Integrated Laboratory Systems, Inc.

The industrial-scale growth of dielectrics on top of a 2D material transistor channel without deterioration of its transport characteristics remains challenging today. Here, we investigate the origin of the performance degradation issue by constructing several atomistic interface models between a WS2 monolayer and an amorphous Al2O3 or HfO2 thin film. We then computed their properties using first-principles methods. We show that, while it is in principle possible to achieve a van der Waals interface between these materials, surface defects (e.g., undercoordinated metal atoms at the surface) are detrimental since they create localized states close to the bottom of the conduction band of WS2. Even in their absence, the inhomogeneity of the surface topology creates a nonuniform potential that is felt by charge carriers in WS2. While surface defects can potentially be kept under control with an appropriate oxide choice, the surface inhomogeneity appears to act as a bottleneck, limiting the performance of WS2 as a transistor channel and, in general, for all 2D materials.

The ability of polycyclic aromatic compounds (PACs), most notably benzo(a) pyrene [B(a)P], to suppress antibody responses in experimental animals is well documented. Very little information, however, is available on the immunotoxicity of related PACs despite their widespread presence in the environment. Additionally, there are several weaknesses in existing immunotoxicity databases for PACs in experimental animals, limiting their applicability in quantitative risk assessment. Careful characterization of strong positive and clear negative PACs is needed in order to lay the foundation for generating robust immunotoxicity data for structurally diverse PACs that have not yet been evaluated. In the current study, adult B6C3F1/N female mice were treated daily for 28 consecutive days by oral administration of B(a)P to provide dose levels ranging between 2 and 150mg/kg bodyweight/day. In addition, phenanthrene and pyrene, non-carcinogenic PACs, were tested at dose ranges between 12.5 and 800mg/kg bodyweight/day and 3.1 and 200mg/kg bodyweight/day, respectively. Immune assessments following PAC exposure included organ weights and immunopathology, hematology, quantification of immune cell types in the spleen, and T-dependent antibody response (TDAR) to sheep red blood cells (SRBC). Benzo(a)pyrene exposure resulted in significant decreases in lymphoid organ weights, immune cell populations in the spleen and TDAR. The most sensitive indicator for immunotoxicity from B(a)P treatment was suppression of antibody responses, where an ∼75% decrease occurred at a dose level of 9mg/kg bodyweight/day and ∼32% decrease at the lowest tested dose of 2mg/kg bodyweight/day. Antibody suppression was associated with significant immune cell loss in the spleen; however, it was clear that the suppression of the TDAR was more sensitive than cell loss indicating that cell function impairments were involved. Phenanthrene treatment also resulted in suppression of the antibody response but only at dose levels ≥50mg/kg bodyweight/day without significant effects on other parameters, while pyrene showed no significant immune effects. Suppression of the TDAR to SRBC immunization was the most sensitive immune endpoint being 33 times more sensitive than changes in liver weight, a commonly used outcome for risk assessment for PACs. Benzo(a)pyrene was the most potent PAC regarding suppression of humoral immunity whereas pyrene did not affect the immune responses tested. These studies lay the foundation for evaluating diverse PACs with a range of immunotoxicological potencies.

We used Duplex Sequencing to study the mutagenicity of benzo[ b ]fluoranthene across the mouse genome. Dose-dependent changes in mutation frequency and spectrum quantify its role in PAH-induced carcinogenicity.

DuplexSeq is an ultra-accurate NGS technology that directly quantifies mutationsENU-dependent mutagenesis was detected 24 h post-exposure in proliferative tissuesMultiple tissues exhibited the canonical ENU mutation spectrum 7 d after exposureResults obtained with DuplexSeq were highly concordant between laboratoriesThe Rat-50 Mutagenesis Assay is promising for applications in genetic toxicology.

