No abstract

Two-year treatment with high doses of Metofluthrin produced hepatocellular tumors in both sexes of Wistar rats. To understand the mode of action (MOA) by which the tumors are produced, a series of studies examined the effects of Metofluthrin on hepatic microsomal cytochrome P450 (CYP) content, hepatocellular proliferation, hepatic gap junctional intercellular communication (GJIC), oxidative stress and apoptosis was conducted after one or two weeks of treatment. The global gene expression profile indicated that most genes with upregulated expression with Metofluthrin were metabolic enzymes that were also upregulated with phenobarbital. Metofluthrin induced CYP2B and increased liver weights associated with centrilobular hepatocyte hypertrophy (increased smooth endoplasmic reticulum [SER]), and induction of increased hepatocellular DNA replication. CYP2B1 mRNA induction by Metofluthrin was not observed in CAR knockdown rat hepatocytes using the RNA interference technique, demonstrating that Metofluthrin induces CYP2B1 through CAR activation. Metofluthrin also suppressed hepatic GJIC and induced oxidative stress and increased antioxidant enzymes, but showed no alteration in apoptosis. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. All of these effects were reversible upon cessation of treatment. Metofluthrin did not cause cytotoxicity or peroxisome proliferation. Thus, it is highly likely that the MOA for Metofluthrin-induced liver tumors in rats is through CYP induction and increased hepatocyte proliferation, similar to that seen for phenobarbital. Based on analysis with the International Life Sciences Institute/Risk Science Institute MOA framework, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans, at least at expected levels of exposure.

Prior to the practical application of rechargeable aprotic Li−O 2 batteries, the high charging overpotentials of these devices (which inevitably cause irreversible parasitic reactions) must be addressed. The use of redox mediators (RMs) that oxidatively decompose the discharge product, Li 2 O 2 , is one promising solution to this problem. However, the mitigating effect of RMs is currently insufficient, and so it would be beneficial to clarify the Li 2 O 2 reductive growth and oxidative decomposition mechanisms. In the present work, Nanoscale secondary ion mass spectrometry (Nano-SIMS) isotopic three-dimensional imaging and differential electrochemical mass spectrometry (DEMS) analyses of individual Li 2 O 2 particles established that both growth and decomposition proceeded at the Li 2 O 2 /electrolyte interface in a system containing the Br − /Br 3 − redox couple as the RM. The results of this study also indicated that the degree of oxidative decomposition of Li 2 O 2 was highly dependent on the cell voltage. These data show that increasing the RM reaction rate at the Li 2 O 2 /electrolyte interface is critical to improve the cycle life of Li−O 2 batteries.

Data-driven material discovery has recently become popular in the field of next-generation secondary batteries. However, it is important to obtain large, high quality data sets to apply data-driven methods such as evolutionary algorithms or Bayesian optimization. Combinatorial high-throughput techniques are an effective approach to obtaining large data sets together with reliable quality. In the present study, we developed a combinatorial high-throughput system (HTS) with a throughput of 400 samples/day. The aim was to identify suitable combinations of additives to improve the performance of lithium metal electrodes for use in lithium batteries. Based on the high-throughput screening of 2002 samples, a specific combination of five additives was selected that drastically improved the coulombic efficiency (CE) of a lithium metal electrode. Importantly, the CE was remarkably decreased merely by removing one of these components, highlighting the synergistic basis of this mixture. The results of this study show that the HTS presented herein is a viable means of accelerating the discovery of ideal yet complex electrolytes with multiple components that are very difficult to identify via conventional bottom-up approach.

Various electrolyte components have been investigated with the aim of improving the cycle life of lithium−oxygen (Li−O 2 ) batteries. A tetraglymebased electrolyte containing dual anions of Br − and NO 3 − is a promising electrolyte system in which the cell voltage during charging is reduced because of the redox-mediator function of the Br − /Br 3 − and NO 2 − /NO 2 couples, while the Li-metal anode is protected by Li 2 O formed via the reaction between Li metal and NO 3− . To maximize the potential of this system, the fundamental factors that limit the cycle life should be clarified. In the present work, we used nondestructive electrochemical impedance spectroscopy to analyze the temporal change of the charge transfer resistances during cycles of Li−O 2 batteries with dual anions. The charge transfer resistance at the cathode was revealed to exhibit good correlation with the reduction of the discharge voltage. These results, combined with the results of electrode surface inspections, revealed that irreversible accumulation of insulating deposits such as Li 2 O 2 and Li 2 CO 3 on the cathode surface was a major cause of the short cycle life. Furthermore, the analyses of the time course of the solution resistance suggested that diminished reactivity between the redox mediators and Li 2 O 2 was a critical factor that led to the irreversible accumulation of the lessreactive Li 2 O 2 on the cathode and eventually to a shortened cycle life. These findings indicated that increasing the reactivity between Br 3 − and Li 2 O 2 is essentially important for improving the cycle stability of Li−O 2 batteries and the reactivity can be nondestructively assessed by tracking the dynamic changes in the solution resistance.