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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 775 records · Page 43
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Evaluating the influence of life‐history characteristics on genetic structure: a comparison of small mammals inhabiting complex agricultural landscapes

Abstract Conversion of formerly continuous native habitats into highly fragmented landscapes can lead to numerous negative demographic and genetic impacts on native taxa that ultimately reduce population viability. In response to concerns over biodiversity loss, numerous investigators have proposed that traits such as body size and ecological specialization influence the sensitivity of species to habitat fragmentation. In this study, we examined how differences in body size and ecological specialization of two rodents (eastern chipmunk; Tamias striatus and white‐footed mouse; Peromyscus leucopus ) impact their genetic connectivity within the highly fragmented landscape of the Upper Wabash River Basin ( UWB ), Indiana, and evaluated whether landscape configuration and complexity influenced patterns of genetic structure similarly between these two species. The more specialized chipmunk exhibited dramatically more genetic structure across the UWB than white‐footed mice, with genetic differentiation being correlated with geographic distance, configuration of intervening habitats, and complexity of forested habitats within sampling sites. In contrast, the generalist white‐footed mouse resembled a panmictic population across the UWB , and no landscape factors were found to influence gene flow. Despite the extensive previous work in abundance and occupancy within the UWB , no landscape factor that influenced occupancy or abundance was correlated with genetic differentiation in either species. The difference in predictors of occupancy, abundance, and gene flow suggests that species‐specific responses to fragmentation are scale dependent.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Infrared Spectroscopic Study of Magnetic Behavior of Dysprosium Doped Magnetite Nanoparticles

Dysprosium doped magnetite (Fe{sub 3−x}Dy{sub x}O{sub 4} with x = 0.0–0.1) nanoparticles have been synthesized using the co-precipitation method. Magnetic characterization using vibrating sample magnetometer (VSM) has revealed an enhancement in the saturation magnetization with Dy{sup 3+} doping. The occupancy of the dopant ions in magnetite lattice has been probed using Fourier transform infrared spectroscopy (FTIR). The shifting of ν{sub 2} (Fe–O) band at 452 cm{sup − 1} for undoped samples to 443 cm{sup − 1} for dysprosium-doped samples is indicative of occupancy of dysprosium at the octahedral site. X-ray diffraction (XRD) patterns have been used to calculate the strain and lattice constant. The strain is found to increase with doping level and attained a maximum value for the x = 0.03. This increase in the strain can be attributed to occupancy of large diameter Dy{sup 3+} ions at the octahedral site of spinel structure of the magnetite lattice.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2020

Spectrum of embrittling potencies and relation to properties of symmetric-tilt grain boundaries

Grain boundaries in metallic materials can exist in a wide range of stable and metastable structures. In addition, the properties of a grain boundary may be altered through solute segregation. In this work, we present a formulation that combines the spectrum of embrittling potencies associated with solute segregation with site-occupancy statistics. As a prototype problem, we illustrate the relation between segregation and embrittlement in the case of S segregation to grain boundaries in Ni. To obtain a population of site segregation energies, we perform molecular statics calculations on 378 different symmetric-tilt grain boundaries and their free surface equivalents, using an embedded-atom method interatomic potential developed specifically for studying embrittlement. Our results show that it is important to consider both the energies associated with embrittlement and the probability of occupancy to describe the general embrittling nature of a grain boundary. When analyzed in isolation, certain grain boundaries show large embrittling potencies; however, that effect is diminished when the probability of S segregation to that grain boundary is considered within a polycrystal. We propose a new quantity, the embrittling estimator, which not only categorizes grain boundaries as embrittling or strengthening, but also considers site occupancy probabilities, so that the embrittlement behavior of grain boundaries within a network of grain boundaries can be compared. Finally, we examine the relationship between embrittlement behavior and innate grain boundary properties, such as the free volume, and find statistical evidence that the complex nature of embrittlement cannot be explained by linear correlations with excess volumes or energies. Ultimately, this combined approach provides a theoretical tool to assist grain boundary engineering of metastable alloys.

