World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung.

Exposure to World Trade Center (WTC) dust has been linked to respiratory disease in humans. In the present studies we developed a rodent model of WTC dust exposure to analyze lung oxidative stress and inflammation, with the goal of elucidating potential epigenetic mechanisms underlying these responses. Exposure of mice to WTC dust (20µg, i.t.) was associated with upregulation of heme oxygenase-1 and cyclooxygenase-2 within 3days, a response which persisted for at least 21days. Whereas matrix metalloproteinase was upregulated 7days post-WTC dust exposure, IL-6RA1 was increased at 21days; conversely, expression of mannose receptor, a scavenger receptor important in particle clearance, decreased. After WTC dust exposure, increases in methylation of histone H3 lysine K4 at 3days, lysine K27 at 7days and lysine K36, were observed in the lung, along with hypermethylation of Line-1 element at 21days. Alterations in pulmonary mechanics were also observed following WTC dust exposure. Thus, 3days post-exposure, lung resistance and tissue damping were decreased. In contrast at 21days, lung resistance, central airway resistance, tissue damping and tissue elastance were increased. These data demonstrate that WTC dust-induced inflammation and oxidative stress are associated with epigenetic modifications in the lung and altered pulmonary mechanics. These changes may contribute to the development of WTC dust pathologies.

Preparedness and response to chemical and biological threats: the role of exposure science.

There are multiple components to emergency preparedness and the response to chemical and biological threat agents. The 5Rs framework (rescue, reentry, recovery, restoration, and rehabitation) outlines opportunities to apply exposure science in emergency events. Exposure science provides guidance and refined tools for characterizing, assessing, and reducing risks from catastrophic events, such as the release of hazardous airborne chemicals or biological agents. Important challenges to be met include deployment of assets, including medications, before and after an emergency response situation. Assessment of past studies demonstrates the value of integrating exposure science methods into risk analysis and the management of catastrophic events.

A post-remediation assessment in Jersey City of the association of hexavalent chromium in house dust and urinary chromium in children.

Although all chromite ore processing residue (COPR) sites near residential neighborhoods in Jersey City, New Jersey have undergone remediation, recent studies found widespread, but low levels of hexavalent chromium (Cr(+6)) in house dust both in Jersey City and in communities with no known sources of Cr(+6). This study was designed as a follow-up to determine whether there is an association between current Cr(+6) levels in house dust and urinary chromium concentrations in young children. Dust samples (N=369) were collected from 123 homes. The median Cr(+6) concentration was 3.3 µg/g (mean±SD 5.2±7.5) and the median Cr(+6) loading was 1.1 µg/m(2) (1.9±3.1). These levels were not elevated compared with previously reported levels in background communities (median concentration=3.5 µg/g; median loading=2.8 µg/m(2)). Urinary chromium concentrations were measured in spot urine samples collected from 150 children, ages 3 months to 6 years. The median uncorrected urinary chromium concentration was 0.19 µg/l (0.22±0.16). Current urinary chromium concentrations were significantly lower than those previously reported before and during remediation (t-test; P<0.001). Urinary chromium concentrations were not significantly higher in homes with high (75th or 90th percentile) Cr(+6) dust levels (concentration or loading) compared with other homes. Multiple linear regression was used to examine the relationship between Cr(+6) levels (concentration and loading) in house dust and urinary chromium concentrations (uncorrected and specific gravity corrected). Contrary to pre-remediation studies, we did not find a positive association between Cr(+6) levels in house dust and urinary chromium concentrations. The findings indicate that current Cr(+6) levels in house dust are not positively associated with children's chromium exposure as measured by urinary chromium, and the children's exposure to Cr(+6) in house dust is below the level that could be identified by urine sampling.

Assessment of phthalates/phthalate alternatives in children's toys and childcare articles: Review of the report including conclusions and recommendation of the Chronic Hazard Advisory Panel of the Consumer Product Safety Commission.

