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An overview of the issues: physiological effects of bed rest and restricted physical activity

Reduction of exercise capacity with confinement to bed rest is well recognized. Underlying physiological mechanisms include dramatic reductions in maximal stroke volume, cardiac output, and oxygen uptake. However, bed rest by itself does not appear to contribute to cardiac dysfunction. Increased muscle fatigue is associated with reduced muscle blood flow, red cell volume, capillarization and oxidative enzymes. Loss of muscle mass and bone density may be reflected by reduced muscle strength and higher risk for injury to bones and joints. The resultant deconditioning caused by bed rest can be independent of the primary disease and physically debilitating in patients who attempt to reambulate to normal active living and working. A challenge to clinicians and health care specialists has been the identification of appropriate and effective methods to restore physical capacity of patients during or after restricted physical activity associated with prolonged bed rest. The examination of physiological responses to bed rest deconditioning and exercise training in healthy subjects has provided significant information to develop effective rehabilitation treatments. The successful application of acute exercise to enhance orthostatic stability, daily endurance exercise to maintain aerobic capacity, or specific resistance exercises to maintain musculoskeletal integrity rather than the use of surgical, pharmacological, and other medical treatments for clinical conditions has been enhanced by investigation and understanding of underlying mechanisms that distinguish physical deconditioning from the disease. This symposium presents an overview of cardiovascular and musculoskeletal deconditioning associated with reduced physical work capacity following prolonged bed rest and exercise training regimens that have proven successful in ameliorating or reversing these adverse effects.

NASA Program Space Physiology and Countermeasures

Thermal Systems Modeling of Chemical Integrated Power Source (CHIPS) to Survive Lunar Night Environments

This paper presents the results of the systems level thermal modeling for a conceptual Chemical Heat Integrated Power Source (CHIPS). This proposed system offers a combined thermal and electrical power source to support survival of spacecraft operating in extreme low temperature lunar environments, without the use of radioisotope-based sources. A conceptual design study has been completed for this system, that uses heat generated by an exothermic chemical reaction in place of radioisotope or electrical heat sources. The goal of the study was to evaluate the feasibility of such as system through thermodynamic and chemical analysis and thermal modeling, and to identify technology gaps to inform a technology development and maturation plan. The specific technical objectives focused on delivery of 90-100 Wth thermal power and 30-40 We electrical power for 336 hours to a representative Commercial Lunar Payload Services (CLPS) lander, to support lunar surface survival and limited operations through a lunar night. The total system mass was targeted at ≤50 kg. A highly exothermic chemical reaction system is used to generate on-board electrical power for spacecraft systems, and thermal power to maintain critical spacecraft/lander systems within their allowable flight temperature (AFTs). Based on the very high energy content of the chemical reaction system, a much higher amount of heat per unit mass can be delivered to the spacecraft, relative to a rechargeable lithium-ion battery and electrical heater(s). Since radioisotope heaters or generators are not used, the system will be orders of magnitude lower in cost than a radioisotope heating/power unit, without the attendant regulatory complexities. As part of the CHIPS concept, a fraction of the thermal power generated is converted to electrical power via an appropriate thermal-to-electric converter technology (such as a free piston Stirling converter or a thermoelectric generator module), to provide power to critical loads. This approach is ideally suited to support operation of commercial landers (e.g., via the CLPS program). In most cases, these landers are only designed to operate during a portion of the lunar day, with no provision for survival through the lunar night. By supporting lunar night survival, a mission can be extended through the lunar night and at least into another lunar day, thus turning a nominal eight-day mission into a 36-day mission. Therefore, the current system demonstration will focus on scalability to support at least 336 hours (one lunar night) of continuous thermal and electrical power generation. Although initially targeted to support lunar equatorial landings, the technology is extensible to missions at the lunar poles, other extreme environments in the Solar System or even air-independent applications on Earth (e.g., ocean exploration).

