Funding Opportunities

Development and Characterization of Biological Systems for Studying Low Dose Effects of Endocrine Disrupting Chemicals

Sorting Code Number: 2004-STAR-M1
Catalog of Federal Domestic Assistance (CFDA) Number: 66.509

Technical Contacts: Elaine Francis; Phone: 202-343-9696; email: francis.elaine@epa.gov
Vivian Turner; Phone: 202-343-9697; email: turner.vivian@epa.gov
Eligibility Contact: Thomas Barnwell; Phone: 202-343-9862; email: barnwell.thomas@epa.gov

Opening Date: March 19, 2004
Closing Date: June 1, 2004

Table of Contents:
Summary of Program Requirements
Introduction
Background
Specific Areas of Interest
References
Mechanism of Support/Funding
Eligibility
Cost Sharing
Submitting an Application
Application Processing and Review Information
Contact Points
Authority and Regulations

Access Standard STAR Forms and Instructions (http://es.epa.gov/ncer/rfa/forms/)
View NCER Research Capsules (http://es.epa.gov/ncer/publications/topical/)
View research awarded under previous solicitations (http://es.epa.gov/ncer/rfa/archive/grants/)

SUMMARY OF PROGRAM REQUIREMENTS

Synopsis of Program:

The U.S. Environmental Protection Agency (EPA), Office of Research and Development (ORD) as part of its Science to Achieve Results (STAR) program, is seeking applications proposing to develop and characterize biological systems for studying the nature of the dose-response to endocrine disrupting chemicals. The purpose of the solicitation is to develop a body of information that will allow more informed judgments to be made in designing appropriate toxicology studies for identifying substances with endocrine activity and for interpreting their findings. Research should focus on the estrogen, androgen, or thyroid hormone systems, as these systems are the focus of the Agency’s Endocrine Disruptors Screening Program. The proposals should focus on innovative toxicology studies conducted across a wide range of multiple dose levels to characterize dose-response relationships following in utero or early postnatal exposures to endocrine disruptors. Studies should:

• Identify the critical determinants that dictate the shape of the dose-response relationship. These could include, for example, pharmacokinetics, receptor pharmacology, homeostatic feedback loops and repair capabilities, and how they differ across target end points;
• Identify and evaluate sensitive and, if possible, easily measured molecular or biochemical markers as indicators of low-dose effects of (anti)estrogenic, (anti)androgenic, (anti)thyroid agents;
• Allow a systematic determination of mechanistic events associated with low-dose effects;
• Characterize any critical windows of sensitivity, strain- or sex-differences, and elucidate any qualitative differences in the responses to the various test substances; and
• Allow assessment of the complete time course for any observed effects and a determination of the long-term health consequences of the earlier detected molecular or biochemical markers; that is, studies should characterize whether or not these observations early in life are predictive of or associated with any specific adverse outcomes during later life stages.

This is the initial announcement for this program.

Award Information:
Anticipated Type of Award: Grant
Estimated Number of Awards: Approximately 7 to 11 awards
Anticipated Funding Amount: Approximately $5 million total costs
Potential Funding per Grant:
For studies that include mechanistically based analyses: Up to $200,000 to $250,000/year with a duration of up to 3 years and no more than a total of $750,000 including direct and indirect costs.
For studies that do not include mechanistically based analyses: Up to $150,000 to $200,000/year with a duration of up to 3 years and no more than a total of $600,000 including direct and indirect costs.
Proposals with budgets exceeding the total award limits will not be considered.

Cost Sharing:
None

Eligibility Information:
Institutions of higher education and not-for-profit institutions located in the U.S., and tribal, state and local governments, are eligible to apply. See full announcement for more details.

