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At least 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
NASA NTRS1972

Toxic Hazards Research Unit annual technical report, 1972

The activities of the Toxic Hazards Research Unit (THRU) for the period of June 1971 through May 1972 are reviewed in this report. Acute inhalation toxicity experiments were conducted on hydrogen chloride (HCl) gas and aerosol, ethyl bromide (C2H5Br), hydrogen bromide (HBr), hydrogen sulfide (H2S), ammonia (NH3), chlorine (CL2), and silane (SiH4). Subacute toxicity studies were conducted on chlorine pentafluoride (ClF5), dichloromethane (CH2Cl2) and coal tar volatiles. Further toxicity studies of subacute and chronic responses to inhaled monomethylhydrazine (MMH) are also described.

Macewen, J. D.↗
DOE OSTI2020

Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

The use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pathogens. The haemolytic activity of the compounds was evaluated against four different species and the relative sensitivity against the compounds was highest for canine erythrocytes, intermediate for rat and human cells and lowest for bovine cells. Selected peptides were additionally evaluated against HeLa, HaCaT and HepG2 cells which showed increased stability towards the peptides. Therapeutic indexes of 50–500 suggest significant cellular selectivity in comparison to bacterial cells. Three peptides were administered to rats in intravenous acute dose toxicity studies up to 2– 8 × MIC. None of the injected compounds induced any systemic toxic effects in vivo at the concentrations employed illustrating that the correlation between the different assays is not obvious. This work sheds light on the in vitro and in vivo toxicity of this class of promising compounds and provides insights into the relationship between the different toxicity models often employed in different manners to evaluate the toxicity of novel bioactive compounds in general.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2004

Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation

Nanomaterials are part of an industrial revolution to develop lightweight but strong materials for a variety of purposes. Single-wall carbon nanotubes are an important member of this class of materials. They structurally resemble rolled-up graphite sheets, usually with one end capped; individually they are about 1 nm in diameter and several microns long, but they often pack tightly together to form rods or ropes of microscopic sizes. Carbon nanotubes possess unique electrical, mechanical, and thermal properties and have many potential applications in the electronics, computer, and aerospace industries. Unprocessed nanotubes are very light and could become airborne and potentially reach the lungs. Because the toxicity of nanotubes in the lung is not known, their pulmonary toxicity was investigated. The three products studied were made by different methods and contained different types and amounts of residual catalytic metals. Mice were intratracheally instilled with 0, 0.1, or 0.5 mg of carbon nanotubes, a carbon black negative control, or a quartz positive control and euthanized 7 d or 90 d after the single treatment for histopathological study of the lungs. All nanotube products induced dose-dependent epithelioid granulomas and, in some cases, interstitial inflammation in the animals of the 7-d groups. These lesions persisted and were more pronounced in the 90-d groups; the lungs of some animals also revealed peribronchial inflammation and necrosis that had extended into the alveolar septa. The lungs of mice treated with carbon black were normal, whereas those treated with high-dose quartz revealed mild to moderate inflammation. These results show that, for the test conditions described here and on an equal-weight basis, if carbon nanotubes reach the lungs, they are much more toxic than carbon black and can be more toxic than quartz, which is considered a serious occupational health hazard in chronic inhalation exposures.

Nanotubes, Carbon/adverse effects↗
NASA NTRS2002

Pulmonary toxicity of simulated lunar and Martian dusts in mice: II. Biomarkers of acute responses after intratracheal instillation

Volcanic ashes from Arizona and Hawaii, with chemical and mineral properties similar to those of lunar and Martian soils, respectively, are used by the National Aeronautics and Space Administration (NASA) to simulate lunar and Martian environments for instrument tests. NASA needs toxicity data on these volcanic soils to assess health risks from potential exposures of workers in facilities where these soil simulants are used. In this study we investigated the acute effects of lunar soil simulant (LSS) and Martian soil simulant (MSS), as a complement to a histopathological study assessing their subchronic effects (Lam et al., 2002). Fine dust of LSS, MSS, TiO(2), or quartz suspended in saline was intratracheally instilled into C57Bl/6J mice (4/group) in single doses of 0.1 mg/mouse or 1 mg/mouse. The mice were euthanized 4 or 24 h after the dust treatment, and bronchoalveolar lavage fluid (BALF) was obtained. Statistically significant lower cell viability and higher total protein concentration in the BALF were seen only in mice treated with the high dose of quartz for 4 h and with the high dose of MSS or quartz for 24 h, compared to mice treated only with saline. A significant increase in the percentage of neutrophils was not observed with any dust-treated group at 4 h after the instillation, but was observed after 24 h in all the dust-treated groups. This observation indicates that these dusts were not acutely toxic and the effects were gradual; it took some time for neutrophils to be recruited into and accumulate significantly in the lung. A statistically significant increase in apoptosis of lavaged macrophages from mice 4 h after treatment was found only in the high-dose silica group. The overall results of this study on the acute effects of these dusts in the lung indicate that LSS is slightly more toxic than TiO(2), and that MSS is comparable to quartz. These results were consistent with the subchronic histopathological findings in that the order of severity of lung toxicity was TiO(2) < LSS < MSS < quartz.

