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

对除草剂、杀虫剂和杀菌剂的需求将导致新的 农用化学工业使用的化学品可能对人类健康构成重大威胁。这个 这个项目的目标是开发新的，生理上相关的动物细胞，基于 筛选农药等化学物质的体外器官培养模型。这种动物细胞- 基于模型的模型将通过促进体外推论缩小翻译研究的差距 这一发现将导致体内的生物学反应，最终将导致动物使用量的减少。 第一阶段研究的具体目标是：1)确定最大耐受量(MTD) 使用大鼠细胞器官型呼吸道和肠道组织的20种化学品/杀虫剂，2)使用 微生理灌流多器官芯片(MOC)平台评价其毒性 全身器官(肝脏)的反应和进一步提炼这些化学物质的MTD，3)相互关联 用体内大鼠LD50数据测定体外MTD值并建立危险性预测模型； 开发用于高通量化学筛选的96孔组织平台。在第二阶段， 预测模型将得到进一步的检验和正式验证。 用于化学筛选的动物细胞器官型培养模型的建立 利用监管机构制定的战略路线图，建立新的方法 (NAM)是动物试验的高效、预测性和成本效益高的替代品。海流 这项研究预计将产生一个毒理学平台，它将：1)预测化学/农药 毒性分类，2)提供易于使用、成本更低的动物试验替代方案，以及3)减少 毒物分析中使用的动物数量，并满足监管机构的需要。

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.