Profiling of the Tox21 Chemical Collection for Mitochondrial Function to Identify Compounds that Acutely Decrease Mitochondrial Membrane Potential

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding whether different environmental chemicals and druglike molecules impact mitochondrial function represents an initial step in predicting exposure-related toxicity and defining a possible role for such compounds in the onset of various diseases.Objectives: We sought to identify individual chemicals and general structural features associated with changes in mitochondrial membrane potential (MMP).Methods: We used a multiplexed [two end points in one screen; MMP and adenosine triphosphate (ATP) content] quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 library of 10,000 compounds (~ 8,300 unique chemicals) at 15 concentrations each in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells.Results: Approximately 11% of the compounds (913 unique compounds) decreased MMP after 1 hr of treatment without affecting cell viability (ATP content). In addition, 309 compounds decreased MMP over a concentration range that also produced measurable cytotoxicity [half maximal inhibitory concentration (IC₅₀) in MMP assay/IC₅₀ in viability assay ≤ 3; p < 0.05]. More than 11% of the structural clusters that constitute the Tox21 library (76 of 651 clusters) were significantly enriched for compounds that decreased the MMP.Conclusions: Our multiplexed qHTS approach allowed us to generate a robust and reliable data set to evaluate the ability of thousands of drugs and environmental compounds to decrease MMP. The use of structure-based clustering analysis allowed us to identify molecular features that are likely responsible for the observed activity.Citation: Attene-Ramos MS, Huang R, Michael S, Witt KL, Richard A, Tice RR, Simeonov A, Austin CP, Xia M. 2015. Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Perspect 123:49–56; http://dx.doi.org/10.1289/ehp.1408642     

Improving the Human Hazard Characterization of Chemicals: A Tox21 Update

Background: In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency’s National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on “high throughput screening, toxicity pathway profiling, and biological interpretation of findings.” In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21.Objectives: The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays.Discussion: Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems.Conclusion: Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology.     

高效氯氰菊酯对德国小蠊乙酰胆碱酯酶抑制效应研究

目的　通过研究高效氯氰菊酯与德国小蠊乙酰胆碱酯酶 (AChE)活性水平的量效与时效关系 ,进一步完善高效氯氰菊酯作用机制的研究 ,为德国小蠊的防制工作提供理论基础和参考方法。方法　参照国标GB13 917.1～GB13 917.8-92《农药登记卫生杀虫剂室内药效试验方法》喷施一定剂量不同浓度的高效氯氰菊酯 ,用乙酰胆碱酯酶试剂盒测定德国小蠊AChE活性。结果　 48h内高效氯氰菊酯对德国小蠊AChE活性的抑制作用呈浓度梯度效应 ,高效氯氰菊酯的浓度与德国小蠊 72h的死亡率和 14 4h内对AChE活性的抑制时效呈正相关。结论　德国小蠊的乙酰胆碱酯酶是高效氯氰菊酯的作用靶标之一 ,由于AChE敏感度降低而产生的靶标抗性是德国小蠊对高效氯氰菊酯产生抗药性的原因之一 ,德国小蠊AChE活性水平可做为对拟除虫菊酯类杀虫剂抗性水平检测的指标之一。     

Role of Acetylcholinesterase Inhibition in Toluene Diisocyanate (TDI) Induced Bronchoconstriction

Summary Two groups of subjects (ten controls and 13 with a clinical history of bronchial asthma attributed to TDI exposure in industry), underwent a specific bronchial stimulation test with TDI at concentrations around the MAC. Five other subjects not exposed to TDI, underwent an a specific bronchial stimulation test with carbachol. AChE and CHE activity and respiratory function (FEV₁ and V max 50%) were determined before, immediately after and 4 h after exposure. In vitro, the ID₅₀ and ID₉₀ of TDI on AChE activity is very high (7.2 x 10⁻⁵ and 6.8 × 10⁻⁴ mol/l, respectively). In vivo, AChE activity of the control group and of the group exposed to carbachol is not inhibited, while in TDI professionally exposed subjects, five show only a fall of ACNE activity after 4 h (6% lower than the base, P < 0.005), without respiratory impairment, five show a “late” response with AChE inhibition of 13% (P < 0.001); three show a “dual” response with AChE activity inhibition of 16% (P < 0.001) after 4h. There was no variation of CHE activity in any subject. The authors hypothesized a “biochemical” effect mediated by an immune mechanism due to the presence of antibodies against acetylcholinesterase-TDI complex with a threshold effect on respiratory impairment due to acetylcholinesterase inhibition.     