The Consumer Product Safety Commission (CPSC) convened a Chronic Hazard Advisory Panel (CHAP) on Phthalates found in children's toys, and childcare products, and in products used by women of childbearing age. The CHAP conducted a risk assessment on phthalates and phthalate substitutes, and made recommendations to either ban, impose an interim ban, or allow the continued use of phthalates and phthalate substitutes in the above products. After a review of the literature, the evaluation included toxic end points of primary concern, biomonitoring results, extant exposure reconstruction, and epidemiological results. The health end points chosen were associated with the rat phthalate syndrome, which is characterized by malformations of the epididymis, vas deferens, seminal vesicles, prostate, external genitalia (hypospadias), and by cryptorchidism (undescended testes), retention of nipples/areolae, and demasculinization (~incomplete masculinization) of the perineum, resulting in reduced anogenital distance. Risk assessment demonstrated that some phthalates should be permanently banned, removed from the banned list, or remain interim banned. Biomonitoring and toxicology data provided the strongest basis for a mixture risk assessment. In contrast, external exposure data were the weakest and need to be upgraded for epidemiological studies and risk assessments. Such studies would focus on routes and sources. The review presents recommendations and uncertainties.

Evaluation of Diesel Exhaust Continuous Monitors in Controlled Environmental Conditions.

Diesel exhaust (DE) contains a variety of toxic air pollutants, including diesel particulate matter (DPM) and gaseous contaminants (e.g., carbon monoxide (CO)). DPM is dominated by fine (PM2.5) and ultrafine particles (UFP), and can be representatively determined by its thermal-optical refractory as elemental carbon (EC) or light-absorbing characteristics as black carbon (BC). The currently accepted reference method for sampling and analysis of occupational exposure to DPM is the National Institute for Occupational Safety and Health (NIOSH) Method 5040. However, this method cannot provide in-situ short-term measurements of DPM. Thus, real-time monitors are gaining attention to better examine DE exposures in occupational settings. However, real-time monitors are subject to changing environmental conditions. Field measurements have reported interferences in optical sensors and subsequent real-time readings, under conditions of high humidity and abrupt temperature changes. To begin dealing with these issues, we completed a controlled study to evaluate five real-time monitors: Airtec real-time DPM/EC Monitor, TSI SidePak Personal Aerosol Monitor AM510 (PM2.5), TSI Condensation Particle Counter 3007, microAeth AE51 BC Aethalometer, and Langan T15n CO Measurer. Tests were conducted under different temperatures (55, 70, and 80°F), relative humidity (10, 40, and 80%), and DPM concentrations (50 and 200 µg/m(3)) in a controlled exposure facility. The 2-hr averaged EC measurements from the Airtec instrument showed relatively good agreement with NIOSH Method 5040 (R(2) = 0.84; slope = 1.17±0.06; N = 27) and reported ∼17% higher EC concentrations than the NIOSH reference method. Temperature, relative humidity, and DPM levels did not significantly affect relative differences in 2-hr averaged EC concentrations obtained by the Airtec instrument vs. the NIOSH method (p < 0.05). Multiple linear regression analyses, based on 1-min averaged data, suggested combined effects of up to 5% from relative humidity and temperature on real-time measurements. The overall deviations of these real-time monitors from the NIOSH method results were ≤20%. However, simultaneous monitoring of temperature and relative humidity is recommended in field investigations to understand and correct for environmental impacts on real-time monitoring data.

Manganese concentrations in soil and settled dust in an area with historic ferroalloy production.

Ferroalloy production can release a number of metals into the environment, of which manganese (Mn) is of major concern. Other elements include lead, iron, zinc, copper, chromium, and cadmium. Mn exposure derived from settled dust and suspended aerosols can cause a variety of adverse neurological effects to chronically exposed individuals. To better estimate the current levels of exposure, this study quantified the metal levels in dust collected inside homes (n=85), outside homes (n=81), in attics (n=6), and in surface soil (n=252) in an area with historic ferroalloy production. Metals contained in indoor and outdoor dust samples were quantified using inductively coupled plasma optical emission spectroscopy, whereas attic and soil measurements were made with a X-ray fluorescence instrument. Mean Mn concentrations in soil (4600 µg/g) and indoor dust (870 µg/g) collected within 0.5 km of a plant exceeded levels previously found in suburban and urban areas, but did decrease outside 1.0 km to the upper end of background concentrations. Mn concentrations in attic dust were ~120 times larger than other indoor dust levels, consistent with historical emissions that yielded high airborne concentrations in the region. Considering the potential health effects that are associated with chronic Mn inhalation and ingestion exposure, remediation of soil near the plants and frequent, on-going hygiene indoors may decrease residential exposure and the likelihood of adverse health effects.