Contact Persons:
Technical Contacts: Elaine Francis; Phone: 202-343-9696; email: francis.elaine@epa.gov
Vivian Turner; Phone: 202-343-9697; email: turner.vivian@epa.gov
Eligibility Contact: Thomas Barnwell; Phone: 202-343-9862; email: barnwell.thomas@epa.gov

INTRODUCTION

It has been suggested that exposure to some environmental agents that interfere with the endocrine system have resulted in adverse effects in humans and wildlife species. However, considerable uncertainty exists regarding the relationship(s) between adverse health outcomes and exposure to environmental contaminants. Collectively, chemicals with the potential to interfere with the function of endocrine systems are called endocrine disruptors or endocrine disrupting chemicals (EDCs). An endocrine disruptor has been defined as an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations (IPCS/WHO, 2002).

In 1996, the U.S. Environmental Protection Agency’s (EPA) Office of Research and Development (ORD) identified endocrine disruptors as one of its top six research priorities (USEPA,1996). In the same year, through enactment of the Food Quality Protection Act, the U.S. Congress directed EPA to develop a screening program to determine whether certain substances may have estrogenic or other hormonal effects in humans (PL-104-70). EPA’s research program and the development and implementation of the Endocrine Disruptor Screening Program (EDSP) are on parallel, yet highly interactive, tracks.

The blueprint for EPA’s research program was published in 1998 as ORD’s Endocrine Disruptors Research Plan (http://www.epa.gov/ORD/WebPubs/final/ORD-EDR-Feb1998.pdf) (PDF, 56pp., 648 KB). Since then, ORD has developed a Multi-Year Plan for Endocrine Disruptors (http://www.epa.gov/osp/myp/edc.pdf) (PDF, 79pp., 1.64 MB) that identifies the elements of the Research Plan that specifically will be addressed over the next five to ten years, intramurally, across three national laboratories and one national center and, extramurally, through a competitive grants program. In the Multi-Year Plan, ORD has identified three Long-Term Goals (LTG).

• 1) Provide a better understanding of science underlying the effects, exposure, assessment, and management of endocrine disruptors. Research includes determining: dose-response relationships, the effects of exposure to multiple endocrine disruptors, major sources of exposure, and approaches for managing risks;
• 2) Determine the extent of the impact of endocrine disruptors on humans, wildlife, and the environment. Research includes determining what effects are occurring in human and wildlife populations and what chemical classes are responsible; and
• 3) Support EPA’s screening and testing program. ORD research is developing/improving in vivo and in vitro assays in support of the implementation of EDSP.

A number of uncertainties have been identified regarding the characterization of dose-response relationships of endocrine disruptors. This solicitation for research proposals will lead to the development of a body of information that will be helpful in filling in data gaps in this area.

BACKGROUND

By the end of the 1990s, a number of studies were published that challenged the assumption in toxicology that the incidence or severity of toxic effects increases as the dose level increases (Nagel et al. 1997; vom Saal et al. 1997). The studies conducted in laboratory animals, specifically with endocrine active agents, reported non-monotonic dose response curves when testing was conducted at “low-dose” levels. Other scientists have been unable to replicate these findings (Ashby et al. 1999; Cagen et al. 1999). In addition, questions have been raised regarding whether the general assumption of a threshold for non-cancer effects is valid for chemicals that may interfere with endogenous hormone systems (Sheehan et al. 1999; Welshons et al. 2003). Should the challenges of non-monotonic dose response curves associated with low-dose levels of exposure to endocrine active agents and/or those regarding threshold assumptions be upheld, then there could be a significant impact on the selection of dose levels in toxicological studies and on how data from such studies are incorporated into risk assessments. Therefore, it is important to understand the determinants that influence the biological response over a wide range of dose levels, including those that approximate environmental relevance.

Dose-response assessment is one of the critical components of the risk assessment process (NRC, 1983). Since data on human dose-response relationships are available infrequently, most risk assessments rely on dose-response characterizations based on data from studies performed in laboratory animals. Standard toxicology studies customarily use a control group and two to three dose groups with at least one of the dose groups producing some level of toxicity, to ensure that testing has been conducted over an appropriate range of exposures. The characterization of dose-response includes the identification of levels that cause toxicity as well as those associated with no increased incidence of adverse effects when compared with control animals.