West, William

Thermal Systems Modeling of Chemical Heat Integrated Power Source (CHIPS) to Survive Lunar Night Environments

This paper presents the results of the systems level thermal modeling for a conceptual Chemical Heat Integrated Power Source (CHIPS). This proposed system offers a combined thermal and electrical power source to support survival of spacecraft operating in extreme low temperature lunar environments, without the use of radioisotope-based sources. A conceptual design study has been completed for this system, that uses heat generated by an exothermic chemical reaction in place of radioisotope or electrical heat sources. The goal of the study was to evaluate the feasibility of such a system through thermodynamic and chemical analysis and thermal modeling, and to identify technology gaps to inform a technology development and maturation plan. The specific technical objectives focused on delivery of 90 to 100 Wth thermal power and 30 to 40 We electrical power for 336 hours to a representative Commercial Lunar Payload Services (CLPS) lander, to support lunar surface survival and limited operations through a lunar night. The total system mass was targeted at ≤50 kg. A highly exothermic chemical reaction system is used to generate on-board electrical power for spacecraft systems, and thermal power to maintain critical spacecraft/lander systems within their allowable flight temperature (AFTs). Based on the very high energy content of the chemical reaction system, a much higher amount of heat per unit mass can be delivered to the spacecraft, relative to a rechargeable lithium-ion battery and electrical heater(s). Since radioisotope heaters or generators are not used, the system will be orders of magnitude lower in cost than a radioisotope heating/power unit, without the attendant regulatory complexities. As part of the CHIPS concept, a fraction of the thermal power generated is converted to electrical power via an appropriate thermal-to-electric converter technology (such as a free piston Stirling converter or a thermoelectric generator module), to provide power to critical loads. This approach is ideally suited to support operation of commercial landers (e.g., via the CLPS program). In most cases, these landers are only designed to operate during a portion of the lunar day, with no provision for survival through the lunar night. By supporting lunar night survival, a mission can be extended through the lunar night and at least into another lunar day, thus turning a nominal eight-day mission into a 36-day mission. Therefore, the current system demonstration will focus on scalability to support at least 336 hours (one lunar night) of continuous thermal and electrical power generation. Although initially targeted to support lunar equatorial landings, the technology is extensible to missions at the lunar poles, other extreme environments in the Solar System or even air-independent applications on Earth (e.g., ocean exploration).

West, William

Cell Science and Cell Biology Research at MSFC: Summary

The common theme of these research programs is that they investigate regulation of gene expression in cells, and ultimately gene expression is controlled by the macromolecular interactions between regulatory proteins and DNA. The NASA Critical Path Roadmap identifies Muscle Alterations and Atrophy and Radiation Effects as Very Serious Risks and Severe Risks, respectively, in long term space flights. The specific problem addressed by Dr. Young's research ("Skeletal Muscle Atrophy and Muscle Cell Signaling") is that skeletal muscle loss in space cannot be prevented by vigorous exercise. Aerobic skeletal muscles (i.e., red muscles) undergo the most extensive atrophy during long-term space flight. Of the many different potential avenues for preventing muscle atrophy, Dr. Young has chosen to study the beta-adrenergic receptor (betaAR) pathway. The reason for this choice is that a family of compounds called betaAR agonists will preferentially cause an increase in muscle mass of aerobic muscles (i.e., red muscle) in animals, potentially providing a specific pharmacological solution to muscle loss in microgravity. In addition, muscle atrophy is a widespread medical problem in neuromuscular diseases, spinal cord injury, lack of exercise, aging, and any disease requiring prolonged bedridden status. Skeletal muscle cells in cell culture are utilized as a model system to study this problem. Dr. Richmond's research ("Radiation & Cancer Biology of Mammary Cells in Culture") is directed toward developing a laboratory model for use in risk assessment of cancer caused by space radiation. This research is unique because a human model will be developed utilizing human mammary cells that are highly susceptible to tumor development. This approach is preferential over using animal cells because of problems in comparing radiation-induced cancers between humans and animals.

Source record

Insect gravitational biology: ground-based and shuttle flight experiments using the beetle Tribolium castaneum

Many of the traditional experimental advantages of insects recommend their use in studies of gravitational and space biology. The fruit fly, Drosophila melanogaster, is an obvious choice for studies of the developmental significance of gravity vectors because of the unparalleled description of regulatory mechanisms controlling oogenesis and embryogenesis. However, we demonstrate that Drosophila could not survive the conditions mandated for particular flight opportunities on the Space Shuttle. With the exception of Drosophila, the red flour beetle, Tribolium castaneum, is the insect best characterized with respect to molecular embryology and most frequently utilized for past space flights. We show that Tribolium is dramatically more resistant to confinement in small sealed volumes. In preparation for flight experiments we characterize the course and timing of the onset of oogenesis in newly eclosed adult females. Finally, we present results from two shuttle flights which indicate that a number of aspects of the development and function of the female reproductive system are not demonstrably sensitive to microgravity. Available information supports the utility of this insect for future studies of gravitational biology.

