Grantee Research Project Results

U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Research
Science to Achieve Results (STAR) Program

CLOSED - FOR REFERENCES PURPOSES ONLY

Recipients List

Susceptibility and Variability in Human Response to Chemical Exposure

This is the initial announcement of this funding opportunity.

Funding Opportunity Number: EPA-G2013-STAR-J1

Catalog of Federal Domestic Assistance (CFDA) Number: 66.509

Solicitation Opening Date: June 10, 2013
Solicitation Closing Date: September 10, 2013 Extended to: September 24, 2013, 11:59:59 pm Eastern Time

Eligibility Contact: Ron Josephson (josephson.ron@epa.gov); phone: 703-308-0442
Electronic Submissions: Todd Peterson (peterson.todd@epa.gov); phone: 703-308-7224
Technical Contact: Mitch Lasat (lasat.mitch@epa.gov); phone: 703-347-8099

Access Standard STAR Forms (Forms and Standard Instructions Download Page)
View research awarded under previous solicitations (Funding Opportunities: Archive Page)

SUMMARY OF PROGRAM REQUIREMENTS

Synopsis of Program:
The U.S. Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) program, is seeking applications proposing research to study life stage and/or genetic susceptibility in order to better characterize the sources of human variability in response to chemical exposure.  The adverse outcome pathways (AOP) concept has the potential to serve as a framework for using susceptibility indicators, biomonitoring, and high throughput screening (HTS) data in an integrated manner to predict population responses to novel, potentially harmful, chemicals. While much emphasis has been placed on improved biomonitoring and HTS approaches, research is needed to understand the underlying factors that influence human susceptibility and to develop tools and methods for the identification and use of susceptibility indicators in this context. 

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.B.5.c), 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.

Guidance and training for investigators conducting EPA-funded research involving human subjects may be obtained here:
Ethics, Regulations, and Policies (https://www.epa.gov/osainter/phre/policy.htm)
Human Subjects Research at the Environmental Protection Agency: Ethical Standards and Regulatory Requirements (https://www.epa.gov/osainter/phre/phre_course/index.htm)

Award Information:
Anticipated Type of Award: Grant or Cooperative Agreement
Estimated Number of Awards: Up to 4awards
Anticipated Funding Amount: Up to $2.6 million total for all awards
Potential Funding per Award: Up to a total of $800,000, including direct and indirect costs, with a maximum duration of four years. Cost-sharing is not required.  Proposals with budgets exceeding the total award limits will not be considered.

Eligibility Information:
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.

Application Materials:
To apply under this solicitation, use the application package available at Grants.gov (for further submission information see Section IV.E. “Submission Instructions and other Submission Requirements”).  The necessary forms for submitting a STAR application will be found on the National Center for Environmental Research (NCER) web site, Forms and Standard Instructions Download Page (https://www.epa.gov/research-grants/funding-opportunities-how-apply-and-required-forms). If your organization is not currently registered with Grants.gov, you need to allow approximately one week to complete the registration process.  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, send a webmail message at least 15 calendar days before the submission deadline to assure timely receipt of alternate submission instructions.  In your message  provide the funding opportunity number and title of the program, specify that you are requesting alternate submission instructions, and provide a telephone number, fax number, and an email address, if available.  Alternate instructions will be emailed whenever possible.  Any applications submitted through alternate submission methods must comply with all the provisions of this Request for Applications (RFA), including Section IV, and be received by the solicitation closing date identified above.

Agency Contacts:
Eligibility Contact: Ron Josephson (josephson.ron@epa.gov); phone: 703-308-0442
Electronic Submissions: Todd Peterson (peterson.todd@epa.gov); phone: 703-308-7224
Technical Contact: Mitch Lasat (lasat.mitch@epa.gov); phone: 703-347-8099

I. FUNDING OPPORTUNITY DESCRIPTION

A. Introduction
A high-priority research need identified by the EPA Office of Research and Development (ORD) is to improve the understanding of variability in human response to chemical exposures and factors that affect susceptibility. Currently, EPA risk assessments acknowledge that susceptibility can depend on a number of intrinsic and extrinsic factors including genetics, stage in life, health status, and cumulative lifetime exposure profile. However, better characterization of these factors to provide a more quantitative understanding of susceptibility is needed, particularly for vulnerable groups such as highly exposed populations. As high throughput assays (HTS) are beginning to be adopted in toxicity testing, the development of methods to effectively interpret toxicity results in the context of human susceptibility becomes critical (Zeiss, 2013). In addition, risk assessors at the state, tribal, and federal level are being called upon to better utilize monitoring studies that measure biomarkers of exposure, as well as early indicators of the health effects (GAO, 2009). The use of these data, however, is restricted by a lack of knowledge regarding susceptibility factors and the identification of susceptible individuals within the general population. Advances in the fundamental science, methodology, and tools (e.g., biomarkers of susceptibility) for quantifying individual susceptibility are needed to effectively incorporate population variability in response to chemical exposure and facilitate the incorporation of emerging data streams.