Non-programmatic↗
DOE OSTI2022

Patient-Reported Outcomes in the Acute Phase of the Randomized Hypofractionated Irradiation for Prostate Cancer (HYPRO) Trial

Many patients experience bowel and bladder toxicity during the acute phase of radiation therapy for prostate cancer. Recent literature indicates that hypofractionation (HF) might increase this acute response but little is known on patient-reported outcome during this phase with HF. We evaluated the course of patient-reported acute symptoms during HF versus standard fractionated (SF) radiation therapy within the hypofractionated irradiation for prostate cancer (HYPRO) trial.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS1994

Acute, 2-week, and 13-week inhalation toxicity studies on dimethylethoxysilane vapor in Fischer 344 rats

Dimethylethoxysilane (DMES), a volatile liquid, is used by NASA to waterproof the heat-protective silica tiles and blankets on the Space Shuttle. Acute, 2-wk, and 13-wk inhalation exposures to DMES vapor were conducted in male and female Fischer 344 rats. In the acute study, rats were exposed to 4000, 2000, 1000, 500, or 0 (control) ppm DMES for 4 h and observed for 14 days. There were no deaths. Narcosis and ataxia were observed in rats of the two highest concentrations only. These signs disappeared within 1 h following exposure. There were no DMES-related gross or microscopic tissue lesions in rats of all exposure groups. In the 2-wk study, rats were exposed for 6 h/day, 5 days/wk to 3000, 1000, 300, 100, or 0 ppm DMES. During exposure, narcosis was observed in rats of the 3000 and 1000 ppm groups. There was a mild decrease in body weight gain in rats of the 3000 ppm group. A decrease in platelet count, an increase in bile acids, and reduced weights of the thymus, testis, and liver were observed in rats of the 3000 ppm group. Microscopically, hypospermatogenesis and spermatid giant cells were observed in the seminiferous tubules of the testes of rats exposed to 3000 ppm DMES. In the 13-wk study, rats were exposed 6 h/day, 5 days/wk to 2000, 600, 160, 40, or 0 ppm DMES. During exposure, rats of the 2000 ppm group exhibited mild narcosis and loss of startle reflex. Recovery from these central nervous system signs was rapid. Body weights were mildly decreased for rats of the 2000 ppm group. There were no exposure-related effects in hematology, serum chemistry, or urinalysis. Female rats of the 2000 ppm group had delayed estrous cycles (6 days compared to 5 days in control rats). Noteworthy organ weight changes in rats of the 2000 ppm group included decreases in thymus, liver, and testicular weights; however, pathologic lesions were observed in the testes only. Sperm motility, epididymal sperm count, and testicular spermatid count were dramatically reduced. Microscopic lesions included degeneration of the seminiferous tubular cells, pyknosis or absence of germ cells, and hypospermia in the epididymis. Rats of the 600 ppm group had a slight decrease in thymic weight and a transient decrease in body weight. Results of the acute, 2-wk, and 13-wk inhalation studies indicate DMES concentrations of 1000 ppm and higher produce narcosis that rapidly disappears following exposure. Repeated exposure of rats to DMES at either 3000 ppm for 2 wk or 2000 ppm for 13 wk caused testicular atrophy and hypospermia in male rats. Female rats exposed to 2000 ppm for 13 wk had delayed estrous cycles. Toxicological effects in rats of the 600 ppm group were minimal and equivocal. The 160 ppm concentration was a no-observable-effect level (NOEL) for 13 wk of exposure to DMES.