36 MATERIALS SCIENCE↗
DOE OSTI2017

Modeling of HVAC operational faults in building performance simulation

Operational faults are common in the heating, ventilating, and air conditioning (HVAC) systems of existing buildings, leading to a decrease in energy efficiency and occupant comfort. Various fault detection and diagnostic methods have been developed to identify and analyze HVAC operational faults at the component or subsystem level. However, current methods lack a holistic approach to predicting the overall impacts of faults at the building level—an approach that adequately addresses the coupling between various operational components, the synchronized effect between simultaneous faults, and the dynamic nature of fault severity. This study introduces the novel development of a fault-modeling feature in EnergyPlus which fills in the knowledge gap left by previous studies. This paper presents the design and implementation of the new feature in EnergyPlus and discusses in detail the fault-modeling challenges faced. The new fault-modeling feature enables EnergyPlus to quantify the impacts of faults on building energy use and occupant comfort, thus supporting the decision making of timely fault corrections. Including actual building operational faults in energy models also improves the accuracy of the baseline model, which is critical in the measurement and verification of retrofit or commissioning projects. As an example, EnergyPlus version 8.6 was used to investigate the impacts of a number of typical operational faults in an office building across several U.S. climate zones. Finally, the results demonstrate that the faults have significant impacts on building energy performance as well as on occupant thermal comfort. Finally, the paper introduces future development plans for EnergyPlus fault-modeling capability.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗
DOE OSTI2019

Rethinking HVAC temperature setpoints in commercial buildings: The potential for zero-cost energy savings and comfort improvement in different climates, Building and Environment

Heating, Ventilation, and Air Conditioning (HVAC) systems are responsible for a significant share of the energy consumed in commercial buildings. While energy system retrofits have been found to reduce buildings' carbon footprint substantially, these measures are often hindered by financial, regulatory or design constraints. Recent research sheds light on energy management approaches to energy conservation such as energy-efficient settings of HVAC temperature setpoints. While existing case studies confirm the significant energy saving potential of efficient HVAC operation, there is scarcity of studies quantifying energy savings from optimal HVAC temperature setpoints comprehensively, while controlling for important factors, such as guaranteeing tenant thermal comfort levels and the impact of different climate conditions on the results. In this work, we apply simulation-based multi-objective optimization to fine-tune heating and cooling setpoints of large “typical” office buildings with respect to energy consumption and occupant thermal comfort. We apply the framework in seven climate zones across the US in an effort to examine spatial variations in the energy savings potential due to different climate conditions and propose targeted energy-saving strategies and policies. We show that locations with mild climates, such as San Francisco, CA, can realize up to 60% of annual HVAC-related energy savings without compromising the occupants' thermal comfort. This untapped potential to simultaneously improve building performance and occupants’ comfort drives the discussion on revisiting HVAC setpoint configuration standards in commercial buildings, either as part of individual building retrofit planning or as part of energy policy regulations.

Papadopoulos, Sokratis↗
DOE OSTI2018

Clustering and statistical analyses of air-conditioning intensity and use patterns in residential buildings

Energy conservation in residential buildings has gained increased attention due to its large portion of global energy use and potential of energy savings. Occupant behavior has been recognized as a key factor influencing the energy use and load diversity in buildings, therefore more realistic and accurate air-conditioning (AC) operating schedules are imperative for load estimation in equipment design and operation optimization. With the development of sensor technology, it became easier to access an increasing amount of heating/cooling data from thermal energy metering systems in residential buildings, which provides another possible way to understand building energy usage and occupant behaviors. However, except for cooling energy consumption benchmarking, there currently lacks effective and easy approaches to analyze AC usage and provide actionable insights for occupants. To fill this gap, this study proposes clustering analysis to identify AC use patterns of residential buildings, and develops new key performance indicators (KPIs) and data analytics to explore the AC operation characteristics using the long-term metered cooling energy use data, which is of great importance for inhabitants to understand their thermal energy use and save energy cost through adjustment of their AC use behavior. We demonstrate the proposed approaches in a residential district comprising 300 apartments, located in Zhengzhou, China. Main outcomes include: Representative AC use patterns are developed for three room types of residential buildings in the cold climate zone of China, which can be used as more realistic AC schedules to improve accuracy of energy simulation; Distributions of KPIs on household cooling energy usage are established, which can be used for household AC use intensity benchmarking and performance diagnoses.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2020

State-of-the-art on research and applications of machine learning in the building life cycle

