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Exploring Dose-Response Models Using TCDD: A Detailed Case Study Proposal

This case study proposal outlines the exploration of three conceptual models for individual and population dose-response relationships, using 2,3,7,8-tetrachlorodibenzodioxin (TCDD) as a primary example. TCDD is a data-rich compound that enables the thorough investigation of these models. Additionally, the proposal discusses the biological implications of three nuclear receptors (AHR, CAR/PXR, PPARα) in defining modes of action and dose-response for liver tumors in rodent studies. The break-out group aims for a comprehensive link between related proposals, facilitating continued scientific discourse in the upcoming Nuclear Receptor Workshop.

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Exploring Dose-Response Models Using TCDD: A Detailed Case Study Proposal

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  1. Breakout Group C Jennifer Seed (Chairwoman), Allison Jenkins (Rapporteur ), Janet Kester, Daniele Staskal, Gulan Sun, Valerie Meyers (phone), Andy Maier (phone), Bob Budinsky (phone), Ted Simon (phone)

  2. Case Study Proposal #8 • Exploring three conceptual models for individual/population dose response using 2,3,7,8-trachlorodibenzodioxin (TCDD) as an example. TCDD is data-rich and would permit exploration of all three models. • Ted Simon, Bob Budinsky, J. Craig Rowlands • Very well described, draft proposal completed • Existing publication (Simon 2009) and Simon et al. (unpublished)

  3. Case Study Proposal #20 • #20 – Three nuclear receptors, AHR, CAR/PXR and PPARα, will be used as examples for how their biology can be used to define mode of action and dose-response for liver tumors in rodents. • Teams are in the process of developing case studies for September 2010 Nuclear Receptor Workshop • Breakout Group C proposes to link case study proposals #20 (general) and #8 (specific example) • #20 (or similar) will be prepared for September 2010 Nuclear Receptor Workshop.

  4. Case Study Proposals #6, #25 • Screening proposals • Easily Accomplished • Recommend problem formulations are expanded in both case study proposals

  5. Case Study Proposal #15 • Ongoing chromium MOA study to address data gaps in the knowledge of its mode of action. • Data will not be completed by date of 2nd ARA Workshop • Breakout Group C proposes to ‘table’ Proposal #15 for consideration at ARA Workshop 2

  6. Idea for Case Study • DNA damage by intracellularly generated formaldehyde has been proposed as a carcinogenic mode of action for several chemicals (e.g., methanol, MTBE). • Data on formaldehyde-DNA adduct formation can be used to evaluate this hypothesis. • Unknown if sufficient data exist. • Janet Kester is contact person.

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