For the most part, the current approaches to toxicity testing and safety assessment rely on a complex array of traditional studies that evaluate observable outcomes in whole animals, such as clinical signs or pathological changes that are indicative of a disease state. As noted by MacDonald and Robertson, “The approaches that have been taken to assess human risk of adverse effects from chemical exposure have changed very little over the last several decades.” For example, “The global regulatory requirements for registration of new human pharmaceutical chemicals—the data requirements have changed very little since their establishment three and sometimes four decades ago despite the dramatic advances in the sciences that are used for this activity.” Margaret Hamburg, FDA Commissioner, echoes these themes, “Most of the toxicology tools used for regulatory assessment rely on high-dose animal studies and default extrapolation procedures, and have remained relatively unchanged for decades, despite the scientific revolutions of the past half-century.” Indeed, when the FDA released its strategic plan in August 2011, the need to modernize toxicology to enhance product safety was the first of eight science priority areas identified.
Changing Paradigms in Toxicology
Battelle recognized that significant improvements to the current “menu-driven” approach to nonclinical toxicology assessments are long overdue. Three steps were taken to achieve a new paradigm.
Step one was to move towards systems toxicology, a natural offshoot of systems biology—a holistic approach to focusing on complex interactions in biological systems. Systems toxicology is the study of perturbations of biological systems by chemicals and stressors using a holistic approach to describe the functioning organism.
Battelle then decided to build on existing strengths and capabilities. Panomics was used to monitor changes in molecular expression, imaging and other new endpoints to further characterize the perturbations, pharmacodynamics-pharmacokinetic modeling to characterize the dosimetry, and bioinformatics to iteratively integrate response data. Providing in vivo safety services to anchor systems toxicology findings with conventional toxicological parameters is consistent with the perspective offered by MacDonald and Robertson. “We feel that it is imperative that data from the newest technologies not be applied to the process of human risk assessment until the means to assess the relevance of the data that are derived from these assays are fully developed.
For step three, Battelle engaged the external strengths and capabilities of scientists and engineers from four U.S. Department of Energy national laboratories (NLs). Specifically, cooperative research and development agreements (CRADAs) were established with Brookhaven NL, Lawrence Livermore NL, Oak Ridge NL and Pacific Northwest NL to create the Battelle Center for Fundamental and Applied Systems Toxicology (B-FAST).
Read the entire paper on Drug Discovery & Development at dddmag.com.