The human body is exposed to hundreds of chemicals every day. Many of these toxicants have unknown effects on the body that can be deleterious. Furthermore, chemicals can have a synergistic effect, resulting in toxic responses of cocktails at relatively low individual exposure levels. The gastrointestinal (GI) tract and the liver are the first organs to be exposed to ingested pharmaceuticals and environmental chemicals. As a result, these organs often experience extensive damage from xenobiotics and their metabolites. In vitro models offer a promising method for testing toxic effects. Many advanced in vitro models have been developed for GI and liver toxicity. These models strive to recapitulate the in vivo organ architecture to more accurately model chemical toxicity. In this review, we discuss many of these advances, in addition to recent efforts to integrate the GI and the liver in vitro for a more holistic toxicity model.

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