Enabling novel paradigms: a biological questions-based approach to human chemical hazard and drug safety assessment.

Throughput needs, costs of time and resources, and concerns about the use of animals in hazard and safety assessment studies are fueling a growing interest in adopting new approach methodologies for use in product development and risk assessment. However, current efforts to define "next-generation risk assessment" vary considerably across commercial and regulatory sectors, and an a priori definition of the biological scope of data needed to assess hazards is generally lacking. We propose that the absence of clearly defined questions that can be answered during hazard assessment is the primary barrier to the generation of a paradigm flexible enough to be used across varying product development and approval decision contexts. Herein, we propose a biological questions-based approach (BQBA) for hazard and safety assessment to facilitate fit-for-purpose method selection and more efficient evidence-based decision-making. The key pillars of this novel approach are bioavailability, bioactivity, adversity, and susceptibility. This BQBA is compared with current hazard approaches and is applied in scenarios of varying pathobiological understanding and/or regulatory testing requirements. To further define the paradigm and key questions that allow better prediction and characterization of human health hazard, a multidisciplinary collaboration among stakeholder groups should be initiated.