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U.S. Environmental Protection Agency
USEPA Mid-Continent Ecology Division
Office of Research and Development
National Health and Environmental Effects Research Laboratory

CLOSED - FOR REFERENCES PURPOSES ONLY

METHODS FOR IDENTIFYING CHEMICALS THAT ELICIT ADVERSE BIOLOGICAL EFFECTS

SOLICITATION NUMBER: DUL-00-0306

OPENING DATE: April 28, 2000
CLOSING DATE: June 28, 2000

CONTACT: Gerald T. Ankley - Project Officer, 218-529-5147

Background
Proposal Submission and Evaluation
Requirements for Proposals
Evaluation Criteria
 

Background

The National Health and Environmental Effects Research Laboratory (NHEERL) in the Office of Research and Development (ORD) of the U.S. Environmental Protection Agency (EPA) requests proposals focused upon modeling methodologies suitable for identifying chemicals that could elicit adverse biological effects through specific modes/mechanisms of action associated with endocrine function. The EPA has received a legislated mandate to develop, validate and implement screening and testing methods for endocrine-disrupting chemicals (EDCs), and research in this area has been identified as a high priority within ORD. The models developed in response to this RFA will be used by scientists to screen large databases of chemicals for potential EDC activity. This information can then be used as a basis for prioritizing chemicals for subsequent testing.

The models developed for this activity should be based upon established principles relating chemical structure to biological activity. To achieve this in a technically-defensible fashion, several criteria must be met. First, the models must be based upon a thorough understanding of the interaction of chemicals of concern with the biological system/process under consideration. Those biological systems of particular interest from an EDC perspective are pathways controlled by estrogens, androgens, and retinoid and thyroid hormones. Modeling of chemical effects should be focused upon a definable aspect of the system (e.g., binding to receptor or transport proteins, gene transactivation by the receptor-ligand complex, hormone synthesis/degradation, etc), and should reflect an understanding (to the extent possible) of the molecular basis of chemical interactions with biological components. For example, models developed for predicting chemical binding to receptors should utilize molecular descriptors reflective of likely steric and/or charge constraints associated with receptor-ligand complexes. Therefore, modeling approaches that emphasize better understanding of the relationship of the molecular descriptors to the biological endpoint will be encouraged. However, models focused on enhanced statistically-robust treatments of broad suites of molecular descriptors, that do not enhance understanding of the linkage of chemical descriptors to the biological endpoint, are not encouraged.

A second technical issue that must be addressed by proposed modeling approaches involves recognition, and explicit consideration of conformational flexibility of chemicals that could act as EDCs. Various empirical and theoretical studies indicate that multiple conformers of a particular chemical can be involved in producing biological activity/responses (e.g., binding to a receptor). Therefore, modeling techniques that focus, for example, only on the lowest energy conformer of a test chemical(s) may underestimate their potential to elicit biological effects. To address this, the modeling undertaken in response to this RFA must explicitly address the issue of conformational flexibility of chemicals of concern. This should be achieved in the context of considering any energetically reasonable conformer in the development of structure-activity relationships.

A third technical issue that must be considered in developing the proposal involves the ability of resultant model(s) to consider chemicals that potentially are very dissimilar from a molecular perspective. This requirement arises from the need to screen databases comprised of chemicals with diverse structures. Therefore, techniques/approaches selected for this work must have a sound theoretical basis for dealing with chemical diversity.

A final requirement for this work is that the screening technique(s)/model(s) must be capable of dealing with large databases (10,000-100,000 chemicals) in a logistically reasonable manner, to identify potential EDCs (again, with an emphasis on compounds that affect biological systems controlled by estrogens, androgens, and thyroid and retinoid hormones). Ideally this screening ability could be achieved through the use of personal computers (as opposed to super computers) that would execute an appropriate screening algorithm and provide output within minutes to hours. A long-term goal of this research is to develop technically robust methods that could be applied by scientists involved in risk assessment activities, who would not have advanced training or experience in computational chemistry or modeling. Therefore, in responding to this RFA, consideration should be given to how the methods would be developed to ensure a "user-friendly" interface in the public domain.

Proposal Submission and Evaluation

The amount awarded in response to this RFA will be a total of up to $150,000 (US) over a two year period, with ideally a planned start date of September, 2000.

Only colleges or universities of higher education (not for profit) are eligible applicants for this program. Research will be funded under the statutory authority of the Clean Water Act (P.L. 92-500, as amended) Section 104(r). Interested applicants must be eligible to receive Federal assistance under this Act and the Code of Federal Regulations (CFR) Part 30 - General Regulation for Assistance, and Part 40 - Research and Demonstration Grants.