For non-cancer effects, where, in general, the assumption is that there is a level of exposure below which no adverse effect is observed, the following approach is used to characterize dose-response. Each study results in the determination of the no observed adverse effect level (NOAEL) which is the highest dose at which no statistically or biologically significant increase in the frequency of an adverse effect is observed. A LOAEL is the lowest dose at which there is a statistically or biologically significant increase in the frequency of an adverse effect when compared with controls. The dose response data in the observed range in the study may also be modeled to derive a benchmark dose. In determining a reference dose or reference concentration, uncertainty factors are applied to the NOAEL, LOAEL, and/or benchmark dose. This information is used in developing a risk characterization, the culmination of the risk assessment process. Therefore, the selection of the dose levels in toxicological studies and the subsequent characterization of the dose-response relationships are critical to the risk assessment process.

Recognizing the need to address the controversy and debate, EPA requested the National Toxicology Program (NTP)/National Institute of Environmental Health Sciences (NIEHS) to convene an independent peer review Panel of experts to evaluate the scientific evidence on low-dose effects and dose-response relationships (http://ntp-server.niehs.nih.gov/htdocs/liason/LowDoseWebPage.html ; Melnick et al. 2002). The purpose of the review was to establish a sound scientific foundation upon which EPA and other agencies could determine whether modification of testing paradigms for developmental and reproductive toxicity was warranted. For the peer review, “low dose effects” referred to biological changes that occur in the range of human exposures or at doses lower than those used typically in standard testing paradigms.

One subpanel found that for some estrogenic compounds, low-dose effects were clearly demonstrated. That is, according to this subpanel’s definition, “low-dose effects were considered to be occurring when a non-monotonic dose-response resulted in significant effects below the presumed NOEL [sic] expected by the traditional testing paradigm.” They also pointed out that the shape of the dose-response curves varied with the end point and dosing regimen. For the chemical that started the debate, Bisphenol A (BPA), another subpanel concluded that:

“There is credible evidence that low doses of BPA can cause effects on specific end points. However, due to the inability of other credible studies in several different laboratories to observe low dose effects of BPA, and the consistency of these negative studies, the subpanel is not persuaded that a low dose effect of BPA has been conclusively established as a general or reproducible finding.”

Complicating these issues is the fact that different effects may be seen at low doses than at higher doses; these effects may or may not be correlated/associated. Some effects that may be seen at low doses are transient in nature, but the long-term impact of these findings are unclear. Are these low-dose effects biomarkers of other effects not assessed by current toxicology testing paradigms?

To address the low-dose effect hypothesis, the Panel recommended additional research to: 1) duplicate previously reported key low-dose findings, 2) characterize target tissue dosimetry during critical periods of development, 3) identify sensitive molecular markers that would be useful in understanding mechanistic events associated with low-dose effects, and 4) determine the long-term health consequences of low-dose effects of endocrine active agents.

Before the EPA/NTP expert peer review, EPA received recommendations regarding the low-dose hypothesis. In its 1998 report to the EPA, the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) stated that if low-dose phenomena are reproducible, generalizable, and related to adverse effects, the implications for regulatory toxicity testing and risk assessment are profound (http://www.epa.gov/scipoly/oscpendo/edspoverview/finalrpt.htm). EDSTAC recognized there are divergent scientific opinions and advised that more research is necessary to resolve the underlying uncertainties and controversy with regard to low-dose selection and identification of NOAELs. It proposed research to address the nature of the dose-response curves for exogenous endocrine active substances in order to allow more informed judgements about appropriate toxicology study designs and how to apply these data in risk assessments. EDSTAC also encouraged exploratory studies to evaluate potential new end points and compare effects across species, sexes, environmental agents, potencies, and laboratories, if possible.