Definitions of Key Terms

1. Sensitivity – Differences in toxic response resulting from toxicodynamics differences and/or toxicokinetics differences.  These differences can arise due to numerous biological factors such as lifestage (windows of enhanced sensitivity), genetic polymorphisms, gender, disease status, nutritional status, etc.
2. Susceptibility – Differences in risk resulting from variation in both toxicity response (sensitivity) and exposure (as a result of gender, lifestage, and behavior).
3. Vulnerability – Differences in risk resulting from the combination of both intrinsic differences in susceptibility and extrinsic social stress factors such as low socioeconomic status, crime and violence, lack of community resources, crowding, access to health care, education, poverty, segregation, geography, etc.
4. Lifestage – A distinguishable time frame in an individual's life characterized by unique and relatively stable behavioral and/or physiological characteristics that are associated with development and growth.
5. Subpopulation – A population group that forms a relatively fixed portion of the population. These groups may share vulnerability factors based on ethnicity, shared genetic polymorphisms, common social stress factors, etc.

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.B.5.c), 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.

Guidance and training for investigators conducting EPA-funded research involving human subjects may be obtained here:
Ethics, Regulations, and Policies (https://www.epa.gov/osainter/phre/policy.htm)
Human Subjects Research at the Environmental Protection Agency: Ethical Standards and Regulatory Requirements (https://www.epa.gov/osainter/phre/phre_course/index.htm)

B. Background
In 2009, the National Research Council (NRC) issued a report evaluating the current state of the science for risk assessment and recommended improvements for the future (NRC, 2009). Of the six recommended principles provided for uncertainty and variability analysis, four were primarily focused on improvements in methodology.  Two principles, however, rely heavily on new and innovative research. The first recommends that “attention should be directed to vulnerable individuals and subpopulations¹ that may be particularly susceptible or more highly exposed”. This requires additional research to identify susceptible subpopulations or lifestages and monitor them in a manner suitable for risk assessment.  The second recommendation is to “explain the basis and results of the uncertainty analysis with sufficient clarity to be understood by the public and decision-makers”. For the issue of variability in susceptibility and response, responding to this recommendation requires a better understanding of the factors that contribute to this variability. While there were many sources of variability reviewed, the panel noted that “variability in susceptibility and vulnerability has received less detailed evaluation in most EPA health effects assessments, although there are notable exceptions such as lead, ozone, and sulfur oxides” (NRC, 2009).

Research is Needed to Support Better Incorporation of Susceptibility and Variability in Risk Assessment
Regulatory bodies at the state, tribal, and federal level within the U.S. and throughout the world are now being asked to consider the toxicity of all chemicals in commerce many of which have little or no toxicity information (NRC 2007; Schoeters, 2010). In response, large initiatives are underway in the U.S. and Europe to develop high throughput methods for assessing chemical toxicity.  The advantage of these methods is that they are capable of rapidly screening most commercial chemicals before they enter the environment.  However, these methods cannot quantitatively predict in vivo effective concentrations in humans in part due to differences in sensitivity.  In fact, a NRC report has stated that “there is the promise of improved capacity for assessing risks posed by new chemicals and risks to sensitive populations that are left unaddressed by current methods”, but “such advances will bring new challenges and an increased need for wisdom and creativity in addressing uncertainty and variability” (NRC, 2009). Clearly, to aid in the interpretation of the new HTS toxicity testing results, new methods and tools addressing susceptibility and variability in human response to chemical exposure need to be developed.

In addition, biomonitoring studies which highlight the prevalence of certain chemicals in the general population underscore the increased need for assessment of overall disease risk from cumulative lifetime exposure to these chemicals (NRC, 2006; 2008). Exposome research, which is defined as the combined lifetime exposure to natural and anthropogenic stressors contributing to an individual’s overall disease risk (Wild, 2005) represents an example of such needed efforts. The overarching goal of this research is to develop a rich set of biomarkers for monitoring  exposure to chemicals in the environment as well as early effects biomarkers that are predictive of increased disease risk.  However, the utility of this effort will also be highly dependent on understanding the susceptibility factors that contribute to the individual disease risk.

Adverse outcome pathways (AOPs) represent an organizing framework that promises to facilitate the integration of these emerging data streams (Ankley et al., 2010).  Though initially proposed to support ecotoxicology risk assessment, the AOP concept represents a powerful generalization of the mode of action (MOA) concept utilized for human risk assessment.  AOPs describe the sequence of events from a molecular initiating event to the organism and population level responses resulting from that event.  This allows the output from HTS to be interpreted in light of downstream events and thus predict the influence of a chemical on adverse outcomes at the organismal or population level.  In addition, biomonitoring data can be used to evaluate these predictions via chemical exposure biomarkers coupled with effects biomarkers linked to key events in the AOP.  If susceptibility factors are then linked with key events in this AOP, all data streams can be interpreted using systems-based modeling approaches.

