The U.S. Environmental Protection Agency's (EPA) ToxCast program is testing a large library of Agency-relevant chemicals using in vitro high-throughput screening (HTS) approaches to support the development of improved toxicity prediction models. Launched in 2007, Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay end points. In Phase II, the ToxCast library was expanded to 1878 chemicals, culminating in the public release of screening data at the end of 2013. Subsequent expansion in Phase III has resulted in more than 3800 chemicals actively undergoing ToxCast screening, 96% of which are also being screened in the multi-Agency Tox21 project. The chemical library unpinning these efforts plays a central role in defining the scope and potential application of ToxCast HTS results. The history of the phased construction of EPA's ToxCast library is reviewed, followed by a survey of the library contents from several different vantage points. CAS Registry Numbers are used to assess ToxCast library coverage of important toxicity, regulatory, and exposure inventories. Structure-based representations of ToxCast chemicals are then used to compute physicochemical properties, substructural features, and structural alerts for toxicity and biotransformation. Cheminformatics approaches using these varied representations are applied to defining the boundaries of HTS testability, evaluating chemical diversity, and comparing the ToxCast library to potential target application inventories, such as used in EPA's Endocrine Disruption Screening Program (EDSP). Through several examples, the ToxCast chemical library is demonstrated to provide comprehensive coverage of the knowledge domains and target inventories of potential interest to EPA. Furthermore, the varied representations and approaches presented here define local chemistry domains potentially worthy of further investigation (e.g., not currently covered in the testing library or defined by toxicity "alerts") to strategically support data mining and predictive toxicology modeling moving forward.

Chemical toxicity can arise from disruption of specific biomolecular functions or through more generalized cell stress and cytotoxicity-mediated processes. Here, responses of 1060 chemicals including pharmaceuticals, natural products, pesticidals, consumer, and industrial chemicals across a battery of 815 in vitro assay endpoints from 7 high-throughput assay technology platforms were analyzed in order to distinguish between these types of activities. Both cell-based and cell-free assays showed a rapid increase in the frequency of responses at concentrations where cell stress/cytotoxicity responses were observed in cell-based assays. Chemicals that were positive on at least 2 viability/cytotoxicity assays within the concentration range tested (typically up to 100 μM) activated a median of 12% of assay endpoints whereas those that were not cytotoxic in this concentration range activated 1.3% of the assays endpoints. The results suggest that activity can be broadly divided into: (1) specific biomolecular interactions against one or more targets (eg, receptors or enzymes) at concentrations below which overt cytotoxicity-associated activity is observed; and (2) activity associated with cell stress or cytotoxicity, which may result from triggering specific cell stress pathways, chemical reactivity, physico-chemical disruption of proteins or membranes, or broad low-affinity non-covalent interactions. Chemicals showing a greater number of specific biomolecular interactions are generally designed to be bioactive (pharmaceuticals or pesticidal active ingredients), whereas intentional food-use chemicals tended to show the fewest specific interactions. The analyses presented here provide context for use of these data in ongoing studies to predict in vivo toxicity from chemicals lacking extensive hazard assessment.

No abstract

No abstract

Dynamic contrast-enhanced MR urography provides superior anatomic and functional information when compared with ultrasound and diuretic renal scintigraphy. The information is gathered in a single study that does not use ionizing radiation. It is likely that MR urography will replace renal scintigraphy in the evaluation of hydronephrosis in children.

Combining signal-intensity-versus-time-curve analysis with the other parameters that can be derived from the same MR urography data set provides a powerful tool for the diagnosis of obstruction.

In this article we introduce the topic of MR urography in children, focusing on the details required to obtain consistently high-quality scans. Much of the information presented is based on our experience during the last 7 years. We have performed almost 1,000 MR urograms in children, and the technique has evolved considerably during this time. We have learned through trial and error and have improved our protocols to the point that our approach is now standardized and reliably generates high-quality studies. From this standardized protocol, further refinements in technique can be readily implemented. It is important to remember that this clinical application is in its infancy and will improve significantly with further technical development. This paper provides an overview of the practical issues associated with obtaining high-quality scans as well as an introduction into the interpretation of MR urograms.

BACKGROUND AND PURPOSE:Children with a shunt for hydrocephalus often undergo multiple follow-up head CT scans, increasing the risk for long-term effects of ionizing radiation. The purpose of our study was to evaluate if an unenhanced low-dose head CT could consistently provide acceptable image quality and diagnostic information.