Fueled by big data, powerful and affordable computing resources, and advanced algorithms, machine learning has been explored and applied to buildings research for the past decades and has demonstrated its potential to enhance building performance. This study systematically surveyed how machine learning has been applied at different stages of building life cycle. By conducting a literature search on the Web of Knowledge platform, we found 9579 papers in this field and selected 153 papers for an in-depth review. The number of published papers is increasing year by year, with a focus on building design, operation, and control. However, no study was found using machine learning in building commissioning. There are successful pilot studies on fault detection and diagnosis of HVAC equipment and systems, load prediction, energy baseline estimate, load shape clustering, occupancy prediction, and learning occupant behaviors and energy use patterns. None of the existing studies were adopted broadly by the building industry, due to common challenges including (1) lack of large scale labeled data to train and validate the model, (2) lack of model transferability, which limits a model trained with one data-rich building to be used in another building with limited data, (3) lack of strong justification of costs and benefits of deploying machine learning, and (4) the performance might not be reliable and robust for the stated goals, as the method might work for some buildings but could not be generalized to others. Finally, findings from the study can inform future machine learning research to improve occupant comfort, energy efficiency, demand flexibility, and resilience of buildings, as well as to inspire young researchers in the field to explore multidisciplinary approaches that integrate building science, computing science, data science, and social science.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2025

Framework to select robust energy retrofit measures for residential communities

Residential building energy retrofits are essential for enhancing environmental sustainability and reducing energy costs. The selection of retrofit measures is influenced by factors such as building systems, occupant behavior, government policy, weather variability, and climate change, all of which can significantly impact energy performance. Compared to retrofitting individual homes, evaluating and selecting optimal retrofit solutions for an entire community is challenging due to diverse residential compositions and variability present. Therefore, engineering robustness is crucial for ensuring consistent energy performance and resilience across different conditions. In this context, robustness refers to the ability of a retrofit measure to maintain its functionality and remain an optimal choice despite external disturbances or changes in inputs and conditions. This study presents a framework for evaluating the robustness of multiple retrofit measures across various building systems, occupant behaviors, and environmental scenarios at the community level. The framework comprises five key steps: scenario model development, integration of the National Residential Efficiency Measures database, energy performance simulation, cost-benefit aggregation, and retrofit solution selection. Each step enhances the framework’s robustness by incorporating the diversity of building characteristics, occupant behaviors, environmental conditions, retrofit options, and evaluation criteria. The framework’s effectiveness is demonstrated through a case study in southern Michigan in the United States, which includes 63 one-story single-family houses, 121 two-story single-family houses, and 8 townhouses. The study identifies furnace retrofits as the most robust solution for the entire community, consistently achieving source energy reductions of 4.7 %–8.0 % and payback period of 10–20 years across various scenarios. These findings are consistent with previous research, indicating the framework’s potential for broader applications in optimizing community-scale residential energy retrofits.

Shu, Lei↗
DOE OSTI2024

Assessing thermal comfort and participation in residential demand flexibility programs

Residential space-conditioning-based demand flexibility (DF) has become an increasingly sought-after method for demand-side load management to enhance grid reliability and facilitate integration of renewable energy generation. However, predicting the effectiveness and flexibility of residential DF resources is challenging due to the variability in household energy use behaviors. Current estimates show that only 50 % of projected savings from DF resources are actualized due to regulatory, technological, and social barriers. From a household perspective, concerns over thermal comfort during space conditioning-based DF events significantly impact participation decisions. Currently, there is a very limited understanding of how thermal comfort during space-conditioning-based DF events in real-world settings impacts household energy use behaviors and, consequently, the success of DF programs in achieving targeted savings. This paper proposes a method to comprehensively assess the thermal comfort implications of DF strategies and presents results of their impacts on DF event participation decisions and demand savings. Here, the proposed method was applied to a heat pump DF field study in Cordova, Alaska. The study’s key findings are: 1) DF event setpoint offsets that maintain indoor operative temperatures between 18 to 22 °C (65 to 71°F) may be preferred in Cordova, Alaska; 2) Household-level thermal comfort is more sensitive to the duration of the DF event than to the degree of temperature offset from baseline conditions; 3) The delayed impact of changes in indoor operative temperature in response to setpoint offsets, both during and after a DF event, influences occupants’ thermal comfort perceptions and willingness to persistently participate in events. The findings from application of the proposed method can help inform future larger-scale occupant-centric DF programs as it can capture information not readily available through utility and device-level energy use data. Thus, it can supplement these sources and help program administrators develop occupant-centric DF strategies, enabling more accurate predictions of participation rates and savings estimates for space-conditioning-based DF programs.

