AMERICAN CHEMISTRY COUNCIL LONG-RANGE RESEARCH INITIATIVE REQUEST FOR PROPOSALS

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1 AMERICAN CHEMISTRY COUNCIL LONG-RANGE RESEARCH INITIATIVE REQUEST FOR PROPOSALS RfP Title Physiological Parameters and Physiologically Based Pharmacokinetic Modeling for the Perinatal Period RfP Number NT Proposal Due Date August 30, :00 p.m. eastern time INTRODUCTION The American Chemistry Council s (Council) Long-Range Research Initiative (LRI) was created in 1999 to support research to better understand the potential impacts of chemicals on human health, wildlife, and the environment (see for more information). The LRI supports research in various ways, one of the most important of which is through a competitive research project program of which this RfP is a part. One of the priority research areas identified by the LRI concerns the potential effects of exposure to chemicals during fetal life and the early postnatal period (together referred to as the perinatal period). In particular, studies that enhance the relevance, reliability and predictability of test methods, such as the developmental neurotoxicity study and/or the multi-generation reproduction study, are major themes. This specific RfP is intended to encourage research on the development and advancement of physiologically based pharmacokinetic (PBPK) models tailored to the perinatal period, which can help address issues such as study design and extrapolation of results across routes of exposure and between laboratory animals and humans. DESCRIPTION OF RfP Background PBPK computer models simulate the delivered dose of a drug or chemical to various body tissues and fluids under a variety of exposure scenarios. PBPK models are increasingly being incorporated into risk assessments, as they can replace default assumptions with more accurate extrapolations across routes of exposure, across exposure levels, and across species. Most PBPK models have been developed for adults. However, the high level of societal and regulatory concern about children s health, including developmental neurotoxicity, developmental immunotoxicity, and development of the reproductive and endocrine systems, increases the need for PBPK models for the perinatal period. PBPK models can help to deal with some fundamental challenges regarding interspecies extrapolation (namely laboratory animal to human) in the basic biology of pregnancy and postnatal development. For example, laboratory rats are born at a relatively premature stage of development, while in humans, more stages of development occur in utero. Thus, the route by which offspring are exposed during several critical periods of brain development and sexual differentiation varies considerably between rodents (lactational exposure) and humans (placental exposure). PBPK models can help to overcome some of these interspecies extrapolation challenges in the following ways: Page 1 of 6 May 23, 2002

2 Aid in selection of laboratory animal dosing regimens that more realistically model human exposure during appropriate stages of development, Predict the concentration of a chemical in the milk of dams, and Assist in the estimation of dosimetry to critical fetal and neonatal organs (e.g., the developing brain) at various stages of development. PBPK models may also help address exposure route differences. For example, parenteral routes of exposure (i.e., intraperitoneal, subcutaneous) are often used in studies of endocrine-active and neurotoxic chemicals. However, the effects of parenteral injections may be difficult to interpret, as these routes are not reflective of typical human exposures. PBPK models could be used to enhance the relevance of such studies for human risk assessment by estimating dosimetry to fetuses and neonates for various routes of exposure. Perinatal PBPK models build upon a basic adult model framework, but in addition, include dosimetry to the developing embryo, fetus (via placenta) or neonate (via lactation), or even to individual organs within the fetus or neonate. Few developmental PBPK models are currently available, and these vary widely in structure, depending upon the quality and extent of the underlying assumptions in model structures, the sources for biological data, and the methods used to develop and validate the models. A key point is that PBPK models can only be as good as the laboratory data upon which they are supported. PBPK models for the perinatal period rely on laboratory data describing the dynamics of rapid growth (maternal and embryonic), changes in the state of differentiation of developing structures, uniquely expressed or uniquely functioning signal transduction or enzymatic pathways, and modes of distribution (e.g., placental transfer or lactation). The basic physiological parameters needed to generate and refine PBPK models for these life stages are poorly understood, particularly for the developing brain. Therefore, to support the advancement and refinement of perinatal PBPK models, laboratory data on various toxicokinetic and developmental parameters during these life stages in laboratory animals are needed. Such data are intended to provide a foundation upon which to develop and improve computational models for the perinatal period. Research Objectives The objective of this RfP is multidisciplinary and the proposed research should interface the developmental biologist s skills with the expertise of the PBPK modeler (Figure 1). This interface of basic developmental biology and modeling expertise is critical to the advancement of developmental PBPK models, as PBPK models can only be as a good as the biological data upon which they are based. As such, the objective of the research funded under this RfP has two required components: 1) Conduct laboratory investigations that will provide fundamental physiological parameters for normal pregnancy and early postnatal life in the rat (Sprague-Dawley rats are typically recommended for Environmental Protection Agency guideline reproduction studies), and 2) Incorporate these data into an improved PBPK model for the perinatal period. The ideal proposal will involve a high degree of integration between these two components. In fact, the interaction of developmental biology and modeling expertise should be iterative, beginning from initial data gap identification and formulation of experimental approach, continuing to project completion. Scope Page 2 of 6 May 23, 2002

