Full Text ES-97-003 CANCER AND TEFS FOR DIOXIN AND DIOXIN-LIKE CHEMICALS NIH GUIDE, Volume 26, Number 13, April 25, 1997 RFA: ES-97-003 P.T. 34 Keywords: Toxicology Cancer/Carcinogenesis 0705048 National Institute of Environmental Health Sciences Letter of Intent Receipt Date: June 6, 1997 Application Receipt Date: July 9, 1997 PURPOSE Environmental health research carried out by the National Institute of Environmental Health Sciences (NIEHS) provides a solid scientific foundation for understanding interrelationships between the environment, genetics and temporal factors as they relate to human disease and dysfunction. The NIEHS Division of Extramural Research and Training is responsible for developing and directing the investigator-initiated hypothesis-driven mechanistically-based research related to the NIEHS mission. Research conducted by the National Toxicology Program (NTP), centered at the NIEHS, focuses on the evaluation of environmental/industrial agents for their toxic effects using a broad array of test systems and generates data to strengthen the scientific foundations for risk assessment. The goal of this Request for Applications (RFA) is to provide data to aid the NIEHS in defining the mechanisms of action of agents under study by the NTP to improve the risk assessment process, and, thereby, better protect the public health. Therefore, the NTP and the Division of Extramural Research and Training, have designed a program to improve collaboration between government and non-government scientists, thereby providing broad-based input into this process. This program, as outlined in this RFA, utilizes the R03 Small Grants Program to encourage investigator-initiated applications that will utilize animals/tissues/cells or sera from an NTP study involving exposure to dioxin-like chemicals. It is anticipated that this investigator-initiated research will complement the NTP study on dioxin and dioxin-like compounds by providing additional information on their mechanism(s) of action. 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, Cancer and TEFs for Dioxin and Dioxin-like Chemicals is related to the priority area of environmental 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, 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 and organizations are not eligible. Applications from minority individuals and women are encouraged. Submission of an application precludes concurrent submission of a regular research grant application (R01 or R29) containing the same research proposal. In addition, small grant research support may not be used to supplement research projects currently supported by Federal or non-Federal funds or to provide interim support for projects under review by the Public Health Service. MECHANISM OF SUPPORT This RFA will use the NIH Small Grants Program (R03) awards. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The requested costs and project period will be a maximum of $50,000 (direct cost) for a maximum of one year. Small grants are not renewable but may be extended for an additional year with no additional funds at the discretion of the applicant organization. FUNDS AVAILABLE The total estimated funds available for this small grants program is $400,000 which will support approximately six (6) to eight (8) awards. 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 within the financial plans of the NIEHS/NTP, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background The delineation of human cancer risk following exposure to mixtures of chemicals have been difficult to quantify due to the lack of validated models. One methodology used is the Toxic Equivalency Factor (TEFs). The TEF methodology is a relative potency scheme for a strictly defined class of chemicals, namely the 2, 3, 7, 8-chlorine substituted dibenzo-p-dioxin and dibenzofurans. These chemicals are structurally-related and produce the same spectrum of toxic effects in animals. These chemicals bind to the aryl hydrocarbon (Ah) receptor and the subsequent activation of this receptor leads to a cascade of biochemical and toxic effects. There are limited data on the relative carcinogenic potency of almost all of these chemicals since only dioxin and a mixture of hexachlorodibenzo-p-dioxins have been tested. Hence the ability of these relative potency factors to predict the cancer risk of mixtures of these chemicals has been questioned. The TEF methodology does not include the interactions of dioxin-like chemicals with nondioxin-like chemicals. Since human exposures are to mixtures containing both dioxin-like and nondioxin-like chemicals, in order for the TEF methodology to accurately predict the risk of cancer or other endpoints, it must be expanded to include both dioxin-like and nondioxin-like chemicals, singly and in mixtures. Research Goals In order to determine whether the TEFs currently used for dioxin and dioxin-like chemicals are valid for the chemicals tested singly or in mixtures, the NTP proposes to test the following chemicals/mixtures in a two year bioassay: o 2,3,7,8 tetrachlorodibenzo-p-dioxin (cas#74601-6) o 1,2,3,7,8 pentachlorodibenzo-p-dioxin (cas#40321-76-4) o 2,3,4,7,8 pentachlorodibenzofuran (cas#57117-31-4) o 3,31,4,41,5 pentachlorobiphenyl(PCB126) (cas#57465-28-8) o 2,21,4,41,5,51 hexachlorobiphenyl (PCB153)(cas#35065-27-1) Each chemical will be