Variability in bioreactivity linked to changes in size and zeta potential of diesel exhaust particles in human immune cells.

Acting as fuel combustion catalysts to increase fuel economy, cerium dioxide (ceria, CeO2) nanoparticles have been used in Europe as diesel fuel additives (Envirox™). We attempted to examine the effects of particles emitted from a diesel engine burning either diesel (diesel exhaust particles, DEP) or diesel doped with various concentrations of CeO2 (DEP-Env) on innate immune responses in THP-1 and primary human peripheral blood mononuclear cells (PBMC). Batches of DEP and DEP-Env were obtained on three separate occasions using identical collection and extraction protocols with the aim of determining the reproducibility of particles generated at different times. However, we observed significant differences in size and surface charge (zeta potential) of the DEP and DEP-Env across the three batches. We also observed that exposure of THP-1 cells and PBMC to identical concentrations of DEP and DEP-Env from the three batches resulted in statistically significant differences in bioreactivity as determined by IL-1ß, TNF-α, IL-6, IFN-γ, and IL-12p40 mRNA (by qRT-PCR) and protein expression (by ELISPOT assays). Importantly, bioreactivity was noted in very tight ranges of DEP size (60 to 120 nm) and zeta potential (-37 to -41 mV). Thus, these physical properties of DEP and DEP-Env were found to be the primary determinants of the bioreactivity measured in this study. Our findings also point to the potential risk of over- or under- estimation of expected bioreactivity effects (and by inference of public health risks) from bulk DEP use without taking into account potential batch-to-batch variations in physical (and possibly chemical) properties.

A tiered framework for risk-relevant characterization and ranking of chemical exposures: applications to the National Children's Study (NCS).

A challenge for large-scale environmental health investigations such as the National Children's Study (NCS), is characterizing exposures to multiple, co-occurring chemical agents with varying spatiotemporal concentrations and consequences modulated by biochemical, physiological, behavioral, socioeconomic, and environmental factors. Such investigations can benefit from systematic retrieval, analysis, and integration of diverse extant information on both contaminant patterns and exposure-relevant factors. This requires development, evaluation, and deployment of informatics methods that support flexible access and analysis of multiattribute data across multiple spatiotemporal scales. A new "Tiered Exposure Ranking" (TiER) framework, developed to support various aspects of risk-relevant exposure characterization, is described here, with examples demonstrating its application to the NCS. TiER utilizes advances in informatics computational methods, extant database content and availability, and integrative environmental/exposure/biological modeling to support both "discovery-driven" and "hypothesis-driven" analyses. "Tier 1" applications focus on "exposomic" pattern recognition for extracting information from multidimensional data sets, whereas second and higher tier applications utilize mechanistic models to develop risk-relevant exposure metrics for populations and individuals. In this article, "tier 1" applications of TiER explore identification of potentially causative associations among risk factors, for prioritizing further studies, by considering publicly available demographic/socioeconomic, behavioral, and environmental data in relation to two health endpoints (preterm birth and low birth weight). A "tier 2" application develops estimates of pollutant mixture inhalation exposure indices for NCS counties, formulated to support risk characterization for these endpoints. Applications of TiER demonstrate the feasibility of developing risk-relevant exposure characterizations for pollutants using extant environmental and demographic/socioeconomic data.

Modeling Population Exposures to Silver Nanoparticles Present in Consumer Products.

Exposures of the general population to manufactured nanoparticles (MNPs) are expected to keep rising due to increasing use of MNPs in common consumer products (PEN 2014). The present study focuses on characterizing ambient and indoor population exposures to silver MNPs (nAg). For situations where detailed, case-specific exposure-related data are not available, as in the present study, a novel tiered modeling system, Prioritization/Ranking of Toxic Exposures with GIS (Geographic Information System) Extension (PRoTEGE), has been developed: it employs a product Life Cycle Analysis (LCA) approach coupled with basic human Life Stage Analysis (LSA) to characterize potential exposures to chemicals of current and emerging concern. The PRoTEGE system has been implemented for ambient and indoor environments, utilizing available MNP production, usage, and properties databases, along with laboratory measurements of potential personal exposures from consumer spray products containing nAg. Modeling of environmental and microenvironmental levels of MNPs employs Probabilistic Material Flow Analysis combined with product LCA to account for releases during manufacturing, transport, usage, disposal, etc. Human exposure and dose characterization further employs screening Microenvironmental Modeling and Intake Fraction methods combined with LSA for potentially exposed populations, to assess differences associated with gender, age, and demographics. Population distributions of intakes, estimated using the PRoTEGE framework, are consistent with published individual-based intake estimates, demonstrating that PRoTEGE is capable of capturing realistic exposure scenarios for the US population. Distributions of intakes are also used to calculate biologically-relevant population distributions of uptakes and target tissue doses through human airway dosimetry modeling that takes into account product MNP size distributions and age-relevant physiological parameters.

