Integrated Testing Strategy (ITS) - Opportunities to better use existing data and guide future testing in toxicology

The topic of Integrated Testing Strategies (ITS) has attracted considerable attention, and not only because it is supposed to be a central element of REACH, the ambitious European chemical regulation effort. Although what ITSs are supposed to do seems unambiguous, i.e. speeding up hazard and risk assessment while reducing testing costs, not much has been said, except basic conceptual proposals, about the methodologies that would allow execution of these concepts. Although a pressing concern, the topic of ITS has drawn mostly general reviews, broad concepts, and the expression of a clear need for more research on ITS. Published research in the field remains scarce. Solutions for ITS design emerge slowly, most likely due to the methodological challenges of the task, and perhaps also to it its complexity and the need for multidisciplinary collaboration. Along with the challenge, ITS offer a unique opportunity to contribute to the Toxicology of the 21st century by providing frameworks and tools to actually implement 21st century toxicology data in the chemical management and decision making processes. Further, ITS have the potential to significantly contribute to a modernization of the science of risk assessment. Therefore, to advance ITS research we propose a methodical approach to their design and will discuss currently available approaches as well as challenges to overcome. To this end, we define a framework for ITS that will inform toxicological decisions in a systematic, transparent, and consistent way. We review conceptual requirements for ITS developed earlier and present a roadmap to an operational framework that should be probabilistic, hypothesis-driven, and adaptive. Furthermore, we define properties an ITS should have in order to meet the identified requirements and differentiate them from evidence synthesis. Making use of an ITS for skin sensitization, we demonstrate how the proposed ITS concepts can be implemented.