Research is Needed to Better Define Key Sources of Susceptibility and Variability in Human Response
Lifestage represents a critical research need as the current approaches are inadequate to address the factors underlying susceptibility. Currently, a 10-fold intra-species adjustment factor is generally used as a default in risk assessment for threshold (generally non-cancer) effects, but more data are needed to understand whether an order of magnitude is large enough to cover both population variability and lifestage susceptibility due to unique toxicodynamic response and/or toxicokinetic/metabolic variation.    

There is a need to better understand how to utilize HTS values for risk assessment to account for lifestage susceptibility. As an example, humans may be especially vulnerable to a chemical during a critical developmental lifestage.  This critical lifestage is also referred to as a Window of Susceptibility.  In this case, hazard identification tests that do not include the critical lifestage will not necessarily identify any hazard. In addition, knowing the cumulative exposure, or even the estimated exposure throughout a person’s life, will not be informative unless the quantitative relationship between exposure and adverse effects during that critical lifestage has been defined. To address this research need, studies that assess variability/susceptibility at the quantitative level are required to extend molecular and cellular-level insights to inform risk assessment and decision making.  A better understanding of how to characterize and quantify susceptibility considerations associated with lifestage and cumulative lifetime exposure profile is required.

Another strong influence on human susceptibility is genetic variability. The completion of the human genome project and recent technological advantages has revolutionized our understanding of the genetic contribution to common diseases. It is estimated that genetic drivers alone likely account for less than 30% of the increased risk of those individuals who succumb to common diseases in western society, but genetics also plays a large role in determining the susceptibility of humans to diseases related to environmental chemical exposure (Thomas, 2010). In order for the genetic information to inform susceptibility concerns, studies are needed that better characterize the biological pathways perturbed by chemicals and modified by genetic polymorphisms and associate these pathway perturbations with disease.

Traditionally, genetic studies in humans have focused on candidate loci to investigate gene-environment relationships associated with a particular disease outcome. This type of study surveys candidate gene variability across multiple individuals or populations for individual haplotypes associated with a disease. Recent advances such as genomic information, next generation sequencing technologies, bioinformatics tools, and large datasets have dramatically changed the study of human diseases and genetic susceptibility (Schadt, 2009). These advances include the Environmental Genome Project that has used sequencing technology to identify human susceptibility genes to environmental chemicals, with results publicly available on the GeneSNPs database.  Ultimately, results from studies of genetic susceptibility could lead to a comprehensive understanding of the genetic mechanisms by which an environmental chemical exposure leads to a differential response resulting in a particular disease phenotype.

Laboratory animals have traditionally provided valuable information on the toxicity of chemicals through controlled exposures and direct measurements of biological changes in the target tissue. One limitation associated  with studies done in inbred strains of animals is the lack of genetic diversity to provide an understanding of how these responses might vary in a genetically diverse population such as humans. Recent advances such as the Collaborative Cross (Threadgill et al., 2011), which developed a panel of genetically diverse inbred mouse strains, have provided resources that allow for an assessment of effects associated with chemical exposures under a wide variety of genetic backgrounds of known pedigree (Aitman et al., 2011).  In the case of the Collaborative Cross, for example, the genetic diversity is estimated to be approximately twice that found in humans.

Though human susceptibility and variability play a large role in determining the environmental impacts on our health and well-being, relatively little is known about how lifestage, genetics, and other susceptibility factors influence our disease risk. This “can delay the completion of a risk assessment” or “undermine confidence in the public and those who use risk assessments to inform and support their decisions” (NRC, 2009). This knowledge gap will become more apparent as new data streams are developed to support risk assessment that rely heavily on mechanistic assumptions. Research that bridges this knowledge gap is critical to the long term ability of academia, nongovernmental organizations, industry, and non-federal regulatory bodies to protect at risk populations from avoidable environmental hazards.

The specific Strategic Goal and Objective from the EPA’s Strategic Plan that relate to this solicitation are:
Goal 4: Ensuring the Safety of Chemicals and Preventing Pollution, Objective 4.1: Ensure Chemical Safety

More information can be found in EPA’s FY 2014-2018 Strategic Plan

Related research conducted and supported by the EPA through the Chemical Safety for Sustainability program is described at Chemical Safety Research

C. Authority and Regulations
The authority for this RFA and resulting awards is contained in the Toxic Substances Control Act, Section 10, 15 U.S.C. 2609.

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.

Applicable regulations include: 40 CFR Part 30 (Uniform Administrative Requirements for Grants and Agreements with Institutions of Higher Education, Hospitals, and Other Non-Profit Organizations), 40 CFR Part 31 (Uniform Administrative Requirements for Grants and Cooperative Agreements to State and Local Governments) and 40 CFR Part 40 (Research and Demonstration Grants).  Applicable OMB Circulars include: OMB Circular A-21 (Cost Principles for Educational Institutions) relocated to 2 CFR Part 220, OMB Circular A-87 (Cost Principles for State, Local and Indian Tribal Governments) relocated to 2 CFR Part 225, and OMB Circular A-122 (Cost Principles for Non-Profit Organizations) relocated to 2 CFR Part 230.

