SOLICITATION NOTICE
A -- Method of Analysis to Perform a Tissue-Based Cumulative Risk Assessment for Mixtures of Chemicals
- Notice Date
- 2/14/2003
- Notice Type
- Solicitation Notice
- Contracting Office
- Environmental Protection Agency, Ord Service Center, 26 West Martin Luther King Drive, Cincinnati, OH 45268
- ZIP Code
- 45268
- Solicitation Number
- RFQ-OH-03-00035
- Archive Date
- 4/3/2003
- Point of Contact
- Point of Contact, Joshua Bowers, Purchasing Agent, Phone (513) 487-2104
- E-Mail Address
-
Email your questions to U.S. Environmental Protection Agency
(bowers.joshua@epa.gov)
- Description
- NAICS Code: 541620 This is a combined synopsis/solicitation prepared in accordance with the format in FAR Subpart 12.6, as supplemented with additional information included in this notice. This announcement constitutes the only solicitation; proposals and quotations are being requested and a written solicitation will not be issued. Solicitation number RFQ-OH-03-00035 is issued as a Request for Quotation/Request for Proposal. The solicitation document and incorporated provisions and clauses are those in effect through Federal Acquisition Circular 01-07. This simplified acquisition is being processed using full and open competition. The NAICS code is 541620. Title: Method of Analysis to Perform a Tissue-Based Cumulative Risk Assessment for Mixtures of Chemicals A. Background: While most human health chemical risk assessments are based on laboratory findings in animals which were exposed only to the chemical of interest (a single-chemical exposure), humans are not so uniquely exposed. Human exposures to chemical mixtures are the norm, in both therapeutic exposures (solvent, diluent, formulating agents, and active ingredients), environmental exposures to pesticides (active pesticide agents, synergists, surfactants), and through the consumption of drinking water (which may contain more than one hundred disinfectant by-products), as well as pesticides and break-down products, and other contaminants of ground- and surface-water sources not fully removed by treatment. Given the differences in exposure scenarios (acute versus chronic, daily versus seasonal, differences in anticipated exposure routes (oral, dermal and inhalation), exposures may vary by several orders of magnitude. Beyond this, differences in chemical-specific metabolism and blood and tissue solubility produce various dosimetries such that organs and tissues realize qualitatively (chemical moieties - parent chemical versus metabolites) and quantitatively different exposure concentrations. These factors are the determinants of pharmacokinetic (PK) differences among and within animal species. Differences in the manifestation of toxicity are also dependent on the molecular attributes of the chemical, which determine the ability of the chemical to interact with bio-molecules like DNA or proteins (enzymes, receptors) in a specific or non-specific manner to produce their effect. The interaction of toxicant with bio-molecule initiates the pharmacodynamic (PD) phase of the response. This is generally referred to as the mechanism or mode of action which indicates the sequence of events leading to toxicity and suggests a specific mathematical model for describing the process. The interaction of these PK and PD factors describes the response. The PK of toxicants has been studied in quantitative detail for a number of years, successfully employing the physiologically-based pharmacokinetic (PBPK) modeling technique. This, and any other (non-physiological) PK approach, requires that toxicity information be complete enough to determine whether the parent chemical or a metabolite is responsible for the toxicity, and that the target organ or tissue be identified. The approach usually follows the collection of chemical specific information on the "in vivo" PK of the compound of interest, and the development of a mathematical description of the tissue compartments, blood flows and tissue partitioning information for the chemical in the same animal as the PK data were collected. The PBPK model is developed by comparing its predictions against the data collected from whole-animal studies. Then, the model is exercised to simulate another exposure scenario for which data are available, but have not previously been utilized to develop the model. If the simulation of "unknown" data by the model represents a good "fit" then the model is considered validated. The model is then scaled to represent the human and model predictions are compared to data determined in the human, if available. Then, the model is utilized to simulate the exposure of interest in the human and concentrations of the toxic chemical moiety are determined in the target tissue of interest (see Clewell et al., 2002). Recent advances in PBPK modeling have demonstrated the ability of the technique to include extrapolations made from data on chemical metabolism and enzyme contents derived from in vitro- human and research animal tissue preparations (Kedderis, 1997; Kedderis and Held, 1996; Lipscomb et al., 1998; Snawder and Lipscomb, 2000), and to adequately simulate the internal concentrations of toxicants following a concomitant exposure to multiple chemicals (Dobrev et al., 2002; Haddad et al., 2002; Yang et al., 1995). This acquisition is in the scientific area of cumulative risk: the risk following the exposure to multiple chemicals via multiple pathways. It is funded from the area of drinking water, and is therefore constrained to address mixtures of drinking water chemicals. However, the approach must be restricted to only the oral pathway; the PBPK model must be described in such detail as to allow for the inclusion of the dermal and inhalation pathways, as well, when supporting data are available. The prime goal of this acquisition is to organize and communicate a method by which to translate external exposure concentrations/durations to tissue concentrations of toxicologically active chemical moieties specifically for the purpose of risk assessment. The method shall specifically address the dose-dependency of chemical toxicity with respect to identifying