Purchasing And Contracts Management Branch, Environmental Protection Agency, Fairchild Building -- 7th Floor, 499 S. Capitol Street, S.W. Washington, DC 20024

A -- A STOCHASTIC MODEL OF MULTIPLE PATHWAY CARCINOGENESIS WITH PIECE-WISE CONSTANT PRAMETERS SOL 319026 DUE 041097 POC -- Jacqueline Walters WEB: NOT AVAILABLE, NOT AVAILABLE. E-MAIL: NOT AVAILABLE, chen.chao@epamail.epa.gov or walters.jacqueline@epamail.epa.gov. The EPA is issuing a request for proposal for services to which the Government intends to award a firm fixed price contract using the Simplified Acquisition Procedures of FAR Part 13. The EPA is FACNET certified. Any contractor/vendor able to meet requirements must demonstrate in writing by closing date. All responsible sources solicited may submit a bid, proposal, or quotation, which shall be considered. Interested person may identify their interest and capability to respond for competitive proposals. All proposals received within 15 days after the date of publication of this synopsis will be considered by the Government. Statement of Work Title: A stochastic model of multiple pathway carcinogenesis with piece-wise constant parameters Background and Objectives The National Center of Environmental Assessment -- Washington (NCEA-W) in the Office of Research and Development (ORD) is currently assessing the cancer risk of trichloroethylene (TCE) and its two major metabolites, dichloroacetic acid (DCA) and trichloroacetic acid (TCA). In addition to using the linearized multistage model as a default dose-response model for tumor response, it is also desirable to develop a dose-response model which incorporate available biological mechanisms, and then use the biologically based model to evaluate impact of various mechanistic assumptions on cancer risk assessment. NCEA-W has developed several versions of two-stage models assuming that tumors originates from a normal target cell and then undergo steps of initiation, conversion and progression. However, this class of models appears inadequate for the assessment of DCA because data strongly suggest that CDA-induced carcinomas may involve different mechanisms (i.e. multiple pathways), rather than by a single and identical mechanism as implied by the two-stage models. It has been proposed that hepatocellular carcinomas induced by DCA may involve multiple pathways of carcinogenesis (nesnow and DeAngelo, 1996). There is evidence showing that at leastfive pathways are involved for the dichloroacetic acid (DCA)-induced hepatocellular carcinomas in BC63F1 mice. A carcinoma may be preceded by hyperplastic nodules, adenomas or dysplastic foci (DF). When BC63F1 mice were exposed to DCA, three types of foci are observed: eosinophilic, basophilic (or mixed cell), and dysplastic foci. The eosinophilic foci could lead to adenomas with ras+/- and p21 over-expression, basophilic or mixed cell foci could lead to hyperplastic nodules with ras- and p21 over-expression which in turn could lead to either adenomas or carcinomas with ras- and p21 over-expression, and dysplastic foci could also lead to adenomas or carcinomas. A stochastic model of multiple (5) pathway carcinogenesis has recently been developed by Dr. Chao Chen of NCEA-W (a copy is attached). However, the model is applicable only when values of model parameters could be assumed constant over time (age). To be biologically realistic, the model needs further extension to allow for varying parameters (i.e. piece-wise constant) over time. A high level of mathematical sophistication is required to construct such a model. Task Descriptions The contractor shall develop a stochastic model of the multiple pathway of carcinogenesis with piece-wise constant parameters based on the biological mechanism of carcinogenesis involving the following scenarios: (1) a normal (target) cell (N) that could be transformed into an initiated cell (I1) which grows into a hyperplastic nodule (HN) and then into carcinomas, i.e. N I1(HN) T (CA); (2) an HN that could turn into an adenoma and then becomes a carcinoma, i.e. N I1 (HN) I3 (AD) T; (3) an N cell that could be transformed into an initiated cell (I3) which grows into an adenoma and then becomes a carcinoma, i.e. N I3 (AD) T; (4) an N cell that could become initiated (I2) which grows into a pre-neoplastic focus and then becomes a carcinoma, i.e. N I2 (Foci) T; and (5) an I2 cell than could also convert into an I3 cell, i.e. N I2 (DF) I3 (AD) T. Deliverables: 1. Within 7 calendar days of the award date of this contract: NCAA-W shall hold discussions with contractor via tele-conference on Scope of Work. Specific date depends on award date of this contract. 2. Within 14 calendar days of the contract's award date: Contractor submits a draft of work plan; NCAA-W will comment back to contractor within two working days. 3. Within 21 days of the contract award date: Contractor shall furnish NECA-W with a Work Plan. 4. Within 70 calendar days of the contract's award date: Contractor shall submit a progress report. 5. Within 100 calendar days of the contract's award date: Contractor should submit a draft final report. Ancillary Documents and Reporting Requirements: 1. Contractor shall provide the Project Officer all theorems, proofs, derivation, and any mathematical formulations which are relevant to construction of the stochastic model being developed by this contract. 