Occupational exposure to formaldehyde, hematotoxicity, and leukemia-specific chromosome changes in cultured myeloid progenitor cells

Abstract

There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing, and other industries. Epidemiologic studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on the ability of formaldehyde to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures.

Fig. 1. Myeloid, erythroid and lymphocyte blood cell counts in formaldehyde-exposed and unexposed workers

A total of 43 workers exposed to formaldehyde and 51 controls were studied. Differences in cell counts were tested by linear regression, adjusting for relevant covariates as indicated in Methods. The p values are indicated as: * p < 0.05; ** p < 0.01; and *** p < 0.001. (WBC, white blood cells; RBC, red blood cells; Hgb, hemoglobin in g/deciliter; and, MCV, mean corpuscular volume in femtoliters as fl).

Fig. 2. Colony formation from the colony-forming unit–granulocyte/macrophage (CFU- GM) hematopoietic progenitors in formaldehyde-exposed and unexposed workers

Hematopoietic progenitor cells from the peripheral blood of 43 exposed workers and 51 frequency-matched controls were cultured in methylcellulose-based media without erythropoietin. Differences in cell counts were tested by negative binomial regression, adjusting for relevant covariates as indicated in Methods. The lower and higher edges of box are the 25 and 75 percentiles of the data, respectively. The lower and higher whiskers are 10 and 90 percentiles, respectively. The central line in the box presents the median and the cross is the mean. One outlier is indicated as a circle in the exposed group.

Fig. 3. Colony formation from human myeloid progenitor cells following formaldehyde exposure in cell culture

Hematopoietic myeloid progenitor cells were cultured from the peripheral blood of a volunteer of Chinese origin in methylcellulose-based media in the absence and presence of erythropoietin (EPO), after treatment with formaldehyde. The number of BFU-E (filled circles,–●–), CFU-GM (squares, –■–) and CFU-GEMM (triangles, –▲–) colonies were scored in 6 petri dishes after 14 days of culture. CFU-GM colony counts in the absence of EPO are presented for consistency with the in vivo data. The results shown are the means and standard errors of 6 separate experiments. The p values are indicated as p _trend calculated using negative binomial regression and robust standard errors adjusting for possible residual correlation due to being on the same dish using a sandwich-type estimate (GEE approach).

Fig. 4. Levels of monosomy of chromosome 7 and trisomy of chromosome 8 in the hematopoietic progenitor cells of formaldehyde-exposed and unexposed workers

Leukemia-specific chromosome changes in CFU-GM cells, such as loss (monosomy) of chromosome 7 and gain (trisomy) of chromosome 8, were examined in metaphase spreads of 10 formaldehyde-exposed workers and 12 unexposed matched controls. The data represent the percentage of the metaphases in which each abnormality is found. Rates of monosomy are considerably higher in the controls than trisomy because of artifactual chromosome loss during metaphase spread preparation. Differences in aneuploidy were tested by negative binomial regression, adjusting for relevant covariates as indicated in Methods. The p values are indicated as: * p < 0.05 and ** p < 0.01.