Long-term Exposure to Air Pollution and Development of Cardiovascular Disease

Long-term Exposure to Air Pollution and Development of Cardiovascular Disease is sponsored by U.S. Environmental Protection Agency (EPA). This opportunity supports mission-aligned projects and measurable outcomes.

Long-term Exposure to Air Pollution and Development of Cardiovascular Disease | US EPA Long-term Exposure to Air Pollution and Development of Cardiovascular Disease U.S. Environmental Protection Agency Office of Research and Development National Center for Environmental Research Science to Achieve Results (STAR) Program Long-term Exposure to Air Pollution and Development of Cardiovascular Disease CLOSED - FOR REFERENCES PURPOSES ONLY This is the initial announcement of this funding opportunity.

Funding Opportunity Number: EPA-G2016-STAR-B1 Catalog of Federal Domestic Assistance (CFDA) Number: 66. 509 Solicitation Opening Date: May 18, 2016 Solicitation Closing Date: August 2, 2016, 11:59:59 pm Eastern Time Technical Contact: Vito Ilacqua (ilacqua. vito@epa.

gov); phone: 202-564-4512 Eligibility Contact: Ron Josephson (josephson. ron@epa. gov); phone: 202-564-7823 Electronic Submissions: Debra M.

Jones (jones. debram@epa. gov); phone: 202-564-7839 I.

FUNDING OPPORTUNITY DESCRIPTION C. Authority and Regulations D. Specific Areas of Interest/Expected Outputs and Outcomes III.

ELIGIBILITY INFORMATION IV. APPLICATION AND SUBMISSION INFORMATION A. Grants.

gov Submittal Requirements and Limited Exception Procedures B. Application Package Information C. Content and Form of Application Submission D.

Submission Dates and Times F. Submission Instructions and Other Submission Requirements V. APPLICATION REVIEW INFORMATION C.

Human Subjects Research Statement (HSRS) Review E. Additional Provisions for Applicants Incorporated into the Solicitation VI. AWARD ADMINISTRATION INFORMATION C.

Administrative and National Policy Requirements Access Standard STAR Forms ( How to Apply and Required Forms ) The U.S. Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) program, is seeking applications proposing to expand and inform the understanding of the mechanism(s) by which air pollution contributes to the development of cardiovascular disease.

Specifically, research is needed to estimate the total cardiovascular risk associated with exposure to air pollution, including indicators of early subclinical damage and novel endpoints, in addition to established morbidity and mortality outcomes. Research is also needed to understand related endpoints such as markers of cardio-metabolic responses and cerebrovascular disease.

In consideration of the implications of this research and of regulations promoting open access to federally funded data, the Agency is seeking applications that develop innovative methods for broad access to data generated in response to this solicitation. This solicitation provides the opportunity for the submission of applications for projects that may involve human subjects research.

Human subjects research supported by the EPA is governed by EPA Regulation 40 CFR Part 26 (Protection of Human Subjects). This includes the Common Rule at subpart A and prohibitions and additional protections for pregnant women and fetuses, nursing women, and children at subparts B, C, and D.

Research meeting the regulatory definition of intentional exposure research found in subpart B is prohibited by that subpart in pregnant women, nursing women, and children. Research meeting the regulatory definition of observational research found in subparts C and D is subject to the additional protections found in those subparts for pregnant women and fetuses (subpart C) and children (subpart D).

All applications must include a Human Subjects Research Statement (HSRS, as described in Section IV. C. 5.

c of this solicitation), and if the project involves human subjects research, it will be subject to an additional level of review prior to funding decisions being made as described in Sections V. C and V. D of this solicitation.

Additional information can be found in Section I. A of the full announcement.

Guidance and training for investigators conducting EPA-funded research involving human subjects may be obtained here: Basic Information about Human Subjects Research Basic EPA Policy for Protection of Subjects in Human Research Conducted or Supported by EPA Anticipated Type of Award: Grant Estimated Number of Awards: One (1) award Anticipated Funding Amount: Approximately $3 million total for all awards Potential Funding per Award: Up to a total of $3,000,000 , including direct and indirect costs, with a maximum duration of 5 years.

Cost-sharing is not required. Proposals with budgets exceeding the total award limits will not be considered.

Public nonprofit institutions/organizations (includes public institutions of higher education and hospitals) and private nonprofit institutions/organizations (includes private institutions of higher education and hospitals) located in the U.S., state and local governments, Federally Recognized Indian Tribal Governments, and U.S. territories or possessions are eligible to apply. See full announcement for more details.