tested individually. A mixture containing all four chemicals and a binary mixture of dioxin and PCB153 will also be tested. The objective of these NTP studies is to test the following hypotheses: o The USEPA interim TEFs for dioxins, dibenzofurans and PCBs can predict the relative carcinogenic potency of single congeners in female Sprague-Dawley rats. o The USEPA interim TEFs for dioxins, dibenzofurans, and planar PCBs can predict the relative carcinogenic potency of an environmentally relevant mixture of these chemicals in the female Sprague-Dawley rat. o The carcinogenicity of a dioxin is not altered by the presence of a nondioxin-like PCB. o The relative potencies for biochemical endpoints, such as CYP1A1 induction, in the two-year studies are equivalent to the relative potency for carcinogenesis when estimated based on administered dose. o The relative carcinogenic potencies of the individual congeners, based on target tissue dose, are the same as the relative potencies based on CYP1A1 induction using the same-target tissues. o The relative carcinogenic/biochemical potencies based on administered dose are the same as those based on tissue dose. o The relative potencies based on serum or whole blood concentrations are equivalent to administered dose and target tissue dose. To aid the NTP in developing the scientific data set necessary to substantiate these hypotheses and to provide additional information on the mechanism of tumor development by these agents or on the sites or mechanisms of additional toxicities of these chemicals/mixtures, the NTP, in coordination with the Division of Extramural Research and Training, proposes to add additional investigator-initiated studies from this RFA to these studies. Projects that will provide additional support for these hypotheses are requested. They include but are not limited to proposals that will: o Establish the relationship between changes in tissue receptor levels for estrogen, epidermal growth factor or glucocorticoids and time, dose, chemical/mixture and TEF of chemicals. o Establish the relationship between measurements of tissue oxidative stress, tissue vitamin A metabolism, liver induction of porphyrins or other aspects of the pleotrophic action of dioxin-like chemicals and time, dose, chemical/mixture and TEF of chemical. o Establish the relationship between changes in the activity of cell cycle regulatory proteins like CDC2 or the protooncogene SRC and time, chemical/mixture and TEF of chemical. o Characterize the immunotoxicity of these chemicals singularly or in mixtures proposed and its relation to time, dose, carcinogenicity and TEF. o Characterize the reproductive, neuro- and other non-cancer organ toxicity of these chemicals/mixtures and their relationship to carcinogenicity and the TEFs. Research proposed needs to be hypothesis driven, mechanistically-based and must be justified as to how the animals from this NTP study are unique in providing tissues needed for the studies proposed and how the studies can be accomplished within the budget and personnel proposed. Study Design Considerations A detailed statement of work, including test doses and tissues that will be analyzed by the NTP as well as special groups of animals available for investigator-initiated studies under this RFA, may be obtained from the NIEHS home page at the following address: http://www.niehs.nih.gov/dert/dioxin.htm The following additional information is intended to complement the information found on the web-site. o Tissues and sera from the "grantee" animals will be shared by those successful applicants to this RFA. Applicants should check with NTP (see inquiries section) for tissue/sera availability before finalizing their proposals and also take into account sharing tissues/sera with the NTP and other investigators. o Investigators must, in their proposal, be specific as to number of animals/tissues/cells/sera needed, preparation of tissues needed, doses needed, shipping requirements and ages (104 weeks or interim). Investigators requiring fresh tissues should fully define the tissue and shipping requirements. Attendance to the necropsy may be impractical depending on the extent of the study proposed. o Since these seven (7) studies will probably start one or more months apart, it will take a minimum of 18 months for the conclusion of the 52-week necropsies. Investigators must state in the application how they will account for this time factor in their study design and explain how they will analyze and control for variability of time (fresh or frozen) of samples, i.e., show a time-line of tissue availability and analysis with proper controls (will samples be collected and analyzed together or monthly?). o Because of the nature of the R03 Program (i.e., two-year maximum time frame; one year grant with one year no-cost extension) it will not be practical to design a study that encompasses the 13, 30, 52 and 104 week necropsies. Thus, investigators should concentrate on the 13, 30 and 52 week times or specify other times points needed. o Proposals need not cover all seven (7) studies or all time points or all dose levels. Investigators should carefully examine the protocol and design a proposal to specifically address a particular question related to the hypothesis being tested using the minimum number of animals, chemicals and necropsy times