Inhibition of Acetyl-CoA Carboxylase Causes Malformations in Rats and Rabbits: Comparison of Mammalian Findings and Alternative Assays.

Acetyl-CoA carboxylase (ACC) is an enzyme within the de novo lipogenesis (DNL) pathway and plays a role in regulating lipid metabolism. Pharmacologic ACC inhibition has been an area of interest for multiple potential indications including oncology, acne vulgaris, metabolic diseases such as type 2 diabetes mellitus, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. A critical role for ACC in de novo synthesis of long-chain fatty acids during fetal development has been demonstrated in studies in mice lacking Acc1, where the absence of Acc1 results in early embryonic lethality.

Characterizing sources of variability in zebrafish embryo screening protocols.

There is a need for fast, efficient, and cost-effective hazard identification and characterization of chemical hazards. This need is generating increased interest in the use of zebrafish embryos as both a screening tool and an alternative to mammalian test methods. A Collaborative Workshop on Aquatic Models and 21st Century Toxicology identified the lack of appropriate and consistent testing protocols as a challenge to the broader application of the zebrafish embryo model.

High-Mileage Light-Duty Fleet Vehicle Emissions: Their Potentially Overlooked Importance.

State and local agencies in the United States use activity-based computer models to estimate mobile source emissions for inventories. These models generally assume that vehicle activity levels are uniform across all of the vehicle emission level classifications using the same age-adjusted travel fractions. Recent fuel-specific emission measurements from the SeaTac Airport, Los Angeles, and multi-year measurements in the Chicago area suggest that some high-mileage fleets are responsible for a disproportionate share of the fleet's emissions.

Reactive Nitrogen Species Emission Trends in Three Light-/Medium-Duty United States Fleets.

Repeated, fuel-specific, emission measurements in Denver (2005/2013), Los Angeles (LA) (2008/2013), and Tulsa (2005/2013) provide long-term trends in on-road reactive nitrogen emissions from three light-/medium-duty U.S. fleets.

Stem cell-derived systems in toxicology assessment.

Industrial sectors perform toxicological assessments of their potential products to ensure human safety and to fulfill regulatory requirements. These assessments often involve animal testing, but ethical, cost, and time concerns, together with a ban on it in specific sectors, make appropriate in vitro systems indispensable in toxicology. In this study, we summarize the outcome of an EPAA (European Partnership of Alternatives to Animal Testing)-organized workshop on the use of stem cell-derived (SCD) systems in toxicology, with a focus on industrial applications.

On-road heavy-duty vehicle emissions monitoring system.

The introduction of particulate and oxides of nitrogen (NOx) after-treatment controls on heavy-duty vehicles has spurred the need for fleet emissions data to monitor their reliability and effectiveness. The University of Denver has developed a new method for rapidly measuring heavy-duty vehicles for gaseous and particulate fuel specific emissions. The method was recently used to collect 3088 measurements at a Port of Los Angeles location and a weigh station on I-5 in northern California.

The recession of 2008 and its impact on light-duty vehicle emissions in three western United States cities.

The global economic recession of 2008-2010 severely depressed light-duty vehicle sales in the United States. On-road fleets observed with a remote vehicle exhaust sensor in 2013 at three historical sampling locations in Denver, Los Angeles, and Tulsa showed large reductions in the fleet fractions of 2009 model year vehicles of 40%, 38%, and 35%, respectively, when compared to prerecession 2007 levels with the light-duty truck category suffering the largest percentage declines. The fleet fraction for these ∼ 5 year old vehicles is normally reserved for vehicles more than twice their age.

Fishing for teratogens: a consortium effort for a harmonized zebrafish developmental toxicology assay.

A consortium of biopharmaceutical companies previously developed an optimized Zebrafish developmental toxicity assay (ZEDTA) where chorionated embryos were exposed to non-proprietary test compounds from 5 to 6 h post fertilization and assessed for morphological integrity at 5 days post fertilization. With the original 20 test compounds, this achieved an overall predictive value for teratogenicity of 88% of mammalian in vivo outcome [Gustafson, A. L.

Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies.

A set of molecules that advanced into exploratory animal toxicology studies (two species) was examined to determine what properties contributed to success in these safety studies. Compounds were rigorously evaluated across numerous safety end points and classified as "pass" if a suitable in vivo therapeutic index (TI) was achieved for advancement into regulatory toxicology studies. The most predictive end point contributing to compound survival was a predicted human efficacious concentration (Ceff) of ≤250 nM (total drug) and ≤40 nM (free drug).

Heavy-duty truck emissions in the South Coast Air Basin of California.

California and Federal emissions regulations for 2007 and newer heavy-duty diesel engines require an order of magnitude reduction in particulate matter and oxides of nitrogen spurring the introduction of new aftertreatment systems. Since 2008, four emission measurement campaigns have been conducted at a Port of Los Angeles location and an inland weigh station in the South Coast Air Basin of California. Fuel specific oxides of nitrogen emissions at the Port have decreased 12% since 2010 while infrared opacity (a measure of particulate matter) remained low, showing no diesel particulate filter deterioration.

Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes.

To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors.

Comparison of the MOVES2010a, MOBILE6.2, and EMFAC2007 mobile source emission models with on-road traffic tunnel and remote sensing measurements.

Unlabelled: The Desert Research Institute conducted an on-road mobile source emission study at a traffic tunnel in Van Nuys, California, in August 2010 to measure fleet-averaged, fuel-based emission factors. The study also included remote sensing device (RSD) measurements by the University of Denver of 13,000 vehicles near the tunnel. The tunnel and RSD fleet-averaged emission factors were compared in blind fashion with the corresponding modeled factors calculated by ENVIRON International Corporation using U.

Multispecies remote sensing measurements of vehicle emissions on Sherman Way in Van Nuys, California.

Unlabelled: As part of the 2010 Van Nuys tunnel study, researchers from the University of Denver measured on-road fuel-specific light-duty vehicle emissions from nearly 13,000 vehicles on Sherman Way (0.4 miles west of the tunnel) in Van Nuys, California, with its multispecies Fuel Efficiency Automobile Test (FEAT) remote sensor a week ahead of the tunnel measurements. The remote sensing mean gram per kilogram carbon monoxide (CO), hydrocarbon (HC), and oxide of nitrogen (NO(x)) measurements are 8.

Embryo-fetal transfer of bevacizumab (Avastin) in the rat over the course of gestation and the impact of neonatal Fc receptor (FcRn) binding.

Background: There is concern about embryo-fetal exposure to antibody-based biopharmaceuticals based on the increase of such therapies being prescribed to women of childbearing potential. Therefore, there is a desire to better characterize embryo-fetal exposure of these molecules. The pregnant rat is a standard model for evaluating the potential consequences of exposure but placental transfer of antibody-based biopharmaceuticals is not well understood in this model.

Reproductive toxicity assessment of sunitinib, a multitargeted receptor tyrosine kinase inhibitor, in male and female rats.

Background: Sunitinib (SUTENT, Pfizer Inc., New York, NY) is a multitargeted inhibitor of selected receptor tyrosine kinases, which produces an antiproliferative and antiangiogenic effect by blocking pathways fundamental to tumor growth and survival. We investigated the effects of sunitinib on male and female fertility and early embryonic development in the rat.

Emission changes resulting from the San Pedro Bay, California Ports Truck Retirement Program.

Recent U.S. Environmental Protection Agency emissions regulations have resulted in lower emissions of particulate matter and oxides of nitrogen from heavy-duty diesel trucks.

Developmental toxicity testing for safety assessment: new approaches and technologies.

The ILSI Health and Environmental Sciences Institute's Developmental and Reproductive Toxicology Technical Committee held a 2-day workshop entitled "Developmental Toxicology-New Directions" in April 2009. The fourth session of this workshop focused on new approaches and technologies for the assessment of developmental toxicology. This session provided an overview of the application of genomics technologies for developmental safety assessment, the use of mouse embryonic stem cells to capture data on developmental toxicity pathways, dynamical cell imaging of zebrafish embryos, the use of computation models of development pathways and systems, and finally, high-throughput in vitro approaches being utilized by the EPA ToxCast program.