If your organization is not currently registered with Grants. gov, you need to allow approximately one month to complete the registration process. Please note that the registration process also requires that your organization have a unique entity identifier (formerly ‘DUNS number’) and a current registration with the System for Award Management (SAM) and the process of obtaining both could take a month or more.

Applicants must ensure that all registration requirements are met in order to apply for this opportunity through Grants. gov and should ensure that all such requirements have been met well in advance of the submission deadline. This registration, and electronic submission of your application, must be performed by an authorized representative of your organization.

If you do not have the technical capability to utilize the Grants. gov application submission process for this solicitation, see Section IV. A below for additional guidance and instructions.

Technical Contact: Vito Ilacqua (ilacqua. vito@epa. gov); phone: 202-564-4512 Eligibility Contact: Ron Josephson (josephson.

ron@epa. gov); phone: 202-564-7823 Electronic Submissions: Debra M. Jones (jones.

debram@epa. gov); phone: 202-564-7839 I. FUNDING OPPORTUNITY DESCRIPTION The effects of air pollution on the cardiovascular system account for the largest portion of the public health and economic benefits of the Clean Air Act.

The evidence for these effects is based on associations observed in a number of epidemiological studies ( Mustafić et al. 2012; Hoek et al. 2013; Shah et al.

, 2013; Newby et al. , 2014), with biological plausibility supported by numerous mechanistic investigations (Mills et al. , 2009; Sun et al.

, 2010; Zanobetti et al. , 2011). While several mechanisms are involved, chronic cardiovascular disease (CVD) is a slowly progressing condition, whose natural history develops through most of the human life span (Grundy et al.

, 1999; Jardim et al. , 2015). The relationship between long-term exposure to PM 2.

5 and cardiovascular health effects has been determined as causal (U.S. EPA, 2009; Brook et al. , 2010). However, long-term prospective studies that can inform and reduce uncertainties about the shape of the concentration-response relationship, especially at low ambient concentrations of PM 2.

5 , or that will aid in the identification and/or further characterization of potentially at-risk groups and adult lifestages will be especially useful for public health protection strategies. Much uncertainty remains about the effects of ozone and nitrogen oxides on cardiovascular health.

Prospective studies of long-term exposure that can support or challenge an inference of causality between these gaseous air pollutants and the development of cardiovascular disease are necessary to establish a causal association.

Furthermore, information of the associations with these air pollutants and other health endpoints, especially cardiometabolic, cerebrovascular, and neurological endpoints, would be informative for clinical and public health interventions.

Epidemiological analysis examining a range of effects across these health endpoints, from biomarkers of subclinical changes to fully-developed disease, in the same population can help address these research areas. This solicitation provides the opportunity for the submission of applications for projects that may involve human subjects research.

Human subjects research supported by the EPA is governed by EPA Regulation 40 CFR Part 26 (Protection of Human Subjects). This includes the Common Rule at subpart A and prohibitions and additional protections for pregnant women and fetuses, nursing women, and children at subparts B, C, and D.

Research meeting the regulatory definition of intentional exposure research found in subpart B is prohibited by that subpart in pregnant women, nursing women, and children. Research meeting the regulatory definition of observational research found in subparts C and D is subject to the additional protections found in those subparts for pregnant women and fetuses (subpart C) and children (subpart D).

All applications must include a Human Subjects Research Statement (HSRS, as described in Section IV. C. 5.

c of this solicitation), and if the project involves human subjects research, it will be subject to an additional level of review prior to funding decisions being made as described in Sections V. C and V. D of this solicitation.

Please note that surveys, interviews, and focus groups with individuals may constitute human subjects research. The additional level of review is conducted by the EPA Human Subjects Research Review Official (HSRRO). In making a determination about conditional and later final approval, the HSRRO will apply both EPA Regulation 40 CFR 26 and EPA Policy Order 1000.

17 Change A1, where human exposure research is interpreted as any intervention that manipulates subjects’ environment (i.e., modifies subjects’ exposure).

For more specific information including guidance and training, see: Basic Information about Human Subjects Research Basic EPA Policy for Protection of Subjects in Human Research Conducted or Supported by EPA EPA recognizes that it is important to engage all available minds to address the environmental challenges the nation faces.

At the same time, EPA seeks to expand the environmental conversation by including members of communities which may have not previously participated in such dialogues to participate in EPA programs. For this reason, EPA strongly encourages all eligible applicants identified in Section III, including minority serving institutions, to apply under this opportunity.

