Formaldehyde carcinogenicity research: 30 years and counting for mode of action, epidemiology, and cancer risk assessment

Abstract

Formaldehyde is a widely used high production chemical that is also released as a byproduct of combustion, off-gassing of various building products, and as a fixative for pathologists and embalmers. What is not often realized is that formaldehyde is also produced as a normal physiologic chemical in all living cells. In 1980, chronic inhalation of high concentrations of formaldehyde was shown to be carcinogenic, inducing a high incidence of nasal squamous cell carcinomas in rats. Some epidemiologic studies have also found increased numbers of nasopharyngeal carcinoma and leukemia in humans exposed to formaldehyde that resulted in formaldehyde being considered a Known Human Carcinogen. This article reviews the data for rodent and human carcinogenicity, early Mode of Action studies, more recent molecular studies of both endogenous and exogenous DNA adducts, and epigenetic studies. It goes on to demonstrate the power of these research studies to provide critical data to improve our ability to develop science-based cancer risk assessments, instead of default approaches. The complexity of constant physiologic exposure to a known carcinogen requires that new ways of thinking be incorporated into determinations of cancer risk assessment for formaldehyde, other endogenous carcinogens, and the role of background endogenous DNA damage and mutagenesis.

Figure 1

Incidence of squamous cell carcinoma of the nasal passages and cell proliferation in rats exposed to formaldehyde. □ shows tumor incidence (%) from the 24 month study versus formaldehyde concentration (ppm) (Kerns et al., 1983). ○ shows tumor incidence from the 24-month study (Monticello et al., 1996). ▲ shows cell proliferation (mean unit length labeling index) from the 6 month study as fold increase over control (Monticello et al., 1990). ◆ shows cell proliferation (mean unit length labeling index) from the 12 month study as fold increase over control (Monticello et al., 1990). ● shows cell proliferation (mean unit length labeling index) as fold increase over control (Monticello, Morgan, and Hurtt, 1990).

Figure 2

Nonlinear formation of formaldehyde DNA-protein cross-links following inhalation exposure of rats and normalization per ppm. Adapted from Casanova et al.,1984.

Figure 3

Analytical approach for the quantitation of endogenous and exogenous formaldehyde DNA adducts. The left panel outlines the methodology for the determination of the DNA adducts. The upper right panel shows the formation of the endogenous (upper route) and exogenous (lower route) N²-OHMedG adducts. The lower right panel shows the representative LC-MS/MS chromatograms of endogenous, exogenous and isotope-labeled internal standard.

Figure 4

The half-life of [¹³CD²]-N²-OHMedG adducts in rat nasal mucosa. Data was transformed using natural log and a linear regression was accomplished using the last 5 time points.