Revisions to Limits for Toluene in Spacecraft Air.

INTRODUCTION: The original Spacecraft Maximal Allowable Concentrations (SMACs) for toluene (set for 1 h, 24 h, 7 d, 30 d, and 180 d) were first established by NASA in 1996 based on a human study in which no irritation or neurotoxicity was reported following 6-h exposure to 40 ppm toluene vapors. While the toluene SMACs were updated in 2008 to account for auditory, visual, and hormonal effects (for 7 d, 30 d, and 180 d) and to include a long-term SMAC (1000 d) in anticipation of longer spaceflight exploration missions, the short-term SMAC limits (1 h and 24 h) remained unchanged. Acute toluene exposure is reported to result in ocular and nasal irritation, although it is not a primary irritant, as well as central nervous system effects including headaches and dizziness. Long-term exposure to toluene can elicit hepatotoxicity, nephrotoxicity, neurotoxicity, and endocrine toxicity.RESULTS AND DISCUSSION: Since publication of the original and revised toluene SMACs, the National Academy of Sciences developed interim Acute Exposure Guideline Limits reviewed by the National Research Council Committee. Based on these data, we have increased the limits for toluene in crewed spacecraft to 40 ppm for 1 h, 24 h, 7 d, and 30 d. SMACs for durations of 180 and 1000 d will remain unchanged.changed.Tapia CM, Langford SD, Ryder VE. Revisions to limits for toluene in spacecraft air. Aerosp Med Hum Perform. 2024; 95(7):399-402.

A review of pulmonary neutrophilia and insights into the key role of neutrophils in particle-induced pathogenesis in the lung from animal studies of lunar dusts and other poorly soluble dust particles.

The mechanisms of particle-induced pathogenesis in the lung remain poorly understood. Neutrophilic inflammation and oxidative stress in the lung are hallmarks of toxicity. Some investigators have postulated that oxidative stress from particle surface reactive oxygen species (psROS) on the dust produces the toxicopathology in the lungs of dust-exposed animals. This postulate was tested concurrently with the studies to elucidate the toxicity of lunar dust (LD), which is believed to contain psROS due to high-speed micrometeoroid bombardment that fractured and pulverized lunar surface regolith. Results from studies of rats intratracheally instilled (ITI) with three LDs (prepared from an Apollo-14 lunar regolith), which differed 14-fold in levels of psROS, and two toxicity reference dusts (TiO2 and quartz) indicated that psROS had no significant contribution to the dusts' toxicity in the lung. Reported here are results of further investigations by the LD toxicity study team on the toxicological role of oxidants in alveolar neutrophils that were harvested from rats in the 5-dust ITI study and from rats that were exposed to airborne LD for 4 weeks. The oxidants per neutrophils and all neutrophils increased with dose, exposure time and dust's cytotoxicity. The results suggest that alveolar neutrophils play a critical role in particle-induced injury and toxicity in the lung of dust-exposed animals. Based on these results, we propose an adverse outcome pathway (AOP) for particle-associated lung disease that centers on the crucial role of alveolar neutrophil-derived oxidant species. A critical review of the toxicology literature on particle exposure and lung disease further supports a neutrophil-centric mechanism in the pathogenesis of lung disease and may explain previously reported animal species differences in responses to poorly soluble particles. Key findings from the toxicology literature indicate that (1) after exposures to the same dust at the same amount, rats have more alveolar neutrophils than hamsters; hamsters clear more particles from their lungs, consequently contributing to fewer neutrophils and less severe lung lesions; (2) rats exposed to nano-sized TiO2 have more neutrophils and more severe lesions in their lungs than rats exposed to the same mass-concentration of micron-sized TiO2; nano-sized dust has a greater number of particles and a larger total particle-cell contact surface area than the same mass of micron-sized dust, which triggers more alveolar epithelial cells (AECs) to synthesize and release more cytokines that recruit a greater number of neutrophils leading to more severe lesions. Thus, we postulate that, during chronic dust exposure, particle-inflicted AECs persistently release cytokines, which recruit neutrophils and activate them to produce oxidants resulting in a prolonged continuous source of endogenous oxidative stress that leads to lung toxicity. This neutrophil-driven lung pathogenesis explains why dust exposure induces more severe lesions in rats than hamsters; why, on a mass-dose basis, nano-sized dusts are more toxic than the micron-sized dusts; why lung lesions progress with time; and why dose-response curves of particle toxicity exhibit a hockey stick like shape with a threshold. The neutrophil centric AOP for particle-induced lung disease has implications for risk assessment of human exposures to dust particles and environmental particulate matter.

