Sielken & Associates - Statistical Research and Consulting | Components of High-to-Low-Dose Extrapolation and D

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Monday, September 06, 2010

Components of High-to-Low-Dose Extrapolation and Dose-Response Modeling:

Sielken & Associates has helped develop and has implemented several useful alternatives to many of the regulatory default choices for the following components of high-to-low-dose extrapolation and dose-response modeling. Knowledge of these alternatives and their scientific foundations can lead to fairer and more appropriate risk characterizations.

Biologically Based Models

Physiologically-Based Pharmacokinetic Models

Age-Dependent Doses

Administered Dose and its Time Dependence

Background Dose and its Time Dependence

Distribution of Background Dose Levels

Delivered Dose

Biologically Effective Dose

Experimental Data

Confidence Estimates

Interspecies Extrapolation

Individual Variability

3. Human Health Risk Assessment
3.1      Quantitative Risk Assessment and Statistical Analysis
3.2      Importance of Dose and Dose-Response Relationships
3.3      Misuse of Regulatory Upper-Bound Risