CYTOTOXICITY ASSESSMENT OF HIGH-NITROGEN COMPOUNDS USING A NOVEL IN VITRO MULTI-CELLULAR APPROACH

The production and use of explosives, to include high-nitrogen (high-N) compounds such at 2,6-trinitrotoluene (TNT), for use in testing on training sites have been shown to contaminate terrestrial and aquatic sites, leading to an increase risk of adverse health effects. The toxicological impacts of soil and natural waters contaminated with high-N compounds are not well understood. In this regard, the use of live animal testing has many advantages, but the high cost of in vivo testing, in terms of resource consumption, animal usage, and time, only allows for the testing of a limited number of compounds. Furthermore, current in vitro systems are limited by screening cells in isolation, underestimating the cytotoxicity of metabolites.

The goal of this research is to develop an efficient in vitro tool capable of assessing the toxicity of high-N compounds as they are being developed. The Integrated discrete Multiple Organ Co-Culture (IdMOC) system addresses these limitations by permitting the co-culture of up to 6 discrete organ cell types (in this research: kidney, liver, lung, heart and vascular endothelium); demonstrating cell-specific toxicity of parent compounds in a population of cells found within an organ system, as well as cell-specific toxicity due to metabolites generated by other cells. The cell lines were chosen in order to allow for broad representation of organ systems to maximize coverage toxicity screening. While the IdMOC system in this research was developed to increase the efficacy of toxicity assessment of high-N compounds, the system offers the potential to assess the toxicity of a large scale of soil, air and water contaminants, natural or industrial; and a better understanding of the impact of these contaminants on human health.