the critical organ and the possibility that chemical exposures, in a mixture setting, may increase target tissue concentrations to recruit additional organ toxicity. While this acquisition specifies two separate water-relevant chemical mixtures, one of the mixtures will be comprised of methyl-parathion, parathion, chlorpyrifos, fenthion, diazinon, and fenitrothion. The second mixture shall be comprised of four chemicals, and the selection of those chemicals shall be made by and justified by the contractor. B. Purpose: The purpose of this acquisition is to obtain 1) a method or framework consistent with and summarizing US EPA guidance (US EPA, 2000; 2002), to identify relevant mixtures and exposure scenarios for environmental contaminants for humans, an approach to link the exposure information to tissue concentrations of toxic moieties in appropriate target tissues/organs, and to perform a cumulative risk assessment for the mixture based on sound mixtures-toxicity- principles, 2) descriptions of two chemical mixtures (one specified above) to which the method can be applied, and 3) a presentation of findings to the EPA in Cincinnati, Ohio. This work shall address a mixture in which the component chemicals are deemed to act through the same toxic mechanism or mode of action, and a mixture in which the components are deemed not to act through the same mechanism or mode of action. In that respect, the method developed shall go beyond that proposed by US EPA (2002). C. Quality Requirements: This acquisition is to integrate existing data and information on health risk assessment, including pharmacokinetic, metabolic and mechanistic information, to better enable the assessment of the cumulative risk of chemical mixtures. As such, published and peer-reviewed works on these subjects, developed for this purpose will serve as reference material (see reference section for some examples of pertinent literature). If the contractor is aware of other significant and relevant information available in the peer reviewed literature which relates to the cumulative risk of chemical mixtures, then that information shall also be included. The final report from this acquisition shall communicate a logical framework on which to organize and interpret complex data related to the pharmacokinetics, metabolism and mechanism of action of individual components of chemical mixtures. It shall contain a concise approach (specifically including considerations of dose-dependency of toxic mechanism and target organ) to guide the interpretation of mechanistic information such that the appropriate choice of mixtures toxicity models (e.g., dose addition, response addition, etc) can be developed and sufficiently defended. US EPA (2002) has produced significant and thoughtful guidance on the identification of mixture components which act through the same mechanism of action, and the approach to developing a cumulative risk for mixtures of chemicals acting through a common mechanism. However, that guidance does not address metabolic interactions or pharmacokinetic considerations. This acquisition will broaden the existing guidance by developing considerations and an approach to identify the key events in the mechanism of action for chemicals acting through different mechanisms, to identify possible overlap between the mechanisms of chemicals which are dissimilar but which share a common facet of underlying biochemistry or physiology, and to expand the approach to include metabolic and pharmacokinetic information. Specific attention shall be devoted to addressing metabolic interactions by specifying which types of data should be included to identify the enzyme or family of enzymes responsible for metabolism, interdependence of enzymes acting on different components of the chemical mixture on endogenous cofactors which are related, the potential for competition for metabolism by the same enzyme, and the risk-related effects of such metabolic competition including substrate concentrations attained in vivo from experimental exposures of research animals and environmental exposures of humans and consideration of enzyme kinetics. The approach developed shall specify the information required and demonstrate how such information should be used to integrate metabolic interactions in a pharmacokinetic framework. To summarize, the final report shall contain a framework through which to address chemical mixtures' cumulative risk, and clearly demonstrate a step-wise series of considerations aimed at integrating information on mechanism of action, metabolism and pharmacokinetics, culminating with tissue doses of toxicologically-active chemical moieties and choice of mixtures toxicity model (dose-addition, response-addition). It shall include a summarization of key points included in guidance developed by US EPA (2000, 2002) and shall communicate that summarization at a level of detail sufficient for presentation to a toxicologically-oriented audience. The report shall be developed and formatted so that minimal changes are required for publication in the peer-reviewed literature. The evaluation of the two mixtures of chemicals shall be presented as separate sections in the report and shall be organized according to the framework developed. The presentation at EPA in Cincinnati shall be made from Microsoft PowerPoint slide file(s) and shall be made available to the EPA Project Officer at least one week before the presentation so that review and revision (if necessary) can be accomplished. D. Tasks: The contractor shall: 1. Prepare Quality Assurance Project Plan (QAPP). Develop and submit within 15 days after the purchase order award as the first deliverable before the literature search or data compilation work begins. The contractor shall not perform any work under this purchase order until the QAPP is reviewed and approved by the P.O. Address in the QAPP how the contractor is going to consider or evaluate the quality of the secondary data that is to be used to carry out this purchase order. Secondary data is defined as the review or use of someone else's environmental or health data that was developed for purposes different from that covered in this purchase order. This includes data used from citations in the published literature, from hard copies of published reports or from computer data bases (reference http://www.epa.gov/oei). 