental exposures to formaldehyde may be associated with an increased risk of leukemia in exposed individuals. However, risk assessment of formaldehyde and leukemia has been challenging due to inconsistencies in human and animal studies and the lack of a known mechanism for leukemia induction. Here, we provide a summary of the symposium at the Environmental Mutagen Society Meeting in 2008, which focused on the epidemiology of formaldehyde and leukemia, potential mechanisms, and implication for risk assessment, with emphasis on future directions in multidisciplinary formaldehyde research. Updated results of two of the three largest industrial cohort studies of formaldehyde-exposed workers have shown positive associations with leukemia, particularly myeloid leukemia, and a recent meta-analysis of studies to date supports this association. Recent mechanistic studies have shown the formation of formaldehyde-induced DNA adducts and characterized the essential DNA repair pathways that mitigate formaldehyde toxicity. The implications of the updated findings for the design of future studies to more effectively assess the risk of leukemia arising from formaldehyde exposure were discussed and specific recommendations were made. A toxicogenomic approach in experimental models and human exposure studies, together with the measurement of biomarkers of internal exposure, such as formaldehyde-DNA and protein adducts, should prove fruitful. It was recognized that increased communication among scientists who perform epidemiology, toxicology, biology, and risk assessment could enhance the design of future studies, which could ultimately reduce uncertainty in the risk assessment of formaldehyde and leukemia.

Figure 1

Proposed model of DNA damage response pathways for DNA damage caused by formaldehyde (FA). Adapted with modifications from [Jacquemont and Taniguchi 2007]. In response to DNA damage (e.g., DPC) caused by formaldehyde, the FANCD2 protein is monoubiquitylated on lysine 561 (K561) in a Fanconi anemia core complex- and UBE2T-dependent manner that also requires ATR and RPA. Monoubiquitylation of FANCD2 is thought to target the protein into nuclear foci where it co-localizes with BRCA1, FANCD1/BRCA2, FANCN/PALB2, RAD51, FANCJ/BRIP1 and other proteins. Many of these factors appear to be required for cellular resistance to formaldehyde. Monoubiquitylation of PCNA on lysine 164 (K164) may require RAD6 as an E2 and RAD18 as an E3. In turn, modification of PCNA may cause recruitment of translesion synthesis (TLS) DNA polymerases at the site of stalled replication forks.

Figure 2

Liquid Chromatography-electrospray ionization-tandem mass spectrometry-selected ion monitoring (LC-ESI-MS-SIM) analysis of an enzymatic hydrolysate of hepatic DNA from a rat treated with NDMA [Wang et al., 2007]. Peaks corresponding to the retention times of standard 7-Me-dGuo, N⁶-HOCH₂-dAdo and O⁶-Me-dGuo were observed. (A) The peak eluting at 47.0 min had a base peak at m/z 282 [M + H]⁺, similar to standard N⁶-HOCH₂-dAdo. (B) LC-ESI-MS-SIM analysis (m/z 515) showed a peak at 85.8 min, corresponding to the retention time of dAdo-CH₂-dAdo.