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.

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.

Estimating safe human exposure levels for lunar dust using benchmark dose modeling of data from inhalation studies in rats.

The pulmonary toxicity of airborne lunar dust was assessed in rats exposed by nose-only inhalation to 0, 2.1, 6.8, 20.8 and 60.6 mg/m3 of respirable size lunar dust. Rats were exposed for 6 h/d, 5 d/week, for 4 weeks (120 h). Biomarkers of toxicity were assessed in bronchial alveolar lavage fluid (BALF) collected at 1 d, 1 week, 4 weeks or 13 weeks post-exposure for a total of 76 endpoints. Benchmark dose (BMD) analysis was conducted on endpoints that appeared to be sensitive to dose. The number of endpoints that met criteria for modeling was 30. This number was composed of 13 endpoints that produced data suitable for parametric analysis and 17 that produced non-normal data. Mean BMD values determined from models generated from non-normal data were lower but not significantly different from the mean BMD of models derived from normally distributed data. Thus BMDs ranged from a minimum of 10.4 (using the average BMD from all 30 modeled endpoints) to a maximum of 16.6 (using the average BMD from the most restricted set of models). This range of BMDs yields safe exposure estimate (SEE) values of 0.6 and 0.9 mg/m3, respectively, when BMDs are extrapolated to humans, using a species factor of 3 and extrapolated from a 1-month exposure to an anticipated 6-month lunar surface exposure. This estimate is very similar to a no-observable-adverse-effect-level (NOAEL) determined from the same studies (0.4 mg/m3) and a SEE derived from a study of rats that were intratracheally instilled with lunar dusts (0.5-1.0 mg/m3).

Estimate of safe human exposure levels for lunar dust based on comparative benchmark dose modeling.

Brief exposures of Apollo astronauts to lunar dust occasionally elicited upper respiratory irritation; however, no limits were ever set for prolonged exposure to lunar dust. The United States and other space faring nations intend to return to the moon for extensive exploration within a few decades. In the meantime, habitats for that exploration, whether mobile or fixed, must be designed to limit human exposure to lunar dust to safe levels. Herein we estimate safe exposure limits for lunar dust collected during the Apollo 14 mission. We instilled three respirable-sized (∼2 µ mass median diameter) lunar dusts (two ground and one unground) and two standard dusts of widely different toxicities (quartz and TiO2) into the respiratory system of rats. Rats in groups of six were given 0, 1, 2.5 or 7.5 mg of the test dust in a saline-Survanta® vehicle, and biochemical and cellular biomarkers of toxicity in lung lavage fluid were assayed 1 week and one month after instillation. By comparing the dose--response curves of sensitive biomarkers, we estimated safe exposure levels for astronauts and concluded that unground lunar dust and dust ground by two different methods were not toxicologically distinguishable. The safe exposure estimates were 1.3 ± 0.4 mg/m³ (jet-milled dust), 1.0 ± 0.5 mg/m³ (ball-milled dust) and 0.9 ± 0.3 mg/m³ (unground, natural dust). We estimate that 0.5-1 mg/m³ of lunar dust is safe for periodic human exposures during long stays in habitats on the lunar surface.

Toxicity of lunar dust assessed in inhalation-exposed rats.

Humans will again set foot on the moon. The moon is covered by a layer of fine dust, which can pose a respiratory hazard. We investigated the pulmonary toxicity of lunar dust in rats exposed to 0, 2.1, 6.8, 20.8 and 60.6 mg/m(3) of respirable-size lunar dust for 4 weeks (6 h/day, 5 days/week); the aerosols in the nose-only exposure chambers were generated from a jet-mill ground preparation of a lunar soil collected during the Apollo 14 mission. After 4 weeks of exposure to air or lunar dust, groups of five rats were euthanized 1 day, 1 week, 4 weeks or 13 weeks after the last exposure for assessment of pulmonary toxicity. Biomarkers of toxicity assessed in bronchoalveolar fluids showed concentration-dependent changes; biomarkers that showed treatment effects were total cell and neutrophil counts, total protein concentrations and cellular enzymes (lactate dehydrogenase, glutamyl transferase and aspartate transaminase). No statistically significant differences in these biomarkers were detected between rats exposed to air and those exposed to the two low concentrations of lunar dust. Dose-dependent histopathology, including inflammation, septal thickening, fibrosis and granulomas, in the lung was observed at the two higher exposure concentrations. No lesions were detected in rats exposed to ≤6.8 mg/m(3). This 4-week exposure study in rats showed that 6.8 mg/m(3) was the highest no-observable-adverse-effect level (NOAEL). These results will be useful for assessing the health risk to humans of exposure to lunar dust, establishing human exposure limits and guiding the design of dust mitigation systems in lunar landers or habitats.

Informed consent, shared-decision making and a reasonable patient's wishes based on a cross-sectional, national survey in the USA using a hypothetical scenario.

OBJECTIVE: In approximately half the states in the USA, and more recently in the UK, informed consent is legally defined as what a reasonable patient would wish to know. Our objective was to discern the information needs of a hospitalised, 'reasonable patient' during the informed-consent process. DESIGN: We performed a cross-sectional study to develop a survey instrument and better define 'reasonable person' in relation to informed consent in a hypothetical scenario where an invasive procedure may be an option. SETTING: A 10-question survey was administered from April 19 through 22 October 2018 to three groups: student nurses (n=76), health professions educators (n=63) and a US national population (n=1067). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the average intensity, on a 5-point scale, by which survey groups wished to have each of 10 questions answered. The secondary outcome was to discern relationships between survey demographics and the intensity by which participants wanted an answer. RESULTS: Despite substantial demographic differences in the nursing-student group and health-professions-educator group, the average intensity scores were within 0.2 units on nine of 10 questions. The national survey revealed a strong desire to have an answer to each question (range 3.98-4.60 units). It showed that women desired answers more than men and older adults desired answers more than younger adults. CONCLUSIONS: Based on responses to 10 survey questions regarding wishes of people in a situation where an invasive procedure may be necessary, the vast majority want an answer to each question. They wanted to know about all treatment options, risky drugs, decision aids, who will perform the procedure, and the cost. They wanted their advocate present, periodic review of their medical record, a full day to review documents and expected outcomes and restrictions after the procedure.

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.

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.

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.