D. Specific Research Areas of Interest/Expected Outputs and Outcomes
Note to applicant:  The term “output” means an environmental activity or effort, and associated work products, related to a specific environmental goal(s), (e.g., testing a new methodology), that will be produced or developed over a period of time under the agreement. The term “outcome” means the result, effect, or consequence that will occur from the above activit(ies) that is related to an environmental, behavioral, or health-related objective.

This RFA encourages a systems biology approach to study lifestage and/or genetic susceptibility in order to increase scientific understanding and ability to predict and/or test for: (1) variability in susceptibility to environmental contaminants among humans; and (2) lifestage susceptibility to novel, potentially harmful chemicals (including endocrine disrupting chemicals), particularly during early development (e.g., embryonic, fetal, infancy, and adolescence) and through adulthood.  This could include conducting multiple studies designed as part of an integrated systems biology approach (in humans, animal and in vitro systems) or human studies that augment prior results.

Proposals are solicited for studies to investigate key sources of susceptibility and variability in human response to chemical exposure.   The use of innovative research approaches is encouraged, especially in the area of developing novel biomarkers for use in evaluating human susceptibility and variability in the context of adverse outcome pathways.  Emphasis should be on biomarker discovery, research to bridge data streams, and extension of molecular and cellular-level insights to inform risk assessment.

The investigation of human variability in susceptibility as covered by this solicitation can be approached by one or both research areas described below:

1. Laboratory animal experiments that utilize a genetically diverse laboratory animal model with demonstrated relevance to human disease to characterize gene and environment interactions for environmentally relevant chemicals or utilize an animal model to evaluate the relative impact of chemicals at different life stages. Example science questions include but are not limited to:
   1. What is the AOP describing the key events driving disease, and what are the genetic and chemical influences on disease in terms of their perturbations of these key events?
   2. How can the susceptibility factors identified be used to interpret the results from a HTS assay, and are there additional assays required to adequately cover all genetic or lifestage considerations?
   3. What biomarkers from blood, urine, or another accessible matrix could be used to monitor key events from the AOP in human observational studies?
2. Human studies could provide valuable information to characterize human genetic variability and susceptibility to environmental chemicals.  Such examples include but are not limited to i) human population studies that take advantage of existing exposed  cohorts and known polymorphism in susceptibility genes, and ii) toxicogenomic studies (including genome-wide association studies [GWAS] for susceptibility genes) and studies of differential response to a chemical at different lifestages.

Outputs expected from the research funded under this RFA may include novel mechanistic insights into the genetic basis for susceptibility in humans, novel biomarkers to identify at-risk individuals and characterize chemical effects on those people, and better characterization of non-genetic susceptibility factors in humans. The outcome of this research should be a better use of susceptibility indicators, along with biomonitoring and high throughput screening data to predict responses of at-risk individuals to novel, potentially harmful chemicals.

To the extent practicable, research proposals must embody innovation and sustainability.  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.B.5.a).  The concept of sustainability is based on language in the U.S. National Environmental Policy Act of 1969 (NEPA).  This definition is reiterated in Executive Order 13514, Federal Leadership in Environment, Energy, and Economic Performance, stating that the goal of sustainability is to, “create and maintain conditions, under which humans and nature can exist in productive harmony, that permit fulfilling the social, economic, and other requirements of present and future generations.” Research proposals must include a discussion on how the proposed research will seek sustainable solutions that protect the environment and strengthen our communities (see Section IV.B.5.a).  ORD will draw from all of the above-mentioned innovation and sustainability definitions in the review/evaluation process of recommending research proposals (see Section V.A).

E. References
[Journals]

1. Zeiss, L, Bois, RY, Chiu, WA, Hattis, D, Rusyn, I, Guyton, KZ, Addressing Human Variability in Next-Generation Human Health Risk Assessments of Environmental Chemicals. Environ Health Perspect, 2013; 121:23–31.
2. Schoeters, G. The REACH perspective: Toward a new concept of toxicity testing. J. Toxicol Environ Health B Crit Rev. 2010; 13(2-4): 232-241
3. Wild , CP. Completing the genome with an “exposome”: The outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev. 2005;  14(8): 1847-1850.
4. Ankley GT, Bennett RS, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL,  Schmieder PK, Serrano JA, Tietge JE, Villeneuve DL. Adverse  outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 2010; 29(3): 730-741
5. Thomas, D. (2010). "Gene--environment-wide association studies: emerging approaches." Nat Rev Genet 11(4): 259-272
6. Schadt, E. E. (2009). "Molecular networks as sensors and drivers of common human diseases." Nature 461(7261): 218-223
7. Threadgill DW, Miller DR, Churchill GA, de Villena FP-M. The collaborative cross: A recombinant inbred mouse population for the system genetic era. ILAR. 2011; 52(1): 24-31
8. Aitman TJ, Boone C, Churchill GA, Hengartner MO, Mackay TFC, Stemple DL. The future of model organisms in human disease research. Nature Reviews Genetics. 2011; 12(8): 575-582