Revisions to Acute/Off-Nominal Limits for Benzene in Spacecraft Air.

BACKGROUND: The previous short-term (1-h and 24-h) Spacecraft Maximal Allowable Concentrations (SMACs) for benzene were established at 10 and 3 ppm by NASA in 1996, based on a study of mice in which no hematological effects were noted following two 6-h exposures to benzene. When the benzene SMACs were updated in 2008, there was no revision to the short-term SMAC limits. Rather, that effort developed a long-term SMAC (1000-d) for Exploration mission scenarios.Acute benzene exposures can cause numerous neurological effects, and long-term exposure to low levels is well-known to cause acute myeloid leukemia. Since publication of the original benzene SMACs, the National Academy of Sciences developed interim Acute Exposure Guideline Limits (AEGLs) for unintentional releases of benzene into the air. Based on the data used to establish the AEGLs, we have increased our short-term, off-nominal limits for benzene in crewed spacecraft to 40 ppm and 6.7 ppm for 1-h and 24-h, respectively.Ryder VE, Williams ES. Revisions to acute/off-nominal limits for benzene in spacecraft air. Aerosp Med Hum Perform. 2023; 94(7):544-545.

Spaceflight Recovery Considerations for Acute Inhalational Exposure to Hydrazines.

INTRODUCTION: Inhalation of hydrazine or hydrazine-derivative (for example, monomethylhydrazine) vapors during spaceflight operations remains a risk to crew and ground support personnel. Here we sought to provide an evidence-based approach to inform acute clinical treatment guidelines for inhalational exposures during a noncatastrophic contingency spaceflight recovery scenario.METHODS: A review of published literature was conducted concerning hydrazine/hydrazine-derivative exposure and clinical sequelae. Priority was given to studies that described inhalation though studies of alternative routes of exposure were additionally reviewed. Where possible, human clinical presentations were prioritized over animal studies.RESULTS: Rare human case reports of inhalational exposure and multiple animal studies provide evidence of varied clinical sequelae, including mucosal irritation, respiratory concerns, neurotoxicity, hepatotoxicity, hemotoxicity (including Heinz body development and methemoglobinemia), and longitudinal risks. In an acute timeframe (minutes to hours), clinical sequelae are likely to be limited to mucosal and respiratory risk; neurological, hepatotoxic, and hemotoxic sequelae are unlikely without recurrent, longitudinal, or noninhalational exposure.CONCLUSIONS: Acute clinical management should focus on likely clinical concerns as supported by existing data; recovery medical personnel should be prepared to manage mucosal irritation and respiratory concerns, including the potential need for advanced airway management. There is little evidence supporting the need for acute interventions for neurotoxicity and there is no evidence that acute hemotoxic sequelae would drive the need for on-scene management of methemoglobinemia, Heinz body development, or hemolytic anemia. Training that overemphasizes neurotoxic or hemotoxic sequelae or specific treatments for such conditions potentially raises the risk for inappropriate treatment or operational fixation.Hanshaw BC, Ryder VE, Johansen BD, Pattarini JM, Nguyen HN, Nowadly CD, Blue RS. Spaceflight recovery considerations for acute inhalational exposure to hydrazines. Aerosp Med Hum Perform. 2023; 94(7):532-543.

Persistent changes in expression of genes involved in inflammation and fibrosis in the lungs of rats exposed to airborne lunar dust.

