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Funding Opportunities

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

Computational Toxicology Research Centers: in vitro and in silico Models Of Developmental Toxicity Pathways

This is the initial announcement of this funding opportunity.

Funding Opportunity Number: EPA-G2008-STAR-W1

Catalog of Federal Domestic Assistance (CFDA) Number: 66.509

Solicitation Opening Date: November 4, 2008
Solicitation Closing Date: January 29, 2009, 4:00 pm Eastern Time

Eligibility Contact: William Stelz (stelz.william@epa.gov); phone: 202-343-9802
Electronic Submissions: Ron Josephson (Josephson.Ron@epa.gov); phone: 202-343-9643
Technical Contact: Deborah Segal (segal.deborah@epa.gov); phone: 202-343-9797

Table of Contents:
SUMMARY OF PROGRAM REQUIREMENTS
	Synopsis of Program
	Award Information
	Eligibility Information
	Application Materials
	Agency Contacts
I. FUNDING OPPORTUNITY DESCRIPTION
	A. Introduction
	B. Background
	C. Authority and Regulations
	D. Specific Areas of Interest/Expected Outputs and Outcomes
	E. References
	F. Special Requirements
II. AWARD INFORMATION
III. ELIGIBILITY INFORMATION
	A. Eligible Applicants
	B. Cost Sharing
	C. Other
IV. APPLICATION AND SUBMISSION INFORMATION
	A. Internet Address to Request Application Package
	B. Content and Form of Application Submission
	C. Submission Dates and Times
	D. Funding Restrictions
	E. Submission Instructions and Other Submission Requirements
V. APPLICATION REVIEW INFORMATION
	A. Peer Review
	B. Programmatic Review
	C. Funding Decisions
VI. AWARD ADMINISTRATION INFORMATION
	A. Award Notices
	B. Disputes
	C. Administrative and National Policy Requirements
VII. AGENCY CONTACTS

Access Standard STAR Forms (http://www.epa.gov/ncer/rfa/forms/)
View research awarded under previous solicitations (http://www.epa.gov/ncer/rfa/archive/grants/)

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 to develop in vitro and in silico (computational) models for developmental toxicity pathways. The STAR program is issuing this request for applications (RFA) for research that in conjunction with in vivo data, will seek to integrate in vitro biochemical and cellular response data with computational models and theoretical or applied mathematic techniques. The research conducted under this RFA will facilitate the development of a predictive capacity for estimating outcomes or risk associated with particular toxicity processes as a result of developmental exposure to environmental pollutants and toxicants. Predictive computational modeling of core processes that drive development, including patterning, morphogenesis, selective growth and cell differentiation, and the detailed understanding of biological pathways that regulate these processes have the potential to address environmental and human health factors with broad scientific or economic impacts.

The goals of the computational research effort supported by the U.S. EPA are to develop the use of computational approaches to provide tools for quantitative risk assessment and develop more efficient strategies for prioritizing chemicals for screening and testing. Through the support of the computational toxicology initiative, EPA’s STAR program will fund research that addresses data gaps in human health risk assessment and will strengthen the ability of predictive scientific data to guide future scientific research, policy, and decisions.

To support the development of predictive models and simulations, the Center will be funded for up to 4 years. The Center should be comprised of multiple scientists with different backgrounds and capabilities, from a single or a variety of institutions, working collaboratively as a team. Each Center must foster the professional development of junior faculty and facilitate the training of students or postdoctoral fellows in the application of computational systems biology. Proposals must have an ultimate focus on risk assessment and improving the use of biological data in quantitative models of developmental toxicity. The proposed research must be consistent with the strategic objectives of the computational toxicology program: (1) improve understanding of the linkages in the continuum between the source of a chemical in the environment and adverse health and/or ecological outcomes; (2) provide predictive models for screening and testing; and (3) improve quantitative risk assessment.

This is the initial announcement for this year’s program. Although not anticipated, should modifications of this announcement be necessary, they will be posted.

Award Information:
Anticipated Type of Award: Grant or Cooperative Agreement
Estimated Number of Awards: Approximately 1 award
Anticipated Funding Amount: Approximately $3.2 million total for all awards
Potential Funding per Award: Up to a total of $3,200,000, including direct and indirect costs, with a maximum duration of 4 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, http://www.epa.gov/ncer/rfa/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, call 1-800-490-9194 or send a webmail message to http://www.epa.gov/ncer/contact_us.html at least 15 calendar working 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 e-mailed whenever possible. Any applications submitted through alternate submission methods must comply with all the provisions of this RFA, including Section IV, and be received by the solicitation closing date identified above.

Agency Contacts:
Eligibility Contact: William Stelz (stelz.william@epa.gov); phone: 202-343-9802
Electronic Submissions: Ron Josephson (Josephson.Ron@epa.gov); phone: 202-343-9643
Technical Contact: Deborah Segal (segal.deborah@epa.gov); phone: 202-343-9797

I. FUNDING OPPORTUNITY DESCRIPTION

A. Introduction
Computational modeling of biological systems at different scales is gaining momentum as a tool in cell biology and disease studies. Advancements in the ability to implement and develop highly improved computer-based approaches to modeling biological systems are key elements in facilitating the development of a predictive capacity for estimating outcomes or risk associated with exposure of organisms during their development to environmental toxicants. Therefore, we seek to fund research in developmental toxicology, computer science and systems biology that address the environmental problems and research needs facing the scientific community by applying sophisticated computing techniques and resources to in silico multi-scale modeling applications at the molecular, cellular, organ, and system-wide levels.

In assessing risk associated with exposure to a chemical or other environmental stressor, a number of scientific uncertainties exist along a “source-to-adverse outcome” continuum. This pathway from exposure to biological effect ranges from: (1) the presence of the chemical in the environment, (2) the uptake and distribution of the chemical in the organism or environment, (3) the presence of the active chemical at a systemic target site, (4) and the series of biological events that lead to the manifestation of an adverse human health or ecological outcome that can be used for risk assessment. The “Human Health Research Strategy” (http://www.epa.gov/nheerl/humanhealth/HHRS_final_web.pdf (67 pp 1.5 MB)) developed by the U.S. Environmental Protection Agency’s (EPA) Office of Research and Development (ORD) describes the scientific uncertainties and some of the multidisciplinary approaches that are needed to build linkages between exposure, dose and effects. ORD’s research program in Computational Toxicology (http://www.epa.gov/comptox/comptox_framework.html) supports the use of emerging technologies to improve risk assessment and reduce uncertainties in this source-to-adverse outcome continuum. The first strategic objective of the Computational Toxicology Initiative is to develop improved linkages across the source-to-outcome continuum, including the areas of chemical transformation and metabolism, better diagnostic/prognostic molecular markers, improved dose metrics, characterization of toxicity pathways, metabonomics, systems biology approaches, modeling frameworks, and uncertainty analysis. The second strategic objective is to provide improved predictive models for hazard identification, including the areas of Quantitative Structure Activity Relationships (QSARs) and other computational approaches, improved pollution prevention strategies, and high-throughput (HTP) screening approaches. The third strategic objective is to apply computational toxicology to enhance quantitative risk assessment in the areas of dose-response assessment, cross-species extrapolation, and chemical mixtures.

The EPA is committed to the development and application of novel technologies, derived from computational chemistry, molecular biology, systems biology, and bioinformatics in toxicological risk assessment and seeks to fund research that will develop computational models and simulations that use a broad range of biological information, including genomics, proteomics and cellular data. Further development of advanced, mechanistic models will allow scientists to create new hypotheses as well as analyze the ever-expanding mass of biological data. New in vitro and in silico toxicological methods are needed to provide solutions that can be applied to the HTP screening and evaluation of large numbers of chemicals, filling data gaps for hazard and risk assessment, and rapidly prioritizing substances of high concern. Therefore, this STAR Computational Toxicology RFA seeks to fund a Research Center that will generate new in vitro data and in silico models of developmental processes that will advance scientific understanding of developmental toxicities and predictive ability in vivo. This RFA seeks applicants who propose to integrate in vitro biochemical and cellular response data with computational models, and theoretical or applied mathematic techniques, to facilitate the development of a predictive capacity for estimating outcomes or risk associated with developmental exposure to environmental toxicants.

B. Background
The mission of the U.S. EPA is to protect human health and the environment from harmful effects that may be caused by exposure to pollutants in the air, water, soil, and food. Protecting human health and the environment carries the challenge of assessing the risk that is posed by tens of thousands of chemicals. The large number of chemicals present in our surroundings has made it impossible to evaluate every chemical with the most rigorous testing strategies; consequently, standard toxicity tests have been limited to only a relatively small number of chemicals. For example, in over 30 years since the enactment of the Toxic Substances Control Act of 1976 the EPA has acquired data on about 200 of approximately 80,000 chemicals in the U.S. market. REACH (Registration, Evaluation, and Authorization of Chemicals) legislation passed by the European Parliament in 2006 will require toxicity evaluations of up to 30,000 chemicals in a short time (11-year time frame for registering 30,000 chemicals under REACH, http://ec.europa.eu/enterprise/reach/index_en.htm ). Information from toxicity tests conducted on laboratory animals to evaluate the potential for chemicals to cause cancer, birth defects, and other adverse health outcomes have traditionally served as part of the basis for public health and regulatory decisions regarding the toxic health risks posed by chemicals found at low levels in the environment. Current animal test methods that have evolved over the last half-century require a number of assumptions and extrapolations to translate in vivo toxicity data and exposure data into predictions of human health effects. In the most basic form of extrapolation of a critical effect in a laboratory animal study to the human situation, little or no information about the metabolism of the chemical or potential mode of action is involved in estimating the safe level of exposure. Furthermore, whole animal testing studies are time consuming and costly.