Glyphosate, the most heavily used herbicide world-wide, is applied to plants in complex formulations that promote absorption. The National Toxicology Program reported in 1992 that glyphosate, administered to rats and mice at doses up to 50,000 ppm in feed for 13 weeks, showed little evidence of toxicity, and no induction of micronuclei was observed in the mice in this study. Subsequently, mechanistic studies of glyphosate and glyphosate-based formulations (GBFs) that have focused on DNA damage and oxidative stress suggest that glyphosate may have genotoxic potential. However, few of these studies directly compared glyphosate to GBFs, or effects among GBFs. To address these data gaps, we tested glyphosate, glyphosate isopropylamine (IPA), and (aminomethyl)phosphonic acid (AMPA, a microbial metabolite of glyphosate), 9 high-use agricultural GBFs, 4 residential-use GBFs, and additional herbicides (metolachlor, mesotrione, and diquat dibromide) present in some of the GBFs in bacterial mutagenicity tests, and in human TK6 cells using a micronucleus assay and a multiplexed DNA damage assay. Our results showed no genotoxicity or notable cytotoxicity for glyphosate or AMPA at concentrations up to 10 mM, while all GBFs and herbicides other than glyphosate were cytotoxic, and some showed genotoxic activity. An in vitro to in vivo extrapolation of results for glyphosate suggests that it is of low toxicological concern for humans. In conclusion, these results demonstrate a lack of genotoxicity for glyphosate, consistent with observations in the NTP in vivo study, and suggest that toxicity associated with GBFs may be related to other components of these formulations.

Skin sensitization testing is a regulatory requirement for safety evaluations of pesticides in multiple countries. Globally harmonized test guidelines that include in chemico and in vitro methods reduce animal use, but no single assay is recommended as a complete replacement for animal tests. Defined approaches (DAs) that integrate data from multiple non-animal methods are accepted; however, the methods that comprise them have been evaluated using monoconstituent substances rather than mixtures or formulations. To address this data gap, we tested 27 agrochemical formulations in the direct peptide reactivity assay (DPRA), the KeratinoSens™ assay, and the human cell line activation test (h-CLAT). These data were used as inputs to evaluate three DAs for hazard classification of skin sensitization potential and two DAs for potency categorization. When compared to historical animal results, balanced accuracy for the DAs for predicting in vivo skin sensitization hazard (i.e., sensitizer vs. nonsensitizer) ranged from 56 to 78%. The best performing DA was the “2 out of 3 (2o3)” DA, in which the hazard classification was based on two concordant results from the DPRA, KeratinoSens, or h-CLAT. The KE 3/1 sequential testing strategy (STS), which uses h-CLAT and DPRA results, and the integrated testing strategy (ITSv2), which uses h-CLAT, DPRA, and an in silico hazard prediction from OECD QSAR Toolbox, had balanced accuracies of 56–57% for hazard classification. Of the individual test methods, KeratinoSens had the best performance for predicting in vivo hazard outcomes. Its balanced accuracy of 81% was similar to that of the 2o3 DA (78%). For predicting potency categories defined by the United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS), the correct classification rate of the STS was 52% and that of the ITSv2 was 43%. These results demonstrate that non-animal test methods have utility for evaluating the skin sensitization potential of agrochemical formulations as compared to animal reference data. While additional data generation is needed, testing strategies such as DAs anchored to human biology and mechanistic information provide a promising approach for agrochemical formulation testing.

The National Toxicology Program (NTP) reported that chronic exposure to varying dietary concentrations of 4-methylimidazole (4-MeI) increased lung tumors in female and male mice [1]. In this study, mice (male and female B6C3F1 mice) were either administered 4-MeI by oral gavage (0, 50, 100, 200, or 300 mg/kg/day) for 2 days or exposed for 5 and 28 days to 4-MeI in the diet (0, 150, 300, 1250, or 2500 ppm) and whole transcriptome (RNA-Sequencing) data from 4-MeI-exposed B6C3F1 mice to determine whether changes occurred in the target (lung) and nontarget (liver) tissues. This analysis was conducted to provide information with which to evaluate biological processes affected by exposure to 4-MeI, with a focus on identifying key events that could be used to propose a plausible mode of action (MoA) for mouse lung tumors [2].