An original proposal signed by an authorized representative plus three copies, must be sent to EPA, postmarked no later than June 28, 2000, if by U.S. Mail, or received by June 28, 2000, if by express mail or courier delivery. Send to:

U.S. EPA
NHEERL\Mid-Continent Ecology Division
Attn: Craig L. Johnson
6201 Congdon Boulevard
Duluth, Minnesota 55804

Telephone: (218) 529-5016

Proposals postmarked after that date will not be considered for funding. EPA expects to announce the successful recipient during the Summer of 2000.

Requirements for Proposals

The proposals must contain two standard federal forms, a work plan with budget, a Quality Assurance Project Plan, and appendices, as described below. Please follow instructions and do not submit additional items. EPA will make copies of proposals for use by the peer reviewers. Funds will be provided for Fiscal Year (FY) 2000 and FY 2001, with a final report submitted by July 31, 2002.

Application for Federal Assistance (SF-424) and Budget Information (SF-424A): The SF-424 and SF-424A are required for all federal cooperative agreements and must be submitted as part of your proposal. Only finalists will be asked to submit additional federal forms needed to process their proposals.

Work Plan and Appendices: A work plan describes your proposed research project, and your appendices establish your timeline, your qualifications, and your partnerships with other organizations, where applicable.

(a) Timeline-Include a "time line" to link your activities to a clear project schedule and indicate at what point over the months of your budget period each action, event, product, development, etc. occurs.

(b) Key Personnel-Attach a one page resume for the key personnel conducting the project (maximum of five resumes, please).

(c) Letters of Commitment-If there are partners, include one page letters of commitment form the partners explaining their role in the proposed project.

(d) Institution cost-share is not required. However, the degree of recipient cost sharing incorporated into the proposal, such as in-kind contributions, including facilities, equipment, materials, professional services or volunteer staff provided by non-Federal public agencies, organizations, or individuals, will be considered in the selection process.

Quality Assurance Project Plan: Instructions for preparing a Quality Assurance Project Plan can be found in EPA QA/G-5, Guidance for Quality Assurance Project Plans, which is on INTERNET site http://www.epa.gov/quality1/qa_docs.html.

Evaluation Criteria

All proposals received will be submitted to both internal (EPA) and external peer-review for critique and ranking. Proposals will be evaluated on the following factors:

(1) Adherence to the technical requirements described above, (30%) specifically:

(a) model(s) must have a mechanistic basis with regard to the relationship of the biological process to molecular descriptors;

(b) model(s) must explicitly consider conformational flexibility of the test chemicals in the context of potential biological activity; and

(c) model(s) should be conceptually appropriate for dealing with diverse chemical structures.

(2) Proposals also will be assessed with respect to the ability of the proposed technique(s)/model(s) to be used to screen large chemical data sets, in a reasonable time frame, using commonly-available computer hardware (30%) .

(3) The grantees must have a demonstrated expertise in the area of structure-activity relationship modeling, particularly for chemical-biological interactions, (30%) as reflected by the following:

(a) participation in, and presentations at international technical meetings concerning computational chemistry and structure-activity relationship modeling,

(b) a substantial (e.g., >10) number of publications on these topics in the peer-reviewed international literature, and

(c) an active research program in the areas of computational chemistry and structure-activity relationship modeling as evidenced, for example, by current funding from diverse organizations (e.g., government, industry) and mentoring relationships (e.g., postdoctoral associates, graduate students).

The total number of points possible for each proposal is 100. Each of the above sections of the work plan is assigned points which add up to 90. Reviewers will be given the flexibility to provide up to 10 bonus points for exceptional projects based on the overall quality of the proposal, evidence that the research will be advanced by the project, and that it will provide a good return on the investment.

Please note that this is a competitive request for assistance program. Limited funding is available, and many cooperative agreement applications are expected to be received. Therefore, the Agency cannot fund all applications. EPA expects to announce the successful recipient of one cooperative agreement during the Summer of 2000. Applicants should anticipate project start dates for the Autumn of 2000, and for planning purposes may use September 1, 2000, as the earliest project start date. Please remember, however, that EPA's Grants Administration Division must issue an assistance award before EPA's offer for assistance is official. Applicants that were not selected for award will be notified at the time the selection decision has been tentatively approved by the award official.

For further technical information contact Dr. Gerald T. Ankley (email, ankley.gerald@epa.gov; Telephone, (218) 529-5147). For details concerning the application process, contact Mr. Craig Johnson (email, johnson.craig@epa.gov; Telephone, (218) 529-5016)

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