ABSTRACT

The assessment of drug safety is highly important in order to ensure human safety. Before administrating drugs to humans in early clinical trials, toxicity testing is performed in animal models, where acute toxicity end points, including behavior and clinical signs, are monitored. In addition to this, end points evolving from more chronic exposures—such as effects on reproduction, long-term survival and carcinogenicity—are also studied. Animal studies are costly, time consuming and not concordant with the 3Rs principle (replacement, reduction and refinement) that aims at the replacement, reduction and refinement of animal use (Russell and Burch, 1959). In addition, clinical observations and biomarkers of toxicity derived from these animal studies are not necessarily predictive for the human situation. This contributes to the high drug attrition rate. In fact, only ~10% of drugs tested in clinical trials reach ultimate approval (Plenge, 2016), with toxicity in preclinical and phase I clinical trials as one of the leading causes (~30%) to cancel the further development of originally conceived drug candidates (Kola and Landis, 2004).