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.

USTUR Special Session Roundtable-US Transuranium and Uranium Registries (USTUR): A Five-decade Follow-up of Plutonium and Uranium Workers.

The US Transuranium and Uranium Registries is a human tissue program that collects tissues posthumously from former nuclear workers and radiochemically analyzes them for actinides such as plutonium, americium, and uranium. It was established in 1968 with the goal of advancing science and improving the safety of future workers. Roundtable participants recalled various aspects of this multidisciplinary research program, from establishing consistent autopsy protocols to comparing the registries' findings to those of other programs, such as the historical beagle dog studies and the Russian Radiobiological Human Tissue Repository. The importance of meeting ethical and legal requirements, including written consent forms, was emphasized, as was the need to know whether workers were exposed to nonradiological hazards such as beryllium or asbestos. At Rocky Flats, a bioassay program was established to follow workers after they terminated employment. The resulting data continue to help researchers to improve the biokinetic models that are used to estimate intakes and radiation doses. After 50 y, the US Transuranium and Uranium Registries continues to contribute to our understanding of actinides in humans, which is a testament to the vision of its founders, the generosity of its tissue donors, and the many dedicated scientists who have worked together to achieve a common goal.

Reanalysis of Diesel Engine Exhaust and Lung Cancer Mortality in the Diesel Exhaust in Miners Study Cohort Using Alternative Exposure Estimates and Radon Adjustment.

The Diesel Exhaust in Miners Study (DEMS) (United States, 1947-1997) reported positive associations between diesel engine exhaust exposure, estimated as respirable elemental carbon (REC), and lung cancer mortality. This reanalysis of the DEMS cohort used an alternative estimate of REC exposure incorporating historical data on diesel equipment, engine horsepower, ventilation rates, and declines in particulate matter emissions per horsepower. Associations with cumulative REC and average REC intensity using the alternative REC estimate and other exposure estimates were generally attenuated compared with original DEMS REC estimates. Most findings were statistically nonsignificant; control for radon exposure substantially weakened associations with the original and alternative REC estimates. No association with original or alternative REC estimates was detected among miners who worked exclusively underground. Positive associations were detected among limestone workers, whereas no association with REC or radon was found among workers in the other 7 mines. The differences in results based on alternative exposure estimates, control for radon, and stratification by worker location or mine type highlight areas of uncertainty in the DEMS data.

Providing Context for Ambient Particulate Matter and Estimates of Attributable Mortality.

Four papers on fine particulate matter (PM2.5 ) by Anenberg et al., Fann et al., Shin et al., and Smith contribute to a growing body of literature on estimated epidemiological associations between ambient PM2.5 concentrations and increases in health responses relative to baseline notes. This article provides context for the four articles, including a historical review of provisions of the U.S. Clean Air Act as amended in 1970, requiring the setting of National Ambient Air Quality Standards (NAAQS) for criteria pollutants such as particulate matter (PM). The substantial improvements in both air quality for PM and population health as measured by decreased mortality rates are illustrated. The most recent revision of the NAAQS for PM2.5 in 2013 by the Environmental Protection Agency distinguished between (1) uncertainties in characterizing PM2.5 as having a causal association with various health endpoints, and as all-cause mortality, and (2) uncertainties in concentration--excess health response relationships at low ambient PM2.5 concentrations below the majority of annual concentrations studied in the United States in the past. In future reviews, and potential revisions, of the NAAQS for PM2.5 , it will be even more important to distinguish between uncertainties in (1) characterizing the causal associations between ambient PM2.5 concentrations and specific health outcomes, such as all-source mortality, irrespective of the concentrations, (2) characterizing the potency of major constituents of PM2.5 , and (3) uncertainties in the association between ambient PM2.5 concentrations and specific health outcomes at various ambient PM2.5 concentrations. The latter uncertainties are of special concern as ambient PM2.5 concentrations and health morbidity and mortality rates approach background or baseline rates.

Influence of Alternative Exposure Estimates in the Diesel Exhaust Miners Study: Diesel Exhaust and Lung Cancer.

The landmark Diesel Exhaust in Miners Study (DEMS) studied the relationship between diesel exhaust exposure (DEE) and lung cancer mortality of workers at eight nonmetal mines who were followed from beginning of dieselization of the mines (1947-1967) through December 31, 1997. The original analyses quantified DEE exposures using exposure to respirable elemental carbon (REC) to represent DEE, and CO as a surrogate for REC. However, this use of CO data, and the CO data themselves, have numerous shortcomings. We developed new estimates of REC exposures using historical data on use of diesel equipment, diesel engine horsepower (HP), mine ventilation rates, and the documented reduction in particulate matter emissions per HP in diesel engines from 1975 through 1995. These new REC estimates were applied in a conditional logistic regression of the DEMS nested case-control data very similar to the one applied in the original DEMS analyses. None of the trend slopes calculated using the new REC estimates were statistically significant (p > 0.05). Moreover, these trend slopes were smaller by roughly factors of five without control for radon exposure and factors of 12 with control for radon exposure compared to those estimated in the original DEMS analyses. Also, the 95% confidence intervals for these trend slopes had only minimal overlap with those for the slopes in the original DEMS analyses. These results underscore the uncertainty in estimates of the potency of diesel exhaust in causing lung cancer based on analysis of the DEMS data due to uncertainty in estimates of exposures to diesel exhaust.

