Predicting In vivo Toxicity.
The objective of toxicity testing is to generate information that will help establish the safety of new products. Successful new in vitro tests will identify those endpoints and cell systems which provide evidence of pathologic change that can be used in determining safety. Chronic in vivo toxicity studies usually document adverse changes that are indicative of cell death in a target organ. For example, leakage of tissue specific enzymes is indicative of membrane damage and correlated with microscopic observation of cell death. Tissues, like the liver, can mount an effective regenerative response to moderate cell loss, but cell proliferation may be accompanied by the possibility of carcinogenesis. The balance between cell death and cell proliferation can make the difference between recovery, organ failure or tumour induction. Consequently, in vitro studies of toxicity have often focused on cell death as an endpoint. Molecular events preceding the irreversible commitment of a cell to die or proliferate are currently being investigated as additional potentially useful endpoints for in vitro toxicity studies. As molecular mechanisms become better understood, the number of potential endpoints for in vitro toxicity testing has greatly increased. However, at the earliest stages of interaction with the cell, it is difficult to predict whether changes induced by the xenobiotic are reversible (pharmacologic) or irreversible (pathologic) change. Changes in second messenger systems, binding to receptors, or early gene induction may explain the induction of toxicity by agents previously studied in vivo, but are potentially reversible changes that may not be useful for predicting the safety of untested products. Later changes that can be more easily identified as irreversible may provide more useful endpoints. One example is the activation of caspases in the cell as a precursor to apoptosis.
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