3 The first component of the research funded under this RfP, dealing with physiological and biochemical parameters during the perinatal period (at least covering rat gestation day 15 to lactation day 10), involves the characterization of parameters that can be generically incorporated into PBPK models for the perinatal period. Data of this sort could ultimately add to or refine existing databases of biological parameters that are critical inputs for PBPK models. Examples of the type of data needed to advance perinatal PBPK models include: characterization of physiological changes in the maternal organism through gestation/lactation, and in the neonate to adolescent, such as, regional blood flow, urine clearance rates, adipose tissue volume, active transport proteins, milk production and consumption, protein binding to xenobiotics, etc. (if not already available from the literature). Data are also needed to improve our understanding of the ontogeny of absorption, distribution, metabolism, and excretion (ADME) processes through pregnancy and lactation in general, and of metabolizing enzymes, in particular, which could be studied using prototypical substrates over the course of development in key organ systems (maternal and fetal/neonatal). Another generic issue is localized dosimetry in litter-bearing rats, how such information could be used to address and predict the relative distribution of a test compound in dams (direct exposure), as well as in fetuses (placental exposure) and pups (lactational exposure or direct administration to pups), and how it could be extrapolated to human pregnancy. The second component of the research funded under this RfP is the incorporation of the aforementioned physiological data into perinatal PBPK models. This could be accomplished by replacing default assumptions with laboratory-derived data, and/or by increasing the level of precision in the model. Ideally, the revised models should include the developing nervous system or reproductive system as a fetal/neonatal compartment. As mentioned above, the involvement of the modeling component need not strictly be sequential, but can be more iterative in nature. As physiological data are obtained, the modeler can help focus subsequent research on those parameters that will most effectively improve the ability of perinatal PBPK models to extrapolate across species, route and dose. Ultimately, improved PBPK models will need to be evaluated with test chemicals to determine if computer-derived simulations accurately predict conditions in vivo. However, based on the available research budget for this RfP, it is not clear whether enough funds would be available for formal model evaluation. If such model evaluation is possible (perhaps by accessing pre-existing data or data from related projects), it certainly would be desirable to see it incorporated into the project. This is keeping with the long-range objective of advancing PBPK models for the extrapolation from one developmental stage to another, from one dose to another (high to low dose), and ultimately from animals to humans. For chemicals used in the various components of this RfP, preference will be given to neuroor endocrine-active chemicals. Justification for chemical selection should be provided in the proposal. Consideration should be given to allow for more than one compound in the model (e.g., parent compound and metabolite) and for several routes of administration commonly recommended in EPA guidelines (e.g., diet, gavage). The rationale for the selection of the test doses should be described, including the relationship to likely environmental exposures. Page 3 of 6 May 23, 2002

4 Figure 1 Interaction of Developmental Biologists and Modelers to Advance Perinatal PBPK Devel. Biologist Provide biological/ physiological data to replace model assumptions Modeler Incorporate new data into model Evaluate improved model using test chemicals SPECIAL REQUIREMENTS A goal of the LRI is to share broadly the results of funded projects. Thus, it is expected that results be submitted for publication in peer-reviewed scientific journals and presented at scientific meetings, conferences, and/or symposia. The Council s policy is to support the public release of research findings from the LRI. All proposals should include costs for preparing manuscripts for submission to peerreviewed scientific journals and supplying the Council with five reprints of each journal article. Annual progress reports are required for all funded research projects. Any other reporting requirements will be negotiated as part of the development of the research contract. All proposals should include reasonable and necessary travel and related expenses. Please include in the proposed travel plan at least one trip to the American Chemistry Council in Arlington, Virginia, per year for each year of the contract (except for the first year) for the purpose of presenting research results. Foreign travel costs (defined as any travel outside the country of the Contractor's principal place of business) will require additional approvals. American Chemistry Council member companies have a time-sensitive legal requirement under the Toxic Substances Control Act (TSCA) to report to the U.S. Environmental Protection Agency (EPA) information which reasonably supports the conclusion that a substance or mixture presents a substantial risk of injury to health or the environment (unless the information is already in the public domain). If information you submit results in such TSCA reporting, you shall be informed. The Office of Management and Budget (OMB) has issued rules and guidelines regarding data and information used in regulations, which require that all data developed with federal funding and used in regulations be available to the public upon request. In addition, quality standards apply to information used for these purposes. The application of these guidelines to federally funded research is clear; however, the application to third party supported research (e.g., research sponsored by the American Chemistry Council) has not yet been decided. To help ensure that research pursuant to this Agreement is fully eligible for consideration by the EPA, the Council will require the Contractor to comply with the standards set forth in OMB Circular A-110 (65 Federal Register (March 16, 2000)). In addition, the Council may require the Contractor to abide by additional OMB or other regulatory information guidelines applicable to research data, even though they are Page 4 of 6 May 23, 2002

