Abstract
An important goal of neurotoxicological research is to provide relevant and accurate risk assessment of environmental and pharmacological agents for populations and individuals. Owing to the challenges of human subject research and the real possibility of species specific toxicological responses, neuronal lineages derived from human embryonic stem cells (hESCs) and human neuronal precursors have been offered as a potential solution for validation of neurotoxicological data from model organism systems in humans. More recently, with the advent of induced pluripotent stem cell (iPSC) technology, there is now the possibility of personalized toxicological risk assessment, the ability to predict individual susceptibility to specific environmental agents, by this approach. This critical advance is widely expected to facilitate analysis of cellular physiological pathways in the context of human neurons and the underlying genetic factors that lead to disease. Thus this technology opens the opportunity, for the first time, to characterize the physiological, toxicological, pharmacological and molecular properties of living human neurons with identical genetic determinants as human patients. Furthermore, armed with a complete clinical history of the patients, human iPSC (hiPSC) studies can theoretically compare patients and at risk groups with distinct sensitivities to particular environmental agents, divergent clinical outcomes, differing co-morbidities, and so forth. Thus iPSCs and neuronal lineages derived from them may reflect the unique genetic blueprint of the individuals from which they are generated. Indeed, iPSC technology has the potential to revolutionize scientific approaches to human health. However, before this overarching goal can be reached a number of technical and theoretical challenges must be overcome. This review seeks to provide a realistic assessment of hiPSC technology and its application to risk assessment and mechanistic studies in the area of neurotoxicology. We seek to identify, prioritize, and detail the primary hurdles that need to be overcome if personalized toxicological risk assessment using patient-derived iPSCs is to succeed.