For purposes of this solicitation, the following are considered MSIs: Historically Black Colleges and Universities, as defined by the Higher Education Act (20 U.S.C. § 1061). A list of these schools can be found at White House Initiative on Historically Black Colleges and Universities ; Tribal Colleges and Universities, as defined by the Higher Education Act (20 U.S.C.

§ 1059(c)). A list of these schools can be found at American Indian Tribally Controlled Colleges and Universities ; Hispanic-Serving Institutions (HSIs), as defined by the Higher Education Act (20 U.S.C. § 1101a(a)(5).

There is no list of HSIs.

HSIs are institutions of higher education that, at the time of application submittal, have an enrollment of undergraduate full-time equivalent students that is at least 25% Hispanic students at the end of the award year immediately preceding the date of application for this grant; and Asian American and Native American Pacific Islander-Serving Institutions; (AANAPISIs), as defined by the Higher Education Act (20 U.S.C. § 1059g(a)(2)).

There is no list of AANAPISIs. AANAPISIs are institutions of higher education that, at the time of application submittal, have an enrollment of undergraduate students that is not less than 10 % students who are Asian American or Native American Pacific Islander. The mechanism by which air pollution contributes to the pathophysiology of CVD is complex and not yet completely understood.

Evidence is accumulating for PM 2. 5 (Mills et al. 2009; Forastiere and Agabiti, 2013) regarding a cascade of events triggered by inhalation of fine particles that results in oxidative stress and inflammation, and continues in altered endothelial, thrombotic, and autonomic function, as well as promotion of atheroma.

In addition to oxidative stress, direct central nervous system activation may be implicated as well, with further consequences for rhythm control.

Several of these mechanisms are important for acute CVD morbidity and mortality in people with chronic CVD, but a critical public health question is whether exposure to air pollution is a contributing risk factor for the development of CVD in a healthy population, as the resulting burden of disease of air pollution could be substantially larger than is currently estimated.

Less is known about the mechanism by which long-term exposure to gaseous pollutants may contribute to CVD and other health endpoints, especially cardiometabolic, cerebrovascular, and neurological endpoints, or the mechanisms by which co-exposures to gaseous pollutants may modify the effects of PM 2. 5 on CVD.

The concept of premature vascular aging has been proposed as a framework to estimate burden for the transition between healthy and subclinical status (Adar et al. 2010; Kuenzli et al. 2011; Krishnan et al.

2012). A few toxicological (Sun et al. , 2005; Araujo et al.

, 2008) and epidemiological studies (Kuenzli et al. 2005; Bauer et al. 2010; Gill et.

al, 2011) have examined the association between air pollution and atherosclerosis in particular, as this progressive insidious disease is the leading cause of mortality worldwide (Barquera et al. , 2015), a trend that is anticipated to continue (Fonarow, 2007). New research that can be readily integrated and synthesized into this existing, multi-disciplinary body of literature will be especially informative.

To fully characterize the relationship between exposure to air pollution and subclinical development of CVD (and other health endpoints), knowledge of the concentration-response relationship at low ambient concentrations is critical to formulate public health strategies (state and local regulation and implementation, behavioral, clinical) that manage risk appropriately (Pope et al. , 2015).

As the link between air pollution and incidence of subclinical CVD (rather than its clinical endpoints) remains poorly understood, so is the form of its concentration-response relationship. A few estimates of concentration-response relationships have been formulated to assess the burden of CVD morbidity and mortality attributable to air pollution (Schwartz & Zanobetti, 2000; Aunan & Pan, 2004; Pope et al. , 2009; Burnett et al.

, 2014). These estimates of concentration-response relationships have greater precision where there is the most information on population exposures. In most cases, this has been at higher levels of exposure, although studies in locations with generally lower PM 2.

5 concentrations are becoming more prevalent in developed countries (Crouse et al, 2015). While some studies at low concentrations are now being conducted, substantial uncertainty remains at concentrations near or below current air quality standards that are experienced by a majority of the population in developed countries (Shin et al. , 2015).

More information is needed at these ambient concentrations particularly in light of the apparent supralinear relationships at low concentrations of PM 2. 5 suggested in some of these estimates (Pope et al. , 2015, Nasari et al, 2016).

Exploration of nonlinear relationships is also especially needed to evaluate risk in realistic exposure scenarios that involve multipollutant interactions (Oakes et al. , 2014; Zanobetti et al. , 2014).

