Flight safety assessment based on an integrated human reliability quantification approach.
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ABSTRACT:
SUBMITTER: Guo Y
PROVIDER: S-EPMC7161990 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Integrated Approaches to Testing and Assessment (IATA) are emerging as a means to strategically assess and test chemicals for toxicity, using existing information, and helping to identify potential data gaps. Adverse Outcome Pathways (AOPs) have recently been shown to be a good starting point for IATA development. Our interest in IATAs and AOP Networks (AOPNs) focuses on developing efficient testing and risk assessment strategies for new materials, new chemical entities, and setting environmental cleanup goals. We combine the maths logic of causality, specifically the notion of sufficiency to infer an adverse outcome, with AOPNs to develop Minimally Sufficient Sets of Key Events (MinSSKEs). These MinSSKEs represent a set of key events (can just be one key event) that taken together allow assessors to predict if an adverse outcome is likely or not. For our case study we use the military explosive trinitrotoluene (TNT). TNT is a relatively data rich chemical where the US Environmental Protection Agency has set a reference dose of 0.0005mg/kg-day, based on a point of departure for liver toxicity in dogs of 0.5mg/kg-day (a lowest observed adverse effect level; LOAEL) with uncertainty of 1,000X. Our IATA measures gene expression for genes in involved in our AOPN for energy metabolism, steatosis and oxidative stress in human induced pluripotent stem cells differentiated to hepatocytes exposed to TNT. We used a Bayesian statistical approach to identify differentially expressed genes, and a nonlinear data-driven dose-response modeling approach (Good Risk Assessment Values for Environmental Exposures; GRAVEE) to estimate points of departure for reference dose estimation. We obtained an RfD of 0.12mg/kg-day, with a 90% credible interval spanning from 0.02-0.19mg/kg-day using our IATA approach. Our RfD is based on a POD of 1.22mg/kg-day with a 90% credible interval spanning from 0.24-1.94mg/kg-day, and uncertainty of 10X after applying the IRIS uncertainty factors. Our PODs are highly comparable, with a difference of only 0.72mg/kg-day (or 2.44x). Our RfDs differ by 240x, owing to the fact that we have only a 10x uncertainty factor for human variability, whereas the IRIS assessment uses 1000x uncertainty for 10x animal-to-human extrapolation, 10x LOAEL-to-NOAEL extrapolation, and 10x for subchronic-to-chronic extrapolation. In this case study, our IATA resulted in a highly similar POD compared to the IRIS assessment, and an overall decrease in the uncertainty factors that needed to be applied. Our IATA approach worked well in this instance, and demonstrated several advantages by focusing on using a human-relevant in vitro model, data-driven POD modeling, and a net decrease in the overall risk assessment uncertainty factors, while maintaining the uncertainty associated with the data.
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Project description:A growing challenge for risk, vulnerability, and resilience assessment is the ability to understand, characterize, and model the complexities of our joint socioecological systems, often delineated with differing natural (e.g., watershed) and imposed (e.g., political) boundaries at the landscape scale. To effectively manage such systems in the increasingly dynamic, adaptive context of environmental change, we need to understand not just food web interactions of contaminants or the flooding impacts of sea level rise and storm surges, but rather the interplay between social and ecological components within the inherent and induced feedforward and feedback system mechanisms. Risk assessment, in its traditional implementation, is a simplification of a complex problem to understand the basic cause-and-effect relationships within a system. This approach allows risk assessors to distill a complex issue into a manageable model that quantifies, or semiquantifies, the effects of an adverse stressor. Alternatively, an integrated risk and resilience assessment moves toward a solution-based assessment with the incorporation of adaptive management practices as 1 of 4 parts of system resilience (i.e., prepare, absorb, recover, and adapt), and directly considers the complexities of the systems being modeled. We present the Multilevel Risk and Resilience Assessment Parameterization framework for the systematic parameterization and deconstruction of management objectives and goals into assessment metrics and quantifiable risk measurement metrics and complementary resilience measurement metrics. As a proof-of-concept, the presented framework is paired with the Bayesian Network-Relative Risk Model for a human-focused subset of a larger risk and resilience assessment of climate change impacts within the Charleston Harbor Watershed of South Carolina. This new parameterization framework goes beyond traditional simplification and embraces the complexity of the system as a whole, which is necessary for a more representative analysis of an open, dynamic complex system. Integr Environ Assess Manag 2021;17:131-146. © 2020 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).
