Is the Arrhenius-correction of biodegradation rates, as recommended through REACH guidance, fit for environmentally relevant conditions? An example from petroleum biodegradation in environmental systems.

Biodegradation is a major determinant of chemical persistence in the environment and an important consideration for PBT and environmental risk assessments. It is influenced by several environmental factors including temperature and microbial community structure. According to REACH guidance, a temperature correction based on the Arrhenius equation is recommended for chemical persistence data not performed at the recommended EU mean surface water temperature. Such corrections, however, can lead to overly conservative P/vP assessments. In this paper, the relevance of this temperature correction is assessed for petroleum hydrocarbons, using measured surface water (marine and freshwater) degradation half-time (DT50) and degradation half-life (HL) data compiled from relevant literature. Stringent screening criteria were used to specifically select data from biodegradation tests containing indigenous microbes and conducted at temperatures close to their ambient sampling temperature. As a result, ten independent studies were identified, with 993 data points covering 326 hydrocarbon constituents. These data were derived from tests conducted with natural seawater, or freshwater, at temperatures ranging from 5 to 21 °C. Regressions were performed on the full hydrocarbon dataset and on several individual hydrocarbons. The results were compared to the trend as predicted by the Arrhenius equation and using the activation energy (Ea) as recommend in the REACH Guidance. The comparison shows that the correction recommended in REACH Guidance over predicts the effect of temperature on hydrocarbon biodegradation. These results contrast with temperature manipulated inocula where the test temperature is different from the ambient sampling temperature. In these manipulated systems, the effect of temperature follows the Arrhenius equation more closely. In addition, a more striking effect of temperature on the lag phase was observed with longer lag phases more apparent at lower temperatures. This indicates that the effect of temperature may indeed be even lower when considering hydrocarbon biodegradation without the initial lag phase.

Biodegradability assessment of complex, hydrophobic substances: Insights from gas-to-liquid (GTL) fuel and solvent testing.

The assessment of substances of Unknown or Variable composition, Complex reaction products or Biological materials (UVCBs) presents significant challenges when determining biodegradation potential and environmental persistence for regulatory purposes. An example of UVCBs is the gas-to-liquid (GTL) products, which are synthetic hydrocarbons produced from natural gas using a catalytic process known as the Fischer-Tropsch process. These synthetic hydrocarbons are fractionated into a wide array of products equivalent in function to their petroleum-derived analogues. Here we summarise the results of an extensive testing program to assess the biodegradability of several GTL products. This program highlights the challenges associated with UVCBs and provides a case study for the assessment of such substances that are also poorly soluble and volatile. When tested with the appropriate methods, all the GTL products assessed in this study were found to be readily biodegradable indicating they are not likely to be persistent in the environment.

In-Office Tympanostomy Tube Placement in Children Using Iontophoresis and Automated Tube Delivery.

OBJECTIVES/HYPOTHESIS: Evaluate technical success, tolerability, and safety of lidocaine iontophoresis and tympanostomy tube placement for children in an office setting. STUDY DESIGN: Prospective individual cohort study. METHODS: This prospective multicenter study evaluated in-office tube placement in children ages 6 months through 12 years of age. Anesthesia was achieved via lidocaine/epinephrine iontophoresis. Tube placement was conducted using an integrated and automated myringotomy and tube delivery system. Anxiolytics, sedation, and papoose board were not used. Technical success and safety were evaluated. Patients 5 to 12 years old self-reported tube placement pain using the Faces Pain Scale-Revised (FPS-R) instrument, which ranges from 0 (no pain) to 10 (very much pain). RESULTS: Children were enrolled into three cohorts with 68, 47, and 222 children in the Operating Room (OR) Lead-In, Office Lead-In, and Pivotal cohorts, respectively. In the Pivotal cohort, there were 120 and 102 children in the <5 and 5- to 12-year-old age groups, respectively, with a mean age of 2.3 and 7.6 years, respectively. Bilateral tube placement was indicated for 94.2% of children <5 and 88.2% of children 5 to 12 years old. Tubes were successfully placed in all indicated ears in 85.8% (103/120) of children <5 and 89.2% (91/102) of children 5 to 12 years old. Mean FPS-R score was 3.30 (standard deviation [SD] = 3.39) for tube placement and 1.69 (SD = 2.43) at 5 minutes postprocedure. There were no serious adverse events. Nonserious adverse events occurred at rates similar to standard tympanostomy procedures. CONCLUSIONS: In-office tube placement in selected patients can be successfully achieved without requiring sedatives, anxiolytics, or papoose restraints via lidocaine iontophoresis local anesthesia and an automated myringotomy and tube delivery system. LEVEL OF EVIDENCE: 2b Laryngoscope, 130:S1-S9, 2020.

Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short-term inhalation exposure to copper oxide nanoparticles.

Our recent studies revealed a dose-dependent proinflammatory response to copper oxide nanoparticles (CuO NPs) in rats following short-term inhalation exposure for five consecutive days. Here transcriptomics approaches were applied using the same model to assess global gene expression in lung tissues obtained 1 day post-exposure and after a recovery period of 22 days from rats exposed to clean air or 6 hour equivalent doses of 3.3 mg m-3 (low dose) and 13.2 mg m-3 (high dose). Microarray analyses yielded about 1000 differentially expressed genes in the high-dose group and 200 in low-dose compared to the clean air control group, and less than 20 after the recovery period. Pathway analysis indicated cell proliferation/survival and inflammation as the main processes triggered by exposure to CuO NPs. We did not find significant perturbations of pathways related to oxidative stress. Upregulation of epithelial cell transforming protein 2 (Ect2), a known oncogene, was noted and ECT2 protein was upregulated in the lungs of exposed animals. Proliferation of alveolar epithelial cells was demonstrated based on Ki67 expression. The gene encoding monocyte chemoattractant protein 1 (or CCL2) was also upregulated and this was confirmed by immunohistochemistry. However, no aberrant DNA methylation of inflammation-associated genes was observed. In conclusion, we have found that inhalation of CuO NPs in rats causes upregulation of the oncoprotein ECT2 and the chemokine CCL2 and other proinflammatory markers as well as proliferation in bronchoalveolar epithelium after a short-term inhalation exposure. Thus, pathways known to be associated with neoplastic processes and inflammation were affected in this model.

Serum enhanced cytokine responses of macrophages to silica and iron oxide particles and nanomaterials: a comparison of serum to lung lining fluid and albumin dispersions.

The potential hazard to humans exposed to nanomaterials such as silica and iron oxide was investigated using an in vitro macrophage cell culture system. Amorphous silica and iron oxide particles and nanomaterials (NMs) were dispersed in cell culture medium supplemented with either bovine serum albumin (BSA), lung lining fluid (LLF) or serum, in order to mimic the body fluids encountered during different routes of exposure in the body. End points investigated included macrophage viability and cytokine production. Silica NMs and particles (50 and 200 nm, respectively) were unmodified (plain) or aminated (NH2 ). Iron oxide NMs and particles, Fe3 O4 45 nm and Fe2 O3 280 nm were also used in this study. Silica particles and NMs induced a dose-dependent increase in cytotoxicity as measured by lactate dehydrogenase (LDH) release. Serum enhanced silica-induced interleukin (IL)-6, IL-10, IL-1ß and MCP-1 release, whereas albumin partially inhibited MCP-1 release. Aminated silica, 50 nm was more potent than the 200-nm particles at inducing monocyte chemoattractant protein-1 (MCP-1) production when dispersed in medium or LLF, suggesting a size specific effect for these particles and this cytokine. Iron oxide particles were relatively inert compared with the silica particles and NMs; however, serum and albumin did affect cytokine release in some treatments. In conclusion, the data suggests that serum, compared with medium, BSA and LLF is very potent at enhancing macrophage responses to silica and iron oxide particles and NMs. Size was only influential in LLF for a limited number of parameters, whereas surface chemistry was not of consequence in this in vitro macrophage system.

Inspiratory loading intensity does not influence lactate clearance during recovery.

