Toxicity Ratio Research Articles

Combined toxicity of imidacloprid, acetochlor, and tebuconazole to zebrafish (Danio rerio): acute toxicity and hepatotoxicity assessment.

Compound pollution refers to two or more kinds of pollutants with different properties, a pollutant from different sources, or the simultaneous existence of two or more different types of pollutants in the same environment. In this study, we aimed to investigate the individual and combined toxicity of the insecticide imidacloprid (IMI), the herbicide acetochlor (ACT), and the fungicide tebuconazole (TBZ) to zebrafish. The acute toxicity test results showed that the 96-h LC50 values of IMI, ACT, and TBZ were 276.84 (259.62-294.35)mg active ingredient (a.i.)L-1, 1.52 (1.34-1.74)mg a.i.L-1, and 8.16 (7.7-8.6)mg a.i.L-1, respectively. The combinations of IMI, ACT, and TBZ with toxicity ratios of 1:2:2, 1:4:4, 2:4:1, and 4:1:4 displayed synergistic toxic effects on zebrafish, while the toxicity ratios of 1:1:1, 1:1:2, 2:1:2, 2:2:1, and 4:2:1 of IMI, ACT, and TBZ, respectively, exhibited antagonistic toxic effects on zebrafish. The following experiments were performed with a toxicity ratio of 1:4:4 (IMI:ACT:TBZ). The activities of four enzyme biomarkers related to oxidative stress in the liver, catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), and malondialdehyde (MDA) content were evaluated in each exposure group on days 7, 14, 21, and 28. Compared with those of the control group, the activities of CAT, SOD, and GST and the MDA content were significantly altered at different time points in the individual and combined exposure groups. Additionally, the activities of CAT, SOD, and GST and the MDA content were significantly altered in the combined group compared with those of the individual group after 14days or 21days of exposure. Therefore, it was confirmed that combined toxicity studies are indispensable in risk assessment. Graphical abstract .

A quantitative structure-activity relationships approach to predict the toxicity of narcotic compounds to aquatic communities.

Species may vary markedly in terms of their sensitivity to toxicants, and such variation can be described through the species sensitivity distribution (SSD) approach. Using SSD cumulative functions, it is possible to calculate the hazardous concentration for 5% of the species (HC5), namely the contaminant concentration at which 5% of species will be affected. HC5 is often utilised to derive the predicted no-effect concentration, or the concentration at which a chemical will likely have no toxic effects on the different species present in an ecosystem. However, the lack of sufficient ecotoxicological data frequently obstructs the derivation of SSD curves and consequently the HC5. In the last 30 years, quantitative structure-activity relationship (QSAR) models have been widely used to predict the toxicity of chemicals to single species. The aim of this study was to evaluate the possibility of extending the applicability domain of these models from single species to the community level by predicting the HC5 values for aquatic communities and bypassing the need to derive SSD curves. This approach's practical advantage is that it would allow information on the toxicity of contaminants to be obtained on a hierarchical scale (aquatic community), which is ecologically more relevant than on the scale of single species, without the need for a robust toxicity data set. In the first part of the study, two simple QSAR models were developed for narcotic and polar narcotic compounds. Then, the QSAR model developed for narcotic compounds was utilised to define the baseline toxicity for aquatic communities and to calculate the toxicity ratios for various specifically acting compounds (insecticides and herbicides).

Ultrasound-Sensitive Liposomes for Triggered Macromolecular Drug Delivery: Formulation and In Vitro Characterization.

Mistletoe lectin-1 (ML1) is a nature-derived macromolecular cytotoxin that potently induces apoptosis in target cells. Non-specific cytotoxicity to normal cells is one of the major risks in its clinical application, and we therefore propose to encapsulate ML1 in a nanocarrier that can specifically release its cargo intratumorally, thus improving the efficacy to toxicity ratio of the cytotoxin. We investigated the encapsulation of ML1 in ultrasound-sensitive liposomes (USL) and studied its release by high-intensity focused ultrasound (HAccessedIFU). USL were prepared by entrapment of perfluorocarbon nanodroplets in pegylated liposomes. The liposomes were prepared with different DPPC/cholesterol/DSPE-PEG2000 lipid molar ratios (60/20/20 for USL20; 60/30/10 for USL10; 65/30/5 for USL5) before combination with perfluorocarbon (PFC) nanoemulsions (composed of DPPC and perfluoropentane). When triggered with HIFU (peak negative pressure, 2–24 MPa; frequency, 1.3 MHz), PFC nanodroplets can undergo phase transition from liquid to gas thus rupturing the lipid bilayer of usl. Small unilamellar liposomes were obtained with appropriate polydispersity and stability. ML1 and the model protein horseradish peroxidase (HRP) were co-encapsulated with the PFC nanodroplets in USL, with 3% and 7% encapsulation efficiency for USL20 and USL10/USL5, respectively. Acoustic characterization experiments indicated that release is induced by cavitation. HIFU-triggered release of HRP from USL was investigated for optimization of liposomal composition and resulted in 80% triggered release for USL with USL10 (60/30/10) lipid composition. ML1 release from the final USL10 composition was also 80%. Given its high stability, suitable release, and ultrasound sensitivity, USL10 encapsulating ML1 was further used to study released ML1 bioactivity against murine CT26 colon carcinoma cells. Confocal live-cell imaging demonstrated its functional activity regarding the interaction with the target cells. We furthermore demonstrated the cytotoxicity of the released ML1 (I.E., After USL were treated with HIFU). The potent cytotoxicity (IC50 400 ng/ml; free ML1 IC50 345 ng/ml) was compared to non-triggered USL loaded with ML1. Our study shows that USL in combination with HIFU hold promise as trigger-sensitive nanomedicines for local delivery of macromolecular cytotoxins.