Historically, the effects of short- and long-term exposures to air pollution have been considered separately, with different risk estimates associated with acute and chronic morbidity and short- and long-term mortality effects (Schwartz, 2000; Zanobetti et al, 2003; Pope & Dockery, 2006).

This paradigm, shared with analyses of risk for other environmental pollutants, has been driven both by physiological understanding of the mechanisms of action and by limited availability of reliable data for exposure assessment.

With the accumulation of air quality monitoring data that allows better retrospective exposure assessment for longer time-series analyses, it may be possible now to explore how health effects are associated with different aspects of exposure, including cumulative of exposures, latency between exposure and health response, and a continuum of exposure durations.

For cardiovascular disease with variable progression rates during a lifetime, such as atherosclerosis (Kiechl et al. , 1999), analyses of association at different long-term time scales could provide valuable information to estimate the fraction of attributable burden from subclinical disease development (perhaps over several decades) and the fraction of burden from clinical manifestations of the disease (perhaps over several years).

New research that evaluates health effects due to past and recent long-term exposures and that improves the understanding of the relevant latency period will be informative. Aside from the public health value of understanding burden of disease, the analysis could provide insights for prevention and clinical management for people at different stages of disease.

The evaluation of effect modification can contribute to the identification and characterization of potentially at-risk populations and adult lifestages. New research that evaluates effect modifiers (e.g., pre-existing disease, race/ethnicity, sociodemographic and behavioral factors) will be informative.

Regardless of exposure duration and concentration, exposure misclassification has long been recognized as an inherent limitation of air pollution epidemiology (Zeger et al. , 2000). Spatial misalignment of exposure measurements can occur when fixed monitoring data are used for spatially heterogeneous pollutants, while attempts to model personal exposures from limited microenvironmental information can introduce additional error.

A variety of methods and approaches for air pollution exposure has been evaluated (Jerrett et al. , 2005; Szpiro et al. , 2010; Sheppard et al.

, 2012; Ozkaynak et al. , 2013), especially to correct biases towards null results. Yet, it is important to advance the exposure science and understanding to clearly separate the effects that exposure modeling assumptions and choices have on estimated health effects from those they have on error estimates themselves.

Such analyses would allow consideration of the advantages and disadvantages of model complexity independently of assumptions about health effects of exposures (Baxter et al. , 2013; Dionisio et al. , 2015).

Studies that make critical contributions to the body of evidence supporting public health policy and clinical practice deserve a correspondingly high level of scrutiny, which can be best ensured by independent verification of their conclusions. To that end, ensuring verification and reproducibility requires accessibility of data to other qualified researchers, over a period of time that extends well beyond the publication of results.

While regulatory requirements exist for sharing data from publicly funded research, these are focused on awardee responsibilities that are necessarily limited in time and scope, rather than on solutions that actively facilitate access by independent investigators.

Additionally, data that contain geospatial information, as much air pollution exposure data do, are simultaneously subject to regulations intended to protect the privacy of participants in a research project. The debate around the perceived conflict between these requirements (Wartenberg and Thompson, 2010; Rothenstein, 2010; Vayena et al.

, 2015, etc.) is made more acute by growing demand for direct citizen access to the science underpinning public and environmental health protection. Some methods may exist to anonymize geospatial data without loss of exposure-relevant information (Rodgers et al.

, 2012; Kounadi and Leitner, 2016), but they have not been widely applied to environmental data sets, and the question of how to maximize accessibility of environmental health data while preserving researchers’ rights and participants confidentiality does not yet have satisfactory answers. Goal 1: Addressing Climate Change and Improving Air Quality, Objective 1. 2: Improve Air Quality C.

Authority and Regulations The authority for this RFA and resulting awards is contained in the Clean Air Act, Section 103, 42 U.S.C. 7403. For research with an international aspect, the above statutes are supplemented, as appropriate, by the National Environmental Policy Act, Section 102(2)(F).

Note that a project’s focus is to consist of activities within the statutory terms of EPA’s financial assistance authorities; specifically, the statute(s) listed above. Generally, a project must address the causes, effects, extent, prevention, reduction, and elimination of air pollution, water pollution, solid/hazardous waste pollution, toxic substances control, or pesticide control depending on which statute(s) is listed above.

These activities should relate to the gathering or transferring of information or advancing the state of knowledge. Proposals should emphasize this “learning” concept, as opposed to “fixing” an environmental problem via a well-established method.

