Zebrafish in Drug Discovery: Safety Assessment

New drug attrition due to unforeseen adverse effects in clinical trials wastes money and precious time needed to develop drugs that improve and save human lives. Preclinical toxicity studies are impactful in identifying safe compounds as drug candidates but are not infallible. Investigative Toxicology, including studies with human cells, tissue models, machine learning, and alternative animal models, seeks to improve preclinical identification of safe compounds. Zebrafish offer an alternative animal model that, due to the small size of the early life stages, provides high throughput toxicity data on a scale similar to cell culture. But data from zebrafish studies are from a whole vertebrate organism; many questions can be asked from a single study using small amounts of test article. This chapter explains the rationale for the use of zebrafish in drug discovery toxicology, describes the life stages as they relate to typical laboratory practices, discusses the challenges inherent to working with such a tiny animal, and gives three case studies that demonstrate how zebrafish can expose mechanisms of toxicity, predict toxic endpoints, and identify safer treatments of diseases.