In recognition of the need for innovative approaches to toxicity testing the U.S. EPA commissioned the National Research Council (NRC) to develop a long-range vision and a strategy to advance toxicity testing in the 21st century. The NRC strategy [1] builds from recent advances in the genomic sciences, including bioinformatics and computational biology, coupled with technological advances in HTP and high-content screening (HCS) assays for cells and tissues. These methodologies have a potential to fundamentally change the way chemicals are tested for risks that they may pose to humans and wildlife populations. Implementation of this strategy requires a collaborative network of investigators and organizations focused on HTP and HCS assays, utilizing novel in vitro and in silico (computational) toxicological methods. These methods will be utilized to provide solutions for screening and assessment of large numbers of chemicals to which humans are potentially exposed, and for assessing the risk of environmental chemicals at different exposure scenarios, dose levels, susceptible individuals and sensitive life-stages for substances of high concern [2].

In November 2005, the U.S. EPA funded two STAR Environmental Bioinformatics Research Centers to foster research focused on the design, development, and application of computer systems and software enabling scientists to explore HTP data from gene expression microarray experiments, mass spectrometry-based peptide and protein identification experiments, and various quantitative measures on metabolic state and metabolites. In April 2008, the U.S. EPA funded a third STAR Computational Toxicology Research Center, to stimulate the development of predictive environmental and biomedical computer-based simulations and models that will span from mechanistic to discovery-based efforts.

This STAR Computational Toxicology RFA seeks to fund a new Research Center that will generate in vitro data and computational models of developmental processes that will further the predictive ability and understanding of developmental toxicities. The research funded under this RFA should promote the interface of data generation and model development. Models developed should utilize data from high-information content (HTP, HCS) assays, and where possible incorporate data, methods, and approaches from EPA STAR Computational Toxicology initiative grantees, complementary research programs in EPA’s intramural laboratories, other U.S. government laboratories, laboratories supported by the European Union’s Work Program ENV 2009.3.3.1.1, or other academic or industry research laboratories from the broader scientific community.

Through its application, computational toxicology can provide a novel framework for in silico modeling and simulation to validate and predict key aspects of biology that are difficult to analyze experimentally due to cost, scale or complexity. Simulation models of biological systems should ideally contain sufficient detail to reconstruct normal functions and predict major disease states. As these models become more widely developed, simulation modeling will aid in the targeting of current knowledge gaps, as well as in providing solutions for filling them through providing a research tool for selecting critical factors from multiple simulations for actual experimental design. Utilizing network models of biological systems, scientists may gain a better understanding of how cells sense their environment and respond to environmental stimuli. In turn, this understanding can help unravel complex relationships across biological systems and support a scientifically sound process of projecting human health risks posed by chemical compounds. Through the application of today's powerful computational research platforms to the genomic sciences, the scientific community is now able to begin to identify, analyze, and compare the fundamental biological components and processes that result from exposures to environmental toxicants with their predicted impact on human health.

The envisaged long term end product will be in silico models that describe signatures of biological activity and environmental response for various organ systems undergoing development, and ‘virtual tissue’ models that draw from new data, database repositories, bioinformatics and computational resources to build:

• knowledgebases to extract, organize and store data, facts and concepts about developing tissues and structures;
• classification of ‘toxicity pathways’ through which chemical perturbation at a molecular level invokes perturbations in embryogenesis and development;
• multi-scale models to help users analyze key events during chemical toxicity and understand the progression of altered events from cells to phenotype (developmental defects).

The overall goal of the computational research effort supported by the U.S. EPA’s STAR program is to develop the use of computational approaches to provide tools for quantitative risk assessment and more efficient strategies for prioritizing chemicals for screening and testing. Relevant embryological systems might include, for example, vertebrate segmentation, neural tube morphogenesis and neural crest migration, early eye development, craniofacial and branchial arch development, morphogenesis and differentiation of the urogenital tract, and cardiac development. Other tissues and systems may be appropriate study models. Proposals addressing the use of simpler organismal models (e.g., Echinoderm, Drosophila) must be accompanied by coherent approaches to translate data to human developmental affects and health outcomes.

The specific Strategic Goal and Objective from the EPA’s Strategic Plan that relate to this solicitation are:

Goal 4: Healthy Communities and Ecosystems, Objective 4.4: Enhance Science and Research

The EPA’s Strategic Plan can be found at http://www.epa.gov/ocfo/plan/2006/entire_report.pdf (PDF) (184 pp, 11.56 MB, about PDF)

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, and the Federal Insecticide, Fungicide, and Rodenticide Act, Section 20, 7 U.S.C. 136r.

For research with an international aspect, the above statutes are supplemented, as appropriate, by the National Environmental Policy Act, Section 102(2)(F).

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, OMB Circular A-102 (Grants and Cooperative Agreements With State and Local Governments), OMB Circular A-110 (Uniform Administrative Requirements for Grants and Other Agreements with Institutions of Higher Education, Hospitals and Other Non-Profit Organizations) relocated to 2 CFR Part 215, 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.

Introduction

The U.S. Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) program, is seeking applications proposing to develop in vitro data and in silico models of core developmental processes.  Developmental processes of interest include patterning, morphogenesis, selective growth and cell differentiation, as well as projects that will provide detailed understanding of biological pathways that regulate these processes during normal embryogenesis and in response to environmental toxicants.  The STAR program is issuing this request for applications (RFA) for research that will seek to apply data from state-of-the-art HTP and/or HCS to embryonic tissues and systems developing in vivo or in vitro.  In order to facilitate the development of a predictive capacity for estimating outcomes or risk associated with toxicity processes as a result of developmental exposure to pollutants and toxicants, these data must be amenable to the application of high-performance computing and theoretical mathematical techniques.  The research sponsored through this RFA must seek to better understand how developing tissues react to chemical exposures, and to improve the ability of biomedical research to address the increasingly complex array of exposure profiles in human health risk assessments.  Because of the inherent complexity of real biological systems, computational models of virtual tissues based qualitatively on actual experimental data are necessary in order to produce validated predictive systems for quantitative risk assessment.  Through this RFA, EPA seeks to fund centers to conduct research in developmental biology and developmental toxicology that will bridge the interface of in vitro data generation and in silico model development to answer critical biological questions related to toxicity pathways important to human development, hereafter referred to as ‘developmental toxicity pathways.’

The outcome of this model development research has the potential to increase the understanding and ability to predict the biological pathways that regulate processes during normal embryogenesis and in response to environmental toxicants.  Because of the inherent complexity of real biological systems, development and analysis of computational models based directly on experimental data are necessary to achieve this understanding.

The output of this research will include the creation of simulation models for predicting toxicity pathways, mechanisms, and health impacts as a result of environmental exposures.  This research effort will generate in vitro data and computational models of developmental processes that will further the predictive ability and understanding of developmental toxicities.  

Proposals are expected to include multiple investigators working in collaboration.  A proposed center must have a Center Director who will have the responsibility of assuring that resources are utilized in an optimal way, and that the efforts of each team are focused on their proposed research project. The Center Director will also be responsible for reports and reviews of the teams’ research progress.  Centers are obligated to engage the expertise of a minimum of two multidisciplinary teams focused on basic and applied research projects needed to fill human health risk assessment knowledge gaps.  Each team should have its own unique research focus, denoted as an Investigational Area, and be balanced in such a manner to make the most effective use of available resources in accomplishing its proposed objectives.

Each Center must encompass a minimum of two research teams, with each team’s Investigational Area focus detailed in a Research Plan (for guidance see “Research Plan” in section IV.B.7.a.).  To be responsive to the requirements of this RFA, a Center is to be comprised of a minimum of two Investigational Areas, each with its own research team (2-5 proposed Investigational Areas are expected for each Center).  For each Investigational Area proposed, successful applications will address at least one of the topics listed under Priorities of Model Development in Section I.D. of this RFA.

Research grant applications driven by high-information content assays and integrative biological approaches and their translation to mammalian embryogenesis and human developmental toxicity in principle, design, analysis, or validation will be given highest priority during peer review.

Embryogenesis and developmental toxicity

Embryogenesis is fundamental to all biological systems. The study of embryology entails  questions such as what processes determine anatomical structures (morphogenesis) and tissues (differentiation) and the mechanisms through which these processes are controlled by the genome in interaction with the environment. Modern research has yielded extensive knowledge about the molecular control of embryogenesis and the conservation of cell signaling involved in cell-cell communication and interactions during development and beyond [3]. This knowledge may eventually hold the scientific basis for predicting the health effects arising from prenatal and early life exposure to environmental chemicals.

For humans, developmental toxicity refers to adverse effects produced prior to conception or during pregnancy and postnatally to the time of sexual maturation.  The standard procedure for assessing the safety of chemicals to the developing organism involves the use of pregnant laboratory animals exposed throughout the period of major organogenesis, and subsequent examination of the offspring for growth and morphology. EPA’s guidelines for developmental toxicity risk assessment (FRL-4038-3, December 5, 1991) are recorded in the Federal Register 56(234):63798-63826 and updated in a 1998 workshop (SAP Report No. 99-01C, January 22, 1999). The Office of Prevention, Pesticides and Toxic Substances (OPPTS) has developed a Health Effects Test Guidelines for Prenatal Developmental Toxicity Study (OPPTS 870.3700) through a process of harmonization that blended the testing guidance and requirements that existed in the Office of Pollution Prevention and Toxics (OPPT) and appeared in Title 40, Chapter I, Subchapter R of the Code of Federal Regulations (CFR), the Office of Pesticide Programs (OPP) which appeared in publications of the National Technical Information Service (NTIS) and the guidelines published by the Organization for Economic Cooperation and Development (OECD) [http://www.epa.gov/opptsfrs/publications/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-3700.pdf (11 pp, 29 K)]

The limiting factors in traditional animal studies imposed by the number of chemicals that can be reasonably tested, and the need to reduce uncertainties that give rise during the extrapolation process of high-dose to low-dose and animal-to-humans, have motivated the development of more innovative approaches in biomedicine.  HTP data generation and in silico modeling, combined with and computational analysis techniques, has the potential to integrate various sources of information quantitatively in risk assessment, as well as to improve the understanding of regulatory mechanisms leading to developmental defects.  The capacity to accurately predict dose-dependent toxicity using in vitro and in silico models would greatly aid the risk assessment process by allowing chemical prioritization for animal testing.  However, the complexity and diversity of spatio-temporal changes underlying developmental toxicity make incorporating biological details into risk assessment a difficult task.  This is partly due to the existence of many interrelated molecular interactions, maternal physiology, and tracking the complicated non-linear response to exposures linked to critical biological processes that may vary by dose, genotype, chemical, stage, or tissue, and the resulting manifestation of structural or functional defects following prenatal exposure.

