Has Toxicity Testing Moved into the 21st Century? A Survey and Analysis of Perceptions in the Field of Toxicology.

BackgroundTen years ago, leaders in the field of toxicology called for a transformation of the discipline and a shift from primarily relying on traditional animal testing to incorporating advances in biotechnology and predictive methodologies into alternative testing strategies (ATS). Governmental agencies and academic and industry partners initiated programs to support such a transformation, but a decade later, the outcomes of these efforts are not well understood.ObjectivesWe aimed to assess the use of ATS and the perceived barriers and drivers to their adoption by toxicologists and by others working in, or closely linked with, the field of toxicology.MethodsWe surveyed 1,381 toxicologists and experts in associated fields regarding the viability and use of ATS and the perceived barriers and drivers of ATS for a range of applications. We performed ranking, hierarchical clustering, and correlation analyses of the survey data.ResultsMany respondents indicated that they were already using ATS, or believed that ATS were already viable approaches, for toxicological assessment of one or more end points in their primary area of interest or concern (26-86%, depending on the specific ATS/application pair). However, the proportions of respondents reporting use of ATS in the previous 12 mo were smaller (4.5-41%). Concern about regulatory acceptance was the most commonly cited factor inhibiting the adoption of ATS, and a variety of technical concerns were also cited as significant barriers to ATS viability. The factors most often cited as playing a significant role (currently or in the future) in driving the adoption of ATS were the need for expedited toxicology information, the need for reduced toxicity testing costs, demand by regulatory agencies, and ethical or moral concerns.ConclusionsOur findings indicate that the transformation of the field of toxicology is partly implemented, but significant barriers to acceptance and adoption remain. https://doi.org/10.1289/EHP1435

Sensitivity of the correlation between the depth of shower maximum and the muon shower size to the cosmic ray composition

The composition of ultra-high energy cosmic rays is an important issue in astroparticle physics research, and additional experimental results are required for further progress. Here we investigate what can be learned from the statistical correlation factor r between the depth of shower maximum and the muon shower size, when these observables are measured simultaneously for a set of air showers. The correlation factor r contains the lowest-order moment of a two-dimensional distribution taking both observables into account, and it is independent of systematic uncertainties of the absolute scales of the two observables. We find that, assuming realistic measurement uncertainties, the value of r can provide a measure of the spread of masses in the primary beam. Particularly, one can differentiate between a well-mixed composition (i.e., a beam that contains large fractions of both light and heavy primaries) and a relatively pure composition (i.e., a beam that contains species all of a similar mass). The number of events required for a statistically significant differentiation is ~ 200. This differentiation, though diluted, is maintained to a significant extent in the presence of uncertainties in the phenomenology of high energy hadronic interactions. Testing whether the beam is pure or well-mixed is well motivated by recent measurements of the depth of shower maximum.Comment: Accepted for publication in Astroparticle Physics, LA-UR-12-2008

Control of light transmission through opaque scattering media in space and time

We report the first experimental demonstration of combined spatial and temporal control of light trajectories through opaque media. This control is achieved by solely manipulating spatial degrees of freedom of the incident wavefront. As an application, we demonstrate that the present approach is capable to form bandwidth-limited ultrashort pulses from the otherwise randomly transmitted light with a controllable interaction time of the pulses with the medium. Our approach provides a new tool for fundamental studies of light propagation in complex media and has potential for applications for coherent control, sensing and imaging in nano- and biophotonics

A C. elegans Screening Platform for the Rapid Assessment of Chemical Disruption of Germline Function

Background: Despite the developmental impact of chromosome segregation errors, we lack the tools to assess environmental effects on the integrity of the germline in animals. Objectives: We developed an assay in Caenorhabditis elegans that fluorescently marks aneuploid embryos after chemical exposure. Methods: We qualified the predictive value of the assay against chemotherapeutic agents as well as environmental compounds from the ToxCast Phase I library by comparing results from the C. elegans assay with the comprehensive mammalian in vivo end point data from the ToxRef database. Results: The assay was highly predictive of mammalian reproductive toxicities, with a 69% maximum balanced accuracy. We confirmed the effect of select compounds on germline integrity by monitoring germline apoptosis and meiotic progression. Conclusions: This C. elegans assay provides a comprehensive strategy for assessing environmental effects on germline function