5 currently undefined. To the extent that this latter requirement imposes additional costs, the budget will be adjusted as mutually agreed to by the parties. ELIGIBILITY Proposals may be submitted by any domestic or foreign for-profit, not-for-profit, or nonprofit organization, public or private, such as universities, colleges, hospitals, laboratories, or units of federal, state, and local governments. FUNDS AVAILABLE/PROJECT DURATION It is anticipated that the award from this solicitation will be a single award, fixed price contract. The total cost for the project has been budgeted up to a maximum of $325,000 per year for three years. The project costs are expected to be commensurate with project scope. Proposals should include funds necessary to complete the full scope and deliverables described earlier, including direct and indirect costs (e.g., direct labor, fringe benefits, materials, subcontracts, purchased parts, shipping, indirect costs and rates, fees, status reports, publications, meeting presentations, travel expenses). Projects are expected to begin immediately upon execution of a contract. The duration of the project is expected to be commensurate with the goals of the project. Three years is expected to be the maximum duration, but longer projects will be considered. PROPOSAL GUIDANCE Proposals must be received by the Council no later than August 30 at 5:00 p.m. eastern time. The Project Plan section must be no longer than 15 pages in length, not including literature cited, attachments, and appendices. All proposals must be prepared using the Proposal Form (Attachment A). Budgets, biographies/curricula vitae for the Principal Investigator and all other key personnel, and other submissions specified in the Proposal Form are not part of the 15 page limit. Ten (10) copies of the proposal should be sent to the following address: Ms. Cheryl Morton Managing Director American Chemistry Council Long-Range Research Initiative Team 1300 Wilson Blvd. Arlington, VA (703) The proposal must be signed by an individual who is authorized to sign on behalf of and bind your organization to the proposed rates (including indirect costs). Incomplete or nonresponsive proposals will be returned to applicants without further review. Proposals that are complete and within the framework of the RfP will be peer-reviewed for scientific merit by independent scientists with expertise appropriate to the subject RfP. The following criteria will be used by peer reviewers to evaluate proposals: Scientific merit and feasibility; Expertise of investigator(s); and Quality Assurance (QA) process and animal care/human subject ethical considerations. Page 5 of 6 May 23, 2002

6 Peer reviewers will also assign each proposal an overall rating of Excellent, Very Good, Good, Satisfactory, or Unsatisfactory. Only proposals that receive an overall rating of Excellent or Very Good by the peer reviewers will be considered for funding. For those proposals receiving an overall peer-reviewer rating of excellent or very good, the following criteria will be applied to the proposals for consideration of funding: Relevance to the chemical industry, as described in the RfP; Proposed milestones/timelines; Appropriateness of the budget/cost-effectiveness; and Use of collaborators/leveraging. AWARD CRITERIA The criteria that will be used in making awards include receipt of a sufficient number of proposals of scientific merit, as determined by peer review; relevance to the chemical industry, as described in the RfP; availability of funds; and LRI program balance. The Council reserves the right to make no awards under this RfP. PROPOSAL REVIEW FEEDBACK PROCEDURES Each applicant will receive a copy of the peer-reviewers comments on the Peer-Review Forms (Attachment B) with the reviewers identifying information deleted and the LRI s evaluation on the Proposal Selection Form (Attachment C). All applicants will receive a letter of notification regarding the award/non-award decision from the Council on approximately December 6, TYPE OF AWARD The form of award under the LRI is a contract between the Council and the research institution. To be effective, the contract must be executed by both the Council and the research institution. INQUIRIES More details about the Long-Range Research Initiative can be found on Questions regarding this RfP should be directed in writing, preferably by to: Ms. Katherine Craig ICF Consulting 9300 Lee Highway Fairfax, VA Telephone: KCraig@icfconsulting.com Page 6 of 6 May 23, 2002