NASA Discipline Number 04-10↗
NASA NTRS1993

Toxicity study of dimethylethoxysilane (DMSES), the waterproofing agent for the Orbiter heat protective system

DMES, a volatile liquid, is used by NASA to waterproof the Orbiter thermal protective system. During waterproofing operations at the Oribter Processing Facility at KSC, workers could be exposed to DMES vapor. To assess the toxicity of DMES, acute and subchronic (2-week and 13-week) inhalation studies were conducted with rats. Studies were also conducted to assess the potential of DMES. Inhalation exposure concentrations ranged from 40 ppm to 4000 ppm. No mortality was observed during the studies. Exposures to 2100 ppm produced narcosis and ataxia. Post-exposure recovery from these CNS effects was rapid (less than 1 hr). These effects were concentration-dependent and relatively independent of exposure length. Exposure to 3000 ppm for 2 weeks (5 h/d, 5 d/wk) produced testicular toxicity. The 13-week study yielded similar results. Results from the genotoxicity assays (in vivo/in vitro unscheduled DNA synthesis in rat primary heptaocytes, chromosomal aberrations in rat bone marrow cells; reverse gene mutation in Salmonella typhimurium; and forward mutation in Chinese hamster culture cells) were negative. These studies indicated that DMES is mildly to moderately toxic but not a multagen.

Lam, Chiu-Wing↗
DOE OSTI2021

Preclinical Risk Evaluation of Normal Tissue Injury With Novel Radiosensitizers

Genotoxic damage induced by radiation triggers a highly coordinated DNA damage response, and molecular inhibitors of key nodes within this complex response network can profoundly enhance the antitumor efficacy of radiation. This is especially true for drugs targeting the catalytic subunit of DNA-dependent protein kinase, which is a core component of the nonhomologous end-joining DNA repair pathway, and ataxia telangiectasia mutated, which coordinates cell cycle arrest, apoptosis, and DNA repair functionalities after radiation exposure. Unlike the more modest in vitro radiosensitizing effects seen with classic sensitizing agents such as cisplatin, 5-fluorouracil, or taxanes, DNA-dependent protein kinase or ataxia telangiectasia mutated inhibitors provide much more robust sensitizing effects in vitro, as might be anticipated from targeting these key DNA repair modulators. However, patients with homozygous inactivating mutations of ataxia telangiectasia mutated or mice with homozygous defects in DNA-dependent protein kinase (severe combined immunodeficiency) have profoundly enhanced acute normal tissue radiation reactions. Therefore, there is significant potential that the combination of small molecule inhibitors of these kinases with radiation could cause similar dose-limiting acute normal tissue toxicities. Similarly, although less understood, inhibition of these DNA repair response pathways could markedly increase the risk of late radiation toxicities. Because these potent radiosensitizers could be highly useful to improve local control of otherwise radiation-resistant tumors, understanding the potential for elevated risks of radiation injury is essential for optimizing therapeutic ratio and developing safe and informative clinical trials. In this review, we will discuss 2 straightforward models to assess the potential for enhanced mucosal toxicity in the oral cavity and small intestine established in our laboratories. We also will discuss similar strategies for evaluating potential drug–radiation interactions with regard to increased risks of debilitating late effects.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS1975

Toxicology of the air in closed spaces

Sources and identification of contaminants in artificial gas atmospheres are discussed. They include biological sources (microflora and man), materials, processes, aerosols, and malfunctions. Acute or chronic toxicity may result from spacecraft air contamination. Air quality standards are presented in tabular form.

Ralph C. Wands↗
NASA NTRS1975

Current aspects of occupational chemical carcinogenesis

The history of measures to control occupational exposure to carcinogenic substances is reviewed. Health hazards associated with exposure to a certain chemical substance must be considered not only from the aspects of its acute or chronic toxicity, but also from its potential to produce tumors (latent effect). There can be no clear distinction between classic toxicity and oncogenesis until the mechanisms of both are completely understood for a given chemical substance. The assessment of carcinogenic potential for a specific substance must include the consideration of published information, monitoring and control data from the affected industry, and the in-depth epidemiologic experience of affected employees.

Lassiter, D.↗
NASA NTRS1992

Occupational safety considerations with hydrazine

Hydrazine is a reducing agent that is most commonly used as a propellant and as an oxygen scavenger in boilers. Hydrazine is extremely irritating and has been demonstrated to produce both acute and chronic toxicity. As a result, the established permissible inhalation exposure limits are very low, and respiration protection is required whenever vapors are present. Liquid hydrazine penetrates the skin and produces a chemical burn; therefore, some protective measures must also be taken to protect the skin from liquid contact. Often, however, a cumbersome, whole-body protective suit is worn to protect against skin contact with vapor as well. To what extent it is actually necessary to protect skin from vapor penetration had not previously been demonstrated. In an attempt to answer this question, we conducted a study with rats to compare the dermal penetration of hydrazine vapor with inhalation. Pharmacokinetic modeling was used to compare body burdens resulting from these different routes of exposure. The analysis concluded that the vapor concentration during a skin-only exposure would have to be at least 200 times higher than that during inhalation to achieve the same body burden. This type of estimation illustrates the use of predictive toxicology in occupational exposures.