2. Documentation of results in deliverables # 1 above. The document shall be saved in 3.5 diskettes, using WordPerfect 5.1 or a higher version. The contractor shall submit two hard copies along with computer diskettes. Acceptance Criteria: (1) The mathematical formulation should be able to pass review of journal referee. (2) Technical clarity; detail documentation of mathematical derivation/formulation. The solicitation identifies the office where additional information can be obtained. For additional information you may E-Mail the Project Officer at chen.chao@epamail.epa.gov and cc: walters.jacqueline@epamail.epa.gov. NO PHONE CALLS. Submit two copies of proposal to US EPA, Bid and Proposal Room, 401 M Street, S.W., 3803F, Washington, D.C. 20460, ATTN: Jacqueline Walters. HANDCARRY: US EPA, Bid and Proposal Room 300, 499 South Capitol Street, S.W., Washington, D.C. 20024. The EPA is issuing a request for proposal for services to which the Government intends to award a firm fixed price contract using the Simplified Acquisition Procedures of FAR Part 13. The EPA is FACNET certified. Any contractor/vendor able to meet requirements must demonstrate in writing by closing date. All responsible sources solicited may submit a bid, proposal, or quotation, which shall be considered. Interested person may identify their interest and capability to respond for competitive proposals. All proposals received within 15 days after the date of publication of this synopsis will be considered by the Government. Statement of Work Title: A stochastic model of multiple pathway carcinogenesis with piece-wise constant parameters Background and Objectives The National Center of Environmental Assessment -- Washington (NCEA-W) in the Office of Research and Development (ORD) is currently assessing the cancer risk of trichloroethylene (TCE) and its two major metabolites, dichloroacetic acid (DCA) and trichloroacetic acid (TCA). In addition to using the linearized multistage model as a default dose-response model for tumor response, it is also desirable to develop a dose-response model which incorporate available biological mechanisms, and then use the biologically based model to evaluate impact of various mechanistic assumptions on cancer risk assessment. NCEA-W has developed several versions of two-stage models assuming that tumors originates from a normal target cell and then undergo steps of initiation, conversion and progression. However, this class of models appears inadequate for the assessment of DCA because data strongly suggest that CDA-induced carcinomas may involve different mechanisms (i.e. multiple pathways), rather than by a single and identical mechanism as implied by the two-stage models. It has been proposed that hepatocellular carcinomas induced by DCA may involve multiple pathways of carcinogenesis (nesnow and DeAngelo, 1996). There is evidence showing that at least five pathways are involved for the dichloroacetic acid (DCA)-induced hepatocellular carcinomas in BC63F1 mice. A carcinoma may be preceded by hyperplastic nodules, adenomas or dysplastic foci (DF). When BC63F1 mice were exposed to DCA, three types of foci are observed: eosinophilic, basophilic (or mixed cell), and dysplastic foci. The eosinophilic foci could lead to adenomas with ras+/- and p21 over-expression, basophilic or mixed cell foci could lead to hyperplastic nodules with ras- and p21 over-expression which in turn could lead to either adenomas or carcinomas with ras- and p21 over-expression, and dysplastic foci could also lead to adenomas or carcinomas. A stochastic model of multiple (5) pathway carcinogenesis has recently been developed by Dr. Chao Chen of NCEA-W (a copy is attached). However, the model is applicable only when values of model parameters could be assumed constant over time (age). To be biologically realistic, the model needs further extension to allow for varying parameters (i.e. piece-wise constant) over time. A high level of mathematical sophistication is required to construct such a model. Task Descriptions The contractor shall develop a stochastic model of the multiple pathway of carcinogenesis with piece-wise constant parameters based on the biological mechanism of carcinogenesis involving the following scenarios: (1) a normal (target) cell (N) that could be transformed into an initiated cell (I1) which grows into a hyperplastic nodule (HN) and then into carcinomas, i.e. N I1(HN) T (CA); (2) an HN that could turn into an adenoma and then becomes a carcinoma, i.e. N I1 (HN) I3 (AD) T; (3) an N cell that could be transformed into an initiated cell (I3) which grows into an adenoma and then becomes a carcinoma, i.e. N I3 (AD) T; (4) an N cell that could become initiated (I2) which grows into a pre-neoplastic focus and then becomes a carcinoma, i.e. N I2 (Foci) T; and (5) an I2 cell than could also convert into an I3 cell, i.e. N I2 (DF) I3 (AD) T. Deliverables: 1. Within 7 calendar days of the award date of this contract: NCAA-W shall hold discussions with contractor via tele-conference on Scope of Work. Specific date depends on award date of this contract. 2. Within 14 calendar days of the contract's award date: Contractor submits a draft of work plan; NCAA-W will comment back to contractor within two working days. 3. Within 21 days of the contract award date: Contractor shall furnish NECA-W with a Work Plan. 4. Within 70 calendar days of the contract's award date: Contractor shall submit a progress report. 5. Within 100 calendar days of the contract's award date: Contractor should submit a draft final report. 6. The contractor shall submit the Final Report on or before February 28, 1997. Ancillary Documents and Reporting Requirements: 1. Contractor shall provide the Project Officer all theorems, proofs, derivation, and any mathematical formulations which are relevant to construction of the stochastic model being developed by this contract. 2. Documentation of results in deliverables # 1 above. The document shall be saved in 3.5 diskettes, using WordPerfect 5.1 or a higher version. The contractor shall submit two hard copies along with computer diskettes. Acceptance Criteria: (1) The mathematical formulation should be able to pass review of journal referee. (2) Technical clarity; detail documentation of mathematical derivation/formulation. The solicitation identifies the office where additional information can be obtained. For additional information you may E-Mail the Project Officer at chen.chao@epamail.epa.gov and cc: walters.jacqueline@epamail.epa.gov. NO PHONE CALLS. Submit two copies of proposal to US EPA, Bid and Proposal Room, 401 M Street, S.W., 3803F, Washington, D.C. 20460, ATTN: Jacqueline Walters. HANDCARRY: US EPA, Bid and Proposal Room 300, 499 South Capitol Street, S.W., Washington, D.C. 20024. (0079)

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