Toxicokinetic Model Development for the Insensitive Munitions Component 3-Nitro-1,2,4-Triazol-5-One

2015 ◽  
Vol 34 (5) ◽  
pp. 408-416
Author(s):  
Lisa M. Sweeney ◽  
Elizabeth A. Phillips ◽  
Michelle R. Goodwin ◽  
Desmond I. Bannon
Keyword(s):  
Model Development ◽  
Scientific Basis ◽  
In Vivo Studies ◽  
Limited Data ◽  
Blood Concentrations ◽  
Physiologically Based Pharmacokinetic ◽  
Insensitive Munitions ◽  
Toxicokinetic Model ◽  
Exposure Levels

3-Nitro-1,2,4-triazol-5-one (NTO) is a component of insensitive munitions that are potential replacements for conventional explosives. Toxicokinetic data can aid in the interpretation of toxicity studies and interspecies extrapolation, but only limited data on the toxicokinetics and metabolism of NTO are available. To supplement these limited data, further in vivo studies of NTO in rats were conducted and blood concentrations were measured, tissue distribution of NTO was estimated using an in silico method, and physiologically based pharmacokinetic models of the disposition of NTO in rats and macaques were developed and extrapolated to humans. The model predictions can be used to extrapolate from designated points of departure identified from rat toxicology studies to provide a scientific basis for estimates of acceptable human exposure levels for NTO.

scholarly journals Computational models for contact current dosimetry at frequencies below 1 MHz

2020 ◽  
Author(s):  
Pia Schneeweiss ◽  
Dorin Panescu ◽  
Dominik Stunder ◽  
Mark W. Kroll ◽  
Christopher J. Andrews ◽  
...  
Keyword(s):  
Computational Models ◽  
Scientific Basis ◽  
The Body ◽  
In Vivo Studies ◽  
International Electrotechnical Commission ◽  
Safety Standards ◽  
Body Model ◽  
Current Path ◽  
Cadaver Studies

AbstractElectric contact currents (CC) can cause muscle contractions, burns, or ventricular fibrillation which may result in life-threatening situations. In vivo studies with CC are rare due to potentially hazardous effects for participants. Cadaver studies are limited to the range of tissue’s electrical properties and the utilized probes’ size, relative position, and sensitivity. Thus, the general safety standards for protection against CC depend on a limited scientific basis. The aim of this study was therefore to develop an extendable and adaptable validated numerical body model for computational CC dosimetry for frequencies between DC and 1 MHz. Applying the developed model for calculations of the IEC heart current factors (HCF) revealed that in the case of transversal CCs, HCFs are frequency dependent, while for longitudinal CCs, the HCFs seem to be unaffected by frequency. HCFs for current paths from chest or back to hand appear to be underestimated by the International Electrotechnical Commission (IEC 60479-1). Unlike the HCFs provided in IEC 60479-1 for longitudinal current paths, our work predicts the HCFs equal 1.0, possibly due to a previously unappreciated current flow through the blood vessels. However, our results must be investigated by further research in order to make a definitive statement. Contact currents of frequencies from DC up to 100 kHz were conducted through the numerical body model Duke by seven contact electrodes on longitudinal and transversal paths. The resulting induced electric field and current enable the evaluation of the body impedance and the heart current factors for each frequency and current path.

scholarly journals Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Jane C. Caldwell ◽  
Marina V. Evans ◽  
Kannan Krishnan
Keyword(s):  
Risk Assessment ◽  
Model Development ◽  
Pbpk Modeling ◽  
Human Populations ◽  
Pbpk Models ◽  
Modeling Process ◽  
Physiologically Based Pharmacokinetic ◽  
State Of The Science

Physiologically based Pharmacokinetic (PBPK) models are used for predictions of internal or target dose from environmental and pharmacologic chemical exposures. Their use in human risk assessment is dependent on the nature of databases (animal or human) used to develop and test them, and includes extrapolations across species, experimental paradigms, and determination of variability of response within human populations. Integration of state-of-the science PBPK modeling with emerging computational toxicology models is critical for extrapolation betweenin vitroexposures,in vivophysiologic exposure, whole organism responses, and long-term health outcomes. This special issue contains papers that can provide the basis for future modeling efforts and provide bridges to emerging toxicology paradigms. In this overview paper, we present an overview of the field and introduction for these papers that includes discussions of model development, best practices, risk-assessment applications of PBPK models, and limitations and bridges of modeling approaches for future applications. Specifically, issues addressed include: (a) increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population, (b) exploration of mode of action hypotheses (MOA), (c) application of biological modeling in the risk assessment of individual chemicals and chemical mixtures, and (d) identification and discussion of uncertainties in the modeling process.