NASA is currently planning return missions to the Moon for further exploration and research. The Moon is covered by a layer of potentially reactive fine dust, which could pose a toxicological risk of exposure to explorers. To assess this risk, we exposed rats to lunar dust (LD) that was collected during the Apollo14 mission. Rats were exposed to respirable sizes of LD at concentrations of 0, 2.1, 6.8, 20.8, or 60.6 mg/m3 for 4 weeks. At thirteen weeks after exposure, we assessed 44,000 gene transcripts and found the expression of 614 genes with known functions were significantly altered in the rats exposed to the 2 higher concentrations of LD, whereas few changes in gene expression were detected in the group exposed to the lowest concentration of LD. Many of the significant changes in gene expression involved genes known to be associated with inflammation or fibrosis. Four genes encoding pro-inflammatory chemokines were analyzed further for all the sampling points at 1 day, and 1, 4, and 13 weeks after the 4-week dust exposure, using real-time polymerase chain reaction. The expression of these genes was altered in a dose- and time-dependent manner and persistently changed in the lungs of the rats exposed to the two higher concentrations of LD. Their expressions are consistent with changes we detected in pulmonary toxicity biomarkers and pathology in these animals during a previous study. Because Apollo-14 LD contains common mineral oxides similar to an Arizona volcanic ash, besides revealing the toxicity of LD, our findings could help elucidate the genomic and molecular mechanisms involved in pulmonary toxicity induced by terrestrial mineral dusts.

Spaceflight Maximum Allowable Concentrations for Ethyl Acetate.

INTRODUCTION: Ethyl acetate is a simple organic compound that occurs naturally and is used industrially as a solvent. It has been detected in the ISS atmosphere and is known to off-gas from building materials. As NASA astronauts have been and will be exposed to ethyl acetate during space missions, Spaceflight Maximum Allowable Concentrations (SMACs) were developed following an extensive review of the available literature.METHODS: Toxicological data relevant to SMAC development was collected from electronic databases using principles of systematic review, and from previous assessments and reviews of ethyl acetate.RESULTS: From an initial pool of over 35,000 studies, 10 were identified as studies appropriate to support SMAC development. The toxicological properties of ethyl acetate are relatively straightforward. Ethyl acetate is rapidly absorbed and converted by carboxyesterases to ethanol. At concentrations on the order of 400 ppm for 4-8 h, most volunteers experienced mild irritation but no lasting effects. In subchronic animal studies, mild sedative effects and changes in body weight and weight gain were observed at 750 ppm and above.DISCUSSION: Numerous studies were identified to support the development of both short- and long-duration SMACs. No chronic studies were available, but the high quality of the subchronic studies and the short half-life of ethyl acetate support extrapolation to longer durations.Williams ES, Ryder VE. Spaceflight maximum allowable concentrations for ethyl acetate. Aerosp Med Hum Perform. 2023; 94(1):25-33.

Spacecraft Maximum Allowable Concentrations for Hydrogen Fluoride.

BACKGROUND: Spacecraft maximum allowable concentrations (SMACs) provide guidance on allowable chemical exposures for nominal and emergency situations aboard spacecraft. SMACs are set to mitigate or preclude potential crew health effects and performance degradation. Hydrogen fluoride (HF) gas is highly irritating. Inhaled HF produces irritation primarily in the upper respiratory tract. HF is not routinely present in spacecraft atmospheres. However, it can be produced in spacecraft due to overheating or combustion events involving materials containing fluorinated organics.METHODS: Toxicological data relevant to SMAC development were collected from electronic databases using principles of systematic review, and from previous assessments and reviews of HF.RESULTS: The human inhalation data of Lund (short-term) and Largent (subchronic) showed that HF at approximately 3 ppm caused very mild respiratory irritation. NASA HF SMACs are based on these findings.DISCUSSION: The 1-h and 24-h SMACs are set at 3 ppm, a value consistent with NASA short-term SMAC criteria where crew may experience mild irritation. The 7-d, 30-d, 180-d, and 1000-d SMACs are set at 0.3 ppm to protect against any long-term crew health or performance effects that could be produced from HF exposures.Lam C-W, Ryder VE. Spacecraft maximum allowable concentrations for hydrogen fluoride. Aerosp Med Hum Perform. 2022; 93(10):746-748.

Dynamic ensemble prediction of cognitive performance in spaceflight.

