SOLICITATION NOTICE
R -- State of the Science Report- Low Dose-Response Extrapolation Approaches
- Notice Date
- 8/17/2006
- Notice Type
- Solicitation Notice
- Contracting Office
- Environmental Protection Agency, National Procurement Contract Service Center, 1200 Pennsylvania Avenue, Nw 3803r, Washington, DC 20460
- ZIP Code
- 20460
- Solicitation Number
- RFQ-DC-06-00359
- Response Due
- 9/1/2006
- Archive Date
- 10/1/2006
- Description
- NAICS Code: 541620 NAICS Code: 541610. The U.S. Environmental Protection Agency intends to issue a Firm-Fixed Price Purchase Order using Simplified Acquisition Procedures to the contractor who offers the best value to meet our requirement for a report entitled "State of the Science Report: Low Dose-Response Extrapolation Issues and Approaches. The statement of work is set forth below. Interested parties are advised to visit the following site after 1 September 2006 to obtain a a copy of the RFQ: www.epa.gov/oamhpod1/adm_placement/sapcbd/lowdose.htm This site will contain and constitute our Request for Quotation . Email any questions to U.S. Environmental Protection Agency at dawson.paul@epa.gov. Period of performance: From date of award to March 31, 2008 I. Purpose The purpose of this effort is to create a report entitled "State-of-the-Science: Low Dose-Response Extrapolation: Issues and Approaches". The State-of-the-Science report will summarize the state-of-the-science for low dose-extrapolation, articulate lessons learned from past risk assessment experiences, raise important issues, suggest a framework approaching low-dose extrapolation, and foster discussion in the broad risk assessment community. In particular, the report will seek to foster discussion across sectors of the risk assessment community that currently have limited interaction, e.g. toxics and criteria pollutants. There are seeming inconsistencies within EPA's practices related to estimation of human population risks from environmental exposures. These inconsistencies arise from differences in: conceptualization of issues and approaches regarding low-dose extrapolation. A state-of-the-science report is proposed to evaluate the applicability of lessons learned from the most robust environmental health risk assessments available, to less robust assessments, primarily those that must rely on animal toxicology with limited or no epidemiology data. Specifically, reviews of chemicals/agents such as particulate matter (Samet et al., 2000; EPA, 2004, 2006), environmental tobacco smoke (ETS) (USHHS, 2006) and radiation risk assessments (NRC, 2005) may provide "lessons learned" that could inform other risk assessments. To create this State-of-the-Science report will require multidisciplinary expertise in biostatistics, epidemiology, and mechanisms/mode of action, as well as significant experience with risk assessments and conducting underlying technical analyses for criteria air pollutants, ETS and radiation. Additionally, substantial experience considering analyzing highly technical information in the field of biostatistics and epidemiology, integrating data and information, synthesize findings will be required. Demonstrable substantial skill in building consensus and describing areas of important scientific disagreement among scientific community is also required. II. Background The EPA's new Guideline for Cancer Risk Assessment (2005) raises scientific issues: 1) that have not been previously well address for toxic chemicals in the EPA Integrated Risk Information System (IRIS); 2) continue to be issues of interest in criteria pollutant assessments, ETS and radiation; 3) are relevant to cancer and noncancer effects; and 4) are critical for the Agency's risk assessment work. Low-dose extrapolation issues that must be included, but are not limited to, are: mode of action analyses, human interindividual variability, additivity to existing process, and additivity of background and/or coincident exposures into dose-response assessment. It is the aim of this project to build on the science and past experience with chemicals/agents, such as the criteria air pollutants, ETS and radiation, in order to facilitate the future scientific evaluation of the IRIS chemicals and criteria air pollutants; and raise the level of discourse across different risk assessment communities of practice. The historical backgrounds of chemical risk assessment for cancer and noncancer are somewhat different : Historically, it had been thought that cancer was a fundamentally stochastic process and dose-response were likely to be linear at low doses, while noncancer toxicity was inherently nonlinear, exhibiting a threshold . Thus, one motivation for the development of quantitative cancer risk assessment was a concern that, due to the stochastic nature of the cancer process, even doses of a carcinogen well below the no-observed-adverse-effect level (NOAEL) for tumors in animals could entail an unacceptable risk of cancer to humans. On the basis of this understanding of the carcinogenic process, low-dose risk extrapolation approaches were originally developed for cancer risk assessment (Crump et at., 1976). In contrast, noncancer endpoints have generally been evaluated using a threshold assumption. The origins of this belief are embedded in the early history of toxicology , and the experience of most toxicologist, physicians and individuals with relatively small sample sizes. Additionally, the "thresholds" can depend heavily on the definition of an adverse effect. Among all chemicals in the EPA Integrated Risk Information System database (>500), there are no examples of using a linear low-dose extrapolation for a noncancer endpoint. Rather the standard approach used for noncancer is dividing a NOAEL or lowest observed adverse effect level (LOAEL) by uncertainty factors (to account for uncertainty in extrapolation). Arguments for linear, low dose extrapolation for non cancer endpoint have, however, been made elsewhere (Gaylor, 1989; Lutz et al., 2005; US EPA, 2006). As understanding of both cancer and noncancer effects has advanced, there