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Use of tobacco products expose the consumer to a variety of harmful and potentially harmful constituents (HPHCs) and other toxic chemicals that commonly result in the occurrence of adverse health outc... Use of tobacco products expose the consumer to a variety of harmful and potentially harmful constituents (HPHCs) and other toxic chemicals that commonly result in the occurrence of adverse health outcomes. These HPHCs and other toxic chemicals may interact with each other in ways that enhance their toxic effects. There is a significant research knowledge gap in understanding the mechanisms and magnitude of these interactions between HPHCs and other toxic chemicals and if these interactions result in observable increases in toxic effects. These interactions and resulting enhanced toxicity may partially explain the observed discordance between predicted lifetime cancer risk associated with use of tobacco products and reported epidemiological data. FDA seeks more information on the occurrence of interactions between HPHCs and other toxic chemicals present in tobacco products, and how these interactions may result in enhanced toxic effects. Objectives The objectives of this contract are to develop an aerosol co-exposure system for use with a human relevant in vitro air-liquid interface (ALI) airway tissue model, to characterize the occurrence of cytotoxic and genotoxic responses following exposure to single and combined aldehydes, and to assess the occurrence of enhanced cytotoxic and genotoxic responses following co-exposure to this aldehyde mixture to identify if toxic interactions between these HPHCs occur. The human relevant in vitro ALI airway tissue model will consist of differentiated normal human primary tracheobronchial epithelial cells collected from a single donor. This aerosol co-exposure system will utilize model aldehyde HPHCs (i.e., formaldehyde and acrolein) that likely undergo toxicologically relevant interactions and have complementary mechanisms of toxicity. FDA expects the development of an aldehyde HPHC aerosol co-exposure system, using model aldehyde HPHCs (i.e., formaldehyde and acrolein), paired with a human relevant in vitro ALI airway tissue model consisting of differentiated normal human primary tracheobronchial epithelial cells collected from a single donor. FDA expects that this aerosol exposure system and human relevant in vitro model will be used to evaluate the occurrence of toxic responses following exposure to single aldehyde HPHCs and a mixture of aldehyde HPHCs. The toxicity data produced from this work will be used to evaluate the occurrence of toxicologically relevant interactions (i.e., additive, antagonistic, synergistic) between these aldehyde HPHCs.