Not a walk in the park: the ECVAM whole embryo culture model challenged with pharmaceuticals and attempted improvements with random forest design.

Background: The European Committee for the Validation of Alternative Methods (ECVAM) supported the development of a linear discriminant embryotoxicity prediction model founded on rat whole embryo culture (Piersma et al. (2004). Altern Lab Anim 32:275–307).

On-road emission measurements of reactive nitrogen compounds from three California cities.

The three California cities of San Jose, Fresno, and West Los Angeles (wLA) were visited during March 2008 to collect on-road emission measurements of reactive nitrogen compounds from light-duty vehicles. At the San Jose and wLA sites, comparison with historical measurements showed that emissions of carbon monoxide (CO), hydrocarbons (HC), and nitric oxide (NO) continue to decrease in the on-road fleet, yet the ratio of nitrogen dioxide (NO(2)) to NO in new diesel vehicles appears to be undergoing large increases. A small fleet of 2007 diesel ambulances measured in Fresno was found to have more than 60% of their emitted oxides of nitrogen as NO(2).

Portable emission measurements of Yellowstone Park snowcoaches and snowmobiles.

As part of the National Park Service's Temporary Winter Use Plans Environmental Assessment, the University of Denver has been collecting in-use tailpipe emissions data from snowcoaches and snowmobiles in Yellowstone National Park. During the winter of 2006, using a portable emissions monitoring system, tailpipe data were collected from 10 snowcoaches and 2 four-stroke snowmobiles. These vehicles were operated over a standard route within the park, and the snowcoaches all carried identical passenger loads.

Endless possibilities: stem cells and the vision for toxicology testing in the 21st century.

The National Research Council's (NRC) toxicity testing vision lays out a bold future for our field. It depends heavily on computational algorithms based on the latest knowledge of cellular biochemistry and protein interaction pathways, exposing human cells to novel compounds in vitro, and being able to understand the changes seen. At the same time, significant strides are being made in our understanding of the control, production, and "behavior" of stem cells.

A decade of on-road emissions measurements.

A multiyear, on-road emission measurement program carried out in the cities of Chicago, Illinois; Denver, Colorado; Los Angeles (LA), California; and Phoenix, Arizona shows large, fuel-specific tailpipe emissions reductions at all of the sites for carbon monoxide (CO), hydrocarbons (HC), and nitric oxide (NO). CO emissions decreased between 56% (Denver) and 71% (Chicago), HC emissions decrease between 27% (Phoenix) and 63% (Denver), and NO emissions have dropped between 48% (West LA) and 68% (Chicago). Three observed factors common to all of the sites are that the emission reductions are occurring in vehicles of all ages, that the influence of engine load on fuel-specific emissions, especially for CO and NO, is reduced and that fleet-averaged emission deterioration is near zero for model years newer than 2001 and older than 1990.

Assessment of the Embryonic Stem Cell Test and application and use in the pharmaceutical industry.

Background: The European Centre for the Validation of Alternative Methods (ECVAM) designed the Embryonic Stem Cell Test (EST) as a tool for classifying developmentally toxic compounds. An in vitro tool to assess developmental toxicity would be of great value to the pharmaceutical industry to help with toxicity-associated attrition.

Methods: ECVAM's EST protocol was used, but employing a different mouse embryonic stem cell (ESC) line and an alternative differentiation medium.

Remote sensing of ammonia and sulfur dioxide from on-road light duty vehicles.

This study reports the largest data set of on-road, fuel-based mass emissions of ammonia and sulfur dioxide from vehicles of known make, model year, and fuel type. Ammonia is the first pollutant observed for which the emissions decrease with increasing fleet age from 10 to 20 years. The fixed nitrogen emission ratio is 15.