has been growing recognition that these views are overgeneralizations. Four issues that make low-dose extrapolation complex are discussed below. Mode of Action - The molecular and cellular events that underlie cancer and noncancer toxicity (also termed "mode of action" or "mechanism of action") are likely to be complex phenomena that are a mix of linear and dose-transitional events. A topic of much debate inside and outside EPA is the determination of the linear or nonlinear nature of the events underlying carcinogenicity and toxicity. A common assumption is that if nonlinear or dose-transitional processes can be identified as part of the mode of action that is a sufficient rational for a using a nonlinear population dose-response, with an actual or effective threshold, to estimate population dose-response (US EPA, 2005; Slikker et al., 2004). Biostatistical issues (below) that additionally should be considered in population dose-response assessment have received limited discussion in the "toxics" community. Human Interindividual Variability - Another factor that militates against a simplistic threshold assumption for cancer or noncancer risk assessments is the impact of human interindividual variability on the dose of a chemical that could cause an adverse effect in some portion of a population (Renwick, 1999; Hattis et al. 2002, Gaylor and Kodell, 2002). Thus, in contrast to the historical view, it can be argued that there is no more, or less, justification for the use of low-dose risk extrapolation in the case of cancer risk assessment than noncancer, (Crump et al., 1997) and that low-dose risk extrapolation is as useful, and no less certain, for noncancer risk assessment as for cancer (Hattis et al., 2002). Alternatively, in the "toxic" risk assessment community, an uncertainty factor of 10 generally is incorporated in to the dose-response assessment (lowering the reference value) and is considered sufficient to account for human interindividual variability. It has been suggested that the single most important uncertainty in noncancer risk estimates is the extent of human interindividual variability in the doses of specific chemicals that cause adverse responses. This conclusion is likely to be just as relevant to cancer risk assessment as to noncancer, although population variability has historically received little attention in cancer risk assessment (Clewell and Crump, 2005). Additivity to Existing Process - Careful review of the literature shows that linear low-dose risk extrapolation has also been defended when the effects of a chemical are additive to an existing background process (Crump et al., 1976, Hoel, 1980, Clewell and Crump, 2005). This justification can be applied equally well to the case of a background incidence of noncancer toxicities as it can to a background incidence of cancer. Examples of noncancer effects with an existing background in the general population include cardiovascular events, pulmonary insufficiency, male reproductive deficits, and developmental defects. Many cancers also have a significant background incidence in the general population. Additivity of Dose/Exposure - Additivity of tissue dose for a specific toxic agent - as a result of multiple sources of external exposure and/or metabolic production of the agent from multiple substrates is an important issue for some chemicals. Current examples include chlorinated solvents (e.g., trichloroethylene and perchloroethylene) where different compounds give rise to common metabolites that may contribute to toxicity, such as arsenic where multiple sources of exposure to multiple forms of inorganic and organic arsenicals can result in tissue doses of trivalent methylated metabolites that may be critical to the production of toxic effects (Paul White, personal communication, 2005). III. Scope of Work This scope of purchase order is to produce a report entitled "State-of-the-Science Low Dose-Response Extrapolation: Issues and Approaches" and to hold a 2-day workshop. The contractor shall deliver a written report summarizing the proceedings and the panel's written report reviewing the document. The Contractor shall address in their proposal how secondary data will be considered. Secondary data is defined as data collected for other purposes or from other sources, including literature, industry surveys, compilations from computerized data bases and information systems, results from computerized or mathematical models of environmental processes and conditions. Task 1 - Establish Communications Within one working week of the purchase order award, the Contractor shall convene a conference call with the TPO and appropriate contractor staff to clarify outstanding questions and confirm the schedule, budget and plan for the purchase order. The contractor shall provide weekly status updates to the TPO, either verbally via telephone, or by email. These telephone calls shall not exceed 0.5 hours. The Contractor shall initiate additional communication with the TPO should developments arise that may affect the schedule of this task order or any of the tasks outlined therein. Task 2 - Literature Search and Summary The contractor shall perform a literature (primary or secondary) search on low dose-response extrapolation. The search shall consider, but not be restricted to, the following: (1) Background including history and role of low-dose extrapolation in risk assessment (including criteria pollutants, ETS, radiation and toxics assessments). (2) Key Issues a. Mechanism or mode of action considerations in extrapolation b. Human interindividual variability c. Additivity to Existing Process d. Additivity to Exposure and/or Dose e. Other relevant issues (3) Conceptual and applied approaches to the problem of low dose-response extrapolation that may be useful to chemical risk assessment in general and "toxic" chemicals in particular (4) Tentative identification of 3-5 chemicals that may serve as case-studies The contractor shall summarize the results of the literature search and provide a briefing to the TPO. Task 3 - Report Outline The