The NRC report [1] highlights the need for understanding cellular-response networks that control cellular function, mediate cell-cell communication and signaling, and orchestrate adaptive responses at different levels of chemical exposure.  The term ‘toxicity pathways’ has been used by the NRC to describe the key cellular response pathways that, when sufficiently perturbed, are expected to result in adverse health effects.  Similarly, understanding developmental defects at a systems-level requires elucidating how ‘developmental toxicity pathways’ are integrated with the genomic control of conserved cell signaling pathways that orchestrate morphogenesis and differentiation [4].  This requires substantial investment in research that can model, and ultimately predict, biological outcomes from a myriad of interrelated data and associative relationships covering the exposure-disease continuum.

Developmental toxicity pathways

The potential of an environmental chemical to cause adverse effects in the developing embryo or fetus is an important consideration in any health risk assessment.  Many human health risk assessments have selected developmental endpoints (rather than cancer) for a critical effect, as demonstrated through a sampling of toxicological reviews in the U.S. EPA National Center for Environmental Assessment’s Integrated Risk Information System assessment database, which showed that 28% of cases had critical effects selected for childhood or gender susceptibilities.  These endpoints included altered birth weight, skeletal variations, neurodevelopmental defects, altered maternal or postnatal weight gains in reproductive organs, and testicular lesions.  In most cases the underlying developmental toxicity pathways remain largely uncharacterized. Therefore, in order to help fill scientific knowledge gaps, this RFA seeks to apply computational toxicology resources toward research in developmental toxicity.

Successful modeling of developing systems should describe different cell states (e.g., proliferation, differentiation, migration, apoptosis, shape, adhesivity, matrix remodeling), as well as heterogeneities in cellular competence and metabolic demands that unfold by the hour.  A key challenge for science and technology development is to integrate heterogeneous molecular and cellular data as biological networks, to model developing systems with these networks, and then use these networks to analyze critical steps during toxicant exposure.  In silico models developed must initially provide a qualitative prediction, which as research progresses, can eventually be translated into a quantitative model.  An example of such a two-stage process would be first understanding the form of the dose-response curve, followed by connecting to the underlying model how the flow of molecular regulatory information is distributed across developmental toxicity pathways and intercellular signaling networks.

Modeling complex coordinated cellular behaviors and the many interacting factors that may influence higher-level functions requires information about basic entities at a lower level of the system [5].  Therefore, the scientific output of this RFA includes the collection of these molecular and cellular data for in silico modeling using potentially different kinds of in vitro research model systems.  Two examples of in vitro systems that can be used for modeling vertebrate developmental processes are embryonic stem (ES) cell lines, or ES-like induced pluripotent stem cells, [6] and zebrafish embryos, [7] as these systems are free from direct maternal influence.  Free living zebrafish embryos hold promise for the rapid screening of chemicals based on the potential of toxicants to directly perturb developmental processes [7].  The small eggs of zebrafish fit comfortably into microtiter plates thus enabling robotic handling and analyses of the developing embryo; furthermore, the ease of acquiring reporter fish, knock-out fish, or morpholino-induced ‘morphant’ phenotypes [8] for assessing developmental toxicity pathways is an advantage of using zebrafish over other small fish species.  Because zebrafish embryos are transparent the sequence of development may be directly observed without disturbing the embryo and consequently followed through precisely timed stages as the embryo advances from fertilized egg to a swimming larva.  This progression occurs rapidly, in just 5 days, and recapitulates many of the same anatomical features, morphogenetic processes, and cell signaling pathways used by the early human embryo.  As such, zebrafish embryos provide a powerful alternative to mammalian animal models in research aimed to document and classify the potential developmental toxicity of environmental chemicals and to model these dynamic processes in silico.

Pluripotent ES cells have been considered for their potential in evaluating specific pathways and comparing observations to traditional animal bioassay models for identifying potential teratogens.  HTP cellular screens of pluripotent ES cells can be used to study non-directed multiple endpoints, differentiation outcomes, directed linear-differentiation along various pathways to specific cell/tissue types, cellular plasticity and dedifferentiation, as well as developmental signaling pathways.  Murine ES cell models accurately predict strong teratogenic pharmaceutical compounds but incompletely resolve non-teratogenic from weakly teratogenic compounds [6].  The capacity to identify biological signatures of toxicity in these in vitro models of development, and to map data from high-information content assays in normal embryogenesis, addresses the need for computer-based models that can be utilized to integrate these data into advanced models and simulations.  These models and simulations will improve the understanding of critical steps in developmental toxicity and the ability to predict adverse effects and differentiate them from adaptive responses to chemical injury.

Computer-based models

A challenge for computational systems biology is to build useful multi-scale models that can be used to systematically investigate any or all interactions between the complex variables that are linked with abnormal developmental outcomes [4].  These interactions are potentially influenced by genetic and environmental signals, with the net outcome being the emergent properties associated with normal or abnormal collective cell behavior.  Computational modeling of ‘virtual tissues’ may be useful to predict organ injury due to chemical exposure by: simulating the dynamics and characteristics of exposure and dose, the kinetics of perturbed molecular pathways, their linkage(s) with processes leading to altered cell states, and integration of the molecular and cellular responses into a predictive model.  By placing emphasis on the normal biology of the system and its key regulatory components, virtual tissues represent a significant opportunity to understand the linkage between developmental toxicity pathways and developmental phenotype.  Products from the proposals awarded under this RFA may provide valuable information that will advance the field of computational toxicology and apply this logic to predicting effects that would be difficult or costly to derive by traditional means [5].  Development of virtual tissue models require newly generated data collected across phylogenetic systems to fill the data gaps identified within the iterative process and test the predictive nature of virtual tissue models with real and simulated data.

To be responsive to this RFA studies must include pathways that are fundamentally reliant upon cell signaling (e.g., cell proliferation, apoptosis, adhesion and migration), intermediary metabolism (e.g., glycolysis, oxygen utilization, fatty acid biosynthesis), cell-specific functions (e.g., extracellular matrix remodeling, trans-differentiation, contractility and motility), and other categories to ensure that predictions are broadly applicable.  Such efforts will also help answer how well in vitro experimental systems represent the full range of diverse cells present in the human embryo, how variability observed in the human population can modify quantitative predictions of in vivo dose-response, how exposure conditions influence outcomes, and how well the virtual tissue models represent the underlying biology of the system.

Priorities of Model Development

Areas of interest that will be supported by the program and are relevant to human health risk assessment, are models of a variety of types of networks including cell-cell signaling, signal transduction pathways; biochemical networks; developmental gene regulatory networks; metabolic networks; intracellular dynamics; cell structural dynamics; cell communication and adhesivity/motility. Areas of interest that represent the types of research that will be supported by the program are given below.  Successful proposals must address at least one of these areas of interest listed below, and in doing so they must also highlight the direct relationship between the computational research and the biological applications for developmental processes and toxicities:

• Molecules to cells: Cellular and molecular data could be used to build models of developmental toxicity pathways that integrate biological processes across time and scale (e.g., molecular networks to cell behavior). For example, an integrative model of the embryonic transcriptome would track the ontogeny of specific RNAs or microRNAs and the protein products expressed in developing systems and correlate these measurements with measures of individual cellular behaviors at critical times following chemical insult. Functional analysis of the system through antisense (morpholino) or microRNA based approaches can serve to validate computational models.
• Cells to tissues: The ability to analyze complex cellular changes that follow chemical insult and reconstruct tissue dysfunction or dysmorphogenesis can be enhanced with various cell-based assays. For example, functional assessments of cellular differentiation have been facilitated using molecular reporters such as green fluorescent protein (GFP) coupled to promoter constructs to indicate expression of that phenotypic marker and, coupled with cell sorting techniques may enrich specific cell types for subsequent cellular and molecular analysis.  Confocal microscopy, digital imaging or HCS techniques can provide high resolution analysis of specific intracellular parameters in real-time.  Other technologies such as cell labeling in tissues with ‘quantum dots’, which are nanometer-sized semiconductor particles that can be used for multiplex fluorescence labeling, or Laser Capture Microdissection under optimal conditions extends the ability to characterize molecular phenotypes at the cellular scale.
• Full system modeling: Many computational models have been developed to cover a simple pathway (metabolic, regulatory, or signaling); however critical steps in developmental toxicity likely follow more complex, downstream consequences of pathway-level perturbation. To address these interlacing biological networks in embryonic systems, it would be useful to integrate high-information content data from molecular and cellular assays into computational models for morphogenesis and differentiation.  Validating such methods could draw on techniques used in the development of multi-scale models, or may propose to develop reduced complexity representations of individual networks.