NASA Discipline Developmental Biology

Initial Experimental Airworthiness Certification Guidance for UAS. UAS Experimental Certification Process and Guidance

This paper addresses the regulatory processes and requirements already in place by which an applicant might obtain experimental airworthiness certification for a civil Unmanned Aircraft System (UAS). It is more extensive and subsequent to an earlier, similar deliverable, PD007, which was an interim study of the same topic. Since few regulatory airworthiness and operating standards exist for UAS like those for traditional manned aircraft and since most UAS have historically been developed and operated under military auspices, civil use of UAS in the NAS is a new and unfamiliar challenge requiring specific and unique considerations. Experimental certification is the most basic level of FAA approval toward routine UAS operation in the NAS. The paper reviews and explains existing FAA requirements for an applicant seeking experimental airworthiness approval and details the process for submission of necessary information. It summarizes the limited purposes for which experimental aircraft may be used and addresses pertinent aspects of UAS design, construction and operation in the NAS in harmony with traditional manned aircraft. Policy IPT position is that UAS, while different from manned aircraft, can use the same initial processes to gain civil operating experience under the experimental approval. Particular note is taken of those UAS-unique characteristics which require extra attention to assure equivalent safety of operation, such as the UAS control station and sense-and-avoid. The paper also provides "best practices" guidance for UAS manufacturers and FAA personnel in two appendices. The material in Appendix A is intended to provide guidance on assuring UAS safety to FAA, and provides FAA personnel with a suggested list of items to review, with a focus on UAS unique factors, prior to issuance of an experimental airworthiness certificate. Appendix B provides an outline for a program letter which a manufacturer could use in preparing the application for an UAS experimental airworthiness certificate.

Source record

Developmental gene regulatory network architecture across 500 million years of echinoderm evolution

Evolutionary change in morphological features must depend on architectural reorganization of developmental gene regulatory networks (GRNs), just as true conservation of morphological features must imply retention of ancestral developmental GRN features. Key elements of the provisional GRN for embryonic endomesoderm development in the sea urchin are here compared with those operating in embryos of a distantly related echinoderm, a starfish. These animals diverged from their common ancestor 520-480 million years ago. Their endomesodermal fate maps are similar, except that sea urchins generate a skeletogenic cell lineage that produces a prominent skeleton lacking entirely in starfish larvae. A relevant set of regulatory genes was isolated from the starfish Asterina miniata, their expression patterns determined, and effects on the other genes of perturbing the expression of each were demonstrated. A three-gene feedback loop that is a fundamental feature of the sea urchin GRN for endoderm specification is found in almost identical form in the starfish: a detailed element of GRN architecture has been retained since the Cambrian Period in both echinoderm lineages. The significance of this retention is highlighted by the observation of numerous specific differences in the GRN connections as well. A regulatory gene used to drive skeletogenesis in the sea urchin is used entirely differently in the starfish, where it responds to endomesodermal inputs that do not affect it in the sea urchin embryo. Evolutionary changes in the GRNs since divergence are limited sharply to certain cis-regulatory elements, whereas others have persisted unaltered.

NASA Program Fundamental Space Biology

A mutation in protein phosphatase 2A regulatory subunit A affects auxin transport in Arabidopsis

The phytohormone auxin controls processes such as cell elongation, root hair development and root branching. Tropisms, growth curvatures triggered by gravity, light and touch, are also auxin-mediated responses. Auxin is synthesized in the shoot apex and transported through the stem, but the molecular mechanism of auxin transport is not well understood. Naphthylphthalamic acid (NPA) and other inhibitors of auxin transport block tropic curvature responses and inhibit root and shoot elongation. We have isolated a novel Arabidopsis thaliana mutant designated roots curl in NPA (rcn1). Mutant seedlings exhibit altered responses to NPA in root curling and hypocotyl elongation. Auxin efflux in mutant seedlings displays increased sensitivity to NPA. The rcn1 mutation was transferred-DNA (T-DNA) tagged and sequences flanking the T-DNA insert were cloned. Analysis of the RCN1 cDNA reveals that the T-DNA insertion disrupts a gene for the regulatory A subunit of protein phosphatase 2A (PP2A-A). The RCN1 gene rescues the rcn1 mutant phenotype and also complements the temperature-sensitive phenotype of the Saccharomyces cerevisiae PP2A-A mutation, tpd3-1. These data implicate protein phosphatase 2A in the regulation of auxin transport in Arabidopsis.