[Reports]

1. GAO (2009) BIOMONITORING: EPA Needs to Coordinate Its Research Strategy and Clarify Its Authority to Obtain Biomonitoring Data: Washington, DC.
2. NRC (2009) Science and Decisions: Advancing Risk Assessment. National Academy of Sciences: Washington, DC.
3. NRC (2008) Phthalates and Cumulative Risk Assessment; the Task Ahead. National Academy of Sciences: Washington, DC.
4. NRC (2007) Toxicity Testing in the Twenty-first Century: A Vision and a Strategy. National Academy of Sciences: Washington, DC.
5. NRC (2006) Human Biomonitoring for Environmental Chemicals. National Academy of Sciences: Washington, DC.

F. Special Requirements
Agency policy and ethical considerations prevent EPA technical staff and managers from providing applicants with information that may create an unfair competitive advantage.  Consequently, EPA employees will not review, comment, advise, and/or provide technical assistance to applicants preparing applications in response to EPA RFAs.  EPA employees cannot endorse any particular application.

Multiple Investigator applications may be submitted as: (1) a single Lead Principal Investigator (PI) application with Co-PI(s) or (2) a Multiple PI application (with a single Contact PI).  If you choose to submit a Multiple PI application, you must follow the specific instructions provided in Sections IV. and V. of this RFA.  For further information, please see the EPA Implementation Plan for Policy on Multiple Principal Investigators.

This solicitation provides the opportunity for the submission of applications for projects that may involve human subjects research.  There are many scientific and ethical considerations that must be addressed in such studies by the study sponsor and research team, including, but not limited to, those related to recruitment, retention, participant compensation, third-party issues, researcher-participant interactions, researcher-community interactions, communications, interventions, and education.  All such research must comply with the requirements of 40 CFR Part 26, and any human observational exposure studies must also adhere to the principles set forth in the Scientific and Ethical Approaches for Observational Exposure Studies (SEAOES) (EPA/600/R-08/062) document.  SEAOES, which was published by researchers in EPA and which discusses the principles for the ethical conduct of human research studies, serves as a resource for applicants interested in applying under this solicitation.  References to “SEAOES Principles” in this solicitation refers, in general, to the issues of interest in conducting human subjects research studies that maintain the highest scientific and ethical standards and safety during the conduct of these studies.  All applications must include a Human Subjects Research Statement (HSRS; described in Section IV.B.5.c) 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.

II. AWARD INFORMATION

It is anticipated that a total of up to $2.6 million will be awarded under this announcement, depending on the availability of funds, quality of applications received, and other applicable considerations.  The EPA anticipates funding up to four awards under this RFA.  Requests for amounts in excess of a total of up to $800,000, including direct and indirect costs, will not be considered.  The total project period requested in an application submitted for this RFA may not exceed four years. 

The EPA reserves the right to reject all applications and make no awards, or make fewer awards than anticipated, under this RFA.  The EPA reserves the right to make additional awards under this announcement, consistent with Agency policy, if additional funding becomes available after the original selections are made.  Any additional selections for awards will be made no later than six months after the original selection decisions.

EPA may award both grants and cooperative agreements under this announcement.

Under a grant, EPA scientists and engineers are not permitted to be substantially involved in the execution of the research.  However, EPA encourages interaction between its own laboratory scientists and grant Principal Investigators after the award of an EPA grant for the sole purpose of exchanging information in research areas of common interest that may add value to their respective research activities.  This interaction must be incidental to achieving the goals of the research under a grant.  Interaction that is “incidental” does not involve resource commitments.

Where appropriate, based on consideration of the nature of the proposed project relative to the EPA’s intramural research program and available resources, the EPA may award cooperative agreements under this announcement.  When addressing a research question/problem of common interest, collaborations between EPA scientists and the institution’s principal investigators are permitted under a cooperative agreement.  These collaborations may include data and information exchange, providing technical input to experimental design and theoretical development, coordinating extramural research with in-house activities, the refinement of valuation endpoints, and joint authorship of journal articles on these activities.  Proposals may not identify EPA cooperators or interactions; specific interactions between EPA’s investigators and those of the prospective recipient for cooperative agreements will be negotiated at the time of award. 

III. ELIGIBILITY INFORMATION

A. Eligible Applicants
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.  Profit-making firms are not eligible to receive assistance agreements from the EPA under this program.

Eligible nonprofit organizations include any organizations that meet the definition of nonprofit in OMB Circular A-122, located at 2 CFR Part 230.  However, nonprofit organizations described in Section 501(c) (4) of the Internal Revenue Code that lobby are not eligible to apply.

Foreign governments, international organizations, and non-governmental international organizations/institutions are not eligible to apply.