Model Evaluation

For every area of interest proposed for model development, the proposal must address each of the following aspects of model evaluation:

• Interplay between real and simulated data: Whereas it is expected that each center would generate new experimental data, it would be useful that each center also has access to, or deploys, computational (simulated) data to parameterize and/or validate the models being developed. This may include developing informatics tools for integrating, organizing, managing and providing open access to disparate biological experimental and reference biological data (not database development). It may also include developing visualization tools, because multiscale models are likely to be very complex.
• Model parameterization/validation: A key issue with using predictive models is the problem of determining parameters for the models.  Parameters such as rate constants, reaction orders, and initial conditions that are well-known for metabolic (flux-driven) processes may not be as complete for regulatory (signal-driven) pathways and morphogenetic gradients.  Improved methods are needed to determine key modeling parameters from real and computational data for developmental toxicity pathways.
• Model stability: Many models of individual cell function can produce the same output of collective cell behavior.  Models may have different topology, or identical topology but different parameters, and still yield close to identical dynamic behavior.  This is an issue related to model parameterization, and warrants further investigation due to its potential to impact the plausibility of an embryogenic or morphogenetic model.
• Research on characterization of the uncertainty of biologically based models and of models based on default assumptions in developmental toxicity: This would provide better tools for understanding in a rigorous and reproducible manner how to rank model uncertainty for models incorporating different amounts of biological and toxicological information into a developmental risk assessment.  In other words, given two or more models for a toxicant, the preferred model is the one that is less uncertain (e.g., the model in whose predictions we have more confidence) and most plausible given existing knowledge.

Standard Model Formats, Computational Approaches, and the use of Existing datasets

Data and model exchange: The center must be prepared to exchange data and models in the standard computer language formats, such as systems biology mark-up language (SBML).  Proposals should indicate existing and proposed sources of external data, including those available through currently funded EPA STAR Computational Toxicology initiative grantees, laboratories supported by the European Union’s Work Program ENV.2009.3.3.1.1, complementary research programs in EPA’s intramural laboratories, other U.S. government laboratories, or other academic or industry research laboratories from the broader scientific community.

In addition to the use of community developed model exchange formats, a strategy must be outlined for re-using existing public domain software, or plans for public release of software modules, e.g. bioconductor, bioperl, biolisp.

Modeling and simulation of biomolecular systems is very computationally intensive; therefore applicants should detail allocations of computer time and identification of computational support.

Organization of the Centers

Proposed projects are expected to be collaborative in design, and engage multiple investigators as part of a coordinated research team within an institution, or research network across institutions.  This approach is designed to engage the expertise of researchers from a variety of disciplines to be focused on basic and applied research projects needed to fill human health risk assessment knowledge gaps.  Research centers should consist of computational and biomedical scientists from public nonprofit institutions/organizations (this includes public institutions of higher education and hospitals), private nonprofit institutions/organizations, and national laboratories. The teams should be balanced in such a manner to make the most effective use of the resources in accomplishing their proposed objectives.

Proposed centers will have a Center Director who will have the responsibility to make certain that resources are utilized in an optimal way and the efforts of the team remain focused on the proposed research project. The Center Director will also be responsible for reports and reviews of the team's research progress.

E. References

1. National Research Council, Committee on Toxicity and Assessment of Environmental Agents (2007) Testing in the Twenty-first Century: A Vision and a Strategy. National Academies Press (http://www.nap.edu/catalog/11970.html ), 2007
2. Collins FS, Gray GM and Bucher JR (2008) Transforming environmental health protection. Science 319: 906-907
3. National Research Council (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment. National Academy Press (Washington, D.C.)
4. Knudsen T.B. and Kavlock R.J. (2008) Comparative Bioinformatics and Computational Toxicology. In: Developmental Toxicology 3rd Edition (eds: B Abbott and D Hansen), Taylor and Francis, Target Organ Toxicology Series, Chapter 12, pp 311-360.
5. Thorne BC, Bailey AM, DeSimone DW and Peirce SM (2007) Agent-based modeling of multicell morphogenic processes during development. Birth Def Res (Part C) 81: 344-353
6. Chapin, R., Stedman, D., Paquette, J., Streck, R., Kumpf, S., and Deng, S. Struggles for equivalence: in vitro developmental toxicity model evolution in pharmaceuticals in 2006. Toxicol. in vitro 21, 1545-1551, 2007
7. Yang L, Kemadjou JR, Zinsmeister C, Bauer M, Legradi J, Muller F, Pankratz M, Jakel J and Strahle U (2007) Transcriptional profiling reveals barcode-like toxicogenomics responses in the zebrafish embryo. Genome Biology 8: R227.1-R227.17
8. Knowlton MN, Li T, Ren Y, Bill BR, Ellis LBM and Ekker SC (2008) A PATO-compliant zebrafish screening database (MODB): management of morpholino knockdown screen information. BMC Bioinformatics 9:7

F. Special Requirements
Agency policy prevents EPA technical staff and managers from providing individual 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, nor will they endorse an application or discuss in any manner how the Agency will apply the published evaluation criteria for this competition.

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 (http://rbm.nih.gov/toolkit.htm).

Groups of two or more eligible applicants may choose to form a consortium and submit a single application for this assistance agreement. The application must identify which organization will be the recipient of the assistance agreement and which organizations(s) will be subawardees of the recipient.

The application must include a plan (see “Data Plan” in section IV.B.7.c.) to make available to the public all data generated from observations, analyses, or model development (primary data) and any secondary (or existing) data used under an agreement awarded from this RFA. The data must be available in a format and with documentation such that they may be used by others in the scientific community.

Each application must address the following:

1. Computational Capabilities –
   1. Describe the computational and network resources available as well as the specific types of statistical and bioinformatic approaches that exist within the organization and how such approaches can be applied to the selected Investigative Areas.
   2. Highlight what new developments in computational toxicology analysis, database development, and other areas of de novo programming are proposed, as well as areas where existing computational and database resources will be utilized.
2. Each Investigational Area (with a minimum of 2) should be completely described according to the APPLICATION AND SUBMISSION INFORMATION section of this RFA (see “Research Plan” in section IV.B.7.a.). Each Area is permitted a 15-page description. Individual project descriptions must explain how the Investigational Area fits into the overall Center program and relates to other projects in the proposal.
3. The Center must have a Center Director.
4. The Center must have an Administrative Core Unit.
5. The application must include a "Center Integration Plan."
6. The Center must submit a Communication and Public Outreach Strategy.
7. This proposed research topic is complimentary with that of the European Union’s Work Program ENV 2009, which represents a parallel call that under section "Cooperation", Theme 6 Environment (including climate change), establishes a research grant entitled “Screening methods for assessing the toxicological and eco-toxicological properties of chemicals” (http://cordis.europa.eu/fp7/dc/index.cfm ). The US-EPA strongly encourages applicants to take advantage of datasets developed by this and other academic, government, or industry research laboratories from the broader scientific community. Therefore, in conducting its research, the Center must demonstrate a willingness to use data generated by EPA and other institutions or organizations as the bases for their development and application of computational models. It is not expected for the Center to be solely responsible for the generation of new biological data, but rather focused on advancing the science of developmental toxicity risk assessment and benefiting from the use of existing databases or data available through collaborators such as with the European Union, Environmental Protection Agency, National Institute of Environmental Health Sciences, Department of Energy, Centers for Disease Control, Food and Drug Administration, or other government and academic institutions.
8. New Investigators – To attract new investigators into the application of computer science and mathematics research to biological systems, the Center must partially support at least one newly recruited Center scientist. Up to $70,000 per year, direct cost, may be used for each newly required Center scientist to provide up to 75 percent salary support, technical support, equipment, and supplies. To the extent possible, the types of individuals sought and their expected roles should be described in the application if specific individuals have not been identified.
9. Postdoctoral training - the Center must support a minimum of two postdoctoral scientists (at least one of whom is to be newly recruited) and provide a research environment in leading-edge informatics/computational tools or approaches, as well as a structured mentoring and career development opportunity (see “Center Description” in section IV.B.5.).
10. Grantees Meetings – Centers must budget for an annual grantees meeting that should be attended by the Center director and the appropriate project leads. It can be assumed that all meetings will be held at the U.S. EPA research facility in RTP, NC. Annual meetings will be open to the public and will bring together all researchers currently supported through STAR computational toxicology efforts as well as U.S. EPA scientists.

II. AWARD INFORMATION

It is anticipated that a total of approximately $3.2 million will be awarded under this announcement, depending on the availability of funds and quality of applications received. The EPA anticipates funding approximately 1 award under this RFA. Requests for amounts in excess of a total of $3,200,000, including direct and indirect costs, will not be considered. The total project period requested in an application submitted for this RFA may not exceed 4 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 a grant or cooperative agreement 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 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.

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. Examples are purchase of satellite data, census data tapes, 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 William Stelz (stelz.william@epa.gov) in NCER, phone (202) 343-9802.

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 received by Grants.gov (see Section IV.E. “Submission Instructions and Other Submission Requirements” for further information, or through any authorized alternate submission methods described in Section IV) 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. Applications exceeding the funding limits or project period term described herein will be returned without review. 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. All requirements contained in this announcement that must be addressed for the application to be deemed eligible for funding consideration as set forth in Sections I.D. and I.F. are summarized below.

