t4 workshop report. Nanotoxicology: "the end of the beginning" - signs on the roadmap to a strategy for assuring the safe application and use of nanomaterials.

In October 2010, a group of experts met as part of the transatlantic think tank for toxicology (t4) to exchange ideas about the current status and future of safety testing of nanomaterials. At present, there is no widely accepted path forward to assure appropriate and effective hazard identification for engineered nanomaterials. The group discussed needs for characterization of nanomaterials and identified testing protocols that incorporate the use of innovative alternative whole models such as zebrafish or C. elegans, as well as in vitro or alternative methods to examine specific functional pathways and modes of action. The group proposed elements of a potential testing scheme for nanomaterials that works towards an integrated testing strategy, incorporating the goals of the NRC report Toxicity Testing in the 21st Century: A Vision and a Strategy by focusing on pathways of toxic response, and utilizing an evidence-based strategy for developing the knowledge base for safety assessment. Finally, the group recommended that a reliable, open, curated database be developed that interfaces with existing databases to enable sharing of information.

Food for thought ... on validation. A puzzle or a mystery: an approach founded on new science.

The notion of test method validation, when applied to in vitro models, has been subjected to standards, practices, and regulatory mandates that may represent significant barriers to the development of new methods based on target toxicological pathways, mode of action, and mechanistic endpoints. Currently, there is an expectation that toxicity test methods used for regulatory purposes must be formally validated by a legislated body. In this manuscript, we review the genesis of current formal validation programs, their purpose, their justification for future need, and an examination of the scientific process as the driving force. With the collision of three major international events in the scientific and regulatory communities (viz. EU Cosmetic Directive, EU REACH legislation, and the NRC publication, Toxicity Testing in the 21st Century: A Vision and a Strategy), there may be a need for a shift in the current validation paradigm. Further, test method validity may be recognized by the appropriate authorities when specific criteria and the fundamental precepts of reliability and reproducibility have been adequately met.

A versatile synthetic approach toward diversity libraries using monosaccharide scaffolds.

The pyranose scaffold is unique in its ability to position pharmacophore substituents in various ways in 3D space, and unique pharmacophore scanning libraries could be envisaged that focus on scanning topography rather than diversity in the type of substituents. Approaches have been described that make use of amine and acid functionalities on the pyranose scaffolds to append substituents, and this has enabled the generation of libraries of significant structural diversity. Our general aim was to generate libraries of pyranose-based drug-like mimetics, where the substituents are held close to the scaffold, in order to obtain molecules with better defined positions for the pharmacophore substituents. Here we describe the development of a versatile synthetic route toward peptide mimetics build on 2-amino pyranose scaffolds. The method allows introduction of a wide range of substituent types, it is regio- and stereospecific, and the later diversity steps are performed on solid phase. Further, the same process was applied on glucose and allose scaffolds, in the exemplified cases, and is likely adaptable to other pyranose building blocks. The methods developed in this work give access to molecules that position the three selected binding elements in various 3D orientations on a pyranose scaffold and have been applied for the production of a systematically diverse library of several hundred monosaccharide-based mimetics.