Occupational exposure risk during spraying of biocidal paint containing silver nanoparticles.

The study assessed potential to exceed occupational exposure limits while spraying paint with and without a silver nanoparticle biocidal additive. A tradesperson performed the tasks in a sealed chamber with filtered air supply. Integrated air sampling entailed transmission electron microscopy with energy dispersive X-ray analysis, direct-reading of particle number concentrations, and determination of silver mass concentration by NIOSH Method 7300. Silver nanoparticles were primarily embedded in paint spray droplets but also observed as isolated particles. Using an α-level of 0.05, median nanoparticle number concentrations did not differ significantly when spraying conventional vs. biocidal paint, although statistically significant differences were observed at specific particle size ranges <100 nm. The geometric mean concentration of total silver while spraying biocidal paint (n = 6) was 2.1 µg/m3 (95% CI: 1.5-2.8 µg/m3), and no respirable silver was detected (<0.50 µg/m3). The results address a lack of silver nanoparticle exposure data in construction and demonstrate the feasibility of a practical sampling approach. Given similar conditions, the measurements suggest a low probability of exceeding a proposed silver nanoparticle exposure limit of 0.9 µg/m3 as an airborne 8-hr time-weighted average respirable mass concentration. A full workday of exposure to respirable silver at the highest possible level in this study (<0.50 µg/m3) would not exceed the exposure limit, although limitations in comparing short task-based exposures to an 8-hr exposure limit must be noted. There was airflow in the study chamber, whereas exposure levels could increase over time in work environments lacking adequate ventilation. Potential to exceed the exposure limit hinged upon the respirable fraction of the paint mist, which could vary by material and application method. Additional research would improve understanding of silver nanoparticle exposure risks among construction trades, and biological responses to these exposures. Given the potential for exposure variability on construction jobsites, safety and health professionals should be cognizant of methods to assess and control silver nanoparticle exposures.

Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.

In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).

Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics.

Tandutinib (MLN518/CT53518) is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases: FMS-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor (PDGFR), and KIT. Because of the correlation between FLT3 internal tandem duplication (ITD) mutations and poor prognosis in acute myelogenous leukemia (AML), we conducted a phase 1 trial of tandutinib in 40 patients with either AML or high-risk myelodysplastic syndrome (MDS). Tandutinib was given orally in doses ranging from 50 mg to 700 mg twice daily The principal dose-limiting toxicity (DLT) of tandutinib was reversible generalized muscular weakness, fatigue, or both, occurring at doses of 525 mg and 700 mg twice daily. Tandutinib's pharmacokinetics were characterized by slow elimination, with achievement of steady-state plasma concentrations requiring greater than 1 week of dosing. Western blotting showed that tandutinib inhibited phosphorylation of FLT3 in circulating leukemic blasts. Eight patients had FLT3-ITD mutations; 5 of these were evaluable for assessment of tandutinib's antileukemic effect. Two of the 5 patients, treated at 525 mg and 700 mg twice daily, showed evidence of antileukemic activity, with decreases in both peripheral and bone marrow blasts. Tandutinib at the MTD (525 mg twice daily) should be evaluated more extensively in patients with AML with FLT3-ITD mutations to better define its antileukemic activity.