Kinetics of Glutathione Depletion and Antioxidant Gene Expression as Indicators of Chemical Modes of Action Assessed in Vitro in Mouse Hepatocytes with Enhanced Glutathione Synthesis.

Here we report a vertically integrated in vitro - in silico study that aims to elucidate the molecular initiating events involved in the induction of oxidative stress (OS) by seven diverse chemicals (cumene hydroperoxide, t-butyl hydroperoxide, hydroquinone, t-butyl hydroquinone, bisphenol A, Dinoseb, and perfluorooctanoic acid). To that end, we probe the relationship between chemical properties, cell viability, glutathione (GSH) depletion, and antioxidant gene expression. Concentration-dependent effects on cell viability were assessed by MTT assay in two Hepa-1 derived mouse liver cell lines: a control plasmid vector transfected cell line (Hepa-V), and a cell line with increased glutamate-cysteine ligase (GCL) activity and GSH content (CR17). Changes to intracellular GSH content and mRNA expression levels for the Nrf2-driven antioxidant genes Gclc, Gclm, heme oxygenase-1 ( Hmox1), and NADPH quinone oxidoreductase-1 ( Nqo1) were monitored after sublethal exposure to the chemicals. In silico models of covalent and redox reactivity were used to rationalize differences in activity of quinones and peroxides. Our findings show CR17 cells were generally more resistant to chemical toxicity and showed markedly attenuated induction of OS biomarkers; however, differences in viability effects between the two cell lines were not the same for all chemicals. The results highlight the vital role of GSH in protecting against oxidative stress-inducing chemicals as well as the importance of probing molecular initiating events in order to identify chemicals with lower potential to cause oxidative stress.

Revisions to Acute/Off-Nominal Limits for Benzene in Spacecraft Air.

BACKGROUND: The previous short-term (1-h and 24-h) Spacecraft Maximal Allowable Concentrations (SMACs) for benzene were established at 10 and 3 ppm by NASA in 1996, based on a study of mice in which no hematological effects were noted following two 6-h exposures to benzene. When the benzene SMACs were updated in 2008, there was no revision to the short-term SMAC limits. Rather, that effort developed a long-term SMAC (1000-d) for Exploration mission scenarios.Acute benzene exposures can cause numerous neurological effects, and long-term exposure to low levels is well-known to cause acute myeloid leukemia. Since publication of the original benzene SMACs, the National Academy of Sciences developed interim Acute Exposure Guideline Limits (AEGLs) for unintentional releases of benzene into the air. Based on the data used to establish the AEGLs, we have increased our short-term, off-nominal limits for benzene in crewed spacecraft to 40 ppm and 6.7 ppm for 1-h and 24-h, respectively.Ryder VE, Williams ES. Revisions to acute/off-nominal limits for benzene in spacecraft air. Aerosp Med Hum Perform. 2023; 94(7):544-545.