Interlaboratory Agreement of Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Serologic Assays in the Expedited College of American Pathologists Proficiency Testing Program.

CONTEXT.­: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged, currently pandemic virus, and the etiologic agent of coronavirus disease 2019 (COVID-19). Clinical testing for antibodies to SARS-CoV-2 has rapidly become widespread, but data regarding the interlaboratory performance of these serologic assays are limited. OBJECTIVE.­: To describe the development and initial results of the College of American Pathologists (CAP) SARS-CoV-2 Serology Survey. DESIGN.­: Members from the CAP Microbiology and Diagnostic Immunology and Flow Cytometry Committees formed a working group to support development of a new proficiency testing survey for anti-SARS-CoV-2 antibody assays. Supplemental questions in the survey assessed the state of SARS-CoV-2 serologic testing among participating laboratories as of July 2020. Results were analyzed for agreement by immunoglobulin (Ig) isotype tested, assay manufacturer, and methodology. RESULTS.­: A total of 4125 qualitative results were received from 1110 laboratories participating in the first survey. Qualitative agreement for assays measuring anti-SARS-CoV-2 total antibodies or IgG was greater than 90% for all 3 samples in the survey. Qualitative agreement for IgM and IgA for the negative sample was greater than 95%, but lacked consensus for the other 2 samples. CONCLUSIONS.­: These initial data suggest overall excellent agreement and comparable performance for most qualitative anti-SARS-CoV-2 IgG and total antibody assays across all participating clinical laboratories, regardless of specific target antigen or assay methodology.

Influence of exposure measurement errors on results from epidemiologic studies of different designs.

In epidemiologic studies of health effects of air pollution, measurements or models are used to estimate exposure. Exposure estimates have errors that propagate to effect estimates in exposure-response models. We critically evaluate how types of exposure measurement error influenced bias and precision of effect estimates to understand conditions affecting interpretation of exposure-response models for epidemiologic studies of exposure to PM2.5, NO2, and SO2. We reviewed available literature on exposure measurement error for time-series and long-term exposure epidemiology studies. For time-series studies, time-activity error (daily exposure concentration did not account for variation in exposure due to time-activity during a day) and nonambient (indoor) sources negatively biased the effect estimates and increased standard error, so uncertainty grew with increasing bias while underestimating the true health effect in these studies. Spatial error (deviation between true exposure concentration at an individual's location and concentration at a receptor) was ascribed to negatively biased effect estimates in most cases. Positive bias occurred for spatially variable pollutants when the variance of error correlated with the exposure estimate. For long-term exposure studies, most spatial errors did not bias the effect estimate. For both time-series and long-term exposure studies reviewed, large uncertainties were observed when exposure concentration was modeled with low spatial and temporal resolution for a spatially variable pollutant.

Ambient Air Quality and Cardiovascular Health: Translation of Environmental Research for Public Health and Clinical Care.

Air pollution is intuitively associated with respiratory effects, but evidence has emerged over the past few decades that the cardiovascular effects of air pollution can be much more adverse and represent a greater public health burden. In this article, we present background on the sources, exposures, and health effects of air pollution and discuss the potential for intervention strategies in the health care system to help reduce individual and population exposure and the attendant risk from the cardiovascular effects of air pollution.

Framework for assessing causality of air pollution-related health effects for reviews of the National Ambient Air Quality Standards.

To inform regulatory decisions on the risk due to exposure to ambient air pollution, consistent and transparent communication of the scientific evidence is essential. The United States Environmental Protection Agency (U.S. EPA) develops the Integrated Science Assessment (ISA), which contains evaluations of the policy-relevant science on the effects of criteria air pollutants and conveys critical science judgments to inform decisions on the National Ambient Air Quality Standards. This article discusses the approach and causal framework used in the ISAs to evaluate and integrate various lines of scientific evidence and draw conclusions about the causal nature of air pollution-induced health effects. The framework has been applied to diverse pollutants and cancer and noncancer effects. To demonstrate its flexibility, we provide examples of causality judgments on relationships between health effects and pollutant exposures, drawing from recent ISAs for ozone, lead, carbon monoxide, and oxides of nitrogen. U.S. EPA's causal framework has increased transparency by establishing a structured process for evaluating and integrating various lines of evidence and uniform approach for determining causality. The framework brings consistency and specificity to the conclusions in the ISA, and the flexibility of the framework makes it relevant for evaluations of evidence across media and health effects.