Synthesis, characterization and in vitro toxicity evaluation of doxorubicin-loaded magnetoliposomes on MCF-7 breast cancer cell line

Nanoparticles improve the biodistribution and tumor accumulation of chemotherapeutic drugs boosting the ratio of efficacy and toxicity. One of the promising approaches in cancer treatment is the use of theranostic devices which enable simultaneous diagnosis and therapy of the disease. Recently, iron oxide nanoparticles have attracted increasing attention in cancer therapy, diagnosis, and smart drug delivery. This study is dedicated to introduce a modified coprecipitation method for the synthesis of magnetic iron oxide nanoparticle. Monodispersed biocompatible superparamagnetic iron oxide nanoparticles were successfully synthesized without any significant reduction in the saturation magnetization. The synthesized iron oxide nanoparticles and doxorubicin were passively encapsulated into PEGylated liposomes resulting in stable soluble magnetoliposomes with the size of about 100 nm. The cytotoxicity of doxorubicin loaded magnetoliposomes was investigated on MCF-7 cells.

Application of various cytotoxic endpoints for the toxicity prioritization of fine dust (PM2.5) sources using a multi-criteria decision-making approach.

Fine dust (PM2.5) is generated from various sources, and many studies have reported on the sources of PM2.5. However, the current research on PM2.5 toxicity based on its sources is insufficient. In this study, we developed a framework for the prioritization of fine dust (PM2.5) sources on the basis of the multi-endpoint toxicities using the multi-criteria decision-making method (MCDM). To obtain the multi-endpoint toxicities of PM2.5 sources, cell mortality, reactive oxygen species (ROS), inflammation and mutagenicity were measured for diesel exhaust particles (DEP), gasoline exhaust particles (GEP), rice straw burning particles (RBP), coal combustion particles (CCP) and tunnel dust particles (TDP). The integrative toxicity score (ITS) of the PM2.5 source was calculated using MCDM, which consist of four steps: (1) defining the decision-making matrix, (2) normalization and weighting, (3) calculating the ITS (linear aggregation) and (4) a global sensitivity analysis. The indicator of cell mortality had the highest weight (0.3780) followed by inflammation (0.2471), ROS (0.2178) and mutagenicity (0.1571). Additionally, the ITS based on the sources contributing to PM2.5 resulted in the following order: DEP (0.89), GEP (0.44), RBP (0.40), CCP (0.23) and TDP (0.06). The relative toxicity index (RTI), which represents the ratio of toxicity due to the difference in sources, increases as the contribution of the highly toxic sources increases. The RTI over 1 is closely associated with an increased contribution from highly toxic sources, such as diesel exhaust, gasoline exhaust and biomass burning. It is necessary to investigate the toxicity of various PM2.5 sources and PM2.5 risk based on the sources.

Analysis of local control rate and toxicity of radiotherapy dose of cervical cancer.