Bioaccessibility and Risk of Exposure to Metals and SVOCs in Artificial Turf Field Fill Materials and Fibers.

To reduce maintenance costs, municipalities and schools are starting to replace natural grass fields with a new generation synthetic turf. Unlike Astro-Turf, which was first introduced in the 1960s, synthetic field turf provides more cushioning to athletes. Part of this cushioning comes from materials like crumb rubber infill, which is manufactured from recycled tires and may contain a variety of chemicals. The goal of this study was to evaluate potential exposures from playing on artificial turf fields and associated risks to trace metals, semi-volatile organic compounds (SVOCs), and polycyclic aromatic hydrocarbons (PAHs) by examining typical artificial turf fibers (n = 8), different types of infill (n = 8), and samples from actual fields (n = 7). Three artificial biofluids were prepared, which included: lung, sweat, and digestive fluids. Artificial biofluids were hypothesized to yield a more representative estimation of dose than the levels obtained from total extraction methods. PAHs were routinely below the limit of detection across all three biofluids, precluding completion of a meaningful risk assessment. No SVOCs were identified at quantifiable levels in any extracts based on a match of their mass spectrum to compounds that are regulated in soil. The metals were measurable but at concentrations for which human health risk was estimated to be low. The study demonstrated that for the products and fields we tested, exposure to infill and artificial turf was generally considered de minimus, with the possible exception of lead for some fields and materials.

Measurement of Soluble and Total Hexavalent Chromium in the Ambient Airborne Particles in New Jersey.

Hexavalent chromium (Cr(VI)) in ambient airborne particulate matter (PM) is a known pulmonary carcinogen and may have both soluble and insoluble forms. The sum of the two forms is defined as total Cr(VI). Currently, there were no methods suitable for large-scale monitoring of total Cr(VI) in ambient PM. This study developed a method to measure total Cr(VI) in ambient PM. This method includes PM collection using a Teflon filter, microwave extraction with 3% Na2CO3-2% NaOH at 95°C for 60 minutes, and Cr(VI) analysis by 1,5-diphenylcarbazide colorimetry at 540 nm. The recoveries of total Cr(VI) were 119.5 ± 10.4% and 106.3 ± 16.7% for the Cr(VI)-certified reference materials, SQC 012 and SRM 2700, respectively. Total Cr(VI) in the reference urban PM (NIST 1648a) was 26.0 ± 3.1 mg/kg (%CV = 11.9%) determined by this method. The method detection limit was 0.33 ng/m3. This method and the one previously developed to measure ambient Cr(VI), which is soluble in pH ~9.0 aqueous solution, were applied to measure Cr(VI) in ambient PM10 collected from three urban areas and one suburban area in New Jersey. The total Cr(VI) concentrations were 1.05-1.41 ng/m3 in the winter and 0.99-1.56 ng/m3 in the summer. The soluble Cr(VI) concentrations were 0.03-0.19 ng/m3 in the winter and 0.12-0.37 ng/m3 in the summer. The summer mean ratios of soluble to total Cr(VI) were 14.3-43.7%, significantly higher than 4.2-14.4% in the winter. The winter concentrations of soluble and total Cr(VI) in the suburban area were significantly lower than in the three urban areas. The results suggested that formation of Cr(VI) via atmospheric chemistry may contribute to the higher soluble Cr(VI) concentrations in the summer.

Quantitative assessment of inhalation exposure and deposited dose of aerosol from nanotechnology-based consumer sprays.