Applicants must propose centers to conduct research in developmental biology and developmental toxicology that will bridge the interface of in vitro data generation and in silico model development to answer critical biological questions related to toxicity pathways that are important to human development. Proposed research projects must seek to better understand how developing tissues react to chemical exposures, and to improve the ability of biomedical research to carry out the increasingly complex array of exposure profiles and human health risk assessments. Each Center must include multiple investigators working in collaboration in research teams, be comprised of a minimum of two research teams that each have their own Investigational Area, foster the professional development of junior faculty and facilitate the training of a minimum of two postdoctoral fellows, have an Administrative Core Unit, include a Center Integration Plan, submit a Communication and Public Outreach Strategy, and have a Center Director who will have direct responsibility for the overall Center management as well as the efforts of each Investigational Area. Centers must budget for an annual grantees meeting that should be attended by the Center director and the appropriate project leads. In order to be considered, proposals addressing the use of non-vertebrate species (e.g., Echinoderm, Drosophila) as study models must have accompanying approaches to translate data to human environmental health relevance. Comparative studies must include pathways that are fundamentally reliant upon cell signaling (e.g., cell proliferation, apoptosis, adhesion and migration), intermediary metabolism (e.g., glycolysis, oxygen utilization, fatty acid biosynthesis), cell-specific functions (e.g., extracellular matrix remodeling, trans-differentiation, contractility and motility). Proposals must highlight the direct relationship between the computational and mathematical research and their biological applications, have an ultimate focus on human health risk assessment and improving the use of data in quantitative models of developmental toxicity, as well as address at least one of the areas of interest delineated in Section I.D. Priorities of Model Development. For every area of interest proposed for model development, the proposal must address each of the aspects of model evaluation delineated in Section I.D. Model Evaluation.

To be considered eligible for funding, applicants must propose basic and applied research projects that will fill human health risk assessment knowledge gaps, and be driven by high-information content assays and integrative biological approaches and their translation in principle, design, analysis, or validation to mammalian embryogenesis and human developmental toxicity. Experimental data must be generated in a manner that is amenable to the application of computer modeling and theoretical mathematic techniques, and resultant in silico models developed must initially provide a qualitative prediction, which as research progresses, can eventually be translated into a quantitative model. Center’s should indicate existing and proposed sources of external data, must be prepared to exchange data and models developed, and must outline a strategy for re-using existing public domain software or plans for public release of newly developed software modules. Each application must identify the computational capabilities and resources available to the Center, and highlight what new developments in computational toxicology analysis, database development, and other areas of de novo programming are proposed, as well as areas where existing computational and database resources will be utilized. Applications that propose to conduct environmental monitoring or that rely heavily on standard analytical methods will be considered non-responsive and deemed ineligible for funding.

In addition, to be eligible for funding consideration, a project’s focus must consist of activities within the statutory terms of EPA’s financial assistance authorities; specifically, the statute(s) listed in I.C. 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 in I.C. 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.

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

IV. APPLICATION AND SUBMISSION INFORMATION

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 budget form and the current and pending support form (available at http://www.epa.gov/ncer/rfa/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 424, not simply the proposed first year expenses.) The form must contain the electronic 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 http://www.dnb.com .

   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 http://www.whitehouse.gov/omb/grants/spoc.html. 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 http://www.epa.gov/ncer/rfa/forms. The Key Contacts form should also be completed for major sub-agreements (i.e., primary investigators). 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, strike a balance between highly technical words and phrases and 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: 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 geographical location(s) where the work will be conducted.
   6. Project Cost: Show the total dollars 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 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: http://www.epa.gov/ncer/rfa/forms.
5. Center Description – (5 pages)

   Applications should describe the overall goals, objectives, and approach for the Center, including how the Center will pursue a multidisciplinary and thematic approach to the problems to be investigated. The structure of the Center’s proposed postdoctoral training and mentorship programs should be described herein; this must include a description of career development opportunities and training provided to the postdoctoral fellows in addition to their research activities. Applications should also address how the Center will incorporate new investigators.

6. Administrative Core Unit (10 pages)

   Applications should have an Administrative Core Unit, which provides overall oversight, coordination and integration of the Center’s activities. The Administrative Core Unit will address the personnel expertise/experience for the management of the Center. A Center Integration Plan describing how the program will be integrated internally must be submitted as part of the Administrative Core description. The Center’s Integration Plan, at a minimum, should indicate how programmatic and subagreement decisions will be made; how investigators from different computational disciplines and Investigational Areas within the Center will communicate on a regular basis about the development and progress of each of the Areas; how progress will be monitored and measured; who sets priorities, and who is responsible for implementing the Integration Plan, ensuring compliance with the plan, and evaluating its effectiveness in achieving integration within the Center. A Center Communication and Public Outreach Strategy addressing how research results and other information will be disseminated must also be submitted as part of the Administrative Core description. Publishing research results in scientific journals is essential; however, it is not sufficient. Plans for Center websites and other means of communicating results should be described.

7. Research Plan, Quality Assurance Statement, Data Plan and References
   1. Research Plan (15 pages per Investigational Area, with a minimum of 2 Areas)

      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.

      Each investigational area research plan 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. 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.
      4. General Project Information: Discuss other information relevant to the potential success of the project. This should include facilities, personnel expertise/experience, project schedules, proposed management, interactions with other institutions, etc. 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.
      5. Appendices may be included but must remain within the 15-page limit.
   2. Quality Assurance Statement (3 pages)

      All research Centers and projects that receive EPA funding must develop and implement a Quality System that complies with the national consensus standard ANSI/ASQC E4, Specifications and Guidelines for Quality Systems for Environmental Data Collection and Environmental Technology Programs. To demonstrate compliance with ANSI/ASQC E4, the recipient Center must develop and implement an acceptable Quality Management Plan (QMP) for the Center in accordance with “EPA Requirements for Quality Management Plans (EPA QA/R-2)” (http://epa.gov/quality/qs-docs/r2-final.pdf (30 pp, 87 K)) and “NCER’s Guidance for Quality Management Plans (QMPs)” (http://www.epa.gov/ncer/guidance/guidanceqmps0607.pdf (2 pp, 25 K)) that describes the overall Quality System for the Center. If selected for an award, the recipient will be required to submit an acceptable QMP within 60 days of award for review by the EPA Project Officer and EPA Quality Assurance Manager.

      The Quality Assurance Statement (QAS) must not exceed three (3) consecutively numbered (bottom center), 8.5x11-inch pages of single-spaced, standard 12-point type with 1-inch margins. The QAS must provide the following information:

      1. State the organization's QA policy and how management assures that all programs and PIs understand and implement QA and QC activities. Identify all components of the organization, the position of QA Manager, and the lines of reporting of the QA Manager. (This may be done through an organizational chart.) Discuss the authorities of the QA Manager and staff and demonstrate that the QA Manager is both qualified and independent of data collection or use activities. Discuss technical activities or programs that require quality management and where internal coordination of QA and QC activities among organizations or co-PIs is needed. The Center QA Manager cannot also be the Center Director, one of the PIs, or research personnel for the projects covered by the scope of the agreement.
      2. Briefly describe the principal quality components (e.g., quality program documentation, annual reviews, project-specific quality documentation) along with the responsibilities of management and staff for each component. The QAS submitted with the proposal must indicate the requirement for each project to develop a Quality Assurance Project Plan (QAPP) that is compliant with “EPA Requirements for Quality Assurance Project Plans (EPA QA/R-5)” {http://www.epa.gov/quality/qs-docs/r5-final.pdf (40 pp, 121 K)}. The QAS must also state the following requirements: 1) any type of planned work with environmental data may not begin until the QAPP has been written and 2) the QAPP has been reviewed and approved for completeness and compliance with the R-5 document by the Center’s QA Manager.
      3. Briefly describe the process for reviewing the organization’s quality program, at least annually. Describe the process for planning, implementing and documenting assessments of QA/QC across projects, and how the findings of these assessments will be addressed by management. EPA guidance on different types of assessments (including TSAs) can be found at: http://www.epa.gov/quality/qs-docs/g7-final.pdf (101 pp, 254 K).
   3. Data Plan (2 pages)

      Provide a plan to make all data resulting from an agreement under this RFA available in a format and with documentation/metadata such that they may be used by others in the scientific community. This includes both primary and secondary or existing data, i.e., from observations, analyses, or model development collected or used under the agreement. Applicants who plan to develop or enhance databases containing proprietary or restricted information must provide, within the two pages, a strategy to make the data widely available, while protecting privacy or property rights.

   4. References: References cited are in addition to other page limits (e.g. research plan, quality assurance statement, data plan)
8. Budget and Budget Justification
   1. Budget

      Prepare a budget table for the Center’s Administrative Core Unit and each Investigational Area using the guidance and form found at http://www.epa.gov/ncer/rfa/forms/, and select “All required forms.” Note: The budget table should be attached to the Project Narrative Attachment Form electronic file [see Section IV.E.3.(d) “Project Narrative Attachment Form”]. If a subaward, such as a subagreement with an educational institution is included in the application, provide a separate budget and budget justification for the subaward. Include the total amount for the subaward under “Other” in the master budget. Applicants may not use subagreements to transfer or delegate their responsibility for successful completion of their EPA assistance agreement. Therefore, EPA expects that subawards or subcontracts should not constitute more than 40% of the total direct cost of the total project budget. If a subaward/subcontract constitutes more than 40% of the total direct cost, additional justification may be required before award, discussing the need for the subaward/subcontract to accomplish the objectives of the research project.

      Please note that institutional cost-sharing is not required. However, if cost-sharing is proposed, a brief statement concerning cost-sharing should be added to the budget justification, and estimated dollar amounts must be included in the appropriate categories in the budget table.

      Please note that when formulating budgets for proposals/applications, applicants must not include management fees or similar charges in excess of the direct costs and indirect costs at the rate approved by the applicants cognizant audit agency, or at the rate provided for by the terms of the agreement negotiated with EPA. The term "management fees or similar charges" refers to expenses added to the direct costs in order to accumulate and reserve funds for ongoing business expenses, unforeseen liabilities, or for other similar costs that are not allowable under EPA assistance agreements. Management fees or similar charges may not be used to improve or expand the project funded under this agreement, except to the extent authorized as a direct cost of carrying out the scope of work.

   2. Budget Justification [2 pages in addition to the Section IV.B.7. page limitations, not including additions under Nos. (6) and (7) below to support contracts and subawards]

      For each Investigational Area and the Center’s Administrative Core Unit describe the basis for calculating the personnel, fringe benefits, travel, equipment, supplies, contractual support, and other costs identified in the itemized budget. The budget justification should not exceed two consecutively numbered (bottom center), 8.5x11-inch pages of single-spaced, standard 12-point type with 1-inch margins.