Air Pollution Exposure Model for Individuals (EMI) in Health Studies: Evaluation for Ambient PM2.5 in Central North Carolina.

Air pollution health studies of fine particulate matter (diameter ≤2.5 µm, PM2.5) often use outdoor concentrations as exposure surrogates. Failure to account for variability of indoor infiltration of ambient PM2.5 and time indoors can induce exposure errors. We developed and evaluated an exposure model for individuals (EMI), which predicts five tiers of individual-level exposure metrics for ambient PM2.5 using outdoor concentrations, questionnaires, weather, and time-location information. We linked a mechanistic air exchange rate (AER) model to a mass-balance PM2.5 infiltration model to predict residential AER (Tier 1), infiltration factors (Tier 2), indoor concentrations (Tier 3), personal exposure factors (Tier 4), and personal exposures (Tier 5) for ambient PM2.5. Using cross-validation, individual predictions were compared to 591 daily measurements from 31 homes (Tiers 1-3) and participants (Tiers 4-5) in central North Carolina. Median absolute differences were 39% (0.17 h(-1)) for Tier 1, 18% (0.10) for Tier 2, 20% (2.0 µg/m(3)) for Tier 3, 18% (0.10) for Tier 4, and 20% (1.8 µg/m(3)) for Tier 5. The capability of EMI could help reduce the uncertainty of ambient PM2.5 exposure metrics used in health studies.

Modeling spatial and temporal variability of residential air exchange rates for the Near-Road Exposures and Effects of Urban Air Pollutants Study (NEXUS).

Air pollution health studies often use outdoor concentrations as exposure surrogates. Failure to account for variability of residential infiltration of outdoor pollutants can induce exposure errors and lead to bias and incorrect confidence intervals in health effect estimates. The residential air exchange rate (AER), which is the rate of exchange of indoor air with outdoor air, is an important determinant for house-to-house (spatial) and temporal variations of air pollution infiltration. Our goal was to evaluate and apply mechanistic models to predict AERs for 213 homes in the Near-Road Exposures and Effects of Urban Air Pollutants Study (NEXUS), a cohort study of traffic-related air pollution exposures and respiratory effects in asthmatic children living near major roads in Detroit, Michigan. We used a previously developed model (LBL), which predicts AER from meteorology and questionnaire data on building characteristics related to air leakage, and an extended version of this model (LBLX) that includes natural ventilation from open windows. As a critical and novel aspect of our AER modeling approach, we performed a cross validation, which included both parameter estimation (i.e., model calibration) and model evaluation, based on daily AER measurements from a subset of 24 study homes on five consecutive days during two seasons. The measured AER varied between 0.09 and 3.48 h(-1) with a median of 0.64 h(-1). For the individual model-predicted and measured AER, the median absolute difference was 29% (0.19 h­1) for both the LBL and LBLX models. The LBL and LBLX models predicted 59% and 61% of the variance in the AER, respectively. Daily AER predictions for all 213 homes during the three year study (2010-2012) showed considerable house-to-house variations from building leakage differences, and temporal variations from outdoor temperature and wind speed fluctuations. Using this novel approach, NEXUS will be one of the first epidemiology studies to apply calibrated and home-specific AER models, and to include the spatial and temporal variations of AER for over 200 individual homes across multiple years into an exposure assessment in support of improving risk estimates.

Comparing multipollutant emissions-based mobile source indicators to other single pollutant and multipollutant indicators in different urban areas.

