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Comparative In vivo, Ex vivo, and In vitro Toxicity Studies of Engineered Nanomaterials
Citation:
KIm, Y., E. Boykin, T. Stevens, K. Lavrich, AND Ian Gilmour. Comparative In vivo, Ex vivo, and In vitro Toxicity Studies of Engineered Nanomaterials. Presented at Society of Toxicology, San Diego, CA, March 22 - 26, 2015.
Impact/Purpose:
Assess the relative toxicity of engineered nanoparticles in mice and ex vivo lung slices
Description:
Efforts to reduce the number of animals in engineered nanomaterials (ENM) toxicity testing have resulted in the development of numerous alternative toxicity testing methods, but in vivo and in vitro results are still evolving and variable. This inconsistency could be due to the fact that there is a lack of overall consensus on the relevant dose metric and endpoint(s) for in vitro studies which are typically performed with submerged culture systems. In this study, five ENM (SiO2 (10), CeO2 (23), CeO2 (88), TiO2 (10), and TiO2 (200); parentheses indicate average diameter in nm) were instilled into CD-1 mice (in vivo) at 100 µg via oropharyngeal aspiration, or cultured with mouse lung slices (ex vivo) and alveolar macrophages (in vitro) at concentrations of 2-100 and 22-132 µg/mL, respectively. Biomarkers of lung injury and inflammation were assessed at 4 and/or 24 hr post-exposure. The results showed that small-sized ENM (SiO2 (10), CeO2 (23), but not TiO2 (10)) significantly elicited proinflammatory responses in the mouse lung in vivo. However, only SiO2 (10) significantly increased proinflammatory cytokine levels (e.g., interleukin-6) in both the lung slices ex vivo and alveolar macrophages in vitro. This inconsistency was compensated by considering appropriate exposure dose metric in the in vitro (or ex vivo) system resulting in a similar toxicity ranking of ENM observed in vivo (i.e., SiO2 (10) and CeO2 (23) to display the most toxic ex vivo and in vitro). We conclude that exposure to ENM induced acute lung inflammatory effects in a size- and chemical composition-dependent manner. A better understanding of ENM dosimetry for in vitro systems (i.e., a delivered dose is not always equivalent to an exposure dose) will reduce the disparity between in vitro and in vivo nanotoxicology outcomes.