      Modeling and simulation of biomolecular systems is very computationally intensive; therefore applicants should detail allocations of computer time and identification of computational support.

      Budget information should be supported at the level of detail described below:

      1. Personnel: List all staff positions by title. Give annual salary, percentage of time assigned to the project, and total cost for the budget period.
      2. Fringe Benefits: Identify the percentage used and the basis for its computation.
      3. Travel: Specify the estimated number of trips, locations, and other costs for each type of travel. Explain the need for any travel, paying particular attention to travel outside the United States. Include travel funds for annual STAR program progress reviews (estimate for two days in Washington, D.C.) and a final workshop to report on results.
      4. Equipment: Identify all tangible, non-expendable personal property to be purchased that has an estimated cost of $5,000 or more per unit and a useful life of more than one year. (Personal property items with a unit cost of less than $5,000 are considered supplies.)
      5. Supplies: “Supplies” means tangible property other than “equipment.” Identify categories of supplies to be procured (e.g., laboratory supplies or office supplies). Specifically identify computers to be purchased or upgraded.
      6. Contractual: Identify each proposed contract for services/analyses or consultants and specify its purpose and estimated cost. Contracts must have a separate itemized budget and budget justification, not to exceed one additional page each, included as part of the application.
      7. Other: List each item in sufficient detail for the EPA to determine the reasonableness of its cost relative to the research to be undertaken. Note that subawards, such as those with other universities for members of the research team, are included in this category. Subawards must have a separate itemized budget and budget justification, not to exceed one additional page each, included as part of the application.
      8. Indirect Costs: If indirect costs are included in the budget, indicate the approved rate and base with an explanation of how the indirect costs were calculated.
9. Resumes

   Provide resumes for each investigator and important co-worker. The resume for each individual must not exceed two consecutively numbered (bottom center), 8.5x11-inch pages of single-spaced, standard 12-point type with 1-inch margins.

10. Current and Pending Support

    Complete a current and pending support form (provided at http://www.epa.gov/ncer/rfa/forms) for each investigator and important co-worker. Include all current and pending research regardless of source.

11. Guidelines, Limitations, and Additional Requirements
    1. Letters of Intent/Letters of Support

       Letters of intent to provide resources for the proposed research or to document intended interactions are limited to one brief paragraph committing the availability of a resource (e.g., use of a person's time or equipment) or intended interaction (e.g., sharing of data, as-needed consultation) that is described in the Research Plan. Letters of intent are to be included as an addition to the budget justification documents for each investigational area.

       All letters that do not commit a resource vital to the success of the proposal are considered letters of support. Letters of support, and letters of intent that exceed one brief paragraph (excluding letterhead and salutations), are considered part of the Research Plan and are included in the 15-page Research Plan limit.

       Note: Letters of intent or support must be part of the application; letters submitted separately will not be accepted. Any transactions between the successful applicant and parties providing letters of support or intent financed with EPA grant funds are subject to the funding restrictions described in Section IV. D.

    2. Funding Opportunity Number(s) (FON)

       At various places in the application, applicants are asked to identify the FON.

       The Funding Opportunity Number for this RFA is:

       COMPUTATIONAL TOXICOLOGY RESEARCH CENTERS: IN VITRO AND IN SILICO MODELS OF DEVELOPMENTAL TOXICITY PATHWAYS, EPA-G2008-STAR-W1

    3. Confidentiality

       By submitting an application in response to this solicitation, the applicant grants the EPA permission to make limited disclosures of the application to technical reviewers both within and outside the Agency for the express purpose of assisting the Agency with evaluating the application. Information from a pending or unsuccessful application will be kept confidential to the fullest extent allowed under law; information from a successful application may be publicly disclosed to the extent permitted by law.

       In accordance with 40 CFR 2.203, applicants may claim all or a portion of the application as confidential business information (for example, hypotheses or methodologies contained in the research narrative that the applicant wishes to protect from possible public disclosure). EPA will evaluate confidentiality claims in accordance with 40 CFR Part 2. Applicants must clearly mark applications or portions of applications they claim as confidential. If no claim of confidentiality is made, the EPA is not required to make an inquiry to the applicant as otherwise required by 40 CFR 2.204(c) (2) prior to disclosure.

C. Submission Dates and Times
Applications must be transferred to Grants.gov no later than 4:00 pm Eastern Time on the solicitation closing date. Applications transferred after the closing date and time will be returned to the sender without further consideration.

It should be noted that this schedule may be changed without prior notification because of factors not anticipated at the time of announcement. In the case of a change in the solicitation closing date, a new date will be posted on the NCER web site (http://www.epa.gov/ncer/) and a modification posted on www.grants.gov.

Solicitation Closing Date: January 29, 2009, 4:00 pm Eastern Time (applications must be submitted to Grants.gov by this time, see Section IV.E “Submission Instructions and Other Submission Requirements” for further information).

NOTE: Customarily, applicants are notified about evaluation decisions within six months of the solicitation closing date. Awards are generally made 9-12 months after the solicitation closing date.

D. Funding Restrictions
The funding mechanism for all awards issued under STAR solicitations will consist of assistance agreements from the EPA. All award decisions are subject to the availability of funds. In accordance with the Federal Grant and Cooperative Agreement Act, 31 U.S.C. 6301 et seq., the primary purpose of an assistance agreement is to accomplish a public purpose of support or stimulation authorized by federal statute, rather than acquisition for the direct benefit or use of the Agency. In issuing a grant, the EPA anticipates that there will be no substantial EPA involvement in the design, implementation, or conduct of the research. However, the EPA will monitor research progress through annual reports provided by grantees and other contacts, including site visits, with the Principal Investigator(s).

If you wish to submit applications for more than one STAR funding opportunity you must ensure that the research proposed in each application is significantly different from any other that has been submitted to the EPA or from any other financial assistance you are currently receiving from the EPA or other federal government agency.

Collaborative applications involving more than one institution must be submitted as a single administrative package from one of the institutions involved.

EPA awards funds to one eligible applicant as the recipient even if other eligible applicants are named as partners or co-applicants or members of a coalition or consortium. The recipient is accountable to EPA for the proper expenditure of funds.

Funding may be used to provide subgrants or subawards of financial assistance, which includes using subawards or subgrants to fund partnerships, provided the recipient complies with applicable requirements for subawards or subgrants including those contained in 40 CFR Parts 30 or 31, as appropriate. Applicants must compete contracts for services and products, including consultant contracts, and conduct cost and price analyses to the extent required by the procurement provisions of the regulations at 40 CFR Parts 30 or 31, as appropriate. The regulations also contain limitations on consultant compensation. Applicants are not required to identify subawardees/subgrantees and/or contractors (including consultants) in their proposal/application. However, if they do, the fact that an applicant selected for award has named a specific subawardee/subgrantee, contractor, or consultant in the proposal/application EPA selects for funding does not relieve the applicant of its obligations to comply with subaward/subgrant and/or competitive procurement requirements as appropriate. Please note that applicants may not award sole source contracts to consulting, engineering or other firms assisting applicants with the proposal based solely on the firm's role in preparing the proposal/application.

Successful applicants cannot use subgrants or subawards to avoid requirements in EPA grant regulations for competitive procurement by using these instruments to acquire commercial services or products from for-profit organizations to carry out its assistance agreement. The nature of the transaction between the recipient and the subawardee or subgrantee must be consistent with the standards for distinguishing between vendor transactions and subrecipient assistance under Subpart B Section .210 of OMB Circular A-133 , and the definitions of subaward at 40 CFR 30.2(ff) or subgrant at 40 CFR 31.3, as applicable. EPA will not be a party to these transactions. Applicants acquiring commercial goods or services must comply with the competitive procurement standards in 40 CFR Part 30 or 40 CFR Part 31.36 and cannot use a subaward/subgrant as the funding mechanism.

Section V of the announcement describes the evaluation criteria and evaluation process that will be used by EPA to make selections under this announcement. During this evaluation, except for those criteria that relate to the applicant's own qualifications, past performance, and reporting history, the review panel will consider, if appropriate and relevant, the qualifications, expertise, and experience of:

1. an applicant's named subawardees/subgrantees identified in the proposal/application if the applicant demonstrates in the proposal/application that if it receives an award that the subaward/subgrant will be properly awarded consistent with the applicable regulations in 40 CFR Parts 30 or 31. For example, applicants must not use subawards/subgrants to obtain commercial services or products from for profit firms or individual consultants.
2. an applicant's named contractor(s), including consultants, identified in the proposal/application if the applicant demonstrates in its proposal/application that the contractor(s) was selected in compliance with the competitive procurement standards in 40 CFR Part 30 or 40 CFR 31.36 as appropriate. For example, an applicant must demonstrate that it selected the contractor(s) competitively or that a proper non-competitive sole-source award consistent with the regulations will be made to the contractor(s), that efforts were made to provide small and disadvantaged businesses with opportunities to compete, and that some form of cost or price analysis was conducted. EPA may not accept sole source justifications for contracts for services or products that are otherwise readily available in the commercial marketplace.

EPA will not consider the qualifications, experience, and expertise of named subawardees/subgrantees and/or named contractor(s) during the proposal/application evaluation process unless the applicant complies with these requirements.

Each proposed project must be able to be completed within the project period and with the initial award of funds. Applicants should request the entire amount of money needed to complete the project. Recipients should not anticipate additional funding beyond the initial award of funds for a specific project.

