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In this study, the phytotoxicity of seven metal oxide nanoparticles(NPs)—titanium dioxide (nTiO2), silicon dioxide (nSiO2), cerium dioxide (nCeO2), magnetite (nFe3O4), aluminum oxide (nAl2O3), zinc oxide (nZnO) and copper oxide (nCuO)—was assessed on two agriculturally significant crop plants (maize and rice). The results showed that seed germination was not affected by any of the seven metal oxide NPs. However, at the concentration of 2000 mg·L−1, the root elongation was significantly inhibited by nCuO (95.73% for maize and 97.28% for rice), nZnO (50.45% for maize and 66.75% for rice). On the contrary, minor phytotoxicity of nAl2O3 was only observed in maize, and no obvious toxic effects were found in the other four metal oxide NPs. By further study we found that the phytotoxic effects of nZnO, nAl2O3 and nCuO (25 to 2000 mg·L−1) were concentration dependent, and were not caused by the corresponding Cu2+, Zn2+ and Al3+ ions (0.11 mg·L−1, 1.27 mg·L−1 and 0.74 mg·L−1, respectively). Furthermore, ZnO NPs (<50 nm) showed greater toxicity than ZnO microparticles(MPs)(<5 μm) to root elongation of both maize and rice. Overall, this study provided valuable information for the application of engineered NPs in agriculture and the assessment of the potential environmental risks.

Background: Metal oxide nanoparticles (NPs) have been widely used in industry, cosmetics, and biomedicine. Objectives: We examined hazards of several well-characterized high production volume NPs because of increasing concern about occupational exposure via inhalation. Methods: A panel of well-characterized NPs [cerium oxide (CeO₂NP), titanium dioxide (TiO₂NP), carbon black (CBNP), silicon dioxide (SiO₂NP), nickel oxide (NiONP), zinc oxide (ZnONP), copper oxide (CuONP), and amine-modified polystyrene beads] was instilled into lungs of rats. We evaluated the inflammation potencies of these NPs 24 hr and 4 weeks postinstillation. For NPs that caused significant inflammation at 24 hr, we then investigated the characteristics of the inflammation. All exposures were carried out at equal-surface-area doses. Results: Only CeO₂NP, NiONP, ZnONP, and CuONP were inflammogenic to the lungs of rats at the high doses used. Strikingly, each of these induced a unique inflammatory footprint both acutely (24 hr) and chronically (4 weeks). Acutely, patterns of neutrophil and eosinophil infiltrates differed after CeO₂NP, NiONP, ZnONP, and CuONP treatment. Chronic inflammatory responses also differed after 4 weeks, with neutrophilic, neutrophilic/lymphocytic, eosinophilic/fibrotic/granulomatous, and fibrotic/granulomatous inflammation being caused respectively by CeO₂NP, NiONP, ZnONP, and CuONP. Conclusion: Different types of inflammation imply different hazards in terms of pathology, risks, and risk severity. In vitro testing could not have differentiated these complex hazard outcomes, and this has important implications for the global strategy for NP hazard assessment. Our results demonstrate that NPs cannot be viewed as a single hazard entity and that risk assessment should be performed separately and with caution for different NPs.

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control) 1 . Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors 2 . LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors 3 and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo ( P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.

Background Previous studies have reported adverse effects of either regional or near-roadway air pollution (NRAP) on lung function. However, there has been little study of the joint effects of these exposures. Objectives To assess the joint effects of NRAP and regional pollutants on childhood lung function in the Children's Health Study. Methods Lung function was measured on 1811 children from eight Southern Californian communities. NRAP exposure was assessed based on (1) residential distance to the nearest freeway or major road and (2) estimated near-roadway contributions to residential nitrogen dioxide (NO2), nitric oxide (NO) and total nitrogen oxides (NOx). Exposure to regional ozone (O3), NO2, particulate matter with aerodynamic diameter <10 µm (PM10) and 2.5 µm (PM2.5) was measured continuously at community monitors. Results An increase in near-roadway NOx of 17.9 ppb (2 SD) was associated with deficits of 1.6% in forced vital capacity (FVC) (p=0.005) and 1.1% in forced expiratory volume in 1 s (FEV1) (p=0.048). Effects were observed in all communities and were similar for NO2 and NO. Residential proximity to a freeway was associated with a reduction in FVC. Lung function deficits of 2–3% were associated with regional PM10 and PM2.5 (FVC and FEV1) and with O3 (FEV1), but not NO2 across the range of exposure between communities. Associations with regional pollution and NRAP were independent in models adjusted for each. The effects of NRAP were not modified by regional pollutant concentrations. Conclusions The results indicate that NRAP and regional air pollution have independent adverse effects on childhood lung function.