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.

Time-series analyses of air pollution and mortality in the United States: a subsampling approach.

BACKGROUND: Hierarchical Bayesian methods have been used in previous papers to estimate national mean effects of air pollutants on daily deaths in time-series analyses. OBJECTIVES: We obtained maximum likelihood estimates of the common national effects of the criteria pollutants on mortality based on time-series data from ≤ 108 metropolitan areas in the United States. METHODS: We used a subsampling bootstrap procedure to obtain the maximum likelihood estimates and confidence bounds for common national effects of the criteria pollutants, as measured by the percentage increase in daily mortality associated with a unit increase in daily 24-hr mean pollutant concentration on the previous day, while controlling for weather and temporal trends. We considered five pollutants [PM10, ozone (O3), carbon monoxide (CO), nitrogen dioxide (NO2), and sulfur dioxide (SO2)] in single- and multipollutant analyses. Flexible ambient concentration-response models for the pollutant effects were considered as well. We performed limited sensitivity analyses with different degrees of freedom for time trends. RESULTS: In single-pollutant models, we observed significant associations of daily deaths with all pollutants. The O3 coefficient was highly sensitive to the degree of smoothing of time trends. Among the gases, SO2 and NO2 were most strongly associated with mortality. The flexible ambient concentration-response curve for O3 showed evidence of nonlinearity and a threshold at about 30 ppb. CONCLUSIONS: Differences between the results of our analyses and those reported from using the Bayesian approach suggest that estimates of the quantitative impact of pollutants depend on the choice of statistical approach, although results are not directly comparable because they are based on different data. In addition, the estimate of the O3-mortality coefficient depends on the amount of smoothing of time trends.

Health effects research and regulation of diesel exhaust: an historical overview focused on lung cancer risk.

The mutagenicity of organic solvent extracts from diesel exhaust particulate (DEP), first noted more than 55 years ago, initiated an avalanche of diesel exhaust (DE) health effects research that now totals more than 6000 published studies. Despite an extensive body of results, scientific debate continues regarding the nature of the lung cancer risk posed by inhalation of occupational and environmental DE, with much of the debate focused on DEP. Decades of scientific scrutiny and increasingly stringent regulation have resulted in major advances in diesel engine technologies. The changed particulate matter (PM) emissions in "New Technology Diesel Exhaust (NTDE)" from today's modern low-emission, advanced-technology on-road heavy-duty diesel engines now resemble the PM emissions in contemporary gasoline engine exhaust (GEE) and compressed natural gas engine exhaust more than those in the "traditional diesel exhaust" (TDE) characteristic of older diesel engines. Even with the continued publication of epidemiologic analyses of TDE-exposed populations, this database remains characterized by findings of small increased lung cancer risks and inconsistent evidence of exposure-response trends, both within occupational cohorts and across occupational groups considered to have markedly different exposures (e.g. truckers versus railroad shopworkers versus underground miners). The recently published National Institute for Occupational Safety and Health (NIOSH)-National Cancer Institute (NCI) epidemiologic studies of miners provide some of the strongest findings to date regarding a DE-lung cancer association, but some inconsistent exposure-response findings and possible effects of bias and exposure misclassification raise questions regarding their interpretation. Laboratory animal studies are negative for lung tumors in all species, except for rats under lifetime TDE-exposure conditions with durations and concentrations that lead to "lung overload." The species specificity of the rat lung response to overload, and its occurrence with other particle types, is now well-understood. It is thus generally accepted that the rat bioassay for inhaled particles under conditions of lung overload is not predictive of human lung cancer hazard. Overall, despite an abundance of epidemiologic and experimental data, there remain questions as to whether TDE exposure causes increased lung cancers in humans. An abundance of emissions characterization data, as well as preliminary toxicological data, support NTDE as being toxicologically distinct from TDE. Currently, neither epidemiologic data nor animal bioassay data yet exist that directly bear on NTDE carcinogenic potential. A chronic bioassay of NTDE currently in progress will provide data on whether NTDE poses a carcinogenic hazard, but based on the significant reductions in PM mass emissions and the major changes in PM composition, it has been hypothesized that NTDE has a low carcinogenic potential. When the International Agency for Research on Cancer (IARC) reevaluates DE (along with GEE and nitroarenes) in June 2012, it will be the first authoritative body to assess DE carcinogenic health hazards since the emergence of NTDE and the accumulation of data differentiating NTDE from TDE.