136 Background: The standard of care for treatment of advanced cervical cancer is the combination of external beam radiation therapy (EBRT) and intracavitary brachytherapy with cisplatin based concurrent chemotherapy. Radiotherapy plays a crucial role in treatment of cervical cancer. Recent GEC-ESTRO guidelines recommend that the dose to 90% (D90) of the high-risk clinical target volume (HRCTV) in cervical cancer be at least 85Gy with higher doses for poor response to radiotherapy. This study was aim to analyze our institution’s patients with locally advanced cervical cancer in regards to whether higher brachytherapy dose delivery lead to a better outcome, and to investigate the proper dose to balance the local control rate and toxicity. Methods: A total of 262 patients with local advanced cervical cancer treated at a single institution were retrospectively analyzed for the association between dosimetry and outcomes. Youden index was used to identify the optimal cut-off point of continuous tumor parameters and divide patients into subgroups. Significance of radiotherapy dose parameters on OS, PFS, LRFS and DMFS and toxicity was evaluated. Results: In the univariate analysis, for both HR-CTV and LR-CTV, the high dose group (EQD2 D90 >75Gy, LR-CTV>68Gy, respectively) have a better LRFS than low-dose groups (P<0.05). LR-CTV remains significance after adjusted for age and FIGO stage. Moreover, in the high-dose LR-CTV group, there is no association between dose of LR-CTV and LRFS was found, however, higher dose of HR-CTV significant associated with higher ratio of side effect was found. In addition, no association of dose of HR-CTV or LR-CTV and OS were found for all patients. Conclusions: Our results showed that dose of LR-CTV may be a useful prognostic factor of LRFS of patients with cervical cancer. Moreover, after D90 of LR-CTV reaches 68Gy, increasing dose did not show a better LRFS but lead to higher ratio of toxicity, supporting that LR-CTV at 68Gy might be a safety and efficacy dose of radiotherapy to the patients with cervical cancer. However, further improved in dose had no significant benefit on local control rate, and it might increase the risks of toxicity.

CONTACT TOXICITY OF ESSENTIAL OIL OF Croton pulegiodorus BAILL ON Sitophilus zeamais MOTSCHULSKY

ABSTRACT The objective of this work was to evaluate the contact toxicity of essential oil of Croton pulegiodorus Baill on six populations of Sitophilus zeamais Motschulsky. The S. zeamais populations used were from Crixás-GO, Espírito Santo do Pinhal-SP, Juiz de Fora-MG, Picos-PI, Serra Talhada-PE, and Vicentina-MS, Brazil, and present different susceptibility to synthetic insecticides. The essential oil of C. pulegiodorus used was obtained from plants collected in Triunfo-PE, Brazil. The lethal concentrations (LC50 and LC90), toxicity ratio of the essential oil, and the resistance ratio of the populations were estimated. The S. zeamais population from Serra Talhada-PE presented the lowest LC50 (4.21 μL 20 g-1) and LC90 (6.67 μL 20 g-1) and was the reference for susceptibility to the essential oil of C. pulegiodorus. The S. zeamais population from Espírito Santo do Pinhal-SP presented the highest LC50 (6.02 μL 20 g-1) and LC90 (10.55 μL 20 g-1) and was the reference for tolerance to the essential oil of C. pulegiodorus. The toxicity ratio ranged from 1.01 (Picos-PI) to 1.43 (Serra Talhada-PE); and the resistance ratio ranged from 1.13 (Crixás-GO) to 1.43 (Espírito Santo do Pinhal-SP). The essential oil of C. pulegiodorus reduced the emergence of adult S. zemais and showed residual effect, with contact toxicity, after 30 and 60 days of application.

Sublethal Effects of Four Insecticides on the Seven-Spotted Lady Beetle (Coleoptera: Coccinellidae).

To further develop integrated pest management (IPM) strategies against two sucking insect pests, Aleurocanthus spiniferus (Quaintanca) (Hemiptera: Aleyrodidae) and Toxoptera aurantii Boyer (Hemiptera: Aphididae), in Chinese tea plantations, it is important to evaluate the effects of insecticides on biological control agents, such as the seven-spot lady beetle, Coccinella septempunctata L. (Coleoptera: Coccinellidae). Therefore, we tested the toxicity and sublethal effects of spirotetramat, clothianidin, lambda-cyhalothrin, and bifenthrin on C. septempunctata. The side effects of the active ingredients of the insecticides were evaluated with residual contact tests on the larvae of C. septempunctata in the laboratory. Spirotetramat and clothianidin exhibited lower lethality to C. septempunctata as shown by the higher LC50 values and had higher selectivity for A. spiniferus and T. aurantii based on the selective toxicity ratios being superior to other tested insecticides. Spirotetramat also did not affect survival, longevity, fecundity, and egg hatching of C. septempunctata. Clothianidin and bifenthrin prolonged the duration of larval development stages of C. septempunctata obviously. Clothianidin at >2.5 mg/liter, lambda-cyhalothrin at >0.03 mg/liter, and bifenthrin at >0.125 mg/liter significantly reduced the survival and pupation rates of C. septempunctata larvae. Furthermore, spirotetramat at 3.125 mg/liter was harmless (IOBC class 1) to larvae of this coccinellid species. Based on the results, spirotetramat was innocuous to C. septempunctata larvae compared with clothianidin, lambda-cyhalothrin, and bifenthrin. Therefore, spirotetramat might be incorporated into IPM programs in combination with C. septempunctata for control of A. spiniferus and T. aurantii in the tea plantations.