Non-NASA Center

NASA's Efforts to Commercialize Communications Services for Mission in Near-Earth Space

The National Aeronautics and Space Administration (NASA) Space Communications and Navigation (SCaN)Program enables high speed, robust, secure and cost-effective space communications and navigation services to current and future science and exploration missions. Consistent with National Space Policy, NASA is pursuing the use of demonstrated commercial services for all its future near-Earth requirements through a flexible, multi-provider approach that minimizes risks to the user missions and ensures costs to user missions are reasonable. Progress toward this goal is advancing in multiple key areas including direct to Earth (DTE), space-based relay, technology investments, required spectrum regulatory changes and mission engagement and infusion. The transition to commercial DTE services is already underway, with a target for transition by 2024. The primary functions to execute SCaN’s DTE strategy include increasing commercial service allocations by leveraging current commercial network providers and enabling seamless onboarding of additional providers into the network. Furthermore, moving away from government DTE services will allow operational costs to be optimized. A more gradual approach is planned for the transition to commercial space-based relay services to allow for demonstration and operationalization of commercial services for future users by 2030. In June of 2022, six American SATCOM vendors were awarded a combined $278.5 million through Funded Space Act Agreements (FSAAs) for the first cycle of demonstration and validation activities. The end-to-end service capabilities being targeted are based on existing NASA mission operational needs. Accordingly, each company has proposed a technical approach to lower costs, increase flexibility, and improve performance for a broad range of missions. Successful user mission transition to commercial services, both DTE and space-based relay, are dependent on the technologies and capabilities that address gaps in commercial capability. NASA is investing in technology development and pursuing a new strategic approach to the creation or adoption of space communications standards to move the agency toward a commercial paradigm. Wideband and multi-lingual user terminals are being developed to bridge differences in industry services. Building on ground demonstrations completed in 2021, the Johns Hopkins Applied Physics Lab (APL) will be flight testing a multi-lingual wideband terminal (payload) and demonstrating connectivity to both government and commercial relay services. NASA holds a leadership role in multiple civil space standards bodies and international coordination groups to ensure that standards supporting interoperability are developed with defined functions, interfaces, and performance. However, to successfully meet commercialization objectives, NASA seeks to collaborate with industry, and as applicable adopt or adapt to commercially defined standards. As such, NASA joined the 3rd Generation Partnership Project (3GPP) as an official member in 2021 to advocate for the inclusion of space missions as a unique user segment in future 5G non-terrestrial networks, and to better understand the scope of 3GPP releases and implications for space users. Further, engagement in Spectrum regulatory bodies is being undertaken to augment existing space-Earth and inter-satellite frequency allocations available for both government and commercial space systems. This paper addresses the recent progress toward NASA’s commercial space communications transition objectives and how key challenges are being navigated.

Gregory W Heckler

Nutrition and renal stone disease in space

There is a growing body of evidence from the National Aeronautics and Space Administration and the Russian space program showing that humans exposed to the microgravity environment of space have a greater risk for developing renal stones. Increased bone resorption and the attendant hypercalciuria and hyperphosphaturia contribute significantly to raising the urinary state of saturation with respect to the calcium salts, namely calcium oxalate and calcium phosphate. In addition, other environmental and dietary factors may adversely affect urine composition and increase stone formation risk during space flight. For example, reductions in urinary volume, pH, and citrate contribute to raising stone formation risk. In addition to raising the risk for calcium stone formation, this metabolic profile is conducive to the formation of uric acid stones. Although observations to date have suggested that there may actually be a reduced food intake during the early phase of flight, crew members on longer-duration flights may increase food intake and be at increased risk for stone formation. Taken together, these findings support the use of nutritional recommendations for crew members that would serve to reduce the stone-forming propensity of the urinary environment. Pharmacologic intervention should be directed at raising urinary volumes, diminishing bone losses, and preventing reductions in urinary pH and citrate. Success in reducing the risk for stone formation in astronauts would also be of potential major benefit to the estimated 20 million Americans with nephrolithiasis.

