Occupational Exposure to Formaldehyde, Hematotoxicity and Leukemia-Specific Chromosome Changes in Cultured Myeloid Progenitor Cells – Response

As a follow-up to reports that occupational exposure to formaldehyde is associated with an increased risk of myeloid leukemia, we carried out a cross-sectional study of 43 workers exposed to formaldehyde and 51 unexposed controls to explore whether there is evidence that formaldehyde causes toxicity to the bone marrow. We reported that the total peripheral white blood cell, granulocyte, platelet, and red blood cell counts were statistically significantly decreased in exposed workers compared to controls. In addition, the red blood cell mean corpuscular volume and frequencies of leukemia-related chromosome loss (monosomy 7) and gain (trisomy 8) in myeloid progenitor cells cultured from peripheral blood were significantly elevated compared with controls (Zhang et al., CEBP 19:80–8, 2010). Taken together, these results, which reflect a variety of relevant hematologic and genotoxic endpoints assessed through different and complementary technologies, provide evidence that formaldehyde exposure may have caused damage to hematopoietic cells that originated in the bone marrow of workers in these factories. As such, this provides support for the biological plausibility that formaldehyde causes myeloid leukemia, which was the conclusion reached by the IARC Working Group 100F (Baan et al., Lancet Oncol 10:1143–4, 2009).

The letter by Speit and colleagues raises a variety of concerns on the design, analysis, and interpretation of our study, which took place in factories that manufacture plastic plates and light utensils using a formaldehyde-based resin. Control subjects worked primarily in factories that manufacture clothes and food products and do not use formaldehyde. All study subjects were currently employed workers selected without regard to information on biological endpoints, which were unknown at the time of enrollment. The subgroup of exposed subjects analyzed for myeloid progenitor cytogenetics was selected based on having the highest levels of formaldehyde exposure and technically analyzable samples, and compared to unexposed controls matched to those subjects. The analysis was based on a comparison of group differences (i.e., exposed versus unexposed, shown in the original Fig. 1), which were minimally changed after adjustment for covariates included in the final models (listed in the original Statistical Analysis section). The conclusions of the study were unchanged after taking into account work characteristics, medical history, medication use, recent respiratory infections, and time of day that biological samples were collected. However, as we noted in our article, these findings need to be replicated in larger studies, given that chance findings may occur in any observational study, particularly if the sample size is small.

We are aware of the complex chemistry and biochemistry of formaldehyde and recognize that formaldehyde is also a product of endogenous metabolism. We agree with Speit and colleagues that our results may be difficult to explain given the current fragmentary state of knowledge regarding the toxicokinetics and toxicodynamics of inhaled formaldehyde in humans. Clearly, further research is needed on this important topic.

See the original Letter to the Editor, p. 1882.