PURPOSE: This study examined the effects of different pressure threshold inspiratory loads on lactate clearance and plasma acid-base balance during recovery from maximal exercise. METHODS: Eight moderately trained males (V˙O(2peak) = 4.29 ± 0.46 L·min⁻¹) performed, on different days, four maximal incremental cycling tests (power started at 0 W and increased by 20 W·min⁻¹) of identical duration (exercise time during the first trial was 16.32 ± 1.12 min). During 20-min recovery, subjects either rested passively or breathed through a constant pressure threshold inspiratory load of 10 (ITL10), 15 (ITL15), or 20 (ITL20) cm H2O. Plasma lactate concentration ([La⁻]) was measured, and acid-base balance was quantified using the physicochemical approach, which describes the dependency of [H⁺] on the three independent variables: strong ion difference ([Na⁺] + [K⁺] - [Cl⁻] + [La⁻]), the total concentration of weak acids, and the partial pressure of carbon dioxide. RESULTS: Peak exercise responses were not significantly different between trials. During recovery, the area under the plasma [La] curve was not different between trials (pooled mean = 261 ± 60 mEq) and the [La] measured at the end of the 20-min recovery was also similar (passive recovery = 9.2 ± 3.1 mEq·L⁻¹, ITL10 = 9.3 ± 3.1 mEq·L⁻¹, ITL15 = 8.7 ± 2.8 mEq·L⁻¹, ITL20 = 8.7 ± 3.2 mEq·L⁻¹). Similarly, changes in other strong ions contributing to strong ion difference and total concentration of weak acids, partial pressure of carbon dioxide, and, therefore, [H⁺] were not different between trials. CONCLUSIONS: These data suggest that, in individuals of moderate endurance training status, inspiratory loading at the intensities used in the present study does not accelerate lactate clearance or modify plasma acid-base balance during recovery from maximal exercise.

Original sound compositions reduce anxiety in emergency department patients: a randomised controlled trial.

OBJECTIVE: To determine whether emergency department (ED) patients' self-rated levels of anxiety are affected by exposure to purpose-designed music or sound compositions with and without the audio frequencies of embedded binaural beat. DESIGN, SETTING AND PARTICIPANTS: Randomised controlled trial in an ED between 1 February 2010 and 14 April 2010 among a convenience sample of adult patients who were rated as category 3 on the Australasian Triage Scale. INTERVENTIONS: All interventions involved listening to soundtracks of 20 minutes' duration that were purpose-designed by composers and sound-recording artists. Participants were allocated at random to one of five groups: headphones and iPod only, no soundtrack (control group); reconstructed ambient noise simulating an ED but free of clear verbalisations; electroacoustic musical composition; composed non-musical soundtracks derived from audio field recordings obtained from natural and constructed settings; sound composition of audio field recordings with embedded binaural beat. All soundtracks were presented on an iPod through headphones. Patients and researchers were blinded to allocation until interventions were administered. State-trait anxiety was self-assessed before the intervention and state anxiety was self-assessed again 20 minutes after the provision of the soundtrack. MAIN OUTCOME MEASURE: Spielberger State-Trait Anxiety Inventory. RESULTS: Of 291 patients assessed for eligibility, 170 patients completed the pre-intervention anxiety self-assessment and 169 completed the post-intervention assessment. Significant decreases (all P < 0.001) in anxiety level were observed among patients exposed to the electroacoustic musical composition (pre-intervention mean, 39; post-intervention mean, 34), audio field recordings (42; 35) or audio field recordings with embedded bianaural beats (43; 37) when compared with those allocated to receive simulated ED ambient noise (40; 41) or headphones only (44; 44). CONCLUSION: In moderately anxious ED patients, state anxiety was reduced by 10%-15% following exposure to purpose-designed sound interventions. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN 12608000444381.

Triphendiol (NV-196), development of a novel therapy for pancreatic cancer.

Despite incremental progress in the treatment of pancreatic adenocarcinoma, the prognosis of patients remains poor. Here, we report the preclinical studies in pancreatic cancer cells that demonstrate the efficacy of triphendiol (NV-196, a synthetic isoflavene) both as a monotherapy and as a gemcitabine sensitizer. The in-vitro effects of triphendiol on the pancreatic cancer cell lines HPAC and MIAPaCa-2 were determined using cell proliferation, flow cytometry, and western blot analysis. The antiproliferative activity of triphendiol was also investigated in two xenograft models of pancreatic cancer (HPAC and MIAPaCa-2). As a monotherapy, triphendiol-inhibited cell proliferation-induced p53-independent G2/M cell cycle arrest and activation of the intrinsic (mitochondrial) apoptosis pathway. Triphendiol-induced apoptosis was caspase independent and death receptor independent, whereas cell necrosis was caspase mediated. Using combination index analysis, we have shown that pretreatment of pancreatic cancer cells with triphendiol enhanced the cytotoxic effect of gemcitabine, the standard of care used to treat advanced pancreatic cancer. In xenograft models of pancreatic cancer, the rate of tumor proliferation on mice coadministered with triphendiol and gemcitabine was significantly reduced when compared with the corresponding tumor proliferation rates from the respective monotherapy-control and vehicle-control groups. Triphendiol was recently granted Investigational New Drug status by the US Food and Drug Administration. These data justify the commencement of clinical studies investigating the utility of combining triphendiol and gemcitabine in patients with early-stage and late-stage pancreatic cancer.