It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Research Objectives

This FOA is designed to stimulate the use of population-based model organism resources in exploring environmental health science and toxicology questions relevant to complex human disease outcomes. The ultimate purpose is to support key proof-of-principle studies for addressing gene-environment (G x E) interactions and host susceptibility to environmental exposures using the unique advantages and benefits of the recently developed population-based model organism resources to encourage these resources to be more firmly established as mainstream in the environmental health science field. It is anticipated that multiple unique study designs and approaches that best illustrate the effective use of population-based model organism resources will be supported through this FOA.

Most human diseases result from a complex interplay of multiple genetic, epigenetic, and environmental factors, yet studies of complex trait associations are inherently difficult in human populations. Until now, most laboratory mouse strains were inbred or outbred from a small group of founder animals. Thus, mapping complex traits in mice was also very challenging. However, new genetically-diverse mouse resources have now been developed to better simulate the genetic diversity found in human populations and overcome many of the limitations of linkage mapping in the human population in an experimental model system. For example, two new mouse resources, derived from randomized eight-way outcrosses, have produced the advance intercross recombinant inbred strains of the Collaborative Cross (CC) and a corresponding random breeding population, the Diversity Outbred (DO) mice. (The complementary CC-RIX, which are F1 crosses between CC lines, also allows for parent of origin and individual allele effects to be explored).

A meeting exploring the use of rodent population-based resources to model environmental exposures and G x E interactions in human disease was held on March 18-19, 2015 at the National Institute of Environmental Health Sciences (NIEHS). This meeting included presentations by many current users of these rodent models in the field of environmental health and toxicology and a range of projects using the CC and DO mice and other population-based rodent resources were discussed. An overview of the possible uses of these population-based rodent resources in each step of the risk assessment paradigm and for the environmental health science field in general has been recently published (https://ehp.niehs.nih.gov/ehp1274/). This review was based partly on the extensive discussions from this meeting. The overwhelming consensus from this workshop was that these resources were being underutilized to address hypotheses relevant to the impact of both high and low dose environmental exposures for models of complex human disease outcomes.

The limitations of human epidemiology studies for exploring G x E interactions, in particular, have been associated with the difficulty in assessing exposures. These population-based rodent models allow controlled exposure exploration in a population setting. The reproducibility of CC lines also provides the ability to repeat exposures or test multiple doses in the same genetic context. The integration of multiple separate studies and the integration and/or meta-analysis, particularly with next generation sequencing and other high-throughput technologies, of genomes, with epigenomes, transcriptomes, metabolomes, proteomes, and/or microbiomes of these mice can now be done under various environmental conditions- allowing very sophisticated system genetics applications to be applied to a population-based setting. These population-based rodent resources may especially allow the epigenome's increasingly apparent role in many toxicant responses to be investigated; inter-strain susceptibility to toxicity for many exposures may likely be due to strain-specific epigenetic events in response to an exposure and potential transgenerational effects are also of great interest. Many of these new population-based mouse models are now available from designated resource centers and have been either sequenced or densely genotyped.

The natural genetic variation in these mouse population resources can be beneficial in identifying genetic polymorphisms that drive either differential susceptibility to toxicity or susceptibility to environmental exposures (i.e. variation in cellular response to oxidative stress, variation in metabolism of toxicants, etc.). These models can also potentially enlighten risk assessment. An understanding of genetic drivers of toxicity can inform hazard identification and identification of sensitive subpopulations and can also provide insight into the interindividual variability in toxicokinetics of chemicals and toxicity mode of action. Mouse population models may additionally be utilized to identify quantitative biomarkers that are associated with toxicity sensitivity. Discovery quantitative trait genes (QTGs) in mouse reference populations that affect toxicity or susceptibility have the potential to be translated into humans (especially where there is high sequence homology or reasonable orthology of the resultant protein between mouse and human species for the QTG of interest).

