Full Text ES-96-003 ENDOCRINE DISRUPTING CHEMICALS AND WOMEN'S HEALTH OUTCOMES NIH GUIDE, Volume 24, Number 38, October 27, 1995 RFA: ES-96-003 P.T. 34 Keywords: Endocrinology Hormones Toxicology Epidemiology National Institute of Environmental Health Sciences Office of Research on Women's Health Letter of Intent Receipt Date: December 1, 1995 Application Receipt Date: January 18, 1996 PURPOSE Research on the health effects of chemicals and other exposures that are suspected to disrupt the normal activity of the endocrine system is a high priority of the National Institute of Environmental Health Sciences (NIEHS) and the Office of Research on Women's Health (ORWH) of the National Institutes of Health. Exposure to these chemicals may have broad based systemic effects and alter reproductive, neurologic, and/or immunologic function and may increase a human risk of hormonal cancers. Accordingly, the goal of this Request for Applications (RFA) is to encourage toxicologic, basic science, and epidemiologic research on the human health effects of exposure to chemicals that mimic, antagonize, or indirectly alter the activity of hormones. Of particular interest are the health effects on women, since these affect both the woman herself and may affect future offspring. Research is encouraged to determine the endocrine affecting potential of a variety of chemicals, understand their biological activity, and understand the biologic consequences of exposure during early development, the reproductive period, and later life. Research on the offspring of women who have been exposed is also needed to understand the transgenerational effects of exposures to environmental chemicals that affect endocrine. The NIEHS is the principal Federal funding agency to support research examining human health consequences of exposure to physical and chemical toxicants in the environment. Research supported by NIEHS spans many disciplines, including toxicology, molecular and cellular biology, epidemiology, and clinical research. The Office of Research on Women's Health (ORWH) of the National Institutes of Health (NIH) supports research on diseases, disorders, and conditions that affect women and ensure that research conducted and supported by NIH adequately addresses issues regarding women's health. Research on environmental influences on women's health has been designated as a priority area of ORWH. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Endocrine Disrupting Chemicals and Women's Health Outcomes, is related to the priority areas of environmental health and women's health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone: (202) 512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01), and FIRST (R29) award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The requested costs and project period for an R01 application submitted in response to the present RFA may not exceed $100,000 (direct costs)/per year; R29 applications must be for five years. FUNDS AVAILABLE The total estimated funds available for the first year of support for the entire program is $1.5 million. All awards will be made directly by NIEHS in conjunction with ORWH sponsorship. The ORWH will contribute funds to NIEHS to co-fund projects. The expected range of number of awards is 8 to 10. The level of support is dependent on the receipt of sufficient number of applications of high scientific merit. Although this program is provided for within the financial plans of the NIEHS and ORWH, awards pursuant to this RFA are continent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Many industrial and environmental chemicals mimic, antagonize, or indirectly alter the activity of hormones, particularly steroid hormones. These chemicals have been classified as "endocrine disruptors" because they may bind to the estrogen and/or other hormone receptors, either imitating the action of the hormone or blocking its activity. These chemicals impact endocrine glands and other target organs that depend on the endocrine system for regulation. Endocrine disruptors that have been identified are commonly found in the environment include a variety of herbicides, fungicides, insecticides, nematocides and industrial chemicals such as dioxin, polychlorinated biphenyls (PCBs), and other chlorinated compounds. Some of these chemicals have been shown to be weakly estrogenic, antiestrogenic, antiandrogenic, or effect thyroid hormone function. Exposure to these compounds prenatally or in early postnatal life can disturb the development of the endocrine system and organs that respond to hormonal signals in animals. Women, who were exposed to these chemicals during early development, neonatally, or later in life may have increased risk of endocrine dysfunction leading to infertility, fibroids, endometriosis, early menopause, osteoporosis, autoimmune diseases, and breast and other cancers. Exposure to exogenous sources of estrogens and other endocrine altering chemicals may also occur during critical biological periods, such as puberty and the childbearing years. Exposures at these times may be related to changes in reproductive capacity and an increase in adverse women's health conditions in later life. Untangling issues related to the timing of exposure are especially important to understand the mechanism of action of these compounds and their cellular effects during critical periods of a female's development. Women may be exposed to exogenous sources of estrogens through the use of pharmaceuticals containing synthetic estrogens, in the workplace, through environmental contamination from industrial or agricultural processes, and dietary exposures from consuming contaminated fish or vegetable sources of phytoestrogens. Organochlorine compounds are ubiquitous in the environment and their biologically persistent nature makes their presence a potential hazard for a long time period. Body stores of compounds such as DDT and dioxins accumulate in adipose tissue, have long biological half lives and may be active in the body for more than 20 years. In the exposed pregnant woman, endocrine disrupting chemicals can be passed through the placenta, exposing the fetus, or may be expressed in human milk through breast feeding, exposing the neonate to significant levels of these chemicals. National surveys of pollutants in human milk document the presence of pesticides and chemicals such as dioxins. Exposures to certain pesticides have been shown to shorten the period a woman is able to lactate. Exposures during critical developmental periods during gestation may affect the development of the nervous, endocrine and immunologic systems in the fetus and may impact on the regulation of various physiologic processes within the neuro endocrine axis. Birth defects such as cleft palate and malformations in genitalia may be more common after exposures during gestation to these agents. Abnormalities of growth and development have been reported in cohorts of children accidentally exposed in utero to endocrine disrupting chemicals in Japan and Taiwan. It is not clear whether these chemicals are exhibiting direct neurotoxic and immunotoxic effects or whether these effects are mediated by alterations in the endocrine system. More research is clearly needed to clarify these pathways. In certain ethnic groups, such as some Native American populations where fish eating predominates, pregnant women consuming contaminated fish have substantial exposures to organochlorine compounds that they pass on to the