LAUSR

Formaldehyde is a widely used industrial chemical, a byproduct of combustion, and is generated endogenously. Although classified by many organizations as a carcinogen, the World Health Organization (WHO) has set an exposure guideline of 0.08 ppm based on irritant properties of formaldehyde. The US Environmental Protection Agency has proposed far lower safety values based, in part, on controversial associations between formaldehyde exposure and increased risk of leukemia. Therefore, it is of interest that the National Toxicology Program (NTP), a division of the National Institute of Environmental Health Sciences, recently released an NTP Research Report that explored the potential involvement of p53 mutation in formaldehyde-induced nasal tumors as well as lymphohematopoietic cancers. This study has not been published in the peer-review literature, nor is the report currently indexed in search engines like PubMed and Embase. Because the carcinogenicity of formaldehyde remains controversial and there are ongoing assessments of formaldehyde in the United States, the new NTP Research Report is an important addition to the database for informing the carcinogenicity of inhaled formaldehyde. This commentary highlights some important implications of this study for the risk assessment of formaldehyde. In the new NTP Research Report, 2 mouse strains (note 1) haploinsufficient for TP53 were exposed to 7.5 and 15 ppm formaldehyde for 8 weeks and killed 32 weeks later at *50 weeks of age. At termination, the NTP Research Report indicates that neither hematotoxicity nor lymphohematopoietic neoplasms were observed in either strain. Tp53þ/ mice were designed such that shortened cancer bioassays could be conducted due to their increased sensitivity to carcinogens—particularly genotoxic carcinogens. These mouse strains are also reported to develop spontaneous lymphomas and serve as models for lymphohematopoietic tumors in short-term studies. These findings lend additional weight to the evidence that inhaled formaldehyde is not leukemogenic—including reanalysis of epidemiological studies and animal studies that indicate that inhaled formaldehyde does not distribute beyond the nasal cavity or reach the blood or bone marrow. The new NTP Research Report also provides important insight into the mode of action (MOA) for nasal tumors in rodents. Formaldehyde-induced nasal tumor formation is well-documented in rats at 6 ppm, and research indicates that tumors arise in nasal regions where there is cytotoxicity and regenerative hyperplasia. Research into the MOA for nasal tumors led to the development of one of the few biologically based dose–response (BBDR) models ever developed for use in risk assessment. The BBDR model and supporting research indicate that the tumor response in rats is most likely driven by increased cytotoxicity-induced regenerative hyperplasia with a negligible contribution from direct mutagenicity at noncytotoxic concentrations. Subsequent in vivo genotoxicity studies have shown that exposure to up to 15 ppm for several weeks increases cell proliferation but not micronuclei or mutant frequency of kras or Tp53 in the nasal cavity. These data indicate a negligible contribution from direct mutagenicity at cytotoxic concentrations. The lack of nasal neoplasms in Tp53þ/ mice considered well suited for detecting genotoxic carcinogens lends additional evidence that the MOA for