Toxicokinetic Model Development for the Insensitive Munitions Component 2,4-Dinitroanisole

2015 ◽  
Vol 34 (5) ◽  
pp. 417-432 ◽  
Author(s):  
Lisa M. Sweeney ◽  
Michelle R. Goodwin ◽  
Angela D. Hulgan ◽  
Chester P. Gut ◽  
Desmond I. Bannon
Keyword(s):  
Model Development ◽  
Armed Forces ◽  
Laboratory Animals ◽  
Sprague Dawley ◽  
Exposure Limits ◽  
Tissue Samples ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Insensitive Munitions ◽  
Sprague Dawley Rats

The Armed Forces are developing new explosives that are less susceptible to unintentional detonation (insensitive munitions [IMX]). 2,4-Dinitroanisole (DNAN) is a component of IMX. Toxicokinetic data for DNAN are required to support interpretation of toxicology studies and refinement of dose estimates for human risk assessment. Male Sprague-Dawley rats were dosed by gavage (5, 20, or 80 mg DNAN/kg), and blood and tissue samples were analyzed to determine the levels of DNAN and its metabolite 2,4-dinitrophenol (DNP). These data and data from the literature were used to develop preliminary physiologically based pharmacokinetic (PBPK) models. The model simulations indicated saturable metabolism of DNAN in rats at higher tested doses. The PBPK model was extrapolated to estimate the toxicokinetics of DNAN and DNP in humans, allowing the estimation of human-equivalent no-effect levels of DNAN exposure from no-observed adverse effect levels determined in laboratory animals, which may guide the selection of exposure limits for DNAN.

scholarly journals Azithromycin and Hydroxychloroquine combination: The future pharmacotherapy of COVID-19

2020 ◽  
Vol 7 (2) ◽  
pp. 54-57
Author(s):  
Ananya Shukla ◽  
Pornasha Mohabeer ◽  
Abhishek Kashyap ◽  
Jared Robinson ◽  
Indrajit Banerjee
Keyword(s):  
Macrolide Antibiotic ◽  
Qt Prolongation ◽  
In Vivo Studies ◽  
Specific Drug ◽  
Limited Data ◽  
The World ◽  
The Future ◽  
Future Drug

Background: In response to the urgency of increasing death toll due to COVID-19, caused due to SARS CoV-2, various drugs are under clinical trial, as there is no specific drug for its treatment. In an international survey that was recently conducted in which about 7500 physicians participated from all over the world considered that Hydroxychloroquine and Azithromycin were among the most effective ones for the pharmacotherapy of COVID-19. Azithromycin is a macrolide antibiotic whose mechanism of action against COVID-19 is still unknown, but various theories have been postulated. In vitro and in vivo studies have been conducted; however, their results are quite contradictory. Azithromycin is said to increase the risk of QT prolongation in elderly patients and when given in combination with Hydroxychloroquine can increase the risk of Torsade’s de pointes. Therefore, caution has to be paid before prescribing Azithromycin. Conclusion: The mass loss of human lives is regrettable and needs to be stopped as soon as possible. Azithromycin could be the future drug for COVID-19, but such limited data is insufficient to support the drug's safety or efficacy and needs to be reconsidered.

scholarly journals A Physiologically Based Pharmacokinetic Model for Naphthalene With Inhalation and Skin Routes of Exposure

2020 ◽  
Vol 177 (2) ◽  
pp. 377-391
Author(s):  
Dustin F Kapraun ◽  
Paul M Schlosser ◽  
Leena A Nylander-French ◽  
David Kim ◽  
Erin E Yost ◽  
...  
Keyword(s):  
Pbpk Model ◽  
Human Health Risk ◽  
Blood Concentrations ◽  
Exposure Study ◽  
Skin Exposure ◽  
Human Data ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Abstract Naphthalene, a volatile organic compound present in moth repellants and petroleum-based fuels, has been shown to induce toxicity in mice and rats during chronic inhalation exposures. Although simpler default methods exist for extrapolating toxicity points of departure from animals to humans, using a physiologically based pharmacokinetic (PBPK) model to perform such extrapolations is generally preferred. Confidence in PBPK models increases when they have been validated using both animal and human in vivo pharmacokinetic (PK) data. A published inhalation PBPK model for naphthalene was previously shown to predict rodent PK data well, so we sought to evaluate this model using human PK data. The most reliable human data available come from a controlled skin exposure study, but the inhalation PBPK model does not include a skin exposure route; therefore, we extended the model by incorporating compartments representing the stratum corneum and the viable epidermis and parameters that determine absorption and rate of transport through the skin. The human data revealed measurable blood concentrations of naphthalene present in the subjects prior to skin exposure, so we also introduced a continuous dose-rate parameter to account for these baseline blood concentration levels. We calibrated the three new parameters in the modified PBPK model using data from the controlled skin exposure study but did not modify values for any other parameters. Model predictions then fell within a factor of 2 of most (96%) of the human PK observations, demonstrating that this model can accurately predict internal doses of naphthalene and is thus a viable tool for use in human health risk assessment.

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