Clewell, Harvey J., III↗
DOE OSTI2022

In vivo stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1992

Toxicological approach to setting spacecraft maximum allowable concentrations for carbon monoxide

The Spacecraft Maximum Allowable Concentrations (SMACs) are exposure limits for airborne chemicals used by NASA in spacecraft. The aim of these SMACs is to protect the spacecrew against adverse health effects and performance decrements that would interfere with mission objectives. Because of the 1 and 24 hr SMACs are set for contingencies, minor reversible toxic effects that do not affect mission objectives are acceptable. The 7, 30, or 180 day SMACs are aimed at nominal operations, so they are established at levels that would not cause noncarcinogenic toxic effects and more than one case of tumor per 1000 exposed individuals over the background. The process used to set the SMACs for carbon monoxide (CO) is described to illustrate the approach used by NASA. After the toxicological literature on CO was reviewed, the data were summarized and separated into acute, subchronic, and chronic toxicity data. CO's toxicity depends on the formation of carboxyhemoglobin (COHb) in the blood, reducing the blood's oxygen carrying capacity. The initial task was to estimate the COHb levels that would not produce toxic effects in the brain and heart.

Wong, K. L.↗
NASA NTRS1992

Health-risk based approach to setting drinking water standards for long-term space missions

In order to develop plausible and appropriate drinking water contaminant standards for longer-term NASA space missions, such as those planned for the Space Exploration Initiative, a human health risk characterization was performed using toxicological and exposure values typical of space operations and crew. This risk characterization showed that the greatest acute waterborne health concern was from microbial infection leading to incapacitating gastrointestinal illness. Ingestion exposure pathways for toxic materials yielded de minimus acute health risks unlikely to affect SEI space missions. Risks of chronic health problems were within acceptable public health limits. Our analysis indicates that current Space Station Freedom maximum contamination levels may be unnecessarily strict. We propose alternative environmental contaminant values consistent with both acceptable short and long-term crew health safety.

Macler, Bruce A.↗
NASA NTRS1972

Action of acetylstrophanthidin on experimental myocardial infarction.

An experimental animal model with acute myocardial infarction of a size insufficient to produce profound heart failure or shock was used to study the effects of acute infarction on digitalis tolerance and the hemodynamic changes produced by moderate and large doses of acetylstrophanthidin. With acute myocardial infarction, digitalis toxic arrhythmias could be precipitated with significantly lower doses of digitalis than in animals without myocardial infarction. There was no precise correlation between the size of infarction and the toxic dose of glycoside. Coronary artery ligation produced a stable but relatively depressed circulatory state, as evidenced by lowered cardiac output and stroke volume and elevated systemic vascular resistance and left atrial mean pressure. When digitalis was infused, the following significant changes were observed at nontoxic doses: (1) elevation of aortic and left ventricular pressures; (2) further decline in cardiac output; and (3) decreased left atrial mean pressure.

Nola, G. T.↗
DOE OSTI2026

Connecting ambient toxicity testing with community-level responses of benthic macroinvertebrates in an impacted stream in East Tennessee, USA

Single-species laboratory toxicity tests are a standard tool for evaluating potential impairment of freshwater systems; however, it remains uncertain how well they reflect community-level impacts in natural environments. This study presents a multi-decadal dataset (2005-2025) pairing ambient toxicity testing with macroinvertebrate surveys along Bear Creek on the Oak Ridge Reservation (Tennessee, USA) downstream of an industrial complex to assess the ability of laboratory tests using stream water to track community-level effects. Biannual three-brood Ceriodaphnia dubia tests from 2005 to 2025 often showed reduced reproduction at select sites. Integrating water quality data showed strong positive correlations between sublethal toxicity and specific conductance. Macroinvertebrate diversity metrics, family-level occurrence, and densities were also associated with conductance and contemporaneous C. dubia responses. Laboratory-measured sublethal toxicity was a stronger indicator of macroinvertebrate change than conductance alone, although responses varied among sites and seasons. At the site with the highest diversity, densities and richness of Ephemeroptera, Plecoptera, Trichoptera (EPT) and non-EPT taxa were significantly related to C. dubia reproduction, with greater toxicity corresponding to lower diversity. At the family level, some pollution-tolerant taxa were more prevalent and at higher densities during periods of sublethal toxicity, while some sensitive families were absent or reduced. These patterns may reflect site-specific mixtures of acute and chronic stressors, with laboratory toxicity tests more effectively capturing short-term impacts. Overall, these multi-decadal observations suggest that laboratory toxicity tests can help track water-quality changes linked to shifts in aquatic community diversity, despite variable responses reflecting the complexity of dynamic stressors in this impacted freshwater system.

Stevenson, Louise [ORNL] (ORCID:0000000349679897)↗