During spaceflight, astronauts face a unique set of stressors, including microgravity, isolation, and confinement, as well as environmental and operational hazards. These factors can negatively impact sleep, alertness, and neurobehavioral performance, all of which are critical to mission success. In this paper, we predict neurobehavioral performance over the course of a 6-month mission aboard the International Space Station (ISS), using ISS environmental data as well as self-reported and cognitive data collected longitudinally from 24 astronauts. Neurobehavioral performance was repeatedly assessed via a 3-min Psychomotor Vigilance Test (PVT-B) that is highly sensitive to the effects of sleep deprivation. To relate PVT-B performance to time-varying and discordantly-measured environmental, operational, and psychological covariates, we propose an ensemble prediction model comprising of linear mixed effects, random forest, and functional concurrent models. An extensive cross-validation procedure reveals that this ensemble outperforms any one of its components alone. We also identify the most important predictors of PVT-B performance, which include an individual's previous PVT-B performance, reported fatigue and stress, and temperature and radiation dose. This method is broadly applicable to settings where the main goal is accurate, individualized prediction of human behavior involving a mixture of person-level traits and irregularly measured time series.

Revisions to Limits for Propylene Glycol in Spacecraft Air.

INTRODUCTION: The previous Spacecraft Maximal Allowable Concentrations (SMACs) for propylene glycol were established based on a study of rodents exposed to propylene glycol (PG) aerosol for 6 h/d, 5 d/wk for 90 d. This study has been used as the basis for the few existing limits, but all exposure concentrations were well above the saturated vapor concentration of ∼100 ppm for pure propylene glycol at room temperature. For this reason, the Environmental Protection Agency and the Agency for Toxic Substances and Disease Registry noted that the method used to generate the aerosols for the two published studies of animal exposures are not relevant to exposure conditions for the general public, and most regulatory agencies have not established inhalation limits for propylene glycol, citing lack of data. Since publication of the PG SMACs in 2008, an acute inhalation study was conducted in healthy human subjects which allows us to revise our assessment. This manuscript provides the rationale for increasing the prior limits for PG in spacecraft air from 32 and 17 ppm to 64 and 32 ppm for off-nominal scenarios/releases (1-h and 24-h limits) and from 9, 3, and 1.5 ppm to 32 ppm for all nominal timeframes (7, 30, and 180 d). Due to a lack of longer-term exposure data, NASA has elected to eliminate the 1000-d SMAC limit at this time.Ryder VE, Williams ES. Revisions to limits for propylene glycol in spacecraft air. Aerosp Med Hum Perform. 2022; 93(5):467-469.

Comparative pulmonary toxicities of lunar dusts and terrestrial dusts (TiO2 & SiO2) in rats and an assessment of the impact of particle-generated oxidants on the dusts' toxicities.

Humans will set foot on the Moon again soon. The lunar dust (LD) is potentially reactive and could pose an inhalation hazard to lunar explorers. We elucidated LD toxicity and investigated the toxicological impact of particle surface reactivity (SR) using three LDs, quartz, and TiO2. We first isolated the respirable-size-fraction of an Apollo-14 regolith and ground two coarser samples to produce fine LDs with increased SR. SR measurements of these five respirable-sized dusts, determined by their in-vitro ability to generate hydroxyl radicals (•OH), showed that ground LDs > unground LD ≥ TiO2 ≥ quartz. Rats were each intratracheally instilled with 0, 1, 2.5, or 7.5 mg of a test dust. Toxicity biomarkers and histopathology were assessed up to 13 weeks after the bolus instillation. All dusts caused dose-dependent-increases in pulmonary lesions and toxicity biomarkers. The three LDs, which possessed mineral compositions/properties similar to Arizona volcanic ash, were moderately toxic. Despite a 14-fold •OH difference among these three LDs, their toxicities were indistinguishable. Quartz produced the lowest •OH amount but showed the greatest toxicity. Our results showed no correlation between the toxicity of mineral dusts and their ability to generate free radicals. We also showed that the amounts of oxidants per neutrophil increased with doses, time and the cytotoxicity of the dusts in the lung, which supports our postulation that dust-elicited neutrophilia is the major persistent source of oxidative stress. These results and the discussion of the crucial roles of the short-lived, continuously replenished neutrophils in dust-induced pathogenesis are presented.

Revisions to Limits for Methanol in the Air of Spacecraft.