Selective toxicityof acetamiprid and fipronil as a part of insecticidal baits

Monocomponent and combined insecticidal baits containing acetamiprid and fipronil are proposed to control the housefly Musca domestica at livestock facilities. The combination of active ingredients increases the insecticidal activity of formulations and simultaneously may lead to an increase in their toxicity to animals. The purpose of this work was to assess the selective toxicity of acetamiprid and fipronil as parts of mono- and bicomponent insecticides. The intestinal activity of insecticides against adult houseflies was assessed by no-choice feeding tests. The acute toxicity of insecticidal baits to animals was carried out by feeding to white mice. Probit analysis was used to calculate of median lethal doses of active ingredients and insecticidal baits. The selective toxicity was evaluated by the selective toxicity ratio, which was calculated by dividing the median lethal doses (LD50) of the active ingredients for white mice into LD50 for adult flies. The median lethal doses of acetamiprid and fipronil when applied alone for adult flies were 2.412 (2.023-2.862) and 0.087 (0.0285-0.2659) μg of active ingredient per g of insect weight, respectively. The insecticidal activity of active ingredients, applied in combination, against adult flies increased by 15 and 5 times, respectively. For the toxicity to mice, median lethal doses of acetamiprid and fipronil in formulations containing only one of the active substances were 94.9 (88.5 - 101.8) mg/kg and more than 22.5 mg/kg of animal weight, respectively. The selective toxicity ratio of fipronil in the monocomponent formulation was 6.8 times higher than that of acetamiprid. For the binary formulation, the selectivity of fipronil and acetamiprid activity was equal. The combination of acetamiprid and fipronil resulted in an increase in their toxicity for adults Musca domestica and for white mice and a change in the selectivity of their activity compared to monocomponent formulations.

QSAR for baseline toxicity and classification of specific modes of action of ionizable organic chemicals in the zebrafish embryo toxicity test

The fish embryo toxicity (FET) test with the zebrafish Danio rerio is widely used to assess the acute toxicity of chemicals thereby serving as animal alternative to the acute fish toxicity test. The minimal toxicity of neutral chemicals in the FET can be predicted with a previously published Quantitative Structure-Activity Relationship (QSAR) based on the liposome-water partition coefficient Klipw. Such a QSAR may serve to plan toxicity testing and to evaluate whether an observed effect is caused by a specific mode of action (MoA). The applicability domain of this QSAR was extended to ionizable organic chemicals (IOC) without any modification of slope and intercept simply by replacing the Klipw with the speciation-corrected liposome-water distribution ratio (Dlipw(pH)) as descriptor for the uptake into the embryo. FET LC50 values of IOCs were extracted from an existing FET database and published literature. IOCs were selected that are present concomitantly as neutral and charged, species, i.e., acids with an acidity constant pKa <10 and bases with pKa>5. IOCs were grouped according to their putative MoA of acute aquatic toxicity. The toxic ratios (TR) in the FET were derived by of the experimental FET-LC50 in comparison with the baseline toxicity QSAR. Baseline toxicants were confirmed to align well with the FET baseline toxicity QSAR (TR < 10). Chemicals identified to act as specific or reactive chemicals with the toxic ratio analysis in the FET test (TR > 10) were generally consistent with MoA classification for acute fish toxicity with a few exceptions that were suspected to have had issues with the stability of the pH during testing. One critical aspect for the effect analysis of ionizable chemicals is the pH, since the difference between pH and pKa determines the speciation and thereby the Dlipw(pH).

Low Levels of Neurologic Toxicity with Retained Anti-Lymphoma Activity in a Phase I Clinical Trial of T Cells Expressing a Novel Anti-CD19 CAR