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Project description:The volatilome profile of some biofluids (blood, urine, and human semen) identified by Solid-Phase Microextraction-Gas Chromatography/Mass Spectrometry (SPME-GC/MS) and collected from young men living in two high-pollution areas in Italy, i.e., Land of Fires and Valley of Sacco River, have been coupled to sperm parameters obtained by spermiogram analysis to build general multiple regression models. Panels of volatile organic compounds (VOCs) have been selected to optimize the models and used as predictive variables to estimate the different sperm quality parameters (sperm cell concentration, total and progressive motility/immotile cells, total/head/neck/tail morphology anomalies, semen round cell concentration). The results of the multiple linear regression models based on the different subgroups of data joining VOCs from one/two or three biofluids have been compared. Surprisingly, the models based on blood and urine VOCs have allowed an excellent estimate of spermiogram values, paving the way towards a new method of indirect evaluation of semen quality and preventive screening. The significance of VOCs in terms of toxicity and dangerousness was discussed with the support of chemical databases available online.
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Project description:Mechanistic toxicology provides a powerful approach to inform on the safety of chemicals and the development of safe-by-design compounds. Although toxicogenomics supports mechanistic evaluation of chemical exposures, its implementation into the regulatory framework is hindered by uncertainties in the analysis and interpretation of such data. The use of mechanistic evidence through the adverse outcome pathway (AOP) concept is promoted for the development of new approach methodologies (NAMs) that can reduce animal experimentation. However, to unleash the full potential of AOPs and build confidence into toxicogenomics, robust associations between AOPs and patterns of molecular alteration need to be established. Systematic curation of molecular events to AOPs will create the much-needed link between toxicogenomics and systemic mechanisms depicted by the AOPs. This, in turn, will introduce novel ways of benefitting from the AOPs, including predictive models and targeted assays, while also reducing the need for multiple testing strategies. Hence, a multi-step strategy to annotate AOPs is developed, and the resulting associations are applied to successfully highlight relevant adverse outcomes for chemical exposures with strong in vitro and in vivo convergence, supporting chemical grouping and other data-driven approaches. Finally, a panel of AOP-derived in vitro biomarkers for pulmonary fibrosis (PF) is identified and experimentally validated.
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Project description:The common chemical and biological properties of antisense oligonucleotides provide the opportunity to identify and characterize chemical class effects across species. The chemical class that has proven to be the most versatile and best characterized is the 2'-O-methoxyethyl chimeric antisense oligonucleotides. In this report we present an integrated safety assessment of data obtained from controlled dose-ranging studies in nonhuman primates (macaques) and healthy human volunteers for 12 unique 2'-O-methoxyethyl chimeric antisense oligonucleotides. Safety was assessed by the incidence of safety signals in standardized laboratory tests for kidney and liver function, hematology, and complement activation; as well as by the mean test results as a function of dose level over time. At high doses a number of toxicities were observed in nonhuman primates. However, no class safety effects were identified in healthy human volunteers from this integrated data analysis. Effects on complement in nonhuman primates were not observed in humans. Nonhuman primates predicted safe doses in humans, but over predicted risk of complement activation and effects on platelets. Although limited to a single chemical class, comparisons from this analysis are considered valid and accurate based on the carefully controlled setting for the specified study populations and within the total exposures studied.