First estimate of volcanic SO2 budget for Vanuatu island arc

International audienceThe spatial and temporal coverage of measurements of previous termvolcanicnext term gas emissions remains patchy. However, over the last decade, emissions inventories have improved thanks to new measurements of some of the lesser-known previous termvolcanicnext term areas. We report on one such region - the Vanuatu island arc, in the Southwest Pacific - for which we now have sufficient systematic observations to offer a systematic emissions inventory. Our new estimate is based on SO2 flux measurements made in the period 2004-2009 with ultraviolet spectroscopy techniques for the following volcanoes: Yasur, Lopevi, Ambrym, Ambae, Gaua and Vanua Lava (from south to north). These are the first ever measurements for Lopevi, Gaua and Vanua Lava. The results reveal the Vanuatu arc as one of Earth's prominent sources of previous termvolcanicnext term degassing with a characteristic annual emission to the atmosphere of ~ 3 Tg of SO2 (representing about 20% of hitherto published global estimates). Our new dataset highlights the sustained prodigious degassing of Ambrym volcano, whose 5 Gg d-1 mean flux of SO2 represents nearly two-thirds of the total budget for the Vanuatu arc. This confirms Ambrym as one of the largest previous termvolcanic sources worldwide comparable to Etna, often considered as the most vigorous source of previous termvolcanic emission on Earth. We also report a high degassing for Ambae of ~ 2 Gg d-1 SO2, representing more than 28 % of the Vanuatu arc budget. Thus, 90 % of the SO2 output from Vanuatu is focused in the central part of the arc (from Ambrym and Ambae) where magmas originate from enriched Indian-type mantle and where peculiar tectonic conditions could favour high magma production rates

Comparative global immune-related gene profiling of somatic cells, human pluripotent stem cells and their derivatives: implication for human lymphocyte proliferation.

Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity. The expression levels of global immune-related genes were determined by comparing undifferentiated and differentiated stem cells and three types of human somatic cells: dermal papilla cells, ovarian granulosa cells and foreskin fibroblast cells. We identified the differentially expressed genes CD24, GATA3, PROM1, THBS2, LY96, IFIT3, CXCR4, IL1R1, FGFR3, IDO1 and KDR, which overlapped with selected immune-related gene lists. In further analyses, mammalian target of rapamycin complex (mTOR) signaling was investigated in the differentiated stem cells following treatment with rapamycin and lentiviral transduction with specific short-hairpin RNAs. We found that the inhibition of mTOR signal pathways significantly downregulated the immunogenicity of differentiated stem cells. We also tested the immune responses induced in differentiated stem cells by mixed lymphocyte reactions. We found that CD24- and GATA3-deficient differentiated stem cells including neural lineage cells had limited abilities to activate human lymphocytes. By analyzing the transcriptome signature of immune-related genes, we observed a tendency of the hPSCs to differentiate toward an immune cell phenotype. Taken together, these data identify candidate immune-related genes that might constitute valuable targets for clinical applications

Caenorhabditis Elegans as a Model for Environmental Epigenetics

Purpose of reviewThe burgeoning field of environmental epigenetics has revealed the malleability of the epigenome and uncovered numerous instances of its sensitivity to environmental influences; however, pinpointing specific mechanisms that tie together environmental triggers, epigenetic pathways, and organismal responses has proven difficult. This article describes how Caenorhabditis elegans can fill this gap, serving as a useful model for the discovery of molecular epigenetic mechanisms that are conserved in humans.Recent findingsRecent results show that environmental stressors such as methylmercury, arsenite, starvation, heat, bacterial infection, and mitochondrial inhibitors can all have profound effects on the epigenome, with some insults showing epigenetic and organismal effects for multiple generations. In some cases, the pathways connecting the stressor to epigenetic pathways and organismal responses have been elucidated. For example, a small RNA from the bacterial pathogen Pseudomonas aeruginosa induces transgenerational learned avoidance by activating the RNA interference PIWI-interacting RNA pathways across generations to downregulate, via Cer1 retrotransposon particles and histone methylation, maco-1, a gene that functions in sensory neurons to regulate chemotaxis. Mitochondrial inhibitors seem to have a profound effect on both the DNA methylation mark 6mA and histone methylation, and may act within mitochondrial DNA (mtDNA) to regulate mitochondrial stress response genes. Transgenerational transcriptional responses to alcohol have also been worked out at the single-nucleus resolution in C. elegans, demonstrating its utility when combined with modern sequencing technologies. These recent studies highlight how C. elegans can serve as a bridge between biochemical in vitro experiments and the more associative findings of epidemiological studies in humans to unveil possible mechanisms of environmental influence on the epigenome. The nematode is particularly well-suited to transgenerational experiments thanks to its rapid generation time and ability to self-fertilize. These studies have revealed connections between the various epigenetic mechanisms, and so studies in C. elegans that take advantage of recent advancements in sequencing technologies, including single-cell techniques, to gain unprecedented resolution of the whole epigenome across development and generations will be critical