In addition, new mouse models for complex human disease outcomes are becoming available and characterized through these new population-based rodent resources. These models sometimes better recapitulate the range of phenotypes observed in human populations compared to more traditional mouse models. For example, CC mouse lines have more effectively modeled the wide range of clinical, virologic, and immunological phenotypes observed in some immune-based diseases (such as West Nile Virus Disease, Tuberculosis, Ebola, Spontaneous Colitis, etc.); many DO animals have unexpected or extreme phenotypes as well. Many toxicological effects are also displayed in behavioral phenotypes and these new rodent resources have allowed investigation of mechanisms related to behavioral heterogeneity and complex behavioral traits to be thoroughly explored as well. A number of sophisticated study designs have utilized complementary aspects of both the DO and CC population-based resources to explore complex human phenotypes.

Furthermore, it is now possible to develop a complementary resource of cells and cell lines derived from the CC and DO strains, enabling researchers to perform population-level studies in vitro. These unique resources have proven to be powerful tools for identifying individual quantitative trait loci (QTL) and candidate genes related to G x E interplay in complex human diseases. There are also many potential uses of these cell populations for high throughput in vitro assays, toxicity screens, and functional validation experiments.

A variety of other population-based model organism systems have also been developed in recent years. Although many of these have been adapted widely by the genetics community, these systems have also been underutilized in the environmental health science field. Other rodent population-based models include various mouse diversity panels, including the Mouse Hybrid Diversity Panel, and the emerging Rat Hybrid Diversity Panel as well as genetically heterogeneous rat stocks. The Drosophila Genetics Reference Panel has been utilized to explore evolutionary conservation of basic cellular pathways that respond to exposures and identify neurotoxicological and neurodevelopmental human orthologs. The Drosophila Synthetic Population Resource is a relatively new panel of over 1700 recombinant inbred lines of Drosophila that has been developed as a community resource for high resolution QTL mapping as well.

Research Scope

This FOA supports model organism studies using an appropriate population-based model organism resource(s) to significantly advance an environmental or toxicological health science question(s). In addition to the rodent population-based resources, other population-based model organism systems may be appropriate resources to utilize to address specific questions. However, lower model organism studies will be considered only if the study design and model organism system utilized addresses population variability relevant to human population studies.

Multiple PD/PI projects are encouraged to promote a multidisciplinary or transdisciplinary approach. Proposed projects are expected to lead to an improved understanding of a human environmentally-relevant disease or disorder.

The overall objective is to use population-based model organism resources to better model the differential response to environmental exposures in humans. This FOA supports applications using controlled exposure studies in vivo with or without in vitro approaches to expand the understanding of environmental diseases or exposure effects.

Applications should focus on model organism studies that utilize an environmental chemical(s) or toxicant(s) having clear links to human disease outcomes, either in animals or in epidemiological studies. Environmental agents which are considered of primary interest for NIEHS generally include: industrial chemicals or manufacturing byproducts, metals, pesticides, herbicides, air pollutants and other inhaled toxicants and particulates, as well as biologically derived toxins.

The following factors should not be used as the sole environmental risk factors in the application but can be used in combination with other relevant environmental chemical exposures or toxicants:

• microbiota variation
• psychosocial factors
• dietary factors
• drugs of abuse
• smoking

When possible and appropriate, human population models can be incorporated and comparative analyses across model systems are highly encouraged. Human studies alone, however, will not be considered. If not feasible to extend to the human system, a detailed explanation of how the studies will ultimately inform human population studies and human disease/disorder relevance is expected.

There is a strong need for development of additional analytical and bioinformatics methods and computational tools to maximize the benefit of these population-based model organism resources for the environmental health science community. Therefore, applicants are strongly encouraged to include innovative analytical approaches as part of their applications. Computational approaches alone, however, will not be considered responsive to this FOA.

