8.16 – Aldehydes

Aldehydes are strong electrophiles that can undergo addition reactions with thiols and amines to form toxic adducts in cellular proteins. The most notable adducts are genotoxic DNA–protein cross-links. Low-molecular-weight aldehydes occur naturally in cells and low levels of aldehydes are generated during intermediary metabolism of natural compounds, drugs, and xenobiotics. Aldehydes are also found as industrial or environmental pollutants and volatile aldehydes. Formaldehyde, acetaldehyde, and acrolein have the most significant effects on human health and are found in high concentrations in tobacco smoke and combustion engine exhaust. Occupational exposures occur in industries that manufacture resins, wood products, paper, textiles, carpet, and leather goods. Formaldehyde exposures have also been linked to deterioration of foam insulation used in home building. Aldehydes are metabolized primarily by dehydrogenases or glutathione-dependent pathways, and toxicity results from elevated intracellular concentrations following the overwhelming of these detoxification systems. The mucosal lining of nasopharyngeal tissues is the primary target of inhaled formaldehyde, with a reported association between exposure and nasopharyngeal carcinomas. Both genotoxic and cytotoxic effects have been documented in nasal tissues of rodents and primates following formaldehyde inhalation exposure. Risk assessment for carcinogenic potential of inhaled formaldehyde and acetaldehyde (acrolein has not been shown to be carcinogenic) has traditionally used DNA–protein cross-links as a biomarker and surrogate for tissue-specific exposure patterns. More recent evidence suggests that cytotoxicity-dependent regenerative cellular proliferation may be a more reliable index and genotoxic end point for low-level formaldehyde exposures. The exact biochemical mechanisms involved in aldehyde-induced carcinogenesis are unclear and under intense investigation.