In conjunction with the second International Environmental Omics Symposium (iEOS) conference, held at the University of Liverpool (United Kingdom) in September 2014, a workshop was held to bring together experts in toxicology and regulatory science from academia, government and industry. The purpose of the workshop was to review the specific roles that high-content omics datasets (eg, transcriptomics, metabolomics, lipidomics, and proteomics) can hold within the adverse outcome pathway (AOP) framework for supporting ecological and human health risk assessments. In light of the growing number of examples of the application of omics data in the context of ecological risk assessment, we considered how omics datasets might continue to support the AOP framework. In particular, the role of omics in identifying potential AOP molecular initiating events and providing supportive evidence of key events at different levels of biological organization and across taxonomic groups was discussed. Areas with potential for short and medium-term breakthroughs were also discussed, such as providing mechanistic evidence to support chemical read-across, providing weight of evidence information for mode of action assignment, understanding biological networks, and developing robust extrapolations of species-sensitivity. Key challenges that need to be addressed were considered, including the need for a cohesive approach towards experimental design, the lack of a mutually agreed framework to quantitatively link genes and pathways to key events, and the need for better interpretation of chemically induced changes at the molecular level. This article was developed to provide an overview of ecological risk assessment process and a perspective on how high content molecular-level datasets can support the future of assessment procedures through the AOP framework.

A species sensitivity distribution (SSD) is a probability model of the variation of species sensitivities to a stressor, in particular chemical exposure. The SSD approach has been used as a decision support tool in environmental protection and management since the 1980s, and the ecotoxicological, statistical, and regulatory basis and applications continue to evolve. This article summarizes the findings of a 2014 workshop held by the European Centre for Toxicology and Ecotoxicology of Chemicals and the UK Environment Agency in Amsterdam, The Netherlands, on the ecological relevance, statistical basis, and regulatory applications of SSDs. An array of research recommendations categorized under the topical areas of use of SSDs, ecological considerations, guideline considerations, method development and validation, toxicity data, mechanistic understanding, and uncertainty were identified and prioritized. A rationale for the most critical research needs identified in the workshop is provided. The workshop reviewed the technical basis and historical development and application of SSDs, described approaches to estimating generic and scenario-specific SSD-based thresholds, evaluated utility and application of SSDs as diagnostic tools, and presented new statistical approaches to formulate SSDs. Collectively, these address many of the research needs to expand and improve their application. The highest priority work, from a pragmatic regulatory point of view, is to develop a guidance of best practices that could act as a basis for global harmonization and discussions regarding the SSD methodology and tools. Integr Environ Assess Manag 2016;12:000-000. © 2016 SETAC

Glycoprotein Ib-IX-V (GPIb-IX-V) mediates platelet tethering to von Willebrand factor (VWF), recruiting platelets into the thrombus, and activates integrin ␣IIb␤3 through a pathway that is dependent on Src kinases. In addition, recent reports indicate that activation of ␣IIb␤3 by VWF is dependent on protein kinase G (PKG) and mitogen-activated protein (MAP) kinases. The present study compares the importance of these signaling pathways in the activation of ␣IIb␤3 by GPIb-IX-V. In contrast to a recent report, VWF did not promote an increase in cyclic guanosine monophosphate (cGMP), while agents that elevate cGMP, such as the nitrous oxide (NO) donor glyco-SNAP-1 (N-(␤-Dglucopyranosyl)-N 2 -acetyl-S-nitroso-D,Lpenicillaminamide) or the type 5 phosphosdiesterase inhibitor, sildenafil, inhibited rather than promoted activation of ␣IIb␤3 by GPIb-IX-V and blocked aggregate formation on collagen at an intermediate rate of shear (800 s ؊1 ). Additionally, sildenafil increased blood flow in a rabbit model of thrombus formation in vivo. A novel inhibitor of the MAP kinase pathway, which is active in plasma, PD184161, had no effect on aggregate formation on collagen under flow conditions, whereas a novel inhibitor of Src kinases, which is also active in plasma, PD173952, blocked this response. These results demonstrate a critical role for Src kinases but not MAP kinases in VWF-dependent platelet activation and demonstrate an inhibitory role for cGMP-elevating agents in regulating this process. IntroductionGlycoprotein Ib-IX-V (GPIb-IX-V), the receptor for von Willebrand factor (VWF), plays a critical role in thrombus formation in damaged blood vessels under high shear. [1][2][3][4] A fast on-rate of association between VWF and GPIb-IX-V allows the adhesion protein to tether (or capture) rapidly flowing platelets into the developing thrombus. A fast off-rate of dissociation, however, means that platelets rapidly detach from VWF, unless integrins such as ␣IIb␤3 or ␣2␤1 are activated by intracellular signals, thereby enabling them to bind their ligands and mediate stable adhesion and thrombus growth. Several surface receptors are able to mediate integrin activation, including the collagen receptor GPVI, the G protein-coupled receptors for adenosine diphosphate (ADP) and thromboxanes, P2Y 1 , P2Y 12 , and thromboxane prostanoid (TP) receptors. 5 Significantly, these receptors act in synergy to mediate integrin activation and thrombus growth. [6][7][8][9] It is recognized that GPIb-IX-V is also able to stimulate activation of ␣IIb␤3. However, the GPIb-IX-V complex generates a much weaker signal than many of the other agonists involved in thrombus formation, including collagen and ADP, thereby questioning the significance of this event. Indeed, the extent of activation is heavily dependent on experimental conditions, with activation being more readily seen in plasma than in washed platelets for reasons that remain unclear. [10][11][12][13][14][15] It is also difficult to ascertain the significance of activation of ␣IIb␤3 by GPIb...