Review

Activation of microcarrier-attached lymphocytes in microgravity

A technology has been developed to achieve optimal attachment of adhesion-independent lymphocytes to microcarrier beads. The activation of T-lymphocytes by concanavalin A was tested under microgravity conditions in an experiment carried out in space during the first Spacelab Life Science Mission. Activation, measured as the synthesis of deoxyribonucleic acid (DNA) and the production of interferon-gamma, more than doubled in attached lymphocytes in microgravity. The depression of the activation discovered in previous space experiments is due to an impairment not of the lymphocyte but of the macrophage function. The system described here may be useful for radiobiological investigations on the effect of high-energy particles and for testing the efficiency of the immune system in humans during the long-duration space flight planned in the future. The biotechnological significance of the increased lymphokine production in space remains to be assessed.

Non-NASA Center

Conservation of Endo16 expression in sea urchins despite evolutionary divergence in both cis and trans-acting components of transcriptional regulation

Evolutionary changes in transcriptional regulation undoubtedly play an important role in creating morphological diversity. However, there is little information about the evolutionary dynamics of cis-regulatory sequences. This study examines the functional consequence of evolutionary changes in the Endo16 promoter of sea urchins. The Endo16 gene encodes a large extracellular protein that is expressed in the endoderm and may play a role in cell adhesion. Its promoter has been characterized in exceptional detail in the purple sea urchin, Strongylocentrotus purpuratus. We have characterized the structure and function of the Endo16 promoter from a second sea urchin species, Lytechinus variegatus. The Endo16 promoter sequences have evolved in a strongly mosaic manner since these species diverged approximately 35 million years ago: the most proximal region (module A) is conserved, but the remaining modules (B-G) are unalignable. Despite extensive divergence in promoter sequences, the pattern of Endo16 transcription is largely conserved during embryonic and larval development. Transient expression assays demonstrate that 2.2 kb of upstream sequence in either species is sufficient to drive GFP reporter expression that correctly mimics this pattern of Endo16 transcription. Reciprocal cross-species transient expression assays imply that changes have also evolved in the set of transcription factors that interact with the Endo16 promoter. Taken together, these results suggest that stabilizing selection on the transcriptional output may have operated to maintain a similar pattern of Endo16 expression in S. purpuratus and L. variegatus, despite dramatic divergence in promoter sequence and mechanisms of transcriptional regulation.

NASA Discipline Evolutionary Biology

Planetary protection, legal ambiguity and the decision making process for Mars sample return

As scientists and mission planners develop planetary protection requirements for future Mars sample return missions, they must recognize the socio-political context in which decisions about the mission will be made and pay careful attention to public concerns about potential back contamination of Earth. To the extent that planetary protection questions are unresolved or unaddressed at the time of an actual mission, they offer convenient footholds for public challenges in both legal and decision making realms, over which NASA will have little direct control. In this paper, two particular non-scientific areas of special concern are discussed in detail: 1) legal issues and 2) the decision making process. Understanding these areas is critical for addressing legitimate public concerns as well as for fulfilling procedural requirements regardless whether sample return evokes public controversy. Legal issues with the potential to complicate future missions include: procedural review under National Environmental Policy Act (NEPA); uncertainty about institutional control and authority; conflicting regulations and overlapping jurisdictions; questions about international treaty obligations and large scale impacts; uncertanities about the nature of the organism; and constitutional and regulatory concerns about quarantine, public health and safety. In light of these important legal issues, it is critical that NASA consider the role and timing of public involvement in the decision making process as a way of anticipating problem areas and preparing for legitimate public questions and challenges to sample return missions.

NASA Discipline Number 59-10

A mathematical model of diurnal variations in human plasma melatonin levels

Studies in animals and humans suggest that the diurnal pattern in plasma melatonin levels is due to the hormone's rates of synthesis, circulatory infusion and clearance, circadian control of synthesis onset and offset, environmental lighting conditions, and error in the melatonin immunoassay. A two-dimensional linear differential equation model of the hormone is formulated and is used to analyze plasma melatonin levels in 18 normal healthy male subjects during a constant routine. Recently developed Bayesian statistical procedures are used to incorporate correctly the magnitude of the immunoassay error into the analysis. The estimated parameters [median (range)] were clearance half-life of 23.67 (14.79-59.93) min, synthesis onset time of 2206 (1940-0029), synthesis offset time of 0621 (0246-0817), and maximum N-acetyltransferase activity of 7.17(2.34-17.93) pmol x l(-1) x min(-1). All were in good agreement with values from previous reports. The difference between synthesis offset time and the phase of the core temperature minimum was 1 h 15 min (-4 h 38 min-2 h 43 min). The correlation between synthesis onset and the dim light melatonin onset was 0.93. Our model provides a more physiologically plausible estimate of the melatonin synthesis onset time than that given by the dim light melatonin onset and the first reliable means of estimating the phase of synthesis offset. Our analysis shows that the circadian and pharmacokinetics parameters of melatonin can be reliably estimated from a single model.