National laboratories funded by Federal Agencies (Federally-Funded Research and Development Centers, “FFRDCs”) may not apply.  FFRDC employees may cooperate or collaborate with eligible applicants within the limits imposed by applicable legislation and regulations.  They may participate in planning, conducting, and analyzing the research directed by the applicant, but may not direct projects on behalf of the applicant organization.  The institution, organization, or governance receiving the award may provide funds through its assistance agreement from the EPA to an FFRDC for research personnel, supplies, equipment, and other expenses directly related to the research.  However, salaries for permanent FFRDC employees may not be provided through this mechanism.

Federal Agencies may not apply.  Federal employees are not eligible to serve in a principal leadership role on an assistance agreement, and may not receive salaries or augment their Agency’s appropriations in other ways through awards made under this program.

The applicant institution may enter into an agreement with a Federal Agency to purchase or utilize unique supplies or services unavailable in the private sector to the extent authorized by law.  Examples are purchase of satellite data, chemical reference standards, analyses, or use of instrumentation or other facilities not available elsewhere.  A written justification for federal involvement must be included in the application.  In addition, an appropriate form of assurance that documents the commitment, such as a letter of intent from the Federal Agency involved, should be included.

Potential applicants who are uncertain of their eligibility should contact Ron Josephson (josephson.ron@epa.gov) in NCER, phone: 703-308-0442.

B. Cost-Sharing
Institutional cost-sharing is not required.

C. Other
Applications must substantially comply with the application submission instructions and requirements set forth in Section IV of this announcement or they will be rejected.  In addition, where a page limitation is expressed in Section IV with respect to parts of the application, pages in excess of the page limit will not be reviewed.  Applications must be submitted through grants.gov or by other authorized alternate means (see Section IV.E. “Submission Instructions and Other Submission Requirements” for further information) on or before the solicitation closing date and time in Section IV of this announcement or they will be returned to the sender without further consideration.  Also, applications exceeding the funding limits or project period term described herein will be returned without review.  Further, applications that fail to demonstrate a public purpose of support or stimulation (e.g., by proposing research which primarily benefits a Federal program or provides a service for a Federal agency) will not be funded. 

Applications deemed ineligible for funding consideration will be notified within fifteen calendar days of the ineligibility determination.

IV. APPLICATION AND SUBMISSION INFORMATION

Additional provisions that apply to this solicitation and/or awards made under this solicitation, including but not limited to those related to confidential business information, contracts and subawards under grants, and proposal assistance and communications, can be found at EPA Solicitation Clauses

These, and the other provisions that can be found at the website link, are important, and applicants must review them when preparing applications for this solicitation.   If you are unable to access these provisions electronically at the website above, please communicate with the EPA contact listed in this solicitation to obtain the provisions.

Formal instructions for submission through Grants.gov follow in Section E.

A. Internet Address to Request Application Package
Use the application package available at Grants.gov (see Section E. “Submission Instructions and Other Submission Requirements”).  Note: With the exception of the current and pending support form (available at Forms and Standard Instructions Download Page (https://www.epa.gov/research-grants/funding-opportunities-how-apply-and-required-forms)), all necessary forms are included in the electronic application package.

An email will be sent by NCER to the Lead/Contact PI and the Administrative Contact (see below) to acknowledge receipt of the application and transmit other important information.  The email will be sent from receipt.application@epa.gov; emails to this address will not be accepted.  If you do not receive an email acknowledgment within 30 days of the submission closing date, immediately inform the Eligibility Contact shown in this solicitation.  Failure to do so may result in your application not being reviewed.  See Section E. “Submission Instructions and Other Submission Requirements” for additional information regarding the application receipt acknowledgment.

B. Content and Form of Application Submission
The application is made by submitting the materials described below.  Applications must contain all information requested and be submitted in the formats described.  

1. Standard Form 424

   The applicant must complete Standard Form 424. Instructions for completion of the SF424 are included with the form. (However, note that EPA requires that the entire requested dollar amount appear on the SF424, not simply the proposed first year expenses.) The form must contain the signature of an authorized representative of the applying organization.

   Applicants are required to provide a “Dun and Bradstreet Data Universal Numbering System” (DUNS) number when applying for federal grants or cooperative agreements. Organizations may receive a DUNS number by calling 1-866-705-5711 or by visiting the web site at Dun and Bradstreet.

   Executive Order 12372, “Intergovernmental Review of Federal Programs,” does not apply to the Office of Research and Development's research and training programs unless EPA has determined that the activities that will be carried out under the applicants' proposal (a) require an Environmental Impact Statement (EIS), or (b) do not require an EIS but will be newly initiated at a particular site and require unusual measures to limit the possibility of adverse exposure or hazard to the general public, or (c) have a unique geographic focus and are directly relevant to the governmental responsibilities of a State or local government within that geographic area.

