Full Text ES-94-004 TIMING OF ENVIRONMENTAL EXPOSURES IN BREAST CANCER NIH GUIDE, Volume 23, Number 1, January 7, 1994 RFA: ES-94-004 P.T. 34 Keywords: 0715036 Environmental Effects National Institute of Environmental Health Sciences Letter of Intent Receipt Date: March 8, 1994 Application Receipt Date: April 8, 1994 PURPOSE Research on environmentally related causes of breast cancer and its prevention is a priority of the National Institute of Environmental Health Sciences (NIEHS). Accordingly, the goal of this Request for Applications (RFA) is to stimulate research on the role of environmental factors in the etiology of breast cancer. Of particular interest are aspects related to the timing of the exposures to harmful environmental agents and the subsequent cellular and genetic changes that may lead to breast cancer. Another equally important area of research is to develop a better understanding of what effects environmental agents have on the normal growth and development of mammary gland tissues. In vitro and in vivo studies that further our understanding of the influence of environmental factors on sex steroid hormones, growth factors, and receptors in cellular and genetic processes are encouraged. Much is still unknown regarding the etiology and underlying mechanisms resulting in breast cancer. The objective of this RFA is to enhance our understanding of environmental influences on cellular, genetic, and hormonal mechanisms that are responsible for normal growth and development of breast tissue and how chemical and physical agents influence that development, which may lead to carcinogenesis. The timing of exposures to those agents with respect to specific windows of susceptibility may be critical for defining risk periods in a woman's lifetime and may provide new insight into breast cancer prevention. 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, Timing of Environmental Exposures in Breast Cancer, is related to the priority areas of environmental health and cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone (202) 783-3238). 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 Awards (FIRST) (R29) awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research 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 total project period for R01 applications submitted in response to the present RFA may not exceed four years; R29 applications must be for five years. This RFA is a one-time solicitation for applications for new awards. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE The estimated funds (total costs) available for the first year of support for the entire program is $1.5 million. The expected range of number of awards is five to six. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIEHS, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Although there is convincing evidence that some environmental and industrial chemicals produce mammary tumors in experimental animals, such evidence is lacking for human breast cancer. Most epidemiologic studies of breast cancer risk have focused on reproductive factors and have found factors such as late age at first birth, early age at menarche, late age at menopause, to be associated with breast cancer risk. Several environmental factors such as ionizing radiation, electromagnetic radiation, exposure to tobacco smoke, alcohol, caffeine, and organochlorine pesticides have been suggested to increase breast cancer risk in human populations. The timing of exposure to these or other environmental agents would also be critical for developing future cancers. Endogenous sex steroid hormones are of primary importance in the growth and development of mammary gland tissue and pertubations in the regulation of these hormones may be related to breast cancer risk. Environmental agents that may influence endogenous levels or activity of steroid hormones have not been carefully studied. It is important to determine if exposure to chemicals or other agents that may act as environmental estrogens influence the endogenous levels or activity of all relevant steroid hormones. Research that explores the biologic mechanism of these environmental effects on cell growth and development, genetic regulation of cellular processes, and hormone synthesis and regulation focusing on the timing of these actions will help to better understand the action of these agents. It is important to identify and understand the critical time periods in life at which environmental agents may effect growth and development of the mammary gland and which may ultimately increase the risk of breast cancer. Critical periods of time in ductal morphogenesis are usually considered to be puberty and pregnancy when rapid cell proliferation and differentiation is occurring. Other critical periods of time should be studied in relation to cancer development and latency. Some evidence does exist that suggests that the timing of exposure to selected environmental agents may play a crucial role in determining whether or not cancer occurs. The increased risk seems to be time dependent in these cases such that exposure to these agents during other time periods does not impart as high a risk of breast cancer. In atomic bomb survivors, early studies indicated an increased risk of breast cancer in those exposed before 20 years of age (Tokunaga et al. 1987). This was also true for women irradiated during childhood for a variety of medical conditions (Hrubec et al. 1989, Hildreth et al. 1989). Radiation exposure to young girls during puberty may be critical due to susceptibility of the rapidly growing breast tissue mediated by vast hormonal changes during this time. Later studies with latency periods of 35 years suggest that the a nine-fold risk of breast cancer is found in the subgroup of women who were newborn to four years of age during exposure (Tokunaga et al. 1987). Cigarette smoking and heavy drinking during the prepubertal time period has also been suggested to be related to developing future breast cancers. Palmer et al. (1991) has shown that the risk ratio for heavy smoking was 1.8 among those who started smoking before 16 years and 2.4 if smoking began before age 14. The risk was attributed to the age when the girls began smoking rather than the duration of smoking, suggesting that there may be critical periods during breast development that are more highly susceptible to carcinogenic insults. The induction of DMBA-induced mammary gland tumors has been shown to be dependent on the age of the experimental animal and the extent of cellular