NASA Discipline Number 70-10

Epstein-Barr virus DNA loads in adult human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy

Patients with human immunodeficiency virus type 1 (HIV-1) infection are at high risk of developing Epstein-Barr virus (EBV)-associated lymphoma. However, little is known of the EBV DNA loads in patients receiving highly active antiretroviral therapy (HAART). Using a real-time quantitative polymerase chain reaction assay, we demonstrated that significantly more HIV-1-infected patients receiving HAART than HIV-1-uninfected volunteers had detectable EBV DNA in blood (57 [81%] of 70 vs. 11 [16%] of 68 patients; P=.001) and saliva (55 [79%] of 68 vs. 37 [54%] of 68 patients; P=.002). The mean EBV loads in blood and saliva samples were also higher in HIV-1-infected patients than in HIV-1-uninfected volunteers (P=.001). The frequency of EBV detection in blood was associated with lower CD4+ cell counts (P=.03) among HIV-1-infected individuals, although no differences were observed in the EBV DNA loads in blood or saliva samples in the HIV-1-infected group. Additional studies are needed to determine whether EBV-specific CD4+ and CD8+ cells play a role in the pathogenesis of EBV in HIV-1-infected patients receiving HAART.

NASA Discipline Regulatory Physiology

Regulatory and Technical Issues Concerning the Detection and Treatment of NDMA-Contaminated Groundwater at NASA WSTF

The National Aeronautics and Space Administration (NASA) White Sands Test Facility (WSTF) was established in 1963 primarily to provide rocket engine testing services for several NASA programs. The groundwater underlying the site has been contaminated as a result of historical operations. Groundwater contaminants include several volatile organic compounds (VOCs) and two semi-volatile compounds: N-nitrosodimethylamine (NDMA) and N-nitrodimethylamine (DMN). This paper discusses some of the technical, analytical, regulatory, and health risk issues associated with the contaminant plume. The plume has moved approximately 2.5 miles downgradient of the facility industrial boundary, with evidence of continued migration. As a result, NASA has proposed a pump and treat system using air strippers and ultraviolet (UV) oxidation to stabilize future movement of the contaminant plume. The system has been designed to treat 1,076 gallons (4,073 liters) per minute, with provisions for future expansion. The UV oxidation process was selected to treat NDMA-contaminated groundwater based on successes at other NDMA-contaminated sites. Bench- and pilot-scale testing of WSTF groundwater confirmed the ability of UV oxidation to destroy NDMA and generated sufficient data to design the proposed full-scale treatment system. NDMA is acutely toxic and is a probable human carcinogen. EPA-recommended health risk criteria for the residential consumption of NDMA/DMN-contaminated groundwater was used to determine that a 1.0 x 10(exp -6) excess cancer risk corresponds to 1.7 parts per trillion (ppt). EPA analytical methods are unable to detect NDMA and DMN in the low ppt range. EPA's current Appendix IX analytical method used to screen for NDMA, Method 8270, can detect NDMA only at levels that are orders of magnitude greater than the recommended health risk level. Additionally, EPA Method 607, the most sensitive EPA approved method, has a detection limit of 150 ppt. This corresponds to an excess cancer risk of 9.0 x 10(exp -5), which exceeds the State of New Mexico's water quality standard of a cancer risk less than 1 x 10(exp -5). The treatment system has been engineered to treat contaminated groundwater to levels significantly below the New Mexico standard. However, the inability of EPA-approved analytical methods to detect NDMA and DMN at low ppt levels, and to provide verification of compliance with the 1 x 10(exp -5) cancer risk, introduces a notable risk to the long-term operation of the system. WSTF has been working with Southwest Research Institute to develop a non-EPA analytical method that can achieve a reporting limit of 1 ppt, which corresponds to an excess cancer risk of 7.6 x 10(exp -7). WSTF is currently developing a proposal to obtain approval from the New Mexico Environment Department (NMED) of this non-EPA method.