   If EPA determines that Executive Order 12372 applies to an applicant's proposal, the applicant must follow the procedures in 40 CFR Part 29. The applicant must notify their state's single point of contact (SPOC). To determine whether their state participates in this process, and how to comply, applicants should consult Intergovernmental Review (SPOC List). If an applicant is in a State that does not have a SPOC, or the State has not selected research and development grants for intergovernmental review, the applicant must notify directly affected State, area wide, regional and local entities of its proposal.

   EPA will notify the successful applicant(s) if Executive Order 12372 applies to its proposal prior to award.

2. Key Contacts

   The applicant must complete the “Key Contacts” form found in the Grants.gov application package. An “Additional Key Contacts” form is also available at Forms and Standard Instructions Download Page (https://www.epa.gov/research-grants/funding-opportunities-how-apply-and-required-forms). The Key Contacts form should also be completed for major sub-agreements (i.e., primary investigators). Do not include information for consultants or other contractors. Please make certain that all contact information is accurate.

   For Multiple PI applications: The Additional Key Contacts form must be completed (see Section I.F. for further information). Note: The Contact PI must be affiliated with the institution submitting the application. EPA will direct all communications related to scientific, technical, and budgetary aspects of the project to the Contact PI; however, any information regarding an application will be shared with any PI upon request. The Contact PI is to be listed on the Key Contact Form as the Project Manager/Principal Investigator (the term Project Manager is used on the Grants.gov form, the term Principal Investigator is used on the form located on NCER’s web site). For additional PIs, complete the Major Co-Investigator fields and identify PI status next to the name (e.g., “Name: John Smith, Principal Investigator”).

3. Table of Contents

   Provide a list of the major subdivisions of the application indicating the page number on which each section begins.

4. Abstract (1 page)

   The abstract is a very important document in the review process. Therefore, it is critical that the abstract accurately describes the research being proposed and conveys all the essential elements of the research. Also, the abstracts of applications that receive funding will be posted on the NCER web site.

   The abstract should include the information described below (a-h). Examples of abstracts for current grants may be found on the NCER web site.

   1. Funding Opportunity Title and Number for this proposal.
   2. Project Title: Use the exact title of your project as it appears in the application. The title must be brief yet represent the major thrust of the project. Because the title will be used by those not familiar with the project, use more commonly understood terminology. Do not use general phrases such as “research on.”
   3. Investigators: For applications with multiple investigators, state whether this is a single Lead PI (with co-PIs) or Multiple PI application (see Section I.F.). For Lead PI applications, list the Lead PI, then the name(s) of each co-PI who will significantly contribute to the project. For Multiple PI applications, list the Contact PI, then the name(s) of each additional PI. Provide a web site URL or an email contact address for additional information.
   4. Institution(s): In the same order as the list of investigators, list the name, city and state of each participating university or other applicant institution. The institution applying for assistance must be clearly identified.
   5. Project Period and Location: Show the proposed project beginning and ending dates and the performance site(s)/geographical location(s) where the work will be conducted.
   6. Project Cost: Show the total funding requested from the EPA (include direct and indirect costs for all years).
   7. Project Summary: Provide three subsections addressing: (1) the objectives of the study (including any hypotheses that will be tested), (2) the experimental approach to be used (a description of the proposed project), and (3) the expected results (outputs/outcomes) of the project and how it addresses the research needs identified in the solicitation, including the estimated improvement in risk assessment or risk management that will result from successful completion of the proposed work.
   8. Supplemental Keywords: Without duplicating terms already used in the text of the abstract, list keywords to assist database searchers in finding your research. A list of suggested keywords may be found at: Forms and Standard Instructions Download Page (https://www.epa.gov/research-grants/funding-opportunities-how-apply-and-required-forms).

5. Research Plan, Quality Assurance Statement, Human Subjects Research Statement, and References

    

    

   1. Research Plan (15 pages)

      Applications should focus on a limited number of research objectives that adequately and clearly demonstrate that they meet the RFA requirements. Explicitly state the main hypotheses that you will investigate, the data you will create or use, the analytical tools you will use to investigate these hypotheses or analyze these data, and the results you expect to achieve. Research methods must be clearly stated so that reviewers can evaluate the appropriateness of your approach and the tools you intend to use. A statement such as: “we will evaluate the data using the usual statistical methods” is not specific enough for peer reviewers.

      This description must not exceed fifteen (15) consecutively numbered (bottom center), 8.5x11-inch pages of single-spaced, standard 12-point type with 1-inch margins. While these guidelines establish the minimum type size requirements, applicants are advised that readability is of paramount importance and should take precedence in selection of an appropriate font for use in the proposal.

