Can case study approaches speed implementation of the NRC report: “Toxicity Testing in the 21st Century: A Vision and a Strategy?”

Abstract

The 2007 report “Toxicity Testing in the 21st Century: A Vision and A Strategy” argued for a change in toxicity testing for environmental agents and discussed federal funding mechanisms that could be used to support this transformation within the USA. The new approach would test for in vitro perturbations of toxicity pathways using human cells with high throughput testing platforms. The NRC report proposed a deliberate timeline, spanning about 20 years, to implement a wholesale replacement of current in-life toxicity test approaches focused on apical responses with in vitro assays. One approach to accelerating implementation is to focus on well-studied prototype compounds with known toxicity pathway targets. Through a series of carefully executed case studies with four or five pathway prototypes, the various steps required for implementation of an in vitro toxicity pathway approach to risk assessment could be developed and refined. In this article, we discuss alternative approaches for implementation and also outline advantages of a case study approach and the manner in which the cases studies could be pursued using current methodologies. A case study approach would be complementary to recently proposed efforts to map the human toxome, while representing a significant extension toward more formal risk assessment compared to the profiling and prioritization approaches offered by programs such as the EPA’s ToxCast effort.

Consensus report on the future of animal-free systemic toxicity testing

“…4). the combination of high throughput screening assays with traditional cellular assays has been supplemented by in vitro-in vivo mathematical extrapolations, systems biology (computer models of cell regulation) and other approaches by many leading academic and governmental organizations to provide integrated testing strategies (leist et al, 2012a,b;Sturla et al, 2014;Hartung et al, 2013b;Kavlock et al, 2012;Andersen et al, 2011;Hartung and McBride, 2011;Bouhifd et al, 2014;Rossini and Hartung, 2012).…”

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

“…The "Hamner approach" (Andersen et al, 2011) selected some known relevant pathways to explore the Pot concept. the approach spearheaded by CAAt (Hartung and McBride, 2011) aims for an unsupervised identification of Pot by omics technologies.…”

The need for strategic development of safety sciences

“…CAAT's transatlantic think tank for toxicology (t 4 ) has organized more than 30 workshops to advance concepts of toxicology such as integrated testing strategies (Hartung et al, 2013b;Rovida et al, 2015b), epithelial barrier models (Gordon et al, 2015), 3D cell cultures (Alépée et al, 2014), microphysiological systems (Marx et al, 2016), high-content imaging (van Vliet et al, 2014), and has commissioned a number of white papers. (Andersen et al, 2011. It is most unfortunate that the Hamner Institute ceased to exist a year ago, and we will have to wait and see how much of this work can be sustained in another form.…”