Dosimetry, toxicity and carcinogenicity of inspired acetaldehyde in the rat

Acetaldehyde is a ubiquitous air pollutant. It is an important industrial chemical and is also produced during the combustion of wood or tobacco. In smoky indoor atmospheres concentrations of the aldehyde may reach 100 ppb. Acetaldehyde is metabolized to acetate (releasing hydrogen ion) by aldehyde dehydrogenase a process which, in most tissues, represents a detoxification pathway. In vitro, acetaldehyde forms DNA-DNA and DNA-protein crosslinks. It is a clastogen, and inducer of sister chromatid exchanges, and is, perhaps, a weak mutagen. Inhalation exposure to 1000 ppm may induce DNA-protein crosslink formation in nasal tissues in the rat in vivo. Inhalation toxicity studies have shown acetaldehyde vapor causes chronic tissue injury and tumor formation in nasal tissues at exposure concentrations of 750 ppm or higher, with nasal olfactory mucosa being more sensitive than respiratory mucosa. Dosimetric estimates suggest that marked tissue injury and carcinogenicity occurs only at inspired concentrations which are sufficiently high to overwhelm nasal aldehyde dehydrogenase detoxification capacity. The induction of squamous cell carcinomas in the respiratory mucosa by acetaldehyde displays many analogies to the induction of squamous cell carcinomas by formaldehyde. For both vapors, non-linear concentration response relationships are observed for DNA-protein crosslink formation, tissue injury, and carcinogenicity, suggesting these responses are associated. For both vapors it is possible to document an exposure concentration that produces nasal respiratory epithelial injury without increasing tumor incidence, suggesting that for respiratory mucosa-derived tumors, exposure to non-cytotoxic concentrations may pose limited carcinogenic risk. In addition to squamous cell carcinomas of the respiratory epithelium, acetaldehyde exposure also results in nasal olfactory injury and tumors (adenocarcinomas) in the rat. The studies performed to date have not demonstrated a no observable effect level for these responses, therefore, the precise role of cytotoxicity and regenerative cell proliferation in the carcinogenic process in olfactory tissues can not be evaluated. Acetaldehyde metabolism via aldehyde dehydrogenase results in the formation of two hydrogen ions. The olfactory mucosa is quite sensitive to acid and dosimetric estimates suggest that the intracellular acid production rates that may occur in olfactory mucosa during acetaldehyde exposure may be sufficiently high to cause tissue damage. Such acid-induced tissue damage may enhance the genotoxic and tumorigenic potential of acetaldehyde in olfactory mucosa, and may, therefore, represent an important process in the production of tumors in this tissue.