Future of toxicology--mechanisms of toxicity and drug safety: where do we go from here?

Recent high-profile drug withdrawals increase the pressure on regulators and the pharmaceutical industry to improve preclinical safety testing. Understanding mechanisms of drug toxicity is an essential step toward improving drug safety testing by providing the basis for mechanism-based risk assessments. Nonetheless, despite several decades of research on mechanisms of drug-induced toxicity and the application of various new technologies to preclinical safety assessment, the overall impact on preclinical safety testing has been modest. Assessing the risk of exposing humans to new drug candidates still depends on preclinical testing in animals, which in many, but not all cases, predicts outcomes in humans accurately. The following offers a perspective on the challenges and opportunities facing efforts to improve preclinical safety testing and outlines gaps and needs that must be addressed. A case is built for focusing solutions on defined problems within the current safety testing paradigm rather than imposing wholesale change. Targets for application of new technologies, including in silico screening, biomarkers, surrogate assays and 'omic technologies, are outlined. Improving drug safety testing will depend on improving the application of mechanism-based risk assessment but will also require improving public and private collaborations in order to focus research regarding the mechanism of drug-induced toxicity on the most important problems.