Demand side management↗
DOE OSTI2016

Determinants of serum cadmium levels in a Northern Italy community: A cross-sectional study

Introduction: Cadmium (Cd) is a heavy metal and a serious environmental hazard to humans. Some uncertainties still exist about major sources of Cd exposure in non-occupationally exposed subjects in addition to cigarette smoking, such as diet and outdoor air pollution. We sought to determine the influence of these sources on a biomarker of exposure, serum Cd concentration. Methods: We recruited 51 randomly selected residents from an Italian urban community, from whom we obtained detailed information about dietary habits and smoking habits, and a blood sample for serum Cd determination. We also assessed outdoor air Cd exposure, by modeling outdoor air levels of particulate matter ≤10 µm (PM{sub 10}) from motorized traffic at geocoded subjects’ residence. Results: In crude analysis, regression beta coefficients for dietary Cd, smoking and PM10 on serum Cd levels were 0.03 (95% CI -0.83 to 0.88), 6.96 (95% CI -0.02 to 13.95) and 0.62 (95% CI -0.19 to 1.43), respectively. In the adjusted analysis, regression beta coefficients were -0.34 (95% CI -1-40 to 0.71), 5.81 (95% CI -1.43 to 13.04) and 0.47 (95% CI -0.35 to 1.29), respectively. Conclusion: Cigarette smoking was the most important factor influencing serum Cd in our non-occupationally exposed population, as expected, while dietary Cd was not associated with this biomarker. Outdoor air pollution, as assessed through exposure to particulate matter generated by motorized traffic, was an additional source of Cd exposure. - Highlights: • Smoking markedly increases serum Cd levels in non-occupationally exposed individuals. • Overall dietary Cd intake shows little association with serum Cd levels. • Air pollution from motorized traffic increases serum Cd levels.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Dirty dishes or dirty laundry? Comparing two methods for quantifying American consumers' preferences for load management in a smart home

One challenge of transitioning to renewable energy is that household electricity use and renewable generation are often misaligned. Smart home energy management systems hold promise for shifting usage to match generation, but these systems need to be designed with the occupants’ preferences in mind. The purpose of the present research is to compare two approaches for collecting and modeling consumers’ load management preferences, both of which are amenable to use in a home energy management system. Specifically, we examine the performance of Simple Multi-Attribute Rating Technique Exploiting Ranks (SMARTER) and Analytic Hierarchy Process (AHP) in quantifying consumers’ preferences regarding air temperature (air conditioning and heating), water heating, dishwashing, clothes washing and drying, monetary costs, environmental impacts, and comfort/convenience. Two studies are presented: Study 1 examines the SMARTER approach, and Study 2 focuses on the AHP approach. In both studies, online surveys (N SMARTER = 956 and N AHP = 1023) were conducted to elicit preferences from participants across the United States. The preferences modeled by both approaches were validated based on (a) their ability to predict participants’ choices in a Discrete Choice Experiment and (b) their convergence with previous research on load-shifting behavior. The validation procedure suggests that the SMARTER approach is superior in modeling consumers’ preferences for load management. Overall, this research lays the groundwork for designing a smart home interface capable of collecting occupants’ preferences and using those preferences to deliver improved occupant comfort, lower operating costs, reduced environmental impact, and more significant demand response than exists today.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2019