      The description must provide the following information:

      1. Objectives: List the objectives of the proposed research and the hypotheses being tested during the project, and briefly state why the intended research is important and how it fulfills the requirements of the solicitation. This section should also include any background or introductory information that would help explain the objectives of the study. If this application is to expand upon research supported by an existing or former assistance agreement awarded under the STAR program, indicate the number of the agreement and provide a brief report of progress and results achieved under it.
      2. Approach/Activities: Outline the research design, methods, and techniques that you intend to use in meeting the objectives stated above.
      3. Innovation: Describe how your project shifts current research or engineering paradigms by using innovative theoretical concepts, approaches or methodologies, instrumentation or interventions applicable to one or more fields of research.
      4. Sustainability: Describe how your project embodies the principles of sustainability and seeks sustainable solutions that protect the environment and strengthen our communities. The sustainability primer provides examples of research activities that promote and incorporate sustainability principles.
      5. Expected Results, Benefits, Outputs, and Outcomes: Describe the results you expect to achieve during the project (outputs) and the potential benefits of the results (outcomes). This section should also discuss how the research results will lead to solutions to environmental problems and improve the public’s ability to protect the environment and human health. A clear, concise description will help NCER and peer reviewers understand the merits of the research.
      6. Project Management: Discuss other information relevant to the potential success of the project. This should include facilities, personnel expertise/experience, project schedules with associated milestones and target dates, proposed management, interactions with other institutions, etc. Describe the approach, procedures, and controls for ensuring that awarded grant funds will be expended in a timely and efficient manner and detail how project objectives will be successfully achieved within the grant period. Describe how progress toward achieving the expected results (outputs and outcomes) of the research will be monitored and measured. Applications for multi-investigator projects must identify project management and the functions of each investigator in each team and describe plans to communicate and share data.
      7. Appendices may be included but must remain within the 15-page limit.

   2. Quality Assurance Statement (3 pages)

      For projects involving environmental data collection or processing, conducting surveys, modeling, method development, or the development of environmental technology (whether hardware-based or via new techniques), provide a Quality Assurance Statement (QAS) regarding the plans for processes that will be used to ensure that the products of the research satisfy the intended project objectives. Follow the guidelines provided below to ensure that the QAS describes a system that complies with ANSI/ASQC E4, Specifications and Guidelines for Quality Systems for Environmental Data Collection and Environmental Technology Programs. Do not exceed three consecutively numbered, 8.5x11-inch pages of single-spaced, standard 12-point type with 1-inch margins.

      NOTE: If selected for award, applicants will be expected to provide additional quality assurance documentation.

      Address each applicable section below by including the required information, referencing the specific location of the information in the Research Plan, or explaining why the section does not apply to the proposed research. (Not all will apply.)

       

       

       

      1. Identify the individual who will be responsible for the quality assurance (QA) and quality control (QC) aspects of the research along with a brief description of this person’s functions, experience, and authority within the research organization. Describe the organization’s general approach for conducting quality research. (QA is a system of management activities to ensure that a process or item is of the type and quality needed for the project. QC is a system of activities that measures the attributes and performance of a process or item against the standards defined in the project documentation to verify that they meet those stated requirements.)
      2. Discuss project objectives, including quality objectives, any hypotheses to be tested, and the quantitative and/or qualitative procedures that will be used to evaluate the success of the project. Include any plans for peer or other reviews of the study design or analytical methods.
      3. Address each of the following project elements as applicable:

          

          

          

         1. Collection of new/primary data:
            (Note: In this case the word “sample” is intended to mean any finite part of a statistical population whose properties are studied to gain information about the whole. If certain attributes listed below do not apply to the type of samples to be used in your research, simply explain why those attributes are not applicable.)

            1. Discuss the plan for sample collection and analysis. As applicable, include sample type(s), frequency, locations, sample sizes, sampling procedures, and the criteria for determining acceptable data quality (e.g., precision, accuracy, representativeness, completeness, comparability, or data quality objectives).
            2. Describe the procedures for the handling and custody of samples including sample collection, identification, preservation, transportation, and storage, and how the accuracy of test measurements will be verified.
            3. Describe or reference each analytical method to be used, any QA or QC checks or procedures with the associated acceptance criteria, and any procedures that will be used in the calibration and performance evaluation of the analytical instrumentation.
            4. Discuss the procedures for overall data reduction, analysis, and reporting. Include a description of all statistical methods to make inferences and conclusions, acceptable error rates and/or power, and any statistical software to be used.

         2. Use of existing/secondary data (i.e., data previously collected for other purposes or from other sources):

            1. Identify the types of secondary data needed to satisfy the project objectives. Specify requirements relating to the type of data, the age of data, geographical representation, temporal representation, and technological representation, as applicable.
            2. Specify the source(s) of the secondary data and discuss the rationale for selection.
            3. Establish a plan to identify the sources of the secondary data in all deliverables/products.
            4. Specify quality requirements and discuss the appropriateness for their intended use. Accuracy, precision, representativeness, completeness, and comparability need to be addressed, if applicable.
            5. Describe the procedures for determining the quality of the secondary data.
            6. Describe the plan for data management/integrity.

         3. Method development:
            (Note: The data collected for use in method development or evaluation should be described in the QAS as per the guidance in section 3A and/or 3B above.)

            Describe the scope and application of the method, any tests (and measurements) to be conducted to support the method development, the type of instrumentation that will be used and any required instrument conditions (e.g., calibration frequency), planned QC che