Tumors, nasal, formaldehyde exposure

Formaldehyde has been shown to be carcinogenic in two strains of rats, resulting in squamous cell cancers of the nasal cavity after repeated inhalation of about 14 ppm. In one study, 51 of 117 male and 42 of 115 female Fischer 344 rats developed this tumor, but no nasal tumors were seen at 0 or 2 ppm. No other neoplasm was increased significantly. In a similar study of mice, this nasal tumor occurred in two male mice at 14.3 ppm. None of the excesses was statistically significant except for the high-exposure rats. °... 

In general, observations of increased mortality in the rat bioassays occurred after about one year of exposure and were associated with the development of nasal squamous cell carcinomas. Golden Syrian hamsters exposed to 10 ppm formaldehyde, 5 hours/day, 5 days/week for life showed a small, but statistically significant, increase in mortality compared with controls, but no increased incidence of nasal tumors and only a minimal (5% versus zero in controls) increased incidence of hyperplasia or metaplasia in the nasal epithelium (Dalbey 1982). No exposure-related increased mortality was found in B6C3F1 mice exposed to up to 14.3 ppm for 6 hours/day, 5 days/week for 24 months (Kerns et al. 

Animal Cancer Studies As discussed previously in Section 2.2.1.2 subsection entitled Chronic Inhalation Animal Studies, chronic exposure to airborne formaldehyde concentrations ranging from about 6 ppm to 15 ppm induced increased incidences of nasal tumors (squamous cell carcinomas, squamous cell papillomas, or polyploid adenomas) in three bioassays with Fisher 344 rats (Kamata et al. 1997 Kems et al. 1983b Monticello et al. 1996 Swenberg et al. 1980). Increased incidences of lower respiratory tract tumors or distant site tumors were not found in these studies, and exposure to concentrations of 2 ppm and lower induced no malignant nasal tumors. 

EPA (1991a IRIS 1999) classified formaldehyde in Group BI - probable human carcinogen, based on an evaluation of limited human evidence and sufficient laboratory animal evidence. EPA (1991a) used dose-response data for nasal tumors in rats exposed to high concentrations of formaldehyde (from Kerns et al. 1983b) to extrapolate to human cancer risk at low exposure concentrations, using rates of... 

Pharmacokinetic models to describe, as a function of formaldehyde air concentration, the rate of formation of formaldehyde-induced DNA-protein cross links in different regions of the nasal cavity have been developed for rats and monkeys (Casanova et al. 1991 Heck and Casanova 1994). Rates of formation of DNA-protein cross links have been used as a dose surrogate for formaldehyde tissue concentrations in extrapolating exposure-response relationships for nasal tumors in rats to estimate cancer risks for humans (EPA 1991a see Section 2. 4.3). The models assume that rates of cross link formation are proportional to tissue concentration of formaldehyde and include saturable and nonsaturable elimination pathways, and that regional and species differences in cross link formation are primarily dependent on anatomical parameters (e g., minute volume and quantity of nasal mucosa) rather than biochemical parameters. The models were developed with data from studies in which... 

The use of DNA-protein cross link formation as a fonnaldehyde dosimeter in cancer target tissues is supported by correlative observations of nonlinear (convex) relationships between DNA-protein cross link formation in nasal epithelium of rats and monkeys and formaldehyde air concentrations and similar convex exposure-response relationships for formaldehyde-induced tumors in rats (Casanova et al. 1991 EPA 1991a). The convex nature of these relationships may be explained by a number of mechanisms, including saturation of enzymes involved in metabolism of formaldehyde, a decrease in the functioning of the mucociliary apparatus that may trap and remove formaldehyde before it reaches target tissues, saturation of protein-binding kinetic mechanisms, and saturation of inherent DNA-protein cross link repair mechanisms. 

Studies of animals exposed for life to formaldehyde in air or drinking water also show that formaldehyde primarily damages tissue at portals-of-entry (i.e., the upper respiratory tract and the gastrointestinal tract) evidence for toxic effects at distant sites is less consistent. Replicated inhalation studies have shown that formaldehyde induced malignant nasal tumors in rats at high exposure concentrations (10-15 ppm) that also induced nasal epithelial necrosis and cellular proliferation, but not at lower concentrations (0.3-2 ppm) that did not markedly damage nasal epithelial tissue (Albert et al. 1982 ... 

Morgan KT, Jiang X-Z, Starr TB, et al. 1986b. More precise localization of nasal tumors associated with chronic exposure of F-344 rats to formaldehyde gas. Toxicol Appl Pharmacol 82 264-271. 

Wouterson RA, van Garderen-Hoetmer A, Bruijntjes JP, et al. 1989. Nasal tumors in rats after severe injury to the nasal mucosa and prolonged exposure to 10 ppm formaldehyde. J Appl Toxicol 9 39-46. 

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