Tumors, nasal, formaldehyde

Formaldehyde is another example of a mutagenic compound with evidence of nonlinearity. Based on limited evidence of respiratory cancer in humans and evidence of nasal tumors in rats and mice, ERA classifies formaldehyde as a probable human carcinogen. In rats, the most well-studied animal model for formaldehyde carcinogenesis, there is a threshold for tumor formation at 6 ppm. At levels below 6 ppm, formaldehyde induces DNA crosslinks in a dose-dependent manner wilh apparent low-dose linearity (Conolly et al. 2000 Slikko- et al. 2004). At doses above 6 ppm, concurrent with tumor formation, formaldehyde causes maiked cytotoxicity in the nasal passages of rats. 

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. °... 

The hydrolysis products of BCME are formaldehyde and HC1. Since formaldehyde has been shown to produce nasal tumors in rats (Albert et al. 1982 Sellakumar et al. 1985), it is possible that at least some of the carcinogenic potential of BCME may be due to this degradation product. However, it is apparent from the difference in potency (BCME is much more potent than formaldehyde) that this cannot be the sole mechanism of carcinogenicity. It is also possible that BCME,... 

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. 

Dalbey (1982) exposed groups of male Golden Syrian hamsters to 0 (n=132) or 10 (n=88) ppm fomialdehyde, 5 hours/day, 5 days/week for life (up to about 110 weeks). Exposed hamsters showed reduced survival time compared with controls. End points in this study were restricted to histopathological examinations of respiratory tract tissues. There was no evidence of rhinitis in treated animals, and no tumors were found in the respiratory tract of treated or control animals. Hyperplastic and metaplastic areas were seen in the nasal epithelium of 5% of the treated hamsters but were not seen in controls. Dalbey (1982) also exposed groups of 50 male hamsters to 0 or 30 ppm formaldehyde,... 

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 ... 

Bermudez E, Chen Z, Gross EA, et al. 1994. Characterization of cell lines derived from formaldehyde-induced nasal tumors in rats. Mol Carcinog 9 193-199. 

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. 

A factor that may affect the growth of amino resins is the question of formaldehyde toxicity. Like many other chemicals, aminoformaldehyde resins have encountered questions of product safety in recent years. This has been largely due to reports that formaldehyde causes nasal tumors in rats, although epidemiological studies of workers exposed to formaldehyde have shown no confirmation of this. 

TO Eyes, resp sys [nasal cancer thyroid gland tumors in animals (in the presence of Formaldehyde, Acetaldehyde, or Malonaldehyde)] ... 

In a study on chronic inhalation toxicity of acetaldehyde on rats, the compound was found to effect increased mortality, growth retardation, and nasal tumors (Woutersen et al. 1986). The study indicates that acetaldehyde is both cytotoxic and carcinogenic to the nasal mucosa of rats. Investigating the toxicity of tobacco-related aldehydes in cultured human bronchial epithelial cells, Graft-strom et al. (1985) reported that acetaldehyde was weakly cytotoxic, less so than acrolein and formaldehyde. 

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