2. Develop the Approach. Apply this expertise to develop and communicate a sophisticated and scientifically sound approach which may be used to assess the risks of chemical mixtures. The approach shall culminate in the application of physiologically-based pharmacokinetic modeling, and the description of the approach shall specifically address the identification and collection/development of data describing both the passive phenomena involved in pharmacokinetics (blood flow, blood:tissue partitioning, etc.) as well as the biologically active (interdependent) phenomena, such as chemical metabolism. The approach shall contain scientific valid justifications for the collection, interpretation and inclusion of such data. The contractor is not tasked with developing a review of the multiple laboratory approaches (in vitro protocols) to developing such individual data. The approach shall be presented as a series of steps with an adequate description of each and references for each, attesting to the validity of the step. The approach shall begin with the selection of chemicals and exposures and culminate with steps appropriate to guide the integration of PK data and information on the mechanism of toxicity into a scientifically defensible estimate of the risks of the mixture under evaluation. The selection of four chemicals for the second (unspecified) drinking water chemical mixture shall be defended by presenting information sufficient to justify the logical conclusion that the human is simultaneously exposed to the individual chemical components of the mixture. These four chemicals must have either, 1) the same mode/mechanism of action, 2) the same target organ of toxicity at low doses, or 3) have a toxic sequella manifest as the same biological event. The contractor shall present their professional estimation of whether the toxicity (qualitative and quantitative) of the two mixtures (separately) are likely to be based on metabolic interactions among the components of the mixture at biologically plausible human exposure concentrations. Logical assumptions may be included in the estimation, but must be specifically identified. Later (not in this acquisition), an attempt will be made to apply this approach to the chemical mixture identified by the Contractor. While information on tissue partition coefficients is not as limiting in application of PBPK modeling of mixtures as are data on metabolic interactions, the contractor must select components of the mixture so that the mixture represents a group of no more than four chemicals whose metabolism has been studied to some detail previously. Specifically, the information summarized by the Contractor on the components of the four-chemical mixture must include a description of the information available to determine which enzyme family is responsible for it's metabolism and specific information on enzyme specificity and biochemical rate constants available for that chemical. The approach shall be based on a) similarity or dissimilarity of the toxic mechanism or mode of action and target tissue sufficient to ascertain whether the toxicity of the mixture would represent a summation of the individual doses (target tissue concentrations) of mixture components or whether the toxicity of the mixture might best be represented by adding the responses of the individual components based on their unique concentrations in target tissues, b) the grouping of chemicals according to mechanism of action, c) identification of target organs/tissues, d) the identification of toxicologically active chemical moieties, e) application of a mixtures PBPK approach including metabolism kinetic interactions of components, to ascertain target tissue concentrations of toxicologically active chemical species, f) the selection and application of an appropriate mixtures toxicity approach. 3. Identify two relevant chemical mixtures; develop and categorize the information available to enable the application of the approach to the two chemical mixtures. Submit to the EPA Project Officer the two examples of chemical mixtures for evaluation under the proposed approach, defining the composition of each mixture, and providing an environmental and/or occupational exposure-relevant justification for their assessment as chemical mixtures. This justification shall include pertinent information (including previously published pharmacokinetic investigations) for each component of the mixture which can be used to define or justify the choice of mechanism or mode of action, pertinent pharmacokinetic information, pertinent chemical metabolism information, and other information deemed appropriate for the mixture components under evaluation. The justification is not intended to be a summary of all pertinent literature, simply a series of paragraphs presenting the logic flow that resulted in the decision to consider the components and the mixture, highlighting the feasibility of a successful application of the approach, including data availability. 4. Present the approach in professional seminar in Cincinnati, OH. These approach shall be presented in a professional seminar to EPA scientists at the Andrew W. Breidenbach Environmental Research Center, 26 W. Martin Luther King, Cincinnati, Ohio during September, 2003. The Contractor shall make all arrangements for round trip travel, including overnight lodging if necessary. 5. Compile the final report. E. The EPA will: 1. Review draft deliverables and provide comments within 7 days of receipt. 2. Provide the NCEA Instruction Manual for Contractors (dated March 2002). F. Milestones and Deliverables: Submit QA Project Plan (March, 2003) Submit the draft approach (April, 2003) Submit the final approach (July, 2003) Submit the draft information on chemical mixtures and available information (June, 2003) Submit the draft final report (July, 2003) Subm
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