INTRODUCTION: The previous Spacecraft Maximal Allowable Concentrations (SMACs) for methanol were established by characterizing minor effects upon cognitive functions as a no-observable adverse effects level (NOAEL). However, an increasing awareness of the risk posed by Space-Associated Neuro-ocular Syndrome (SANS) has caused NASA Toxicology to reexamine SMACs for methanol because exposure to it can also adversely affect ocular health. An updated review of the literature indicates that no adjustments to the SMACs due to SANS complications were required, while confirming that effects upon the central nervous system remain the appropriate basis for the SMACs for methanol. Our review, however, identified several issues that provide justification for modest SMAC reductions. It has recently been recognized that inhaled methanol may reach the brain via the olfactory system and be absorbed there into the highly toxic metabolite formaldehyde. A benchmark dose (BMD) for an extra risk of 10%, derived from an analysis of the incidences of neurological lesions in monkeys chronically exposed to methanol, is an order of magnitude less than the Environmental Protection Agency's (EPA's) reference concentration for chronic inhalation of methanol. Reports calling attention to the relative insensitivity of traditional methods of assessing cognitive function erode confidence that adverse effects at the concentration reported as a NOAEL would have been recognizable. Therefore, an additional modest safety factor of three is applied to SMACs for methanol.Scully RR, Garcia H, McCoy JT, Ryder VE. Revisions to limits for methanol in the air of spacecraft. Aerosp Med Hum Perform. 2019; 90(9):807-812.

Spacecraft Maximum Allowable Concentrations for Manganese Compounds in Mars Dust.

INTRODUCTION: Exposure to excess manganese (Mn) can cause multiple toxicological outcomes in humans, most notably neurotoxicity. Ample epidemiological evidence suggests that chronic, low-level exposure causes subclinical cognitive effects. Because NASA astronauts will be exposed to Mars regolith, Spacecraft Maximum Allowable Concentrations (SMACs) were developed following an extensive literature review.METHODS: Multiple databases were searched for information relevant to derivation of Mn SMAC values. An additional search for Mars dust data was performed. Risk assessment approaches were applied, including adjustments for space-relevant susceptibility to Mn effects, to develop limits for 1-h to 1000-d exposures. Rover data informed the assessment and enabled calculation of allowable total dust exposure based on Mn content.RESULTS: Over 400 relevant sources were identified. Applicability of exposure characteristics and data collection methods influenced key study choice. SMACs ranging from 3 mg · m-3 (1 h) - 0.0079 mg · m-3 (1000 d) were set to protect primarily against neurocognitive and respiratory effects. Considering 0.38 wt% total Mn presence in the dust, maximum recommended total dust exposure should not exceed 790 mg · m-3 (1 h) - 2 mg · m-3 (1000 d).DISCUSSION: This literature review allowed for identification of relevant studies to inform SMAC development. Manganese is one of several components to consider when developing an appropriate total dust limit for Martian dust; other dust elements may alter Mn bioavailability. Mission-specific activities may require alteration of assumptions regarding Mn dust concentration and exposure duration. However, based on expected toxicity of particulate matter itself, the acute SMACs are protective, even with transient exposure during activities that could produce higher concentrations.Romoser AA, Ryder VE, McCoy JT. Spacecraft maximum allowable concentrations for manganese compounds in Mars dust. Aerosp Med Hum Perform. 2019; 90(8):709-719.

Effects of acute exposures to carbon dioxide on decision making and cognition in astronaut-like subjects.

Acute exposure to carbon dioxide (CO2) concentrations below those found on the International Space Station are reported to deteriorate complex decision-making. Effective decision-making is critical to human spaceflight, especially during an emergency response. Therefore, effects of acutely elevated CO2 on decision-making competency and various cognitive domains were assessed in astronaut-like subjects by the Strategic Management Simulation (SMS) and Cognition test batteries. The double-blind cross-over study included 22 participants at the Johnson Space Center randomly assigned to one of four groups. Each group was exposed to a different sequence of four concentrations of CO2 (600, 1200, 2500, 5000 ppm). Subjects performed Cognition before entering the chamber, 15 min and 2.5 h after entering the chamber, and 15 min after exiting the chamber. The SMS was administered 30 min after subjects entered the chamber. There were no clear dose-response patterns for performance on either SMS or Cognition. Performance on most SMS measures and aggregate speed, accuracy, and efficiency scores across Cognition tests were lower at 1200 ppm than at baseline (600 ppm); however, at higher CO2 concentrations performance was similar to or exceeded baseline for most measures. These outcomes, which conflict with those of other studies, likely indicate differing characteristics of the various subject populations and differences in the aggregation of unrecognized stressors, in addition to CO2, are responsible for disparate outcomes among studies. Studies with longer exposure durations are needed to verify that cognitive impairment does not develop over time in crew-like subjects.