Opacity of shock-heated boron plasmas

Standard measures of opacity, the imaginary part of the atomic scattering factor f 2 and the x-ray mass attenuation coefficient μ/ρ, are assessed in shock-heated boron, boron carbide and boron nitride plasmas. The Hugoniot equation, relating the temperature T behind a shock wave to the compression ratio ρ/ρ 0 across the shock front, is used in connection with the plasma equation of state to determine the pressure p, effective plasma charge Z* and the K-shell occupation in terms of ρ/ρ 0 . Solutions of the Hugoniot equation (determined within the framework of the generalized Thomas–Fermi theory) show that the K-shell occupation in low-Z ions decreases rapidly from 2 to 0.1 as the temperature increases from 20 eV to 500 eV; a temperature range in which the shock compression ratio is near 4. The average-atom model (a quantum mechanical version of the generalized Thomas–Fermi theory) is used to determine K-shell and continuum wave functions and the photoionization cross section for x-rays in the energy range ω = 1 eV to 10 keV, where the opacity is dominated by the atomic photoionization process. For an uncompressed boron plasma at T = 10 eV, where the K-shell is filled, the average-atom cross section, the atomic scattering factor and the mass attenuation coefficient are all shown to agree closely with previous (cold matter) tabulations [1, 2, 3]. For shock-compressed plasmas, the dependence of μ/ρ on temperature can be approximated by scaling previously tabulated cold-matter values by the relative K-shell occupation; yet, there is a relatively small residual dependence arising from the photoionization cross section. Attenuation coefficients μ for a 9 keV x-ray are given as functions of T along the Hugoniot for B, C, B 4 C and BN plasmas.

52.25.Os: Emission↗
DOE OSTI2017

Large structural modulations in the relaxor ferroelectric and intermediate state of strontium rich members (x>0.6) of the Sr{sub x}Ba{sub 1−x}Nb{sub 2}O{sub 6} (sbn) solid solution series

The amplitudes of the positional, occupational and adp modulations of sbn mixed crystals are strongly enhanced for high strontium contents. The increase of structural modulations is accompanied by reduced spontaneous electric polarization largely due to smaller off-center shifts of the niobium atoms. Beyond the room temperature ferroelectric – intermediate transition near x=0.77, anomal large U{sub 33} atomic displacement parameters of the niobium atoms indicate static disorder caused by loss of orientational coupling between residual shifts of Nb atoms in neighboring NbO{sub 6} octahedra. Change of satellite intensities show a reduction from two-dimensional to one-dimensional modulation which is not consistent with tetragonal symmetry. The pseudo-tetragonally twinned crystal structure of sbn82 was refined in the orthorhombic super-space group A2mm(½0γ)000. The apparent tetragonal symmetry of the other investigated sbn samples also seems to be due to pseudo tetragonal twinning with equal twin volumes. The modulations mainly consist of cooperatively tilted NbO{sub 6} octahedra and wave-like ordered incomplete occupation of the largest cation sites (Me2a and b) by Ba{sup 2+} and Sr{sup 2+}. Furthermore, the atomic displacement parameters of the Me2 sites are strongly modulated. - Graphical abstract: Satellite reflections and modulation coefficients in the solid solution series Sr{sub x}Ba{sub 1−x}Nb{sub 2}O{sub 6}. - Highlights: • The modulationed structures are refined for the whole composition range of sbn32–sbn82 in tetragonal and orthorhombic setting. • The amplitudes of positional, occupational and adp modulations increase strongly with the strontium content. • Evidence is presented that the sbn crystals are pseudo tetragonally twinned. • The ferroelectric–intermediate paraelectric transition is not accompanied by a change of symmetry. • Anomal adp of intermediate (non-ferroelectric) sbn82 indicate loss of coupling between off-center shifts of neighboring niobium.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2017

Quaternary rare-earth sulfides RE{sub 3}M{sub 0.5}GeS{sub 7} (RE=La–Nd, Sm; M=Co, Ni) and Y{sub 3}Pd{sub 0.5}SiS{sub 7}