▪Anti-CD19 chimeric antigen receptor (CAR) T cells have powerful activity against B-cell lymphoma, but improvement is clearly needed. Toxicity, including cytokine-release syndrome (CRS) and neurologic toxicity, occurs after anti-CD19 CAR T cell infusions. Most CAR T-cell toxicity is caused, either directly or indirectly, by cytokines or other proteins that are secreted from CAR T cells.The structure of a CAR is an extracellular antigen-recognition domain connected by hinge and transmembrane (TM) domains to intracellular T-cell signaling moieties. In vitro, T cells expressing CARs with hinge and TM domains from the CD8-alpha molecule released significantly lower levels of cytokines compared with T cells expressing CARs with hinge and TM domains from CD28; however, T cells expressing CARs with hinge and TM domains from CD8-alpha retained sufficient functional capability to eradicate tumors from mice (Alabanza et al. Molecular Therapy. 2017. 25(11) 2452).To reduce cytokine production with a goal of reducing clinical toxicity, we incorporated CD8-alpha hinge and TM domains into an anti-CD19 CAR. The CAR also had a human antigen-recognition domain, a CD28 costimulatory domain, and a CD3-zeta domain. This CAR was designated Hu19-CD828Z and was encoded by a lentiviral vector. Hu19-CD828Z was different from the FMC63-28Z CAR that we used in prior studies. FMC63-28Z had hinge and TM domains from CD28 along with a CD28 costimulatory domain, a CD3-zeta domain, and murine-derived antigen-recognition domains.Twenty patients with B-cell lymphoma were treated on a phase I dose-escalation clinical trial of Hu19-CD828Z T cells (Table). Patients received low-dose cyclophosphamide and fludarabine daily for 3 days on days -5 to -3. Two days later, on day 0, CAR T cells were infused. The overall response rate (ORR) after 1st treatments with Hu19-CD828Z T cells was 70%, and the complete response (CR) rate 55%; the 6-month event-free survival was 55%. The anti-lymphoma activity of Hu19-CD828Z T cells in the current trial was comparable to the anti-lymphoma activity of FMC63-28Z T cells in a similar prior trial that also enrolled patients with advanced B-cell lymphoma. In the prior trial, we observed a 73% ORR, a 55% CR rate, and a 6-month event-free survival of 64% in 22 patients treated with FMC63-28Z T cells (Kochenderfer et al. Journ. Clin. Oncology. 2017 35(16) 1803).In our previous clinical trial of FMC63-28Z T cells, the rate of Grade 3 or 4 neurologic toxicity among 22 patients treated was 55%. Strikingly, in our trial of Hu19-CD828Z T cells, the rate of Grade 3 or 4 neurologic toxicity was only 5% (1/20 patients). In addition, the rate of Grade 2 or greater neurologic toxicity with FMC63-28Z T cells was 77.3% while the rate of Grade 2 or greater neurologic toxicity with Hu19-CD828Z T cells was 15%. To explore the mechanism for the difference in neurologic toxicity in patients receiving FMC63-28Z T cells versus Hu19-CD828Z T cells, we assessed serum levels of 41 proteins in patients treated with these CAR T-cells. This comparison is valid because the same Luminex methodology was used for the serum protein analysis for both trials, and controls of known amounts of each protein were assayed to ensure that protein levels were comparable on the different trials. Lower levels of several serum proteins that might be important in CAR toxicity were found in patients treated with Hu19-CD828Z T cells versus patients treated with FMC63-28Z T cells: Granzyme A (P<0.001), Granzyme B (P<0.001), interferon gamma (P=0.011), interleukin (IL)-15 (P=0.007), IL-2 (P=0.0034), and macrophage inflammatory protein-1A (P<0.001). Median peak patient blood CAR+ cell levels were 44 cells/µL for Hu19-CD828Z and 46.5 cells/µL for FMC63-28Z (P=not significant). We hypothesize that lower levels of potentially neurotoxic proteins in patients receiving Hu19-CD828Z T cells versus FMC63-28Z T cells led to a lower frequency of neurologic toxicity in patients receiving Hu19-CD828Z T cells. The lower levels of immunologically active proteins found in the serum of patients receiving Hu19-CD828Z T cells compared with patients receiving FMC63-28Z T cells is consistent with our in vitro experiments showing lower cytokine production by T cells expressing CARs with CD8 hinge and TM domains versus CD28 hinge and TM domains. Altering CAR hinge and TM domains can affect CAR T-cell function and is a promising approach to improve the efficacy to toxicity ratio of CAR T-cells. DisclosuresRossi:KITE: Employment. Shen:Kite, a Gilead Company: Employment. Xue:Kite, a Gilead Company: Employment. Bot:KITE: Employment. Rosenberg:Kite, a Gilead Company: Research Funding. Kochenderfer:Kite a Gilead Company: Patents & Royalties: CAR technology, Research Funding; Celgene: Research Funding.