Examples of responsive biological topics to be addressed in this FOA might include (but are not limited to) the use of a population-based model organism resource(s) to explore the following:

• G x E interplay for a relevant human disease outcome or disorder
• differential response for susceptibility or resistance to particular toxicants
• exploration of gene variants that influence sensitivity to toxicity (and ultimately environmentally-relevant disease risk)
• risk assessment identification and/or mode of action for a specific toxicant
• molecular/epigenomic signatures of exposure or identification of environmental response networks
• systems genetics approaches for mechanistic understanding of environmentally-relevant pathways/networks
• exposure-based biomarker development
• new mouse model development for an environmentally-relevant human disease outcome

Additional Information:

Applicants are encouraged to review answers to frequently asked questions about this FOA in this link, which will be updated on a regular basis.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Leroy Worth, Ph.D.
NIEHS Scientific Review Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences (NIEHS)
Mail Drop K3-03
Research Triangle Park, NC 27709
Telephone: 984-287-3340
Fax: 301-480-3722
Email: worth@niehs.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed. Applicants must include travel costs for the PD/PI(s) and key personnel to attend one 2-day grantee meeting during year 2 or 3 to be held in the Research Triangle Park, NC area.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy: Investigators should include appropriate rationale for how the studies will inform a human disease or disorder. The rationale for the choice of the genetically diverse population-based model organism system(s) should be clearly articulated and justification for how any lower model organism studies utilized addresses population variability relevant to human population studies must be included. The choice and rationale for the particular exposure(s) utilized and study design(s) incorporated should also be justified (with appropriate support for biological relevance of the dose(s) of the exposure chosen as well). The applicant should justify the numbers of animals needed, including reference to appropriate statistical methods for power and sample size calculations. Appropriate justification should be given if only one sex is considered in the study design, including details regarding given exposures (dose range) for the single sex that is being interrogated.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Investigators are expected to include data management and sharing plans to ensure that the datasets generated are made readily available to the scientific community in a timely fashion. Submission of data to relevant publicly accessible databases (for example, FlyBase, JAX Mouse Phenome database, etc.) is highly encouraged. Plans for data management and sharing will be discussed during the initial scientific merit review. Other biological resources (tissues, samples, etc.) as well as unique protocols and study designs should also be shared when feasible to the broader scientific community.

All applications, regardless of the amount of direct costs requested for any one year, should include a detailed Data Management and Sharing Plan, addressing the following elements:

• A statement expressing the investigator's commitment to sharing their data. At a minimal level, data forming the basis of each scientific publication from such research should be made publicly accessible.
• Description of the type and amount of digital data to be collected or produced over the life of the proposed project.
• Description of the data to be shared and the rationale for selecting those data for sharing (i.e. raw vs processed data, aggregate vs individual level data).
• Description of data standards, including formats, data identifiers, metadata, and other data documentation to be used for collected data and rationale for their selection.
• Description of mechanisms for providing access to or sharing data. Use of publicly accessible data repositories is encouraged (such as MMHCC and MMRRC).
• Delineation of who will be responsible for data management, both during data collection and analysis and after the completion of the project, if applicable.
• Milestones and timelines for making the data publicly accessible. It is expected that data forming the basis of each publication linked to this award will be submitted and made available for sharing no later than the time of publication date.
• Limitations or special considerations for data sharing.
• Applications proposing generation of genomic data should include descriptions of data sharing that are consistent with the NIH Genomic Data Sharing Policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html)

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH's electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by the National Institute of Environmental Health Sciences, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify NIEHS by email at worth@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the project include appropriate rationale for how the studies will inform a human disease or disorder?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? Did the applicant justify the numbers of animals needed, including reference to appropriate statistical methods for power and sample size calculations If a single sex is considered in the study design, is appropriate justification given, including explanation of exposure (dose ranges) for the sex included? Is the rationale for the choice of the genetically diverse population based model organism system(s) clearly articulated and are any lower model organism studies appropriately addressing population variability relevant to human population studies? Are the choice and rationale for the particular exposure(s) utilized and study design(s) incorporated justified (with appropriate support for biological relevance of the dose(s) of the exposure chosen)?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIEHS , in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Environmental Health Sciences Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Compliance with resource sharing policies.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee's business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Kimberly A. McAllister, Ph.D.
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 984-287-3287
Email: mcallis2@niehs.nih.gov

Leroy Worth Jr., Ph.D.
National Institute of Environmental Health Sciences (NIEHS)
Telephone:984-287-3340
Email: worth@niehs.nih.gov

James Williams
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 984-287-3338
Email: williamsjr@niehs.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.