The two metal-deficient series of quaternary Ge-containing sulfides RE{sub 3}M{sub 0.5}GeS{sub 7} (RE = La–Nd, Sm; M = Co, Ni), as well as the related Si-containing sulfide Y{sub 3}Pd{sub 0.5}SiS{sub 7}, were prepared by reactions of the elements at 1050 °C. Single-crystal X-ray diffraction analysis performed on all compounds confirmed noncentrosymmetric hexagonal structures (space group P6{sub 3}, Z =2) with cell parameters in the ranges of a =10.0–10.3 Å and c =5.7–5.8 Å for RE{sub 3}Co{sub 0.5}GeS{sub 7} and RE{sub 3}Ni{sub 0.5}GeS{sub 7}, or a =9.7891(3) Å and c =5.6840(4) Å for Y{sub 3}Pd{sub 0.5}SiS{sub 7}. They are classified as La{sub 3}Mn{sub 0.5}SiS{sub 7}-type structures, with M atoms centred within octahedra (in contrast to La{sub 3}CuSiS{sub 7}-type structures in which M atoms occupy trigonal planar sites) and Ge atoms centred within tetrahedra, both types of polyhedra being arranged in one-dimensional stacks aligned along the c-direction. Charge balance requirements dictate half-occupancy of the M sites. However, bond valence sum arguments indicated that the M atoms are somewhat underbonded within these octahedral sites, so that there is evidence that in some compounds, they can also enter the trigonal planar site at low occupancy (~5%). Magnetic measurements on RE{sub 3}Co{sub 0.5}GeS{sub 7} (RE = Ce, Pr, Sm) revealed paramagnetic behaviour for the Ce and Pr members and apparent antiferromagnetic ordering (T{sub N} =14 K) for the Sm member; fitting to the Curie-Weiss law gave effective magnetic moments consistent with the presence of RE{sup 3+} and Co{sup 2+} species. Band structure calculations on ordered models of La{sub 3}M{sub 0.5}GeS{sub 7} (M = Co, Ni) showed that the Fermi level cuts through M 3d states in the DOS curve and supported the presence of strong M–S and Ge–S bonding interactions. - Graphical abstract: RE{sub 3}M{sub 0.5}GeS{sub 7} (M = Co, Ni) and Y{sub 3}Pd{sub 0.5}SiS{sub 7} contain M atoms partially occupying octahedral and, in some cases, trigonal planar sites within noncentrosymmetric hexagonal structures. - Highlights: • The missing M = Co and Ni series in hexagonal RE{sub 3}M{sub 0.5}GeS{sub 7} have been prepared. • Charge balance is ensured through half occupancy of octahedral M sites. • In some cases, a secondary trigonal planar M site is occupied at very low levels. • Magnetic measurements on RE{sub 3}Co{sub 0.5}GeS{sub 7} support presence of RE{sup 3+} and Co{sup 2+}.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

The Kalahari sediments and hominins in southern Africa

In this study, the temporal coupling of the structural evolution of the Kalahari Basin and the accumulation of the Kalahari Group sediments has been an accepted paradigm leading to the assumption that the Kalahari group sediments have been accumulating gradually since the mid-Cretaceous. Here we review the first actual ages for the Kalahari Group based on cosmogenic ages from six geological localities. These results demonstrate that Kalahari Basin infill was a more dynamic process than previously thought and that the Kalahari Group sediments are mostly Plio-Pleistocene in age (~4 Ma to 1–2 Ma). The hiatus between the initial structural subsidence of the basin, during the Cretaceous, and the general young age of the investigated sediments, implies a dynamic landscape in which significant phases of erosion occurred during the Mesozoic and Cenozoic. The magnitude of erosion is manifested by the fact that in many locations Kalahari Neogene to Quaternary sediments overlie Precambrian basement. The age of the present infill of the Kalahari thus falls within the temporal range of the genus Homo. In light of this new understanding, we provide a review of the archaeological evidence from the Kalahari Basin and along its southern fringe. Initial hominin presence is found at Wonderwerk Cave during the Olduvai Event and there is subsequent high-density occupation along the southern fringe of the Kalahari Basin during the Acheulean and the Fauresmith. Middle Stone Age occupation is limited to localities of limited size and small artifact counts and it appears that the focus of human occupation, particularly in the later stages of the Middle Stone Age, shifts southward, including along the coastal regions.

58 GEOSCIENCES↗
DOE OSTI2015

Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates lower M{sub 2} occupancy at bronchoprotective doses. • Glycopyrrolate demonstrates an improved CV safety profile, versus tiotropium.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling—The importance of homeostatic control for an essential metal

A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. > 10 μg/m{sup 3}) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to “convert” an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls. - Highlights: • Manganese is an essential nutrient, adding complexity to its risk assessment. • Nonlinearities in biological processes are important for manganese risk assessment. • A PBPK model was used to estimate target tissue concentrations of manganese. • An MOS approach also considered target tissue concentrations for ambient exposures. • Relationships between ambient Mn exposures and dose-to-target tissue are not linear.

60 APPLIED LIFE SCIENCES↗