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A1940 - Comparison of In Vitro Rat and Human Airway Epithelial Models for Inhalation Toxicity Testing
Author Block: P. Hayden1, G. R. Jackson1, A. G. Maione2, M. Klausner1; 1Mattek Corp, Ashland, MA, United States, 2MatTek Corporation, Ashland, MA, United States.
Rationale: Accurate assessment of inhalation toxicity potential is important for developing new therapeutics, evaluating environmental air pollutants and for establishing safe handling, labeling and emergency response procedures for chemicals. Traditionally, animal models have been used for determining inhalation toxicity. However, there is concern that in vivo animal models may not accurately predict human outcomes. Therefore, development of in vitro organotypic airway tissue models constructed from primary human cells has become a high priority in the scientific community. Yet, validation of these systems for predicting in vivo human response is problematic because the available in vivo inhalation toxicity data has been primarily produced using rodents. To address this issue, a scalable in vitro organotypic model of rat mucociliary airway epithelium has been developed to allow the direct comparison of chemical toxicity responses with previously developed in vitro human airway models. Methods: Conducting airways epithelial cells were isolated from CD rats, expanded in culture, and cultured at the air-liquid interface for up to 27 days. A comparison of the toxicity responses in the rat vs. human airway models was conducted using 14 chemicals with in vivo GHS inhalation toxicity classifications ranging from categories 1-5. The airway tissue models were exposed to 4 doses of each test chemical for 3 hrs, followed by measurement of tissue viability. IC75 concentrations for chemical toxicity were determined from the dose response data. Results: Histological evaluation of the rat and human airway models demonstrated a high level of organotypic mucociliary differentiation including a pseudostratified epithelial structure with copious development of functional cilia. Robust barrier function was demonstrated by development of transepithelial electrical resistance of up to 800 Ω x cm2. Results of chemical toxicity experiments showed that rat and human tissue responses were similar, within the same order of magnitude, for each chemical. Future work will expand the range of chemicals tested to further define the comparative responses. Conclusions: These results suggest that discrepancies observed between in vivo rat and in vitro human toxicity results are liekly due to key experimental differences in achieved exposure between the in vivo and in vitro systems, rather than intrinsic differences in toxicity response between rat and human airway epithelia. The in vitro rat airway and human airway models will be useful tools to facilitate rodent to human translation of in vitro inhalation toxicology data, and ultimately a more complete transition to human based in vitro models of inhalation toxicity.