contractor shall develop and provide a detailed report outline to the TPO. The outline shall address materials (i.e. workshop slides, presentations, discussion summary) developed prior to and during the workshop. Task 4 - First Draft - State of the Science Report Based on the summary results of Task 2 and approved report outline of Task 3, the contractor shall prepare a draft report to include: (1) Summary of literature search (2) Identification of important conceptual problems regarding dose-response relationships for chemical toxicity, low dose-extrapolation and the implications (3) Articulation of a conceptual framework that may facilitate: a more robust conceptualization of the problems, promote consistency in application of approaches, allow for improved description of uncertainties (4) 3-5 case studies (5) Articulate the state-of-the-science: issues and approaches to low dose-response extrapolation, including for chemical with limited or no human data. (6) Conclusion Task 5 - Workshop on State of the Science A. Identify Expert Workshop Participants The Contractor shall identify 12 expert workshop participants drawn from academia, consulting, industry, or state governments. These participants must have expertise in the areas of biostatistics, epidemiology, or toxicology, and knowledgeable about risk assessment practices. Evidence of experience and expertise include professional record as demonstrated by peer reviewed publications, awards, and service to relevant professional societies. The EPA TPO, may supplement the contractor identified participants. The TPO will provide the contractor with a list of additional participants. All experts must be free of vested interest in the outcome of such a workshop and shall have no conflict of interest concerning the subject matter. The contractor shall provide the TPO a list of proposed experts, including evidence of experience and expertise. The TPO will verify technical qualifications of each proposed expert. Upon approval of the TPO, the Contractor shall contact these experts to ensure that they are available to participate in the workshop. The Contractor is responsible for fee, travel accommodation and expense of all non-federal expert participants. The contractor shall not compensate or reimburse Federal personnel. B. Secure Workshop Facilities and Support Equipment The Contractor shall secure workshop facilities and support equipment for a 2 day workshop to be held during April or May 2007. The final date shall be coordinated with the TPO. The facilities shall be in a location convenient to Washington, DC and accessible by public transportation. The workshop shall begin at approximately 9:00 a.m. each day. The room shall accommodate up to 30 participants (a u-shaped table for expert participants, and limited perimeter seating for observers), and required equipment. The Contractor shall arrange for a projector and screen, computer, laser pointer, overhead projector, overhead markers and transparencies, or easel paper and markers. C. Pre-Workshop Support The Contractor shall send letters of invitation to each workshop participant (including any Federal or state experts identified by the EPA TPO), and provide for an attendance confirmation mechanism. The contractor shall send all participants packages that include a proposed agenda, and general information on the workshop. The packages shall also include pre-workshop materials designated by the EPA TPO. The contractor shall instruct the workshop participants to review the workshop material and submit comments prior to date of workshop. Copies of all mailings shall be sent to the Contracting Officer's Representatives (TPO and PO) for review in advance of mailing. The Contractor shall maintain a current address list of all workshop participants (experts and observers). D. On-site Workshop Support The contractor shall chair and facilitate the meeting in conjunction with the TPO, present draft state-of -the-science paper, lead discussion, ensure orderly progress through planned activities, assign tasks, as needed, and summarize the workshop discussions. The contractor will be responsible for recording workshop discussions and maintaining all materials (e.g. workshop slides, presentations, pre-workshop notes, etc.) to facilitate post-workshop activities. Task 6 - Second Draft - State of the Science Report The contractor shall prepare a second draft State of the Science Report utilizing workshop discussion notes and materials. This draft shall incorporate the general discussion of the issues, comments, conclusions, and recommendations. The contractor shall provide the draft report to the TPO and workshop expert participants for comments or corrections. Task 7 - Final State of the Science Report The contractor shall review comments from TPO and workshop participants and prepare a final State of the Science Report. The final report shall be submitted to the TPO (2 copies, and a Word electronic file) within 6 weeks of receipt of comments on the second draft from the TPO and expert workshop participants. The contractor shall prepare the document according to EPA National Center for Environmental Assessment (NCEA) style and format (guidance available from the TPO). Electronic versions shall include all of the document components (i.e., front matter, reference sections, tables, figures, other illustrative materials, appendices, etc.). V. SCHEDULE AND DELIVERABLES Task 1: weekly Task 2: 3 months after award Task 3: 1 week after task 2 is completed Task 4: 1 month after Task 3 is completed Task 5: Workshop to be held 7-8 months after award. Task 6: 2 months after workshop Task 7: 15 months after award. VI. Notice Regarding Guidance Provided Under This Purchase Order Guidance is strictly limited to technical and analytical support. The contractor shall not engage in activities of an inherent governmental nature such as the following: (1) Formulation of Agency Policy (2) Selection of Agency priorities (3) Development of Agency regulations Should the contractor recei
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