A variety of single pollutant and multipollutant metrics can be used to represent exposure to traffic pollutant mixtures and evaluate their health effects. Integrated mobile source indicators (IMSIs) that combine air quality concentration and emissions data have recently been developed and evaluated using data from Atlanta, Georgia. IMSIs were found to track trends in traffic-related pollutants and have similar or stronger associations with health outcomes. In the current work, we apply IMSIs for gasoline, diesel and total (gasoline + diesel) vehicles to two other cities (Denver, Colorado and Houston, Texas) with different emissions profiles as well as to a different dataset from Atlanta. We compare spatial and temporal variability of IMSIs to single-pollutant indicators (carbon monoxide (CO), nitrogen oxides (NOx) and elemental carbon (EC)) and multipollutant source apportionment factors produced by Positive Matrix Factorization (PMF). Across cities, PMF-derived and IMSI gasoline metrics were most strongly correlated with CO (r = 0.31-0.98), while multipollutant diesel metrics were most strongly correlated with EC (r = 0.80-0.98). NOx correlations with PMF factors varied across cities (r = 0.29-0.67), while correlations with IMSIs were relatively consistent (r = 0.61-0.94). In general, single-pollutant metrics were more correlated with IMSIs (r = 0.58-0.98) than with PMF-derived factors (r = 0.07-0.99). A spatial analysis indicated that IMSIs were more strongly correlated (r > 0.7) between two sites in each city than single pollutant and PMF factors. These findings provide confidence that IMSIs provide a transferable, simple approach to estimate mobile source air pollution in cities with differing topography and source profiles using readily available data.

Evaluating the application of multipollutant exposure metrics in air pollution health studies.

BACKGROUND: Health effects associated with air pollution are typically evaluated using a single pollutant approach, yet people are exposed to mixtures consisting of multiple pollutants that may have independent or combined effects on human health. Development of exposure metrics that represent the multipollutant environment is important to understand the impact of ambient air pollution on human health. OBJECTIVES: We reviewed existing multipollutant exposure metrics to evaluate how they can be applied to understand associations between air pollution and health effects. METHODS: We conducted a literature search using both targeted search terms and a relational search in Web of Science and PubMed in April and December 2013. We focused on exposure metrics that are constructed from ambient pollutant concentrations and can be broadly applied to evaluate air pollution health effects. RESULTS: Multipollutant exposure metrics were identified in 57 eligible studies. Metrics reviewed can be categorized into broad pollutant grouping paradigms based on: 1) source emissions and atmospheric processes or 2) common health outcomes. DISCUSSION: When comparing metrics, it is apparent that no universal exposure metric exists; each type of metric addresses different research questions and provides unique information on human health effects. Key limitations of these metrics include the balance between complexity and simplicity as well as the lack of an existing "gold standard" for multipollutant health effects and exposure. CONCLUSIONS: Future work on characterizing multipollutant exposure error and joint effects will inform development of improved multipollutant metrics to advance air pollution health effects research and human health risk assessment.

GPS-based microenvironment tracker (MicroTrac) model to estimate time-location of individuals for air pollution exposure assessments: model evaluation in central North Carolina.

A critical aspect of air pollution exposure assessment is the estimation of the time spent by individuals in various microenvironments (ME). Accounting for the time spent in different ME with different pollutant concentrations can reduce exposure misclassifications, while failure to do so can add uncertainty and bias to risk estimates. In this study, a classification model, called MicroTrac, was developed to estimate time of day and duration spent in eight ME (indoors and outdoors at home, work, school; inside vehicles; other locations) from global positioning system (GPS) data and geocoded building boundaries. Based on a panel study, MicroTrac estimates were compared with 24-h diary data from nine participants, with corresponding GPS data and building boundaries of home, school, and work. MicroTrac correctly classified the ME for 99.5% of the daily time spent by the participants. The capability of MicroTrac could help to reduce the time-location uncertainty in air pollution exposure models and exposure metrics for individuals in health studies.

Whole-body retention and distribution of orally administered radiolabelled zerovalent iron nanoparticles in mice.

