Xuefei Cao1, Jayme P. Coyle2, Rui Xiong1, Yiying Wang1, Robert H. Heflich1, Baiping Ren1, William M. Gwinn3, Patrick Hayden4, Liying Rojanasakul2
1 Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd., AR Jefferson, USA
2 Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers forDisease Control and Prevention,Morgantown,WV, USA
3 Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Durham, NC, USA
4 BioSurfaces Inc., Ashland, MA, USA
One important element for validating any new assay for making regulatory decisions is determining its performance relative to an accepted standard. Conducting in vivo inhalation toxicity studies using whole-body or nose-only exposure systems is expensive and time-consuming and typically requires a large number of animals. The goal of using alternative methods, like human in vitro ALI airway cultures, ultimately is to replace inhalation toxicity testing in animals with in vitro approaches. Transition from animal- to human-based models is ultimately expected to lead to faster and better predictive toxicity assessments and therapeutic development at lower cost. This study shows the development and validation of alternative in vitro methods for acute toxicity testing, including acute inhalation toxicity testing.
The lung is an organ that is directly exposed to the external environment. Given the large surface area and extensive ventilation of the lung, it is prone to exposure to airborne substances, such as pathogens, allergens, chemicals, and particulate matter. Highly elaborate and effective mechanisms have evolved to protect and maintain homeostasis in the lung. Despite these sophisticated defense mechanisms, the respiratory system remains highly susceptible to environmental challenges. Because of the impact of respiratory exposure on human health and disease, there has been considerable interest in developing reliable and predictive in vitro model systems for respiratory toxicology and basic research. Human air-liquid-interface (ALI) organotypic airway tissue models derived from primary tracheobronchial epithelial cells have in vivo–like structure and functions when they are fully differentiated. The presence of the air-facing surface allows conducting in vitro exposures that mimic human respiratory exposures. Exposures can be conducted using particulates, aerosols, gases, vapors generated from volatile and semi-volatile substances, and respiratory pathogens. Toxicity data have been generated using nanomaterials, cigarette smoke, e-cigarette vapors, environmental airborne chemicals, drugs given by inhalation, and respiratory viruses and bacteria. Although toxicity evaluations using human airway ALImodels require further standardization and validation, this approach shows promise in supplementing or replacing in vivo animal models for conducting research on respiratory toxicants and pathogens.