Organotypic Culture Models (OCM) developed from experimental animals for Chemical Toxicity Screening.

The demand for herbicides, insecticides, and fungicides will lead to increased production of new chemicals by the agrochemical industry which may pose significant risk to human health. The objective of this project is to develop novel, physiologically relevant animal cell based in vitro organotypic culture models for screening chemicals such as pesticides. Such animal cell- based models will narrow the gap in translational research by facilitating extrapolation of in vitro findings to in vivo biological responses and ultimately will lead to reduced animal use. The specific aims of the Phase 1 study are to: 1) Determine the maximum tolerated dose (MTD) for 20 chemicals/pesticides using rat cell based organotypic airway and intestinal tissues, 2) utilize a microphysiological perfused multiorgan on a chip (MOC) platform to assess the toxicity response of a systemic organ (liver) and to further refine the MTD for these chemicals, 3) correlate the in vitro MTD values with in vivo rat LD50 data and establish a hazard prediction model, and 4) develop a 96-well tissue platform for high throughput chemical screening. During Phase 2, the prediction model will be further tested and formally validated. The development of animal cell based organotypic culture models for chemical screening aligns with the strategic roadmap laid out by regulatory bodies to establish new approach methods (NAM) that are efficient, predictive, and cost-effective alternatives to animal testing. The current study is predicted to produce a toxicological platform which will: 1) predict chemical/pesticide toxicity categories, 2) provide an easy-to-use, lower cost alternative to animal tests, and 3) reduce the number of animals used in toxicological assays and meet the needs of regulatory bodies.The day-to-day human exposure to chemicals such as pesticides through contaminated food drinking water, air pollution, and direct contact can impact human and animal health. In order to reduce potential hazard, regulatory bodies are seeking the development of a better and efficient chemical toxicity screening tools using animal-cell based in vitro organotypic culture model (OCM) systems to replace or reduce current animal-based in vivo testing. During this project, we will develop an in vitro assay method to screen pesticides from different classes and hazard levels using three-dimensional rat-cell based (lung, intestine, and liver) based organotypic culture models and a microphysiological platform.