BackgroundAcute pollutant-related lung function changes among children varies across pollutants and lag periods. We examined whether short-term air pollutant fluctuations were related to daily lung function among a panel of children and whether these effects are modified by airway hyperresponsiveness, location and asthma severity.MethodsStudents from randomly selected grade 4 classrooms at seven primary schools in Durban, participated, together with asthmatic children from grades 3–6 (n=423). The schools were from high pollutant exposed communities (south) and compared with schools from communities with lower levels of pollution (north), with similar socioeconomic profiles. Interviews, spirometry and methacholine challenge testing were conducted. Bihourly lung function measurements were performed over a 3-week period in four phases. During all schooldays, students blew into their personal digital monitors every 1.5–2 hours. Nitrogen dioxide (NO2), nitrogen oxide (NO), sulphur dioxide and particulate matter (<10 μm diameter) (PM10) were measured at each school. Generalised estimating equations assessed lag effects, using single-pollutant (single or distributed lags) models.ResultsFEV1 declines ranged from 13 to 18 mL per unit increase in IQR for NO and 14–23 mL for NO2. Among the 5-day average models, a 20 mL and 30 mL greater drop in FEV1 per IQR for NO2 and NO, respectively, among those with airway hyperresponsiveness compared with those without. Effects were seen among those with normal airways.ConclusionsThis first panel study in sub-Saharan Africa, showed significant declines in lung function, in response to NO and NO2 with effects modified by airway hyperresponsiveness or persistent asthma.

Background: There has been concern regarding risks from inhalation exposure to nanoparticles (NPs). The large number of particles requiring testing means that alternative approaches to animal testing are needed. Objectives: We set out to determine whether short-term in vitro assays that assess intrinsic oxidative stress potential and membrane-damaging potency of a panel of metal oxide NPs can be used to predict their inflammogenic potency. Methods: For a panel of metal oxide NPs, we investigated intrinsic free radical generation, oxidative activity in an extracellular environment, cytotoxicity to lung epithelial cells, hemolysis, and inflammation potency in rat lungs. All exposures were carried out at equal surface area doses. Results: Only nickel oxide (NiO) and alumina 2 caused significant lung inflammation when instilled into rat lungs at equal surface area, suggesting that these two had extra surface reactivity. We observed significant free radical generation with 4 of 13 metal oxides, only one of which was inflammogenic. Only 3 of 13 were significantly hemolytic, two of which were inflammogenic. Conclusions: Potency in generating free radicals in vitro did not predict inflammation, whereas alumina 2 had no free radical activity but was inflammogenic. The hemolysis assay was correct in predicting the proinflammatory potential of 12 of 13 of the particles examined. Using a battery of simple in vitro tests, it is possible to predict the inflammogenicity of metal oxide NPs, although some false-positive results are likely. More research using a larger panel is needed to confirm the efficacy and generality of this approach for metal oxide NPs.

The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase inhibitor with MK‐2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Patients were treated with dinaciclib (6–12 mg/m2 i.v.) and MK‐2206 (60–135 mg p.o.) weekly. Tumor biopsies were performed to measure pAKT, pERK, and Ki67 at baseline and after one completed cycle (dose level 2 and beyond). Thirty‐nine patients participated in the study. The maximum tolerated doses were dinaciclib 9 mg/m2 and MK‐2206 135 mg. Treatment‐related grade 3 and 4 toxicities included neutropenia, lymphopenia, anemia, hyperglycemia, hyponatremia, and leukopenia. No objectives responses were observed. Four patients (10%) had stable disease as their best response. At the recommended dose, median survival was 2.2 months. Survival rates at 6 and 12 months were 11% and 5%, respectively. There was a nonsignificant reduction in pAKT composite scores between pretreatment and post‐treatment biopsies (mean 0.76 vs. 0.63; P = 0.635). The combination of dinaciclib and MK‐2206 was a safe regimen in patients with metastatic pancreatic cancer, although without clinical benefit, possibly due to not attaining biologically effective doses. Given the strong preclinical evidence of Ral and AKT inhibition, further studies with better tolerated agents should be considered.