Research needs related to low-dose effects have been identified through other workshop reports (Bigsby et al. 1999; Walker et al. 1999; Andersen et al. 1999). Scientists have identified a number of factors to take into consideration in the design, analysis, and interpretation of studies (Ashby 2001; Haseman et al. 2001; Welshons et al. 2003). A recently published review of dose-response for endocrine active substances (Barton 2003) identifies a range of questions that could impact toxicological testing and risk assessment practices. These include:

Is there a common dose-response shape characterized by threshold, non-linearity, or linearity at low doses for endocrine mediated effects? Do receptor mediated effects exhibit a common dose response relationship? Are effects during early development, i.e., in utero or postnatal through puberty, characterized by linear dose-response? Are endocrine mediated effects characterized by non-monotonic, e.g., U or J shaped, dose response relationships? Are effects commonly observed at low doses relative to the doses used in traditional toxicity studies, such that they are poorly predicted by such studies?

EPA issued a statement, in 2002, that additional research is needed to better understand the low-dose hypothesis and that an improved understanding of the mechanisms of action by which endocrine-active agents exert their effects would determine whether existing testing protocols need modification (http://www.epa.gov/scipoly/oscpendo/docs/edmvs/lowdosepolicy.pdf) (PDF, 1pp., 24 KB). This solicitation responds to the call for more research and takes into consideration the research recommendations from the EPA/NTP Workshop and other workshops and reviews.

SPECIFIC AREAS OF INTEREST

EPA is seeking applications of research proposals that develop and characterize biological systems for studying the nature of the dose-response to endocrine disrupting chemicals. It is expected that the resultant body of information will allow more informed judgements to be made in designing appropriate toxicology studies for identifying substances that have endocrine activity and for interpreting their findings. Research should focus on the estrogen, androgen, or thyroid hormone systems, since these have been recommended by EDSTAC as the appropriate systems for the EPA to include in its Endocrine Disruptors Screening Program. For the purposes of this solicitation, “low-dose” refers to doses below those that are typically used in standard laboratory animal toxicity testing or that approximate environmentally relevant exposures. The proposals should focus on innovative toxicology studies conducted across a wide range of multiple dose levels to characterize dose-response relationships following in utero or early postnatal exposures to endocrine disruptors. Studies should:

• Identify the critical determinants that dictate the shape of the dose-response relationship. These could include, for example, pharmacokinetics, receptor pharmacology, homeostatic feedback loops and repair capabilities, and how they differ across target end points;
• Identify and evaluate sensitive and, if possible, easily measured molecular or biochemical markers as indicators of low-dose effects of (anti)estrogenic, (anti)androgenic, (anti)thyroid agents;
• Allow a systematic determination of mechanistic events associated with low-dose effects
• Characterize any critical windows of sensitivity, strain- or sex-differences, and elucidate any qualitative differences in the responses to the various test substances; and
• Allow assessment of the complete time course for any observed effects and a determination of the long-term health consequences of the earlier detected molecular or biochemical markers; that is, studies should characterize whether or not these observations early in life are predictive of or associated with any specific adverse outcomes during later life stages.

In addition, proposals should include the following elements:

(1) Studies should be conducted in a rat or mouse strain that is customarily used in toxicological testing for developmental or reproductive effects.

(2) Chemicals studied should be known to have (anti)estrogenic, (anti)androgenic, or (anti)thyroid effects. Proposals studying PCBs and dioxins will be considered non-responsive to the solicitation.

(3) Studies should be conducted across a wide range of dose levels using at least 4 treated groups plus controls. Proposals should describe the rationale for dose selection, e.g., low-dose selection should include levels below those for which LOAELs have already been established through other published studies using laboratory animals or based upon known/approximated environmentally relevant levels.

(4) Studies should include descriptions of statistical approaches and/or biomathematical models used for analyses of the biological systems and their perturbations. It is preferred that studies apply mechanistically based biomathematical analyses to characterize dose-response relationships. For studies that propose to incorporate mechanistically based models (e.g., physiologically based pharmacokinetic models) and that characterize dosimetry, a higher level of funding per year may be requested (see below).