Carbon Dioxide Physiological Training at NASA.

INTRODUCTION: Astronauts undergo CO2 exposure training to recognize their symptoms that can arise acutely both on the ground and in spaceflight. This article describes acute CO2 exposure training at NASA and examines the symptoms reported by astronauts during training. METHODS: In a controlled training environment, astronauts are exposed to up to 8% CO2 (60 mmHg) by a rebreathing apparatus. Symptoms are reported using a standard form. RESULTS: Symptom documentation forms between April 1994 and February 2012 were obtained for 130 astronauts. The number of symptoms reported per session out of the possible 24 was related to age and sex, with those older slightly more likely to report symptoms. Women reported more symptoms on average than men (men: 3.7, women: 4.7). Respiratory symptoms (90%), flushing sensation/sweating (56%), and dizziness/feeling faint/lightheadedness (43%) were the top symptoms. Only headache reached statistical significance in differences between men (13%) and women (37%) after adjustment for multiple testing. Among those with multiple training sessions, respiratory symptoms were the most consistently reported. DISCUSSION: CO2 exposure training is an important tool to educate astronauts about their potential acute CO2 symptoms. Wide interindividual and temporal variations were observed in symptoms reported during astronaut CO2 exposure training. Headache could not be relied on as a marker of acute exposure during testing since fewer than half the subjects reported it. Our results support periodic refresher training since symptoms may change over time. Further study is needed to determine the optimal interval of training to maximize symptom recognition and inform operational decisions.Law J, Young M, Alexander D, Mason SS, Wear ML, Méndez CM, Stanley D, Meyers Ryder V, Van Baalen M. Carbon dioxide physiological training at NASA. Aerosp Med Hum Perform. 2017; 88(10):897-902.

Predicting Air Quality at First Ingress into Vehicles Visiting the International Space Station.

INTRODUCTION: NASA regularly performs ground-based offgas tests (OGTs), which allow prediction of accumulated volatile pollutant concentrations at first entry on orbit, on whole modules and vehicles scheduled to connect to the International Space Station (ISS). These data guide crew safety operations and allow for estimation of ISS air revitalization systems impact from additional pollutant load. Since volatiles released from vehicle, module, and payload materials can affect crew health and performance, prediction of first ingress air quality is important. METHODS: To assess whether toxicological risk is typically over or underpredicted, OGT and first ingress samples from 10 vehicles and modules were compared. Samples were analyzed by gas chromatography and gas chromatography-mass spectrometry. The rate of pollutant accumulation was extrapolated over time. Ratios of analytical values and Spacecraft Maximum Allowable Concentrations were used to predict total toxicity values (T-values) at first entry. Results were also compared by compound. RESULTS: Frequently overpredicted was 2-butanone (9/10), whereas propanal (6/10) and ethanol (8/10) were typically underpredicted, but T-values were not substantially affected. Ingress sample collection delay (estimated by octafluoropropane introduced from ISS atmosphere) and T-value prediction accuracy correlated well (R2 = 0.9008), highlighting the importance of immediate air sample collection and accounting for ISS air dilution. DISCUSSION: Importantly, T-value predictions were conservative 70% of the time. Results also suggest that T-values can be normalized to octafluoropropane levels to adjust for ISS air dilution at first ingress. Finally, OGT and ingress sampling has allowed small leaks in vehicle fluid systems to be recognized and addressed.Romoser AA, Scully RR, Limero TF, De Vera V, Cheng PF, Hand JJ, James JT, Ryder VE. Predicting air quality at first ingress into vehicles visiting the International Space Station. Aerosp Med Hum Perform. 2017; 88(2):104-113.