Time-dependent assessment

Time-dependent assessment. This allows for assessing the probability of failure as a function of time and for representing basic events which have a variable probability rate [see NASA Fault Tree Handbook, paragraph 7.7]. 

The complexity of the mathematics for time-dependent assessment and component models mean this type of modelling can only realistically be achieved using computer software, and its usefulness is limited to very specific scenarios where accepted rate-based probabilities cannot be applied or approximated. 

A useftil applicadon of time-dependent PL is the assessment of the quality of thin III-V semiconductor alloy layers and interfaces, such as those used in the fabri-cadon of diode lasers. For example, at room temperature, a diode laser made with high-quality materials may show a slow decay of the acdve region PL over several ns, whereas in low-quality materials nonradiative centers (e.g., oxygen) at die cladding interface can rapidly deplete the free-carder population, resulting in much shorter decay times. Measurements of lifetime are significandy less dependent on external condidons than is the PL intensity. 

Adamo, C., Scuseria, G. E., Barone, V., 1999, Accurate Excitation Energies from Time-Dependent Density Functional Theory Assessing the PBE0 Model , J. Chem. Phys., Ill, 2889. 

The time dependence of the time domain solution is derived entirely from the roots of the polynomial in the denominator (what we will refer to later as the poles). The polynomial in the numerator affects only the coefficients a. This is one reason why we make qualitative assessment of the dynamic response characteristics entirely based on the poles of the characteristic polynomial. 

The O Flaherty Model simulates the age-dependence of lead kinetics on such factors as absorption efficiency, excretion efficiency, uptake into bone and loss from bone, and partitioning between plasma and red blood cells. The model does not incorporate age, dose rate, or time dependence of lead accumulation in every organ (e g., kidney) because the complex patterns of lead accumulation in certain tissues are not known (O Flaherty 1991a) (see Section 2.4.1). However, the basic model structure allows for additional modules to be incorporated, depending on its intended use in risk assessment. For example, additional modules that are currently being developed are a pregnancy model and a model of net bone loss in older women and men. 

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

Crump, K.S., and R.B.Howe. 1984. The multistage model with a time-dependent dose pattern Applications to carcinogenic risk assessment. Risk Anal 4 163-176. 

The research on the flow regimes in packed tubes suggests that laminar flow CFD simulations should be reasonable for Re <100 approximately, and turbulent simulations for Re >600, also approximately. Just as RANS models provide steady solutions that are regarded as time averages of the real time-dependent turbulent flow, it may be suggested that CFD simulations in the unsteady laminar inertial range 100 time-averaged picture of the flow field. As with wall functions, comparisons with experimental data and an improved assessment of what information is really needed from the simulations will inform us as to how to proceed in these areas. 

Thermal stabilities were assessed by the time-dependent change of melt viscosity at a constant temperature and shear rate (290°C, 50 s"1 respectively). Figure 6.4 shows that three ofthe six resins showed a significant drop in viscosity as a function of time at 290°C. The average decrease in viscosity for Kel-F 6050, Alcon 3000, and an experimental suspension is 37%. 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

Atkinson, A., Kenny, J.R. and Grime, K. (2005) Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography-tandem mass spectrometry analysis. Drug Metabolism and Disposition, 33 (11), 1637—1647. 

In addition, the time-dependence of these concentrations also contains (albeit in encoded form) the homogeneous parameters of the particular mechanism being considered. These latter techniques are termed convolutions. Convolution (and its reverse, i.e. deconvolution) are ideal for the electroanalyst because the theoretical calculation of current, and direct comparison with experimental data, is often not viable. This alternative of testing experimental currents via convolutions results in expressions for concentrations at the electrode which arise directly from the data rather than requiring iterations(s). The electrode concentrations thus estimated for a particular mechanism then allow for correlations to be drawn between potential and time, thereby assessing the fit between the data and the model. 

The outputs can create consequences to personnel, structures, and equipment. There are different approaches for assessing consequences. Criteria can be developed that will allow the analyst to compare the results of the calculations to predetermined criteria. The results either meet or exceed the criteria. These criteria can be established based on a conservative approach of assuming a steady-state condition. Another approach is the use of more sophisticated heat transfer techniques, where a time-dependent onset of critical criteria is modeled. 

Because the mechanisms of 1-naphtol complexation with HA obtained by using these three techniques exhibit similar pathways, we present the results only from fluorescence spectroscopy. The ratio of fluorescence intensity in the absence (FJ and in the presence (F) of the quencher (HA) over time, as affected by pH and ionic strength, are illustrated in Fig. 16.20. The fluorescence intensity of a fluorophore in the absence of a quencher is directly proportional to its concentration in solution, and therefore time-dependent changes in E can be used to assess the stability of 1-naphtol under different pH and ionic strength. Quenching (FQ) of 1-naphtol fluorescence by humic acid increased with equilibration time from one to seven days. This time-dependent relationship was found to result from weak complexation of... 

To assess this methodology s diagnostic capability in impaired livers, a partial hepatectomy was surgically performed on three rats, followed by measurement of the time dependence of fluorescence at the ear pre- and post-injection of ICG. Fig. 10 depicts the comparison of clearance rates between normal and impaired functioning livers. The time constants for the rats with normal and dysfunctional livers are shown in Table 1. The difference between the animals with normal and impaired livers is huge and quantifiable. 

Furthermore, since the cell growth arrest is often linked to cell death. The annexin V staining positive cell or the amount of DNA fragmentation assessed by TUNEL and FACS analysis has been interpreted as indicative of apoptosis. The HDACI-induced apoptosis can also be determined by Western blotting of target proteins, detection of mitochondrial membrane potentials, activation of caspases and their substrate cleavages in a dose- and time-dependent manner. 

Yamamoto, T., Suzuki, A. and Kohno, Y. (2004) High-throughput screening for the assessment of time-dependent inhibitions of new drug candidates on... 

New biomarkers will be useful in hepatotoxicity risk assessment if the data quality and validity can be established. The FDA defines a valid biomarker as one that can be measured in an analytical test system with well-established performance characteristics and has an established scientific framework or body of evidence that elucidates the significance of the test results [160]. Although there is no formerly agreed upon path, biomarker validation should include appropriate end-points for study (i.e., toxicology, histopathology, bioanalytical chemistry, etc.) and dose- and time-dependent measurements. An assessment of species, sex and strain susceptibility is also important to evaluate across species differences. More specific considerations for validation of gene and protein expression technologies are reviewed by Corvi et al. and Rifai et al. [144, 147]. 

Characterization Robust assessment of dose- and time-dependent effects Able to identify more sensitive measmes of toxicity Expensive, usually low amoimt of replicates... 

Additional studies have examined time-dependent molecular events associated with developmental toxicity in mouse embryos (102-104) and differentiating cardiomyocytes from embryonic stem cells (105). These initial time-response studies show the power and sensitivity of toxicogenomic assessments to characterize the timing of molecular changes that associate with developmental toxicity outcomes. 

YuXetal (2006) A system-based approach to interpret dose- and time-dependent microarray data quantitative integration of gene ontology analysis for risk assessment. Toxicol Sci 92 560-577. doi kfjl84 (pii)10.1093/ toxsci/kfjl84... 

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