fetus. It will be important to determine the health status of women and their offspring ingesting these contaminants and to follow up the children for future disease risk. Research Goals The goals and scope of this initiative are twofold. The first is to encourage and support mechanistically based research on the health effects of endocrine disruptor concentrations that are commonly found in the environment. Research would be encouraged to define the action of these chemicals on the reproductive, immune, and nervous systems during critical periods of exposure (in utero, neonatal, pubertal, reproductive aged adult, post menopausal) concentrating primarily on women's health. Experimental work on the cellular, molecular, genetic, and systemic effects of exposures are appropriate. The second area of emphasis is to examine emerging hypotheses in human populations that complement the recent findings in the laboratory and in wildlife. Emphasis should be placed on development and validation of methods to precisely measure these exposures in human populations. For the purpose of this RFA, endocrine disruptors are defined as those chemicals that mimic or antagonize directly or indirectly an endocrine system. Examples include, but are not limited to, estrogenic pesticides, naturally occurring phytoestrogens, and pesticides or industrial chemicals with antiestrogenic or antiandrogenic activity. This RFA is not intended to support research that primarily focuses on the health effects of the use of oral contraceptives or menopausal replacement hormones. Toxicologic testing of endocrine disruptors using bioassays or alternative methods, which are necessary for regulatory purposes, will be considered nonresponsive to this RFA. Research on the role of endocrine disruptors in breast cancer development is also not a focus of research in this RFA. Support for research on breast cancer is being provided under the National Action Plan for Breast Cancer, grants from the Department of Defense and other National Cancer Institute and NIEHS initiatives. Areas of research that are encouraged include, but are not limited to: o Studies of the effects of endocrine disrupting chemicals on the following health endpoints. Health effects pertinent to reproduction would include endocrine dysfunction, infertility, endometriosis, pregnancy outcomes, and lactation. Health effects pertinent to women's health would include fibroids, early menopause, osteoporosis, autoimmune diseases, and gynecologic cancers. Of particular interest are studies that focus on exposures during critical periods of development. The development and validation of biomarkers of endocrine disrupting exposure and early health effects are encouraged. o Research that clarifies the transgenerational effects of in utero and neonatal/early postnatal effects of endocrine disrupting chemicals. This would include the occurrence of birth defects, perturbations of growth and development, precocious puberty in young offspring and functional changes that are detected in later life. SPECIAL REQUIREMENTS Applicants should request funds for one trip in years 1 and 3 to the NIEHS in Research Triangle Park, North Carolina for a program meeting. Animal Welfare Considerations Investigators are encouraged to consider alternative methods and approaches in their research applications that do not require the use of whole animals, that use alternative species such as nonmammals or invertebrates, that reduce the number of animals required, and that incorporate refinements to procedures that will result in the elimination of further minimization of pain and distress to animals. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECT It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103 43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research, which have been published in the Federal Register of March 28, 1994 (FR 58 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by December 1, 1995, a letter of intent that includes a descriptive title of the proposed research, the name, address and telephone number of the Principal Investigator, the identities of other key personnel and consultants, the participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent application, the information that it contains is helpful in planning for the review of applications. It allows NIEHS staff to estimate the potential review work load and to avoid conflict of interest in the review. The letter of intent is to be sent to: Ethel B. Jackson, D.D.S. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 111 T.W. Alexander Drive, Building 17, Room 1716 Research Triangle Park, NC 27709 Telephone: (919) 541 7826 FAX: (919) 541 2503 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3034, MSC 7762, Bethesda, MD 20892 7762, telephone 301/710-0267, Email: [email protected]. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. FIRST award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Submit a signed, typewritten original of the application, including the checklist, and three signed, clear, and single sided photocopies in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to: Ethel Jackson, D.D.S. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 111 T.W. Alexander Drive, Building 17, Room 1716 Research Triangle Park, NC 27709 Applications must be received by January 18, 1996. If an application is received after that date, the DRG may contact the applicant to determine whether it will be returned to the applicant or be reviewed with unsolicited applications for the next regular receipt date. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not include the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIEHS in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria o scientific, technical, or medical significance and originality of proposed research as it relates to contributions to knowledge of health outcomes in women as a result of exposure to environmentally derived endocrine disruptors. o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly but not exclusively in the area of the proposed research; o availability of resources necessary to perform the research; and o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated.\ o appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is June 1996. The following will be considered in making funding decisions: o quality of the proposed project as determined by peer review; o availability of funds; and o program balance among research areas of the announcement. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcomed. Direct inquiries regarding programmatic issues to: For Human Studies: Gwen W. Collman, Ph.D. Chemical Exposures and Molecular Biology Branch National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-4500 FAX: (919) 541-2843 Email: [email protected] For Animal Studies: Jerrold Heindel, Ph.D. Organ and Systems Toxicology Branch National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-0781 FAX: (919) 541-2843 Email: [email protected] Direct inquiries regarding fiscal matters to: Mr. David L. Mineo Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.113 and 93.115. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78 410, as amended by Public Law 99 158, 43 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke free workplace and promote the non use of all tobacco products. In addition, Public Law 103 227, the Pro Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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