It is expected that successful proposals will require the establishment of multidisciplinary teams that promote collaboration among molecular biologists, toxicologists, endocrinologists, and mathematical biologists.

REFERENCES

Andersen, ME, RB Conolly, EM Faustman, RJ Kavlock, CJ Portier, DM Sheehan, PJ Wier, L Ziese. (1999) Quantitative mechanistically based dose-response modeling with endocrine-active compounds. Environ Hlth Perspect 107(suppl4):631-638.

Ashby, J. (2001). Testing for endocrine disruption post-EDSTAC: extrapolation of low dose rodent effects to humans. Toxicol Ltrs 120:233-242.

Ashby, J, H Tinwell, J Haseman. (1999). Lack of effects for low dose levels of bisphenol A (BPA) and diethylstilbestrol (DES) on the prostate gland of CF1 mice exposed in utero. Reg Toxicol Pharmacol 30:156-166.

Barton, HA. (2003). Endocrine active substances and dose response for individuals and populations. Pure Appl Chem 75:2159-2166.

Bigsby, R, RE Chapin, GP Daston, BJ Davis, J Gorski, LE Gray, KL Howdeshell, RT Zoeller, FS vom Saal. (1999). Evaluating the effects of endocrine disruptors on endocrine function during development. Environ Hlth Perspect 107(suppl 4):613-618.

Cagen SZ, JM Waechter, SS Dimond, WJ Breslin, JH Butala, FW Jekat, RL Joiner, RN Shiotsuka, GE Veenstra, LR Harris. (1999). Normal reproductive organ development in CF-1 mice following prenatal exposure to bisphenol A. Toxicol Sci 50:36-44.

Haseman, JK, AJ Bailer, RL Kodell, R Morris, K Portier. (2001). Statistical issues in analysis of low-dose endocrine disruptor data. Toxicol Sci 61:201-210.

International Programme on Chemical Safety/World Health Organization (IPCS/WHO). (2002). Global assessment of the state-of-the-science of endocrine disruptors. T Damstra, S Barlow, A Bergman, R Kavlock, G Van Der Kraak, eds.

Melnick, R, G Lucier, M Wolfe, R Hall, G Stancel, G Prins, M Gallo, K Reuhl, S-M Ho, T Brown, J Moore, J Leakey, J Haseman, M Kohn. (2002). Summary of the National Toxicology Program report of the endocrine disruptors low-dose peer review. Environ Hlth Perspect 110(4): 427-431.

Nagel, SC, FS vom Saal, KA Thayer, MG Dhar, M Boechler, WV Welshons. (1997). Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Hlth Perspect 105:70-76.

National Research Council (NRC). (1983). Risk assessment in the federal government: managing the process. Washington, DC: National Academy Press.

Sheehan, DM, E Willingham, D Gaylor, JM Bergeron, J Crews. (1999). No threshold dose for estradiol-induced sex reversal of turtle embryos: how little is too much? Environ Hlth Perspect 107:155-159.

US Environmental Protection Agency (USEPA). (1996). Strategic plan for the Office of Research and Development. Washington, DC, EPA/600R-96-059

vom Saal, FS, BG Timms, MM Montano, P Palanza, KA Thayer, SC Nagel, MD Dhar, VK Ganjam, S Parmigiani, WV Welshons. (1997). Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci, USA 94:2056-2061.

Walker, C, SA Ahmed, T Brown, S-M Ho, L Hodges, G Lucier, J Russo, N Weigel, T Weise, J Vandenbergh. (1999). Species, interindividual, and tissue specificity in endocrine signaling. Environ Hlth Perpsect 107(suppl 4):619-624.

Welshons, WV, KA Thayer, BM Judy, JA Taylor, EM Curran, FS vom Saal. (2003). Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. Environ Hlth Perspect 111(81): 994-1006

MECHANISM OF SUPPORT/FUNDING

It is anticipated that a total of approximately $5 million will be awarded, depending on the availability of funds. EPA anticipates funding approximately seven to eleven grants under this RFA. The allowable level of funding per year will depend upon the degree of complexity of the proposal.

