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Case-Study #D: Framework for Evaluating Alternative Temporal Patterns of Exposure for Risk Characterization Presenters: Lynne Haber and Joseph “Kip” Haney. Group Members: Andy Maier, Lynne Haber, Joseph (Kip) Haney, Debra A. Kaden, Richard Carrier, Elena Craft, and Rick Hertzberg.

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  1. Case-Study #D: Framework for Evaluating Alternative Temporal Patterns of Exposure for Risk CharacterizationPresenters: Lynne Haber and Joseph “Kip” Haney Group Members: Andy Maier, Lynne Haber, Joseph (Kip) Haney, Debra A. Kaden, Richard Carrier, Elena Craft, and Rick Hertzberg

  2. Problem Formulation • How to address differences between the temporal pattern of human exposure and the pattern of exposure or dose administration used in the study that is the basis for health guideline value. • For example: • Repeated acute exposures • Extrapolation from repeated exposure to single acute exposure • Time-varying exposure pattern with intermittent peaks • Caveat: This is a work in progress. The aim is to forward the development of a systematic framework to address a problem frequently encountered in occupational and environmental risk assessment. More development and decision rules are needed.

  3. Tiered approach • Tier 1: Use simplistic time-averaging techniques for the exposure, the dose-response (e.g., point-of-departure), or both • E.g., Haber’s rule, ten Berge modification • Empirical modeling of concentration versus duration data, categorical regression • Tier III: Uses quantitative adjustment to the exposure or dose-response assessment, or both, most commonly using PBPK models to estimate internal dose that directly reflects the exposure pattern. • Tier II: Uses a combination of qualitative and semi-quantitative data based on the chemical’s toxicokinetic (TK) and toxicodynamic (TD) properties to evaluate the potential for a chemical to cause acute or chronic effects under a given exposure scenario.

  4. E1 Define Exposure scenario Tc1/2 C1 E2 A1 Define dose metric (LADD?) for onset of chronic effect MOA Does dose clear before the next exposure? Define daily dose metric for acute effect MOA A3 Potential for acute effect* A2 C2 Single exposure sufficient to induce acute effect? Dose > aHGV no yes yes cHGV available? yes no no C3 C6 A4 Chronic Dose > cHGV Compare with other data Does acute effect or precursor accumulate? yes no C4 C5 yes Te1/2 no Potential for effect* No concern A6 A5 C7 Evaluate for progression of acute effect with repeated exposure Evaluate for acute effect based on single exposure Does chronic effect accumulate? yes Te1/2 no C8 C9 Evaluate potential progression or increased severity with longer duration of exposure at steady state Compare with less-than-chronic data *Evaluate using std risk assessment methods – MOE, etc.

  5. Application: Benzene exposure • Hypothetical exposure scenario based on repeated exceedances of the 1-hour Texas Commission on Environmental Quality (TCEQ) Reference Exposure Value (ReV) for benzene. • Worse than worst-case data used as hypothetical exposure surrogate data • Application of framework to benzene illustrates consideration of multiple endpoints with different concentration-duration-response relationships, and consideration of MOA and TK in context of the exposure scenario

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