This study provides a quantitative assessment of inhalation exposure and deposited aerosol dose in the 14 nm to 20 µm particle size range based on the aerosol measurements conducted during realistic usage simulation of five nanotechnology-based and five regular spray products matching the nano-products by purpose of application. The products were also examined using transmission electron microscopy. In seven out of ten sprays, the highest inhalation exposure was observed for the coarse (2.5-10 µm) particles while being minimal or below the detection limit for the remaining three sprays. Nanosized aerosol particles (14-100 nm) were released, which resulted in low but measurable inhalation exposures from all of the investigated consumer sprays. Eight out of ten products produced high total deposited aerosol doses on the order of 101-103 ng kg-1 bw per application, ~85-88% of which were in the head airways, only <10% in the alveolar region and <8% in the tracheobronchial region. One nano and one regular spray produced substantially lower total deposited doses (by 2-4 orders of magnitude less), only ~52-64% of which were in the head while ~29-40% in the alveolar region. The electron microscopy data showed nanosized objects in some products not labeled as nanotechnology-based and conversely did not find nano-objects in some nano-sprays. We found no correlation between nano-object presence and abundance as per the electron microscopy data and the determined inhalation exposures and deposited doses. The findings of this study and the reported quantitative exposure data will be valuable for the manufacturers of nanotechnology-based consumer sprays to minimize inhalation exposure from their products, as well as for the regulators focusing on protecting the public health.

Impacts of a nanosized ceria additive on diesel engine emissions of particulate and gaseous pollutants.

Fuel additives incorporating nanosized ceria have been increasingly used in diesel engines as combustion promoters. However, few studies have assessed the impact of these nanotechnology-based additives on pollutant emissions. Here, we systematically compare emission rates of particulate and gaseous pollutants from a single-cylinder, four-cycle diesel engine using fuel mixes containing nanoceria of varying concentrations. The test fuels were made by adding different amounts of a commercial fuel additive Envirox into an ultralow-sulfur diesel fuel at 0 (base fuel), 0.1-, 1-, and 10-fold the manufacturer-recommended concentration of 0.5 mL Envirox per liter of fuel. The addition of Envirox resulted in ceria-concentration-dependent emission reductions of CO2, CO, total particulate mass, formaldehyde, acetaldehyde, acrolein, and several polycyclic aromatic hydrocarbons. These reductions at the manufacturer-recommended doping concentration, however, were accompanied by a substantial increase of certain other air pollutants, specifically the number of ultrafine particles (+32%), NO(x) (+9.3%), and the particle-phase benzo[a]pyrene toxic equivalence quotient (+35%). Increasing fuel ceria concentrations also led to decreases in the size of emitted particles. Given health concerns related to ultrafine particles and NO(x), our findings call for additional studies to further evaluate health risks associated with the use of nanoceria additives in various engines under various operating conditions.

Interconversion of chromium species during air sampling: effects of O3, NO2, SO2, particle matrices, temperature, and humidity.

The interconversion between Cr(VI), a pulmonary carcinogen, and Cr(III), an essential human nutrient, poses challenges to the measurement of Cr(VI) in airborne particles. Chamber and field tests were conducted to identify the factors affecting Cr(VI)-Cr(III) interconversion in the basic filter medium under typical sampling conditions. In the chamber tests, isotopically enriched (53)Cr(VI) and (50)Cr(III) were spiked on diesel particulate matter (DPM) and secondary organic aerosol (SOA) that were precollected on a basic MCE filter. The filter samples were then exposed to clean air or the air containing SO2 (50 and 160 ppb), 100 ppb O3, or 150 ppb NO2 for 24 h at 16.7 LPM flow rate at designated temperature (20 and 31 °C) and RH (40% and 70%) conditions. Exposure to 160 ppb SO2 had the greatest effect on (53)Cr(VI) reduction, with (53)Cr(VI) recovery of 31.7 ± 15.8% (DPM) and 42.0 ± 7.9% (SOA). DPM and SOA matrix induced (53)Cr(VI) reduction when exposed to clean air while reactive oxygen species in SOA could promote (50)Cr(III) oxidation. Deliquescence when RH increased from 40% to 70% led to conversion of Cr(III) in SOA, whereas oxidized organics in DPM and SOA enhanced hygroscopicity and thus facilitated Cr(VI) reduction. Field tests showed seasonal variation of Cr(VI)-Cr(III) interconversion during sampling. Correction of the interconversion using USEPA method 6800 is recommended to improve accuracy of ambient Cr(VI) measurements.