Proposals relating to other topics which are sometimes included within the term “environment” such as recreation, conservation, restoration, protection of wildlife habitats, etc., must describe the relationship of these topics to the statutorily required purpose of pollution prevention and/or control. Note: Applications dealing with any aspect of or related to hydraulic fracking will not be funded by EPA through this program.

Applicable regulations include: 2 CFR Part 200, 2 CFR Part 1500, and 40 CFR Part 40 (Research and Demonstration Grants). D. Specific Areas of Interest/Expected Outputs and Outcomes Note to applicant: The term “output” means an environmental activity, effort, and/or associated work products related to an environmental goal or objective, that will be produced or provided over a period of time or by a specified date.

The term “outcome” means the result, effect or consequence that will occur from carrying out an environmental program or activity that is related to an environmental or programmatic goal or objective. The Agency is soliciting research to expand and increase the understanding of the evidence for the associations between air pollution and cardiovascular disease and other related health endpoints.

Specifically, research is needed to estimate the total cardiovascular risk associated with exposure to air pollution, including indicators of early subclinical damage and novel endpoints, in addition to established and emerging morbidity and mortality outcomes (e.g., cardiometabolic disease, cerebrovascular disease, and neurological disease).

This research may take the form of epidemiological analyses of standardized CVD morbidity and mortality measures, or of subclinical physiological changes, associated with exposure to air pollution; or characterizations of the concentration-response relationship between air pollution and health endpoints across a range of exposure levels, including those in areas in attainment of current air pollution standards; or of alternative analyses that would produce similar outputs and outcomes.

Outputs expected from this solicitation may include publications of research results in peer-reviewed journals, among others, as well as state monitoring and implementation plans that reflect the effects of exposure measurement uncertainty and pollutant interactions.

These outputs can be used to achieve public health protection outcomes (e.g. increase in public and physician awareness of lifestyle risks and prevention choices) that take into account the full benefit of improved air quality.

This RFA solicits proposals that should address at least three of the following research areas: What are the associations between health endpoints and exposure to air pollution in a well-characterized study population, including consideration of subclinical cardiovascular damage, such as atherosclerotic lesions, as well as other novel cardiovascular, cardio-metabolic, cerebrovascular, or neurological endpoints?

What is the shape of the concentration-response relationship for PM 2. 5 and gaseous air pollutants, including NO 2 and O 3 , and the development of health endpoints, particularly at concentrations below the levels of the current air pollution standards? How are these relationships affected by regional, socioeconomic, and comorbidity differences, and exposure to other air pollutants?

What is the relative burden, along a continuum of durations, of more recent (years) long-term exposures vs. historical (decades) exposure on the association between health endpoints and air pollution?

Specifically, what are the health effects associated with cumulative exposures during adult life stages, recognizing that early exposures may have greater or lesser impacts compared with later exposures (reflecting latency of disease), and that age range during exposures may also modify the impact of exposures?

What is the impact of exposure measurement error on the health effect estimation, and what is the sensitivity of both effect and error to exposure assumptions? Proposals which do not address at least three of the research areas above may not be rated as highly under the evaluation process described in Section V.

Also, proposals that address all four of the research areas above will not necessarily be rated more highly than those that address at least three of the areas. This RFA encourages innovative methods for access to data.

Desirable data management characteristics, that would enhance a proposal, may include, for example: Innovative data sharing approaches used to increase the accessibility of geospatial exposure data to remain responsive to inquiries, while maintaining participant confidentiality, even when a collaborative approach is not feasible.

Ensuring the availability of the entire data set to other qualified researchers, to promote independent re-analysis and extension of results. (e.g., see HEI re-analyses and extension of ACS data, Krewski et al. , 2009).

Options extending availability for an indefinite period are especially encouraged. Developing a plan to leverage use of this data with other datasets, specifically promoting linking exposure estimates with other health endpoints, and comparison with other epidemiological data sets. Developing provisions to respond to requests for data sets without Personally Identifiable Information, and unprocessed data as collected.

To the extent practicable, research proposals must embody innovation. Innovation for the purposes of this RFA is defined as the process of making changes; a new method, custom or device. Innovative research can take the form of wholly new applications or applications that build on existing knowledge and approaches for new uses.

Research proposals must include a discussion on how the proposed research is innovative (see Section IV. C. 5.

a). ORD will draw from the above-mentioned innovation definition in the review/evaluation process of recommending research proposals (see Section V. A).

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