• The projected award per grant, for studies that include mechanistically based model analyses, is up to $200,000 to $250,000/year with a duration of up to 3 years. Requests for amounts in excess of a total of $750,000, including direct and indirect costs, will not be considered.
• The projected award per grant, for studies that do not include mechanistically based model analyses is up to $150,000 to $200,000/year with a duration of up to 3 years, Requests for amounts in excess of a total of $600,000, including direct and indirect costs, will not be considered.

The total project period for an application submitted in response to this RFA may not exceed 3 years.

ELIGIBILITY

Institutions of higher education and not-for-profit institutions located in the U.S., and tribal, state and local governments, are eligible to apply. Universities and educational institutions must be subject to OMB Circular A-21. Profit-making firms are not eligible to receive grants from EPA under this program.

Eligible nonprofit organizations include any organizations that meet the definition of nonprofit in OMB Circular A-122. However, nonprofit organizations described in Section 501(c)(4) of the Internal Revenue Code that engage in lobbying activities as defined in Section 3 of the Lobbying Disclosure Act of 1995 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 principal investigator, but may not direct projects on behalf of the applicant organization or principal investigator. The principal investigator's institution, organization, or governance may provide funds through its grant from EPA to a 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 a grant, and may not receive salaries or in other ways augment their agency's appropriations through grants made by this program. Nonetheless, federal employees may interact with grantees so long as their involvement is not essential to achieving the basic goals of the grant. EPA encourages interaction between its own laboratory scientists and grant principal investigators 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.

The principal investigator’s 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, along with an assurance from the federal agency involved which commits it to supply the specified service.

Potential applicants who are uncertain of their eligibility should contact Tom Barnwell in NCER, phone 202-343-9862, email: barnwell.thomas@epa.gov

COST-SHARING

Institutional cost-sharing is not required.

SUBMITTING AN APPLICATION

Standard Instructions for Submitting an Application

The Standard Instructions for Submitting a STAR Application including the necessary formats will be found on the NCER web site, http://es.epa.gov/ncer/rfa/forms.

Sorting Code

The need for a sorting code to be used in the application and for mailing is described in the Standard Instructions for Submitting a STAR Application. The sorting code for applications submitted in response to this solicitation is 2004-STAR-M1.

APPLICATION PROCESSING AND REVIEW INFORMATION

Applications must be received by the application receipt date listed in this announcement. If an application is received after that date, it will be returned to the applicant without review.

The following is the schedule for this RFA. It should be noted that this schedule may be changed without prior notification due to factors that were not anticipated at the time of announcement. In the case of a change in the required receipt date, the new date will be posted on the NCER website.

Application Receipt Date: June 1, 2004
Earliest Anticipated Start Date: December 1, 2004

The application review process will be found in the Standard Instructions. Consideration of an application’s merit is based on the following criteria: (1) the originality and creativity of the proposed research, the appropriateness and adequacy of the research methods proposed and the quality assurance statement; (2) the qualifications of the principal investigator(s) and other key personnel; (3) the responsiveness of the proposal to the research needs identified for the topic area; (4) the availability and/or adequacy of the facilities and equipment proposed for the project. Although budget information does not indicate an the application’s scientific merit, the reviewers are also asked to provide their view on the appropriateness and/or adequacy of the proposed budget.

CONTACT POINT(S)

Further information, if needed, may be obtained from the EPA officials indicated below. Email inquiries are preferred.

Elaine Francis; Phone: 202-343-9696; email: francis.elaine@epa.gov
Vivian Turner; Phone: 202-343-9697; email: turner.vivian@epa.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Number 66.509.

The authority for this RFA and resulting awards is contained in Safe Drinking Water Act, Section 1442, as amended, Public Law 93- 523, Toxic Substances Control Act, Section 10, as amended 15 U.S.C. 2609; and Federal Insecticide, Fungicide, and Rodenticide Act, Section 20, as amended 7 U.S.C. 136r.

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