Zerovalent iron nanoparticles (nZVI) are used for in situ remediation of contaminated ground water, raising the possibility that nZVI particles or their altered residues could contaminate the ground water. Therefore, it is important to study their effects on humans and other organisms in vivo. The objective of this study was to assess the whole-body retention and terminal disposition of neutron-activated radioactive nZVI administered by oral gavage in mice. Radioactivity was primarily eliminated in the faeces within 1 day of administration. However, a small amount of iron-derived radioactivity appeared in the liver after three repeated daily doses. This prototypic study further suggests that neutron activation applied judiciously may be broadly applicable to studies of nanoparticles derived from other biologically abundant metals.

Comprehensive environmental assessment: a meta-assessment approach.

With growing calls for changes in the field of risk assessment, improved systematic approaches for addressing environmental issues with greater transparency and stakeholder engagement are needed to ensure sustainable trade-offs. Here we describe the comprehensive environmental assessment (CEA) approach as a holistic way to manage complex information and to structure input from diverse stakeholder perspectives to support environmental decision-making for the near- and long-term. We further note how CEA builds upon and incorporates other available tools and approaches, describe its current application at the U.S. Environmental Protection Agency, and point out how it could be extended in evaluating a major issue such as the sustainability of biofuels.

Partial oxidation ("aging") and surface modification decrease the toxicity of nanosized zerovalent iron.

Nanoscale zero-valent iron (nZVI) is a "redox"-active nanomaterial used in the remediation of contaminated groundwater. To assess the effect of "aging" and surface modification on its potential neurotoxicity, cultured rodent microglia (BV2) and neurons (N27) were exposed to fresh nZVI, "aged" (>11 months) nZVI, magnetite, and polyaspartate surface-modified (SM) nZVI. Increases in various measures of oxidative stress indicated that BV2 microglia responded to these materials in the following rank order: nZVI > "aged" nZVI > magnetite = SM nZVI. Fresh nZVI produced morphological evidence of mitochondrial swelling and apoptosis. In N27 neurons, ATP levels were reduced in the following rank order: nZVI > SM-nZVI > "aged" nZVI = magnetite. Ultrastructurally, nZVI produced a perinuclear floccular material and cytoplasmic granularity. Both SM-nZVI produced intracellular deposits of nanosize particles in the N27. The physicochemical properties of each material, measured under exposure conditions, indicated that all had electronegative zeta potentials. The iron content of nZVI (approximately 35%) and SM-nZVI (approximately 25%) indicated high "redox" activity while that of "aged" and magnetite was neglibile. Sedimentation and agglomeration occurred in the following rank order: nZV > "aged" nZVI > magnetite >> SM-nZVI. Correlating these properties with toxicity indicated that partial or complete oxidation of nZVI reduced its "redox" activity, agglomeration, sedimentation rate, and toxicity to mammalian cells. Surface modification decreased nZVI toxicity by reducing sedimentation which limited particle exposure to the cells.

Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro.

BACKGROUND: Titanium dioxide is a widely used nanomaterial whose photo-reactivity suggests that it could damage biological targets (e.g., brain) through oxidative stress (OS). OBJECTIVES: Brain cultures of immortalized mouse microglia (BV2), rat dopaminergic (DA) neurons (N27), and primary cultures of embryonic rat striatum, were exposed to Degussa P25, a commercially available TiO(2) nanomaterial. Physical properties of P25 were measured under conditions that paralleled biological measures. FINDINGS: P25 rapidly aggregated in physiological buffer (800-1,900 nm; 25 degrees C) and exposure media (approximately 330 nm; 37 degrees C), and maintained a negative zeta potential in both buffer (-12.2 +/- 1.6 mV) and media (-9.1 +/- 1.2 mV). BV2 microglia exposed to P25 (2.5-120 ppm) responded with an immediate and prolonged release of reactive oxygen species (ROS). Hoechst nuclear stain was reduced after 24-hr (>or=100 ppm) and 48-hr (>or=2.5 ppm) exposure. Microarray analysis on P25-exposed BV2 microglia indicated up-regulation of inflammatory, apoptotic, and cell cycling pathways and down-regulation of energy metabolism. P25 (2.5-120 ppm) stimulated increases of intracellular ATP and caspase 3/7 activity in isolated N27 neurons (24-48 hr) but did not produce cytotoxicity after 72-hr exposure. Primary cultures of rat striatum exposed to P25 (5 ppm) showed a reduction of immunohistochemically stained neurons and microscopic evidence of neuronal apoptosis after 6-hr exposure. These findings indicate that P25 stimulates ROS in BV2 microglia and is nontoxic to isolated N27 neurons. However, P25 rapidly damages neurons at low concentrations in complex brain cultures, plausibly though microglial generated ROS.