A discussion of exposure science in the 21st century: a vision and a strategy.

BACKGROUND: The National Research Council (NRC) of the National Academy of Sciences recently published the report Exposure Science in the 21st Century: A Vision and a Strategy. The expert committee undertaking this report included expertise from ecology, chemistry, exposure science, toxicology, public health, bioethics, engineering, medicine, and policy. OBJECTIVE: Our aim is to inform members of the scientific community in fields aligned with environmental and public health so they are more able to appreciate the full breadth of the vision and understand the framework developed in order to move the vision forward. DISCUSSION: Although the NRC report was commissioned by the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences, it is solely the consensus product of the independent volunteer committee, whose findings were subject to the rigorous peer-review procedures of the NRC. In addition to reviewing the history and current status of exposure science, the report lays out a vision for the future and makes recommendations that include both short-term and long-term milestones. CONCLUSION: To accomplish the vision presented in the NRC report, resources will be needed to complete studies, develop and use analyses of exposure, and build databases associated with individual and population exposures, as well as to train the next generation of exposure scientists. Important excerpts as well as paraphrased statements from the report appear in this commentary; however, the general observations and comments are our own.

Two decades of exposure assessment studies on chromate production waste in Jersey City, New Jersey--what we have learned about exposure characterization and its value to public health and remediation.

During much of the twentieth century, Jersey City, New Jersey was the leading center of chromate production in the United States. Chromate production produced huge volumes of chromium ore-processing residue containing many parts per million of hexavalent chromium. Starting in the 1990s, we undertook a series of studies to identify exposed populations, sources and pathways of exposure and the effectiveness of remediation activities in Jersey City. These studies revealed the effectiveness and success of the remediation activities. The sequence of studies presented here, builds on the lessons learned from each preceding study and illustrates how these studies advanced the field of exposure science in important ways, including the use of household dust as a measure of exposure to contaminants originating in the outdoor environment; development of effective and reproducible dust sampling; use of household dust to track temporal changes in exposure; understanding of the spatial relationship between sources of passive outdoor particulate emissions and residential exposure; use of focused biomonitoring to assess exposure under conditions of large inter-individual variability; and utility of linking environmental monitoring and biomonitoring. For chromium, the studies have demonstrated the use of Cr(+6)-specific analytical methods for measuring low concentrations of Cr(+6) in household dust and understanding of the occurrence of Cr(+6) in the background residential environment. We strongly recommend that environmental and public health agencies evaluate sites for their potential for off-site exposure and apply these tools in cases with significant potential as appropriate. This approach is especially important when contamination is widespread and/or a large population is potentially exposed. In such cases, these tools should be used to identify, characterize and then reduce the exposure to the off-site as well as on-site population. Importantly, these tools can be used in a demonstrable and quantifiable manner to provide both clarity and closure to concerned stakeholders.

Exposure indices for the National Children's Study: application to inhalation exposures in Queens County, NY.

Characterization of environmental exposures to population subgroups within the National Children's Study (NCS), or other large-scale human environmental health studies is essential for developing a high-quality data platform for subsequent investigations. A computational formulation utilizing the tiered exposure ranking framework is presented for calculating inhalation exposure indices (EIs) for population subgroups. This formulation employs a probabilistic approach and combines information from diverse, publicly available exposure-relevant databases and information on biological mechanisms, for ranking study locations or population subgroups with respect to potential for specific end point-related environmental exposures. These EIs capture and summarize, within a set of numerical values/ranges, complex distributions of potential exposures to multiple airborne contaminants. These estimates capture spatial and demographic variability within each study segment, and allow for the relative comparison of study locations based on different statistical metrics of exposures. The EI formulation was applied to characterize and rank segments within Queens County, NY, which is one of the Vanguard centers for the NCS. Inhalation EI estimates relevant to respiratory outcomes, and potentially to pregnancy outcomes (low birth weight and preterm birth rates) were calculated at the study segment level. Results indicate that there is substantial variability across the study segments in Queens County, NY, and within segments, and showed an exposure gradient across the study segments that can help guide and target environmental and personal exposure sampling efforts in this county. The results also serve as an example application of the EI for use in other exposure and outcome studies.