differentiation in the mammary gland during that time (Russo and Russo 1978, Russo et al. 1978). Pregnancy, a period of time of extensive cellular proliferation and differentiation, may also be considered a relevant period of susceptibility for environmentally induced damage to breast tissue. Women taking DES during pregnancy to prevent miscarriages have an increased relative risk of 2.5 of developing breast cancer 30 years after taking the drug (Greenberg et al. 1984). Research goals This research program is designed to stimulate experimental work in three important areas to enhance our understanding of environmental influences on normal breast development and breast cancer. These are to understand the cellular and genetic effects of environmental agents on the normal growth and development of the mammary gland, study the role of environmental factors in the development of breast cancer, and explore the role of timing of these agents during critical developmental periods as it pertains to future risk of abnormal development and carcinogenesis. Research into how exposures during these periods effect the latency of the disease is also desirable. It should be noted that research that explores the cellular, genetic, and hormonal aspects of normal and abnormal breast development, without regard to the role of environmental factors will not be considered responsive to this RFA. Population-based studies on the relationship between environmental factors and breast cancer risk are not included in this RFA. Studies should identify chemical and physical agents that affect normal cell growth and development and may act as initiating or promoting carcinogens. These agents could include, but are not limited to, chemicals such as pesticides or industrial products, environmental estrogens, ionizing and electromagnetic radiation, exposure to contaminated drinking water, indoor and ambient air pollution, tobacco smoke products, caffeine, and alcohol. Interaction of these agents and steroid hormones, such as estrogen, progesterone, and prolactin in the regulation of cellular and genetic mechanisms in mammary glands, should also be explored. Periods of time of interest may include the fetal period, the window from birth to puberty, puberty, the window from puberty to first pregnancy, pregnancy, lactation, surgical and natural menopause, and the postmenopausal period. Cellular processes that may be involved include, but are not limited to, cell proliferation, apoptosis, ovarian and pituitary steroid metabolism and bioavailability, growth factor production and activity, estrogen receptor activity, gene mutation and regulation, ductal morphogenesis and mammary gland cell differentiation. Research is encouraged using animal model systems, human cell lines, and tumor and normal breast tissue samples from animals or humans. SPECIAL REQUIREMENTS Applicant should request funds for one trip annually to the National Institute of Environmental Health Sciences 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. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, general and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. The NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including, but not limited to, clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed and the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applications are asked to submit, by March 8, 1994, 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 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 Research Triangle Park, NC 27709 Telephone: (919) 541-7826 FAX: (919) 541-2503 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. 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 2A of the face page of the application form and the YES box must be marked. FIRST 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, photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** 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 104 T.W. Alexander Drive, Building 17, Room 1716 Research Triangle Park, NC 27709 Telephone: (919) 541-7826 Applications must be received by April 8, 1994. If an application is received after that date, it will be returned to the applicant or will be placed in the pool of applications for the next regular receipt date. The Division of Research Grants (DRG) will not accept any application in response to this announcement 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 preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. The subject of this RFA may overlap interests of other Institutes, Centers and Divisions (ICDs). It should be noted that the National Cancer Institute has an interest in the subject matter of this RFA. Applications will be given an Institute assignment based on current referral guidelines for funding components of PHS. REVIEW CONSIDERATIONS Applications will be administratively reviewed by NIH staff for completeness and responsiveness to this announcement. Applications found to be incomplete or nonresponsive will be returned to the applicant without further consideration. Those applications that are complete and responsive may be subjected to triage to determine their scientific merit relative to other applications received in response to this RFA. The NIEHS will administratively withdraw from competition those applications judged to be noncompetitive and so notify the applicant and institutional official. Those applications judged to be competitive will undergo further scientific merit review. These applications will be evaluated in accordance with the criteria stated in the RFA for scientific/technical merit by an appropriate peer review group convened by the NIEHS. The second level of review will be provided by the National Advisory Environmental Health Sciences Council. Review criteria for this RFA are generally the same as those for unsolicited research grant applications: o scientific, technical, or medical significance and originality of proposed research; 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 appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is September 30, 1994. Applications assigned to ICDs other than NIEHS will compete for available funds with all other approved applications assigned to that ICD. 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 welcome. Direct inquiries regarding programmatic issues to: Gwen W. Collman, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-4980 FAX: (919) 541-2843 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. .
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