The cellular and genomic response of an immortalized microglia cell line (BV2) to concentrated ambient particulate matter.

Ambient particulate matter (PM) damages pulmonary tissue through oxidative stress (OS) pathways. Several reports indicate that the brain is another affected target of PM exposure. Since microglia (brain macrophages) are critical to OS-mediated neurodegeneration, the cellular and genomic response of immortalized mouse microglia (BV2) was examined in response to fine (or= 250 microg/ml) and depolarized mitochondrial membranes (>or= 6 microg/ml) within 15 min of exposure. HP and LP CAPs (>or= 25 microg/ml) differentially affected the endogenous scavengers, glutathione and nonprotein sulfhydryl in BV2 microglia after 1.5 h of exposure. Both HP and LP CAPs stimulated the release of proinflammatory cytokines tumor necrosis factor (TNF) alpha and interleukin (IL)-6 after 6 h of exposures. Microarray analysis of BV2 microglia exposed to either HP or LP CAPs (75 microg/ml, 4 h) identified 3200 (HP CAPs) and 160 (LP CAPs) differentially expressed (up- and downregulated) genes relative to media controls. Of the 3200 genes significantly affected by HP CAPs, the most prominent upregulated gene probes related to inflammatory pathways associated with Toll-like receptor signaling, MAPK signaling, T- and B-cell receptor signaling, apoptosis, and various proinflammatory cytokines and their receptors. LP CAPs significantly affected 160 genes that related to pathways associated with cellular maintenance and division, cell cycling and nuclear events. These data suggest that HP CAPs, which contained higher levels of nickel and vanadium than LP CAPs, appear to be more inflammatory and selectively upregulated the expression of inflammatory and innate immunity pathways in BV2 microglia.

Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity.

Concerns with the environmental and health risk of widely distributed, commonly used nanoparticles are increasing. Nanosize titanium dioxide (TiO2) is used in air and water remediation and in numerous products designed for direct human use and consumption. Its effectiveness in deactivating pollutants and killing microorganisms relates to photoactivation and the resulting free radical activity. This property, coupled with its multiple potential exposure routes, indicates that nanosize TiO2 could pose a risk to biological targets that are sensitive to oxidative stress damage (e.g., brain). In this study, brain microglia (BV2) were exposed to a physicochemically characterized (i.e., dispersion stability, particle size distribution, and zeta potential) nanomaterial, Degussa P25, and cellular expressions of reactive oxygen species were measured with fluorescent probes. P25's zeta potentials, measured in cell culture media and physiological buffer were -11.6 +/- 1.2 mV and -9.25 +/- 0.73 mV, respectively. P25 aggregation was rapid in both media and buffer with the hydrodynamic diameter of stable P25 aggregates ranging from 826 nm to 2368 nm depending on the concentration. The biological response of BV2 microglia to noncytotoxic (2.5-120 ppm) concentrations of P25 was a rapid (<5 min) and sustained (120 min) release of reactive oxygen species. The time course of this release suggested that P25 not only stimulated the immediate "oxidative burst" response in microglia but also interfered with mitochondrial energy production. Transmission electron microscopy indicated that small groups of nanosized particles and micron-sized aggregates were engulfed bythe microglia and sequestered as intracytoplasmic aggregates after 6 and 18 h exposure to P25 (2.5 ppm). Cell viability was maintained at all test concentrations (2.5-120 ppm) over the 18 h exposure period. These data indicate that mouse microglia respond to Degussa P25 with cellular and morphological expressions of free radical formation.