新鲜蔬菜中有机磷农药残留的胆碱酯抑制快速检测法

目的开发新鲜蔬菜农药残留量的快速检测技术。方法根据有机磷农药残留的胆碱酯酶抑制法原理,通过单因素和正交试验确定最佳反应条件,由指示剂颜色变化和反应液ApH进行定量。结果确定检测条件为：马血清0．8ml,1．0％氯化乙酰胆碱1．4ml,反应温度为33℃。该方法对常见的几种有机磷农药的检测限均在0．04—10．0mg／kg的范围。结论该方法操作简便,检测快速,成本低,因而在有机磷的快速测定中有广泛的应用价值。     

微板法检测蚊虫体内乙酰胆碱酯酶活性研究

目的：检测不同敏感品系（Ｓ）蚊虫和室内选育的抗性品系淡色库蚊体内乙酰胆碱酯酶活性。方法：微滴定板法。结果：４种Ｓ品系蚊虫中,以中华按蚊体内ＡｃｈＥ水平最高;３种抗性品系蚊虫中,抗残杀威品系的ＡｃｈＥ活性〉抗氯氰区酯品系〉抗ＤＤＶＰ品系,且后者一Ｓ品系差异无显著性。蚊虫体内ＡｃｈＥ活性随发育而逐步增高,以不同浓度残杀威作抑制剂,测定室内不同品系淡色库蚊个体的ＡｃｈＥ活性,表明蚊虫ＡｃｈＥ活性的抑制率     

Profiling the Heavy Blood Donor

No abstract available for this article.     

Data solutions for the 21st century: CEFIC's vision and intentions. The European Chemical Industry Council

Information on workplace exposures to chemicals has a role and importance that goes beyond compliance with occupational exposure limits (OELs). In particular, the increasing use of exposure data in regulatory risk assessment processes places added demands on the need to collect such information. Industry's challenge is to respond to these developments in a manner that ensures data are obtained, archived, and analyzed to standards consistent with evolving stakeholder expectations.     

Cost-Effectiveness of Gene-Expression Profiling for Tumor-Site Origin

ObjectivesGene-expression profiling (GEP) reliably supplements traditional clinicopathological information on the tissue of origin (TOO) in metastatic or poorly differentiated cancer. A cost-effectiveness analysis of GEP TOO testing versus usual care was conducted from a US third-party payer perspective.MethodsData on recommendation changes for chemotherapy, surgery, radiation therapy, blood tests, imaging investigations, and hospice care were obtained from a retrospective, observational study of patients whose physicians received GEP TOO test results. The effects of chemotherapy recommendation changes on survival were based on the results of trials cited in National Comprehensive Cancer Network and UpToDate guidelines. Drug and administration costs were based on average doses reported in National Comprehensive Cancer Network guidelines. Other unit costs came from Centers for Medicare & Medicaid Services fee schedules. Quality-of-life weights were obtained from literature. Bootstrap analysis estimated sample variability; probabilistic sensitivity analysis addressed parameter uncertainty.ResultsChemotherapy regimen recommendations consistent with guidelines for final tumor-site diagnoses increased significantly from 42% to 65% (net difference 23%; P<0.001). Projected overall survival increased from 15.9 to 19.5 months (mean difference 3.6 months; two-sided 95% confidence interval [CI] 3.2–3.9). The average increase in quality-adjusted life-months was 2.7 months (95% CI 1.5–4.3), and average third-party payer costs per patient increased by $10,360 (95% CI $2,982–$19,192). The cost per quality-adjusted life-year gained was $46,858 (95% CI $13,351–$104,269).ConclusionsGEP TOO testing significantly altered clinical practice patterns and is projected to increase overall survival, quality-adjusted life-years, and costs, resulting in an expected cost per quality-adjusted life-year of less than $50,000.     

