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This case study explores a framework for evaluating alternative temporal patterns of exposure for risk characterization, addressing differences in human exposure patterns. The aim is to develop a systematic framework for occupational and environmental risk assessment.

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  1. Case-Study #D: Framework for Evaluating Alternative Temporal Patterns of Exposure for Risk CharacterizationPresenter: Lynne Haber Group Members: Lynne Haber, Andy Maier, Ann Parker, Joseph (Kip) Haney, Debra A. Kaden, Lisa Sweeney, 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 • 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. Exposure Toxicokinetic Model Parent Dose: dP/dt Pt = P0(e-kdPt) Damage (Effect) Accumulation Damage (Effect) Repair Dt = D0(e-ket) Residual Tissue Damage • EXCEL model to evaluate kinetic boundaries (cut-points) for various exposure scenarios • Primary purpose - determine if need to evaluate chronic exposure for an episodic exposure scenario. • Assumes acute exposure scenario is always needed • Next step – user friendly interface Metabolite Dose: dM/dt Mt = kdP*P – kdM*M

  4. Assumptions and Limitations • Assumptions • Toxicity is due to the parent chemical • Exposure occurs in a bolus at the start of the exposure period • Limitations • Categorization is based on a single elimination half-life • Analysis does not change with dose levels (metabolic processes are often saturable)

  5. E1 Define Exposure scenario Tc ½ C1 A1 E2 Define daily dose metric for acute effect MOA Does dose clear before the next exposure? Define dose metric (LADD?) for onset of chronic effect MOA A2 Single exposure sufficient to induce acute effect? Dose > aHGV C2 yes yes no cHGV available? A3 Potential for acute health effects* no yes no C3 C6 A4 Compare with other data Chronic Dose > cHGV Does acute effect or precursor accumulate? Te ½ C5 yes no C4 No concern Potential for effect* no yes A6 A5 C7 Evaluate for progression of acute effect with repeated exposure Evaluate for acute effect based on single exposure Does chronic effect accumulate? Te ½ C8 no yes A7 C9 Evaluate potential progression or increased severity with longer duration of exposure at steady state Compare with less-than-chronic data Compare with cHGV *Evaluate using standard risk assessment methods – MOE, etc.

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