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Project description:PURPOSE:Assess the impact of false-positives (FP), false-negatives (FN), fixation losses (FL), and test duration (TD) on visual field (VF) reliability at different stages of glaucoma severity. DESIGN:Retrospective. PARTICIPANTS:A total of 10?262 VFs from 1538 eyes of 909 subjects with suspect or manifest glaucoma and ?5 VF examinations. METHODS:Predicted mean deviation (MD) was calculated with multilevel modeling of longitudinal data. Differences between predicted and observed MD (?MD) were calculated as a reliability measure. The impact of FP, FN, FL, and TD on ?MD was assessed using multilevel modeling. MAIN OUTCOME MEASURES:?MD associated with a 10% increment in FP, FN, and FL, or a 1-minute increase in TD. RESULTS:FL had little impact on ?MD (<0.2 decibels [dB] per 10% abnormal catch trials), and no level of FL produced ?1 dB of ?MD at any disease stage. FP yielded greater than expected MD, with a 10% increment in abnormal catch trials associated with a ?MD = 0.42, 0.73, and 0.66 dB in mild (MD >-6 dB), moderate (-6 ?MD <-12 dB), and severe (-12 ?MD ?-20 dB) disease, respectively, up to 20% abnormal catch trials, and a ?MD = 1.57, 2.06, and 3.53 dB beyond 20% abnormal catch trials. FNs generally produced observed MDs below expected MDs. FN were minimally impactful up to 20% abnormal catch trials (?MD per 10% increment >-0.14 dB at all levels of severity). Beyond 20% abnormal catch trials, each 10% increment in abnormal catch trials was associated with a ?MD = -1.27, -0.53, and -0.51 dB in mild, moderate, and severe disease, respectively. |?MD| ?1 dB occurred with 22% FP and 26% FN in early, 14% FP and 34% FN in moderate, and 16% FP and 51% FN in severe disease. A 1-minute increment in TD produced ?MDs between -0.35 and -0.40 dB. CONCLUSIONS:FL have little impact on reliability in patients with established glaucoma. FP, and to a lesser extent FNs and TD, significantly affect reliability. The impact of FP and FN varies with disease severity and over the range of abnormal catch trials. On the basis of our findings, we present evidence-based, severity-specific standards for classifying VF reliability for clinical or research applications.
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Project description:Lactiplantibacillus plantarum PMO 08 has been used as a probiotic starter culture for plant-based fermented beverages, with various health-promoting effects such as cholesterol-lowering and anti-inflammatory activities. This study aimed to analyze the genome sequence of Lp. plantarum PMO 08 and identify its safety and probiotic characteristics at the genomic level. For this, complete genome sequencing was conducted to investigate the genes associated with risk and probiotic characteristics by using Pacbio combined with Illumina HiSeq. This bacterial strain has one circular chromosome of 3,247,789 bp with 44.5% G + C content and two plasmids of 50,296 bp with 39.0% G + C content and 19,592 bp with 40.5% G + C content. Orthologous average nucleotide identity analysis showed that PMO 08 belongs to the Lp. plantarum group with 99.14% similarity to Lp. plantarum WCFS1. No deleterious genes were determined in the virulence factor analysis, and no hemolysin activity or secondary bile salt synthesis were detected in vitro test. In the case of antibiotic resistance analysis, PMO 08 was resistant to ampicillin in vitro test, but these genes were not transferable. In addition, the strain showed same carbohydrate utilization with Lp. plantarum WCFS1, except for mannopyranoside, which only our strain can metabolize. The strain also harbors a gene for inositol monophosphatase family protein related with phytate hydrolysis and have several genes for metabolizing various carbohydrate which were rich in plant environment. Furthermore, in probiotic characteristics several genes involved in phenotypes such as acid/bile tolerance, adhesion ability, and oxidative stress response were detected in genome analysis. This study demonstrates that Lp. plantarum PMO 08 harbors several probiotic-related genes (with no deleterious genes) and is a suitable probiotic starter for plant-based fermentation.
| S-EPMC9529155 | biostudies-literature