The toxicity of aluminum oxide (Al 2 O 3 ), copper oxide (CuO), iron oxide (Fe 3 O 4 ), nickel oxide (NiO), zinc oxide (ZnO), and titanium dioxide (TiO 2 ) nanoparticles (NPs) on amphibians and their interaction with high temperatures, remain unknown. In this study, we investigated the survival, developmental, behavioral, and histological reactions of Bufotes viridis embryos and larvae exposed to different NPs for a duration of 10 days, using lethal concentrations (LC25%, LC50%, and LC75% mg/L) under both ambient (AT: 18 °C) and high (HT: 21 °C) temperatures. Based on LC, NiONPs > ZnONPs > CuONPs > Al 2 O 3 NPs > TiO 2 NPs > Fe 3 O 4 NPs showed the highest mortality at AT. A similar pattern was observed at HT, although mortality occurred at lower concentrations and Fe 3 O 4 NPs were more toxic than TiO 2 NPs. The results indicated that increasing concentrations of NPs significantly reduced hatching rates, except for TiO 2 NPs. Survival rates decreased, abnormality rates increased, and developmental processes slowed down, particularly for NiONPs and ZnONPs, under HT conditions. However, exposure to low concentrations of Fe 3 O 4 NPs for up to 7 days, CuONPs for up to 72 h, and NiO, ZnONPs, and TiO 2 NPs for up to 96 h did not have a negative impact on survival compared with the control group under AT. In behavioral tests with larvae, NPs generally induced hypoactivity at AT and hyperactivity at HT. Histological findings revealed liver and internal gill tissue lesions, and an increase in the number of melanomacrophage centers at HT. These results suggest that global warming may exacerbate the toxicity of metal oxide NPs to amphibians, emphasizing the need for further research and conservation efforts in this context.

Nanomaterials or nanoparticles are commonly used in the cosmetics, medicine, and food industries. Many researchers studied the possible side effects of several nanoparticles including aluminum oxide (Al2O3-nps) and zinc oxide nanoparticles (ZnO-nps). Although, there is limited information available on their direct or side effects, especially on the brain, heart, and lung functions. This study aimed to investigate the neurotoxicity, cardiotoxicity, and lung toxicity induced by Al2O3-nps and ZnO-nps or in combination via studying changes in gene expression, alteration in cytokine production, tumor suppressor protein p53, neurotransmitters, oxidative stress, and the histological and morphological changes. Obtained results showed that Al2O3-nps, ZnO-nps and their combination cause an increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG), cytokines, p53, oxidative stress, creatine kinase, norepinephrine, acetylcholine (ACh), and lipid profile. Moreover, significant changes in the gene expression of mitochondrial transcription factor-A (mtTFA) and peroxisome proliferator activator receptorgamma- coactivator-1α (PGC-1α) were also noted. On the other hand, a significant decrease in the levels of antioxidant enzymes, total antioxidant capacity (TAC), reduced glutathione (GSH), paraoxonase 1 (PON1), neurotransmitters (dopamine - DA, and serotonin - SER), and the activity of acetylcholine esterase (AChE) in the brain, heart, and lung were found. Additionally, these results were confirmed by histological examinations. The present study revealed that the toxic effects were more when these nanoparticle doses are used in combination. Thus, Al2O3-nps and ZnO-nps may behave as neurotoxic, cardiotoxic, and lung toxic, especially upon exposure to rats in combination.

Background A standard short-term inhalation study (STIS) was applied for hazard assessment of 13 metal oxide nanomaterials and micron-scale zinc oxide. Methods Rats were exposed to test material aerosols (ranging from 0.5 to 50 mg/m 3 ) for five consecutive days with 14- or 21-day post-exposure observation. Bronchoalveolar lavage fluid (BALF) and histopathological sections of the entire respiratory tract were examined. Pulmonary deposition and clearance and test material translocation into extra-pulmonary organs were assessed. Results Inhaled nanomaterials were found in the lung, in alveolar macrophages, and in the draining lymph nodes. Polyacrylate-coated silica was also found in the spleen, and both zinc oxides elicited olfactory epithelium necrosis. None of the other nanomaterials was recorded in extra-pulmonary organs. Eight nanomaterials did not elicit pulmonary effects, and their no observed adverse effect concentrations (NOAECs) were at least 10 mg/m 3 . Five materials (coated nano-TiO 2 , both ZnO, both CeO 2 ) evoked concentration-dependent transient pulmonary inflammation. Most effects were at least partially reversible during the post-exposure period. Based on the NOAECs that were derived from quantitative parameters, with BALF polymorphonuclear (PMN) neutrophil counts and total protein concentration being most sensitive, or from the severity of histopathological findings, the materials were ranked by increasing toxic potency into 3 grades: lower toxic potency: BaSO 4 ; SiO 2 .acrylate (by local NOAEC); SiO 2 .PEG; SiO 2 .phosphate; SiO 2 .amino; nano-ZrO 2 ; ZrO 2 .TODA; ZrO 2 .acrylate; medium toxic potency: SiO 2 .naked; higher toxic potency: coated nano-TiO 2 ; nano-CeO 2 ; Al-doped nano-CeO 2 ; micron-scale ZnO; coated nano-ZnO (and SiO 2 .acrylate by systemic no observed effect concentration (NOEC)). Conclusion The STIS revealed the type of effects of 13 nanomaterials, and micron-scale ZnO, information on their toxic potency, and the location and reversibility of effects. Assessment of lung burden and material translocation provided preliminary biokinetic information. Based upon the study results, the STIS protocol was re-assessed and preliminary suggestions regarding the grouping of nanomaterials for safety assessment were spelled out.