E. Submission Instructions and Other Submission Requirements
Please read this entire section before attempting an electronic submission through Grants.gov.  If you do not have the technical capability to utilize the Grants.gov application submission process for this solicitation, call 1-800-490-9194 or send a webmail message to http://www.epa.gov/ncer/contact_us.html at least 15 calendar working 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 e-mailed whenever possible.  Any applications submitted through alternate submission methods must comply with all the provisions of this RFA, including Section IV, and be received by the solicitation closing date identified above.

Note:  Grants.gov submission instructions are updated on an as-needed basis.  Please provide your Authorized Organizational Representative (AOR) with a copy of the following instructions to avoid submission delays that may occur from the use of outdated instructions.

1. Preparing for Submission.  The appropriate electronic application package available through the Grants.gov site must be used for electronic submissions.  To begin the application process, go to http://www.grants.gov and click on the “Apply for Grants” tab on the left side of the page.  Then click on “Apply Step 1:  Download a Grant Application Package” to download the compatible Adobe viewer and obtain the application package.  (Note: The PureEdge viewer is not needed to submit an application to this funding opportunity.)  For more information on Adobe Reader please go to http://www.grants.gov/help/help.jsp.

   Note:Grants.gov is aware of a corruption issue when Adobe Reader application packages are saved in different versions of Adobe Reader.  It is recommended that applicants uninstall earlier versions of Adobe Reader and then install the version available and compatible through Grants.gov.

   The application package may be quickly accessed from https://apply07.grants.gov/apply/forms_apps_idx.html using the appropriate FON.  Be sure to download the electronic application package for the appropriate FON.   Please register for announcement change notification emails.  Note: With the exception of the budget form and the current and pending support form (available at http://www.epa.gov/ncer/rfa/forms), all necessary forms are included in the electronic application package.

   The electronic submission of your application package must be made by an official representative of your institution who is registered with Grants.gov and authorized to sign for Federal assistance.  Most submission problems can be avoided by communicating with the AOR well before the solicitation closing date and allowing sufficient time for following the guidance provided below.  Note for organizations not currently registered: the registration process may take a week or longer to complete.  We recommend you designate an AOR and begin the registration process as soon as possible.

   For more information, go to http://www.grants.gov and click on “Get Registered”. 

2. Acknowledgement of Receipt.  The complete application must be transferred to Grants.gov no later than 4:00 pm Eastern Time on the solicitation closing date (see “Submission Dates and Times”).  Grants.gov provides an on-screen notification of successful initial transfer as well as an e-mail notification of successful transfer from Grants.gov to EPA.  While it is advisable to retain copies of these Grants.gov acknowledgements to document submission, the only official documentation that the application has been received by NCER is the e-mail acknowledgement sent by NCER to the Lead/Contact PI and the Administrative Contact.  This email will be sent from receipt.application@epa.gov; emails to this address will not be accepted.  If an email acknowledgment from NCER (not support@grants.gov) has not been received within 30 days of the solicitation closing date, immediately inform the Eligibility Contact shown in this solicitation.  Failure to do so may result in your application not being reviewed.
3. Application Package Preparation.  The application package consists of a. though d. below.
   1. On the initial electronic Grant Application Package page, complete the “Application Filing Name” field by entering the Lead/Contact PI‘s name, starting with the last name.  Note:  Applicants do not need to complete the “Competition ID” field.
   2. Application for Federal Assistance (SF 424):  Complete the form.
   3. EPA Key Contacts Form 5700-54:  Complete the form.  If additional pages are needed, see (d) below.
   4. Project Narrative Attachment Form (click on “Add Mandatory Project Narrative”):  Attach a single electronic file labeled “Application” that contains the items described in Section IV.B.3. through IV.B.11.a (Table of Contents, Abstract, Center Description, Administrative Core Unit, Research Plan, Quality Assurance Statement, Data Plan, References, Budget and Budget Justification, Resumes, Current and Pending Support, and Letters of Intent/Support) of this solicitation.  In order to maintain format integrity, this file must be submitted in Adobe Acrobat PDF.  Please review the PDF file for conversion errors prior to including it in the electronic application package; requests to rectify conversion errors will not be accepted if made after the solicitation closing date and time. If Key Contacts Continuation pages (see http://www.epa.gov/ncer/rfa/forms) are needed, place them before the Table of Contents (Section IV.B.3.).

   Once the application package has been completed, the “Submit” button should be enabled.  If the “Submit” button is not active, please call Grants.gov for assistance at 1-800-518-4726.  Investigators should save the completed application package with two different file names before providing it to the AOR to avoid having to re-create the package should submission problems be experienced or a revised application needs to be submitted.  Note:  Revised applications must be submitted before the solicitation closing date and time.

4. Submitting the application.  The application package must be transferred to Grants.gov by an AOR.  The AOR should close all other software before attempting to submit the application package.  Click the “submit” button of the application package. Your Internet browser will launch and a sign-in page will appear.  Note:  Minor problems are not uncommon with transfers to Grants.gov.  It is essential to allow sufficient time to follow all trouble-shooting instructions, including contacting Grants.gov, before 4:00 pm Eastern Time on the solicitation closing date.

   A successful transfer will end with an on-screen acknowledgement.  For documentation purposes, print or screen capture this acknowledgement.  If a submission problem occurs, reboot the computer – turning the power off may be necessary – and re-attempt the submission.  If submission problems continue, call Grants.gov for assistance (Telephone: 1-800-518-4726).

   Note:  Grants.gov issues a “case number” upon a request for assistance.

5. Transmission Difficulties.  If transmission difficulties that result in a late transmission, no transmission, or rejection of the transmitted application are experienced, and following the above instructions do not resolve the problem so that the application is submitted to Grants.Gov by the deadline date and time, follow the guidance below.  NCER may decide to review the application if it is clearly demonstrated that transmission difficulties were due solely as a result of problems associated with the transfer to Grants.gov and documentation that these instructions were followed is provided.  The decision regarding acceptance of the application for review will be made by NCER management and provided to the applicant within ten working days of the request.  All e-mails, as described below, are to be sent to Ron Josephson (josephson.ron@epa.gov) with the FON in the subject line.
   1. Late transfer due to electronic submission problems:  Should electronic submission problems result in the application being transferred to Grants.gov after 4:00 pm but before 5:00 pm Eastern Time on the solicitation closing date, send an e-mail before 5:00 pm Eastern Time on the deadline date.  The email must document the problem and include the Grants.gov case number.
   2. Unsuccessful transfer of the application package:  If a successful transfer of the application cannot be accomplished even with assistance from Grants.gov due to electronic submission issues, send an email before 5:00 pm Eastern Time on the solicitation closing date.  The email must document the problem, include the Grants.gov case number, and attach the entire application.
   3. Grants.gov rejection of the application package:  If a notification is received from Grants.gov stating that the application has been rejected for reasons other than late submittal, promptly send an email that includes any materials provided by Grants.gov and attach the entire application.

V. APPLICATION REVIEW INFORMATION

A. Peer Review
All eligible grant applications are reviewed by an appropriate external technical peer review panel comprised of individual experts using the criteria below.  This review is designed to evaluate each application according to its scientific merit.  Each peer review panel includes non-EPA scientists, engineers, social scientists, and/or economists who are accomplished in their respective disciplines and proficient in the technical subjects they are reviewing.  Reviewers are asked to individually assign a score of excellent, very good, good, fair, or poor to each application.  EPA translates the average of these individual scores into the final panel review score.

Individual external peer review panel members consider an application’s merit based on the criteria below.  Criteria 1-5 are listed in descending order of importance:

1. Research Proposal (criteria “1a” through “1f” are essentially equal):
   1. The originality and creativity of the proposed research, the appropriateness and adequacy of the proposed research methods, and the Quality Assurance Statement.
   2. Practical and technically defensible approach that can be performed within the proposed time period.
   3. Research contributes to scientific knowledge in the topic area.
   4. Projected benefits of the proposed activity to society, such as improving the environment or human health.
   5. The results are disseminated broadly to enhance scientific and technological understanding.
   6. Theproposal is well prepared with supportive information that is self-explanatory or understandable.
2. Investigators: The qualifications of the Principal Investigator(s) and other key personnel, including research training, demonstrated knowledge of pertinent literature, experience, and publication records.  All key personnel must make a significant time commitment to the project.
3. Responsiveness: The responsiveness of the proposal to the research needs identified for the research area.  The proposal adequately addresses the objectives and special considerations specified by the RFA.
4. Facilities and equipment: The availability and/or adequacy of the facilities and equipment proposed for the project.  Note any deficiencies that may interfere with the successful completion of the research.
5. Budget: Although budget information does not reflect on the application’s scientific merit, the reviewers are asked to provide their view on the appropriateness and/or adequacy of the proposed budget and its implications for the potential success of the proposed research.  Input on requested equipment is of particular interest.

B. Programmatic Review
Applications receiving scores of excellent or very good as a result of the peer review process will then undergo an internal programmatic review, as described below, conducted by technical experts from the EPA, including individuals from the Office of Research and Development (ORD) and program and regional offices involved with the science or engineering proposed.  All other applications are automatically declined.

After the peer review, those applicants who received scores of excellent or very good as a result of the peer review process will be asked to provide additional information for the programmatic review pertaining to the proposed Lead PI’s (in the case of Multiple-PI applications, the Contact PI’s) "Past Performance and Reporting History."  The applicant must provide the EPA Project Officer with information on the proposed Lead/Contact PI's past performance and reporting history under prior Federal agency assistance agreements (assistance agreements include grants and cooperative agreements but not contracts) in terms of: (i) the level of success in performing each agreement, and (ii) how progress towards achieving the results intended under each agreement was reported.  This information is required only for the proposed Lead/Contact PI's performance under Federal assistance agreements initiated within the last three years that were similar in size and scope to the proposed project.

The specific information required for each agreement is shown below, and must be provided within three weeks of EPA's request.  A maximum of three pages will be permitted for the response; excess pages will not be reviewed.  Note: If no prior past performance information and/or reporting history exists, you will be asked to so state.