needed. Investigators are requested to set aside funds for a trip to NIEHS to discuss their results and to be prepared to integrate their results into an NTP final report. Inclusion of data in the NTP final report would not preclude independent publication. The investigator-initiated work may be published independently at the discretion of the investigators. Investigators may also have access to NTP data on, for example, blood, tissue, adipose tissue levels of chemicals which may be needed for analysis and interpretation of their data. SPECIAL REQUIREMENTS LETTER OF INTENT Prospective applicants are asked to submit, by June 6, 1997, 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, 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, MD 17-09 111 T.W. Alexander Drive Research Triangle Park, NC 27709 Telephone: (919) 541-7826 FAX: (919) 541-2503 EMAIL: jackson4@niehs.nih.gov 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: girg@drgpo.drg.nih.gov. THE FOLLOWING ARE SUPPLEMENTAL INSTRUCTIONS: o The application must detail the specific budget categories and percent efforts that will be required. This will be a $50,000 maximum award - direct cost. The budget must be justified. Equipment will be limited to $5,000. o The applicant must be explicit in describing the proposed interface between the NTP study design and the proposed project. o Preliminary data are not required except to indicate the expertise of the Principal Investigator to carry out the proposed studies. o The Research Plan (Specific Aims, Background and Significance, Preliminary Studies, Research Design and Methods sections) is not to exceed Ten (10) pages. Tables and figures are included in the Ten-page limitation. Applications that exceed page limitations or PHS 398 requirements for font size (height or letters), type density (characters per inch), and margins (see PHS 398 directions) will be returned to the investigator. o Do not submit an appendix. The RFA Label available in the PHS 398 (rev. 5/95) 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. 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 be sent to Dr. Ethel Jackson, Chief, Scientific Review Branch (see address below). If these two additional copies are not forwarded to Dr. Jackson, it will adversely affect the review of the grant application. Ethel Jackson, D.D.S. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD 17-09 111 T.W. Alexander Drive Research Triangle Park, NC 27709-2233 Telephone: (919) 541-7846 FAX: (919) 541-2503 EMAIL: jackson4@niehs.nih.gov Applications must be received by July 9, 1997. If an application is received after that date, it will be returned to the applicant without review. 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 preclude 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 and assigned a priority score. Review Criteria The following criteria will be considered: o Hypothesis driven, mechanistically-based nature of the study with justification as to how the animals are unique in providing tissues needed for the proposed studies. o Focus of the study on the relationship among exposure, toxicity endpoint, time and the TEFs of the chemical/mixtures. o Scientific, technical, or medical significance of the proposed research. o Efficiency of study design: Is this the best use of the tissues? o Appropriateness and adequacy of the experimental design and methods proposed to carry out the research; o Innovativeness or promise of the research idea; o Qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o Reasonableness/appropriateness of the requested budget in relation to the proposed research; and o Availability of the investigators resources necessary to perform the research. NOTE: If the project can be completed without the aid of this NTP study, the proposal will not qualify under this RFA. AWARD CRITERIA The anticipated date of award is December 1997 pending availability of funds. 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. Because of the nature of the NTP studies actual funding of these projects may not all be made at the same time. Awards will be made so that the proposed project can be completed within the time frame of the award. INQUIRIES Written, telephone or Email 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: Jerrold J. Heindel, Ph.D. Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD 3-02 111 T.W. Alexander Drive (Fed-x addr) Research Triangle Park, NC 27709-2233 Telephone: (919) 541-0781 FAX: (919) 541-2843 EMAIL: heindelj@niehs.nih.gov Direct inquiries regarding fiscal matters to: Mr. David L. Mineo Chief, Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD 2-01. 111 T.W. Alexander Drive (Fed-x addr) Research Triangle Park, NC 27709-2233 Telephone: (919) 541-7628 FAX: (919) 541-2860 EMAIL: mineo@niehs.nih.gov For clarification of NTP study design or for information on tissue availability contact: John R. Bucher, Ph.D. Environmental Toxicology Program National Institute of Environmental Health Sciences P.O. Box 12233, MD A2-08 111 T.W. Alexander Dr., Bldg. 101, Rm A222 Research Triangle Park, NC 27709-2233 Telephone: (919) 541-4532 FAX: (919) 541-0295 EMAIL: bucher@niehs.nih.gov 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 Public Health Service (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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