RECURRENT GLIOBLASTOMA MANAGEMENT USING STEREOTACTIC RADIOSURGERY AND SYSTEMIC TREATMENT

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system in adults. Dismal survival rates and poor prognosis for recurrent GBM patients still remains a challenging problem. Despite aggressive initial treatment, above 100 % GBM patients have development of recurrent diseases. Management of GBM recurrence is still debatable. The multimodality approaches using combination of stereotactic radiosurgery (SRS), cytostatic agents (Тemozolomide (TMZ)) and antiangiogenic therapy (bevacizumab (BEV)) are often beneficial for such patients and may achieve survival improving. Aim of research: to assess the efficacy and toxicity of combination therapy approach using stereotactic radiosurgery (SRS) and systemic treatment (chemotherapy and antiangiogenic therapy) in glioblastoma multiforme recurrence treatment. Materials and methods: at the State Institution “Institute of Neurosurgery named after acad. A.P. Romodanov of NAMS of Ukraine” (Kyiv, Ukraine) 21 patients (pts) with GBM recurrence were treated (8 females and 11 men; median age at time of diagnosis 52.4 (29.7–69.3) from January 2014 till December 2017. The initial surgical treatment as gross total tumor resection was performed in 12 pts (57.1 %), subtotal resection – 5 pts (23.9 %), biopsy – 4 pts (19 %). 12 pts (57.1 %) were MGMT methylated and 9 pts (42.9 %) were MGMT unmethylated. In all cases adjuvant radiation therapy (60 Gy in 30 fractions) were used, 12 pts of them (57.1 %) – in combination with TMZ followed by 6-12 courses of chemotherapy (TMZ) according Stupp protocol. Recurrent disease was treated by SRS followed by TMZ + BEV. SRS was performed by means of “Trilogy” LINAC (“Varian”, USA) with a median dose and fractions of 19.2 Gy (range, 12.0–36.0) in 1 to 5 fractions. Results: median survival after initial diagnosis was 18.3 months, and 1- and 2-year survival rates of 85.7 % (18 from 21 pts) and 38.1 % (8 from 21 pts) respectively. The median survival from the time of recurrence treatment was 8.3 months. The 6‐ and 12‐months overall survival from SRS were 95.2 % (20 from 21 pts) and 23.8 % (5 from 21 pts), respectively. Adverse radiation effects were noted in 6 (28.6 %) pts and were controlled with corticosteroids. Adverse events grade 1-2 related to the systemic therapy included hematological complications, fatigue, hypertension and proteinuria were observed in 23.8 % (5 from 21 pts) without the occurrence of grade 3 events. Conclusion: recurrent GBM management using combination of SRS, chemotherapy and antiangiogenic therapy is a promising multimodal treatment approach providing survival improving whereas appropriate toxicity ratio. Further studies of combined treatment of GBM relapse are needed.

Linking Herbicide Dissipation to Soil Ecological Risk along Transmission Rights-of-Way in the Yukon Territory, Canada.

In the Yukon Territory, transmission rights-of-way (ROWs) are managed using brushing and mowing techniques alone. When cut, target species such as Michx. and spp. grow rapidly shortening maintenance cycles. Long-term vegetation control may be improved by integrating herbicide application. However, prior to implementation, the dissipation and toxicity of herbicides in northern latitudes needed to be assessed. The dissipation of Garlon XRT (triclopyr) and Arsenal Powerline (imazapyr) in soils was assessed at five ROW locations representative of the main ecoregion types where ROWs occur within the Yukon Territory. Soils from four sites were collected at 1, 30, and 365 d after treatment to determine persistence of herbicides for each of three application methods (backpack spraying, cut stump, and point injection). Increased sampling intervals were added to better determine the dissipation rate of each herbicide in Yukon Territory soils. Soil dissipation data were linked to a series of standardized toxicity tests, including three soil invertebrates (, , and ). Additionally, the dissipation of both herbicides from the target species L. was assessed at one site. Herbicide residues persisted in soils for longer than 365 d after treatment and longer than 30 d after treatment in . However, concentrations were below the concentration that would affect 25% of the invertebrate species tested. Weight of evidence and toxic exposure ratios were used to characterize the risks associated with herbicide application in northern latitudes and provided both qualitative and quantitative means to communicate the results to the public.

Toxicity of some prevalent organic chemicals to tadpoles and comparison with toxicity to fish based on mode of toxic action

Although mode of action (MOA) plays a key role in the understanding of the toxic mechanism of chemicals, the MOAs of class-based compounds to tadpoles have not been investigated. To explore the MOAs, acute toxicity (expressed as log 1/LC50) to Rana chensinensis tadpoles were determined and molecular descriptors were calculated. Quantitative structure-activity relationship (QSAR) showed that toxicity to tadpoles is closely related to the chemical octanol/water partition coefficient (log KOW), energy of the lowest unoccupied molecular orbital (ELUMO), and number of hydrogen bond donors and acceptors (NHDA), representing the bio-uptake potential in tadpoles, the electrophilicity and hydrogen bonding capacity with target site(s), respectively. Comparison of the toxicity values between tadpoles and fish revealed that there were no significant differences for the overlapping compounds (average residual = 0.29 between tadpole and fish toxicity) with P values of interspecies correlation substantially less than 0.001. Classification of MOAs for the class-based compounds based on the excess toxicity calculated from toxicity ratio suggested that baseline, less inert compounds and some reactive or specifically-acting compounds share same MOAs between tadpoles and fish. Fish and tadpoles can serve as surrogates for each other in the safety evaluation of organic pollutants.

Comparison of modes of action between fish and zebrafish embryo toxicity for baseline, less inert, reactive and specifically-acting compounds

The mode of action (MOA) plays a key role in the risk assessment of pollutants in water. Although fish is a key model organism used in the risk assessment of pollutants in water, the MOAs have not been compared between fish and embryo toxicity for classified compounds. In this paper, regression analysis was carried out for fish and embryo toxicities against the calculated molecular descriptors and MOAs were evaluated from toxicity ratio. The toxicity significantly related with the chemical hydrophobicity for baseline and less inert compounds, respectively, indicates that these two classes of compounds share the same MOAs between fish and embryos. Comparison of the toxicity ratios shows that reactive compounds exhibit excess toxicity to both fish and embryos. These compounds can react covalently with biologically target molecules through nucleophilic addition reactions, Michael addition oxidation, or amination. Comparing with baseline, less inert and reactive compounds, many specifically-acting compounds have strong docking capacity with protein molecules. Some specifically-acting compounds, such as fungicides, have very similar toxic effect to both fish and embryos. However, insecticides are more toxic to fish than embryos; herbicides and medications are more toxic to embryos than fish. Differences in the interactions of chemicals with target molecules or bioconcentration potentials between fish and embryos may result in the differences in toxic effects. There are some factors that influence the identification of MOAs, such as quality of toxicity data, bioavailability and ionization. These factors should be considered in the identification of MOAs in the risk assessment of organic pollutants.

Insecticidal and repellent properties of novel trifluoromethylphenyl amides II

This project focused on the design, synthesis, and testing of trifluoromethylphenyl amides (TFMPAs) as potential mosquitocides and repellents. Fourteen compounds were evaluated for toxicity against larvae and adults of Aedes aegypti. Several compounds were toxic against Aedes aegypti (larval, adult and feeding bioassays) and Drosophila melanogaster (glass-surface contact assay), but were much less toxic than fipronil, with toxicity ratios ranging from 100-fold in the larval assay to 100,000-fold for topical application to adult insects. In repellency bioassays to determine minimum effective dosage (MED), compound N-(2,6-dichloro-4-(trifluoromethyl)phenyl)-2,2,3,3,3-pentafluoropropanamide (7b) repelled Ae. aegypti females at lower concentration, 0.017 (±0.006) μmol/cm2, than N, N-diethyl-meta-toluamide (DEET) 0.026 (±0.005) μmol/cm2. 2-Chloro-N-(3-(trifluoromethyl)phenyl)acetamide (6a) performed better than DEET against two species of mosquitoes: it repelled Ae. aegypti females at 0.013 (±0.006) μmol/cm2 and Anopheles gambiae females (in a warm body repellent assay), at a standard exposure of 2 nmol/cm2. These studies revealed novel active structures that could further lead to compounds with better repellent activity.

Methotrexate intoxication: Beyond the adverse events.

Methotrexate (MTX) is the first-line disease-modifying antirheumatic drug in rheumatoid arthritis (RA). However, this anchor may cause some side effects that may range from nausea to mortality. The clinical features of MTX toxicity are under-researched. In this study, we aimed to find out the potential predisposing factors and outcomes of the MTX toxicity (n=31). The data were collected from 31 patients whose ages ranged from 25 to 81years, who were suffering from immune-mediated inflammatory diseases and major MTX-related toxicity. Out of 31 patients, six (19.4%) used MTX every day, and 13 (41.9%) patients had renal insufficiency who were admitted to the hospital because of mucositis (90.3%) and fever (71%). While using MTX, 27 patients (87.1%) were discharged after the treatment and four patients (12.9%) died. Although MTX has high efficacy for the toxicity ratio, wrong use and dosage of MTX may be harmful to patients. Thus, patients should be informed about the proper use of MTX.

Investigation on the relationship between critical body residue and bioconcentration in zebrafish based on bio-uptake kinetics for five nitro-aromatics

It is well known that the critical body residue (CBR) can be estimated via bioconcentration factor (BCF). However, the relationship between CBR and BCF in zebrafish has not been carried out based on bio-uptake kinetics for nitro-aromatics. In this paper, the time-variable concentrations and CBRs in zebrafish were determined for five nitro substituted benzenes. The result shows that CBR values can well be calculated from the BCF and external critical concentrations (LC50). Although CBRs measured from 5 h exposure period are greater than the CBRs obtained from 96 h for the five nitro-aromatics, no significant difference was observed, indicating that the CBR approach is a truer measure of chemical levels in exposed organisms and an ideal indicator to reflect the toxicity of a chemical. The bio-uptake can well be described by first-order kinetics and reach steady-state within 48 h. Almost same BCF values are obtained from the ratio of concentration in the fish (Cf) and in the water (Cw) at apparent steady-state and the ratio of the rate constants of uptake (k1) and depuration (k2) assuming first-order kinetics. The toxicity ratio (TR) can reflect the difference of internal critical concentrations and be used to identify mode of action.