Wiebe, D. T.

Mass balance approaches for estimating the intestinal absorption and metabolism of peptides and analogues: theoretical development and applications

A theoretical analysis for estimating the extent of intestinal peptide and peptide analogue absorption was developed on the basis of a mass balance approach that incorporates convection, permeability, and reaction. The macroscopic mass balance analysis (MMBA) was extended to include chemical and enzymatic degradation. A microscopic mass balance analysis, a numerical approach, was also developed and the results compared to the MMBA. The mass balance equations for the fraction of a drug absorbed and reacted in the tube were derived from the general steady state mass balance in a tube: [formula: see text] where M is mass, z is the length of the tube, R is the tube radius, Pw is the intestinal wall permeability, kr is the reaction rate constant, C is the concentration of drug in the volume element over which the mass balance is taken, VL is the volume of the tube, and vz is the axial velocity of drug. The theory was first applied to the oral absorption of two tripeptide analogues, cefaclor (CCL) and cefatrizine (CZN), which degrade and dimerize in the intestine. Simulations using the mass balance equations, the experimental absorption parameters, and the literature stability rate constants yielded a mean estimated extent of CCL (250-mg dose) and CZN (1000-mg dose) absorption of 89 and 51%, respectively, which was similar to the mean extent of absorption reported in humans (90 and 50%). It was proposed previously that 15% of the CCL dose spontaneously degraded systematically; however, our simulations suggest that significant CCL degradation occurs (8 to 17%) presystemically in the intestinal lumen.(ABSTRACT TRUNCATED AT 250 WORDS).

Non-NASA Center

HRP's Healthcare Spin-Offs Through Computational Modeling and Simulation Practice Methodologies

Spaceflight missions expose astronauts to novel operational and environmental conditions that pose health risks that are currently not well understood, and perhaps unanticipated. Furthermore, given the limited number of humans that have flown in long duration missions and beyond low Earth-orbit, the amount of research and clinical data necessary to predict and mitigate these health and performance risks are limited. Consequently, NASA's Human Research Program (HRP) conducts research and develops advanced methods and tools to predict, assess, and mitigate potential hazards to the health of astronauts. In this light, NASA has explored the possibility of leveraging computational modeling since the 1970s as a means to elucidate the physiologic risks of spaceflight and develop countermeasures. Since that time, substantial progress has been realized in this arena through a number of HRP funded activates such as the Digital Astronaut Project (DAP) and the Integrated Medical Model (IMM). Much of this success can be attributed to HRP's endeavor to establish rigorous verification, validation, and credibility (VV&C) processes that ensure computational models and simulations (M&S) are sufficiently credible to address issues within their intended scope. This presentation summarizes HRP's activities in credibility of modeling and simulation, in particular through its outreach to the community of modeling and simulation practitioners. METHODS: The HRP requires all M&S that can have moderate to high impact on crew health or mission success must be vetted in accordance to NASA Standard for Models and Simulations, NASA-STD-7009 (7009) [5]. As this standard mostly focuses on engineering systems, the IMM and DAP have invested substantial efforts to adapt the processes established in this standard for their application to biological M&S, which is more prevalent in human health and performance (HHP) and space biomedical research and operations [6,7]. These methods have also generated substantial interest by the broader medical community though institutions like the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) to develop similar standards and guidelines applicable to the larger medical operations and research community. DISCUSSION: Similar to NASA, many leading government agencies, health institutions and medical product developers around the world are recognizing the potential of computational M&S to support clinical research and decision making. In this light, substantial investments are being made in computational medicine and notable discoveries are being realized [8]. However, there is a lack of broadly applicable practice guidance for the development and implementation of M&S in clinical care and research in a manner that instills confidence among medical practitioners and biological researchers [9,10]. In this presentation, we will give an overview on how HRP is working with the NIH's Interagency Modeling and Analysis Group (IMAG), the FDA and the American Society of Mechanical Engineers (ASME) to leverage NASA's biomedical VV&C processes to establish a new regulatory standard for Verification and Validation in Computational Modeling of Medical Devices, and Guidelines for Credible Practice of Computational Modeling and Simulation in Healthcare.

Mulugeta, Lealem