Profiling dialysis facilities for adverse recurrent events

Profiling analysis aims to evaluate health care providers, such as hospitals, nursing homes, or dialysis facilities, with respect to a patient outcome. Previous profiling methods have considered binary outcomes, such as 30-day hospital readmission or mortality. For the unique population of dialysis patients, regular blood works are required to evaluate effectiveness of treatment and avoid adverse events, including dialysis inadequacy, imbalance mineral levels, and anemia among others. For example, anemic events (when hemoglobin levels exceed normative range) are recurrent and common for patients on dialysis. Thus, we propose high-dimensional Poisson and negative binomial regression models for rate/count outcomes and introduce a standardized event ratio measure to compare the event rate at a specific facility relative to a chosen normative standard, typically defined as an “average” national rate across all facilities. Our proposed estimation and inference procedures overcome the challenge of high-dimensional parameters for thousands of dialysis facilities. Also, we investigate how overdispersion affects inference in the context of profiling analysis. The proposed methods are illustrated with profiling dialysis facilities for recurrent anemia events.     

Acetylcholinesterase inhibitors for the treatment of Wernicke-Korsakoff syndrome--three further cases show response to donepezil

Three patients diagnosed with Wernicke-Korsakoff syndrome were treated with the acetylcholinesterase inhibitor, donepezil, for periods of 6 to 8 months. Cognitive testing [Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), Mini-mental state examination (MMSE), Clock drawing test and six item 2 min recall] and carer questionnaires [Informant Questionnaire (IQ Code), Neuropsychiatric inventory scale (NPI)] were performed at baseline, mid- and endpoint of the treatment period and post-discontinuation. Progressive partial improvement occurred in cognitive measurements through the treatment period, some of which was sustained after discontinuing donepezil. Carer questionnaires also indicated improvement. Confounding factors necessitate caution when attributing improvements to the medication, but these cases suggest that this option merits further investigation.     

Profiling students for remediation using latent class analysis

While clinical exams using SPs are used extensively across the medical schools for summative purposes and high-stakes decisions, the method of identifying students for remediation varies widely and there is a lack of consensus on the best methodological approach. The purpose of this study is to provide an alternative approach to identification of students for remediation using the latent class analysis (LCA) technique. 147 third year medical students participating in the Clinical Performance Examination (CPX) are included in the study. We used LCA to identify students who potentially need remediation based on their performance on CPX. Three distinct clusters of students with different performance profiles were identified. The identification of two rather than one low performing group has significant implications for identifying cut-points as well as for remediation programs. The two low performing groups in our study had low scores on contrasting sets of cases. LCA presents an alternative approach to identification of borderline or low performing groups. This method provides advantages over traditional statistical techniques such as cluster analysis used for grouping students. Based on the flexibility of the model specification, within the LCA framework, we were able to identify more than one group that may need remediation or instruction support.     

Physician profiling: applications for the Robert Wood Johnson Profiling Project database

An overview of the applications and limitations of the Center for Research in Ambulatory Health Care Administration (CRAHCA) Profiling Project database funded by The Robert Wood Johnson Foundation is presented. The Profiling Project collects data from 77 practices and links organizational, provider, and patient demographics to administrative data. The Project's database has the capacity (1) to profile physicians based on the Resource Based Relative Value Scale (RBRVS) relative value units as a measure of work and (2) to identify practice patterns as defined by procedures used by physicians with the same diagnosis. The Project will further explore variations between physicians and specialties based on systems of care, physician specialty, and patient differences. The comparative reports generated from these data provide comparisons on selected indicators for participating practices.