Laboratory Evaluation of the Effect of Insecticides on Non-target Organisms: 2- The egg parasitoid, Trichogramma evanescens West. (Hymenoptera: Trichogrammatidae)

The present study aimed to evaluate the effect of different groups of insecticides (e.g., Dipel, Dursban, Biover, Malathion and Spintor) on the immature stages and the parasitism rate of the egg parasitoid, Trichogramma evanescens West. (Hymenoptera: Trichogrammatidae) under laboratory conditions. The parasitized eggs of the factitious host, the Mediterranean flour moth, Anagasta (Ephestia) kuehniella Zeller were used. Data were recorded in terms of parasitism rate, emergence rate and female percentages. The calculated values of the Slope (b) of the log-dosage-probit mortality curve, by treating the parasitized A. kuehniella eggs (ranged from 0.6 to 1.34), indicated that the susceptibility of the population was heterogeneous for all the studied insecticides. Results indicated that each of the tested insecticides showed the different degree of toxicity. Malathion was the most toxic insecticide (Toxicity ratio T.R.: 10-39.7), while the bioinsecticide, Dipel was the least toxic one (Toxicity ratio T.R.:0.24-0.47). The parasitoid developmental stage had a significant effect on the toxicity ratio of all the studied insecticides. The eggs treated 7-day post-treatment showed the highest parasitism rate for all insecticides, (65-94%), followed by 5-day old (52-91%), 3-day old (48-90%), and then 1-day old (43-88%). An inverse relationship between the parasitism rate and the insecticide concentration was found. The emergence rate was affected greatly by both the type of insecticide and the treated immature stage. The highest emergence rate, (14-86%) was recorded for the eggs treated 1-day post-treatment, while parasitized eggs, treated after 7 days at all the tested insecticides recorded the lowest rates of adult emergence of T. evanescens (6-49%). The highest emergence rate (42-83%) was found for eggs treated with the fungicide Biover, while the lowest values (7-35%) were recorded for the eggs treated with Spintor compared to a significant high emergence rate for the untreated ones (92%). Sex ratio (female percentage) did not differ significantly between the treated (38-55%) and the untreated parasitized eggs (50-54%).

Change of Amyloid-β 1-42 Toxic Conformer Ratio After Cerebrospinal Fluid Diversion Predicts Long-Term Cognitive Outcome in Patients with Idiopathic NormalPressure Hydrocephalus.

Background:Alzheimer’s disease (AD) pathology in idiopathic normal pressure hydrocephalus (iNPH) contributes to poor shunt responses. Amyloid-β 1– 42 (Aβ42) toxic conformer was recently identified with features of rapid oligomerization, strong neurotoxicity and synaptotoxicity.Objective:This observational study points to Aβ42 toxic conformer as a biomarker for AD pathology and for poor postoperative prognosis in patients with iNPH.Methods:The first cohort consisted of patients with AD (n = 17) and iNPH (n = 17), and cognitively normal individuals (CN, n = 12). The second cohort, consisted of 51 patients with iNPH, was divided into two groups according to phosphorylated Tau (pTau) level (low- and high-pTau groups); the low-pTau group was further subdivided according to one-year postoperative change in Aβ42 toxic conformer ratio (%) [Aβ42 toxic conformer/Aβ42×100] (decreased- and increased-conformer subgroups). Enzyme-linked immunosorbent assay was used to measure pTau, Aβ42, and Aβ42 toxic conformer in cerebrospinal fluid. Outcomes were evaluated using neuropsychological tests one- and two-years postoperatively.Results:In the first cohort, Aβ42 toxic conformer ratio in the iNPH group (10.8%) was significantly higher than that in the CN group (6.3%) and significantly lower than that in the AD group (17.2%). In the second cohort, the high-pTau group showed cognitive decline two-years postoperatively compared to baseline. However, the low-pTau group showed favorable outcomes one-year postoperatively; furthermore, the increased-conformer subgroup showed cognitive decline two-years postoperatively while the decreased-conformer subgroup maintained the improvement.Conclusions:Change in Aβ42 toxic conformer ratio predicts long-term cognitive outcome in iNPH, even in the low-pTau group.