1. Name of Granting Agency.
2. Grant/Cooperative agreement number.
3. Grant/Cooperative agreement title.
4. Brief description of the grant/cooperative agreement.
5. A description of how the agreement is similar in size and scope to the proposed project and whether or not it was successfully performed; if not successfully performed, provide an explanation.
6. Information relating to the proposed Lead/Contact PI's past performance in reporting on progress towards achieving the expected results (outputs/outcomes) under the agreement.  Include the history of submitting timely progress/final technical reports, describe how progress towards achieving the expected results was reported/documented, and if such progress was not being made, provide an explanation of whether, and how, this was reported.
7. Total (all years) grant/cooperative agreement dollar value.
8. Project period.
9. Technical contact (project officer), telephone number, and E-mail address (if available).

The purpose of the programmatic review is to assure an integrated research portfolio for the Agency and help determine which applications to recommend for award.  In conducting the programmatic review, the EPA will consider information provided by the applicant and may consider information from other sources, including prior and current grantors and agency files.

The internal programmatic review panel will assess:

1. The relevance of the proposed science to EPA research priorities.
2. The proposed Lead/Contact PI's past performance [under Federal agency assistance agreements (assistance agreements include grants and cooperative agreements but not contracts) initiated within the last three years that were similar in size and scope to the proposed project] in two areas:  First, in successfully performing these prior Federal assistance projects, including whether there is a satisfactory explanation for any lack of success.  Second, in reporting progress towards achieving results under these agreements, including the proposed Lead/Contact PI's history of submitting timely progress/final technical reports that adequately describe the progress toward achieving the expected results (outputs/outcomes) under the agreements.  Any explanation of why progress towards achieving the results was not made will also be considered.  Applicants whose proposed Lead PI/Contact PI has no relevant past performance and/or reporting history, or for whom this information is not available, will be evaluated neither favorably nor unfavorably on these elements.

C. Funding Decisions
Final funding decisions are made by the NCER Director based on the results of the peer review and internal programmatic review. In addition, in making the final funding decisions, the NCER Director may also consider program balance and available funds. Applicants selected for funding will be required to provide additional information listed below under “Award Notices.” The application will then be forwarded to EPA’s Grants and Interagency Agreement Management Division for award in accordance with the EPA’s procedures.

VI. AWARD ADMINISTRATION INFORMATION

A. Award Notices
Customarily, applicants are notified about evaluation decisions within six months of the solicitation closing date. A summary statement of the scientific review by the peer panel will be provided to each applicant with an award or declination letter.

Applicants to be recommended for funding will be required to submit additional certifications and an electronic version of the revised project abstract. They may also be asked to provide responses to comments or suggestions offered by the peer reviewers, a revised budget, and/or to resubmit their proposal. EPA Project Officers will contact the Lead PI/Contact PI to obtain these materials. Before or after an award, applicants may be required to provide additional quality assurance documentation.

Non-profit applicants that are recommended for funding under this announcement are subject to pre-award administrative capability reviews consistent with Sections 8b., 8c. and 9d. of EPA Order 5700.8 - Policy on Assessing Capabilities of Non-Profit Applicants for Managing Assistance Awards (http://www.epa.gov/ogd/grants/award/5700_8.pdf (9 pp, 31 K)). In addition, non-profit applicants that qualify for funding may, depending on the size of the award, be required to fill out and submit to the Grants Management Office the Administrative Capabilities Form with supporting documents contained in Appendix A of EPA Order 5700.8.

The official notification of an award will be made by the Agency’s Grants and Interagency Agreement Management Division. Applicants are cautioned that only a grants officer is authorized to bind the Government to the expenditure of funds; preliminary selection by the NCER Director in the Office of Research and Development does not guarantee an award will be made.

B. Disputes
Disputes related to this assistance agreement competition will be resolved in accordance with the dispute resolution procedures set forth in 70 FR 3629, 3630 (January 26, 2005) which can be found at http://www.epa.gov/ogd/competition/resolution.htm. Questions regarding disputes may be referred to the Eligibility Contact identified below.

C. Administrative and National Policy Requirements
Expectations and responsibilities of NCER grantees and cooperative agreement holders are summarized in this section, although the terms grant and grantee are used.  See http://www.epa.gov/ncer/guidance for the full terms and conditions associated with an award, including which activities require prior approval from the EPA.

1. Meetings: Centers must budget for and participate in, All-Investigators Meetings (also known as progress reviews or annual grantees meeting) that should be attended by the Center director and the appropriate project leads.  These meetings will be scheduled approximately once per year with EPA scientists and other grantees to report on research activities and discuss issues of mutual interest.
2. Approval of Changes after Award: Prior written approval is required from the EPA if there will be a significant change from the work described in the application.  Examples of these changes are contained in 40 C.F.R. 30.25.  Note: prior written approval is also required from the EPA for incurring costs more than 90 calendar days prior to award.
3. Human Subjects: A grant applicant must agree to meet all EPA requirements for studies using human subjects prior to implementing any work with these subjects.  These requirements are given in 40 CFR § 26.  Studies involving intentional exposure of human subjects who are children or pregnant or nursing women are prohibited by Subpart B of 40 CFR § 26.  For observational studies involving children or pregnant women and fetuses please refer to Subparts C & D of 40 CFR § 26.  U.S. Department of Health and Human Services regulations at 45 CFR § 46.101(e) have long required "... compliance with pertinent Federal laws or regulations which provide additional protection for human subjects."  EPA’s regulation 40 CFR § 26 is such a pertinent Federal regulation.  Therefore, the applicant's Institutional Review Board (IRB) approval must state that the applicant's study meets the EPA's regulations at 40 CFR § 26.  No work involving human subjects, including recruiting, may be initiated before the EPA has received a copy of the applicant’s IRB approval of the project and the EPA has also provided approval.  Where human subjects are involved in the research, the recipient must provide evidence of subsequent IRB reviews, including amendments or minor changes of protocol, as part of annual reports.
4. Animal Welfare: A grant recipient must agree to comply with the Animal Welfare Act of 1966 (P.L. 89-544), as amended, 7 U.S.C. 2131-2156.  The recipient must also agree to abide by the "U.S. Government Principles for the Utilization and Care of Vertebrate Animals used in Testing, Research, and Training" (50 Federal Register 20864-20865. May 20, 1985).
5. Data Access and Information Release: After award, all data (including primary and secondary or existing data) must be made available to the NCER Project Officer without restriction and be accompanied by comprehensive metadata documentation adequate for specialists and non-specialists alike to be able to understand how and where the data were obtained and to evaluate the quality of the data.  If requested, the data products and their metadata must be provided to the NCER Project Officer in a standard exchange format no later than the due date of the grant's final report or the publication of the data product's associated results, whichever comes first.

   Congress, through OMB, has instructed each federal agency to implement Information Quality Guidelines designed to "provide policy and procedural guidance...for ensuring and maximizing the quality, objectivity, utility, and integrity of information, including statistical information, disseminated by Federal agencies." The EPA's implementation may be found at http://epa.gov/quality/exmural.html#genreqts.  These procedures may apply to data generated by grant recipients if those data are disseminated as described in the Guidelines.

   The Office of Management and Budget (OMB) Circular A-110 located at 2 CFR Part 215 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances.  Data that are (1) first produced in a project that is supported in whole or in part with federal funds and (2) cited publicly and officially by a federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA.  If such data are requested by the public, the EPA must ask for it, and the grantee must submit it, in accordance with A-110 and the EPA regulations at 40 C.F.R. 30.36.

6. Reporting:  A grant recipient must agree to provide annual progress reports, with associated summaries, and a final report with an executive summary.  The summaries will be posted on NCER’s website.

   A grant recipient must agree to provide copies of any peer reviewed journal article(s) resulting from the research during the project period.  In addition, the recipient should notify the EPA Project Officer of any papers published after completion of the grant that were based on research supported by the grant.  NCER posts references to all publications resulting from a grant on the NCER web site.

7. Acknowledgement of EPA Support: EPA’s full or partial support must be acknowledged in journal articles, oral or poster presentations, news releases, interviews with reporters and other communications.  Any documents developed under this agreement that are intended for distribution to the public or inclusion in a scientific, technical, or other journal shall include the following statement:

   This publication [article] was developed under STAR Research Assistance Agreement No. __________ awarded by the U.S. Environmental Protection Agency.  It has not been formally reviewed by the EPA.  The views expressed in this document are solely those of [name of recipient] and the EPA does not endorse any products or commercial services mentioned in this publication.

   A graphic that may be converted to a slide or used in other ways, such as on a poster, is located at http://www.epa.gov/ncer/guidance/star_images.html.  EPA expects recipients to use this graphic in oral and poster presentations.

8. Exchange Network: EPA, states, territories, and tribes are working together to develop the National Environmental Information Exchange Network, a secure, Internet- and standards-based way to support electronic data reporting, sharing, and integration of both regulatory and non-regulatory environmental data.  States, tribes and territories exchanging data with each other or with EPA, should make the Exchange Network and the Agency's connection to it, the Central Data Exchange (CDX), the standard way they exchange data and should phase out any legacy methods they have been using.  More information on the Exchange Network is available at www.exchangenetwork.net .

VII. AGENCY CONTACTS

Further information, if needed, may be obtained from the EPA officials indicated below. Information regarding this RFA obtained from sources other than these Agency Contacts may not be accurate. Email inquiries are preferred.

Eligibility Contact: William Stelz (stelz.william@epa.gov); phone: 202-343-9802
Electronic Submissions: Ron Josephson (Josephson.Ron@epa.gov); phone: 202-343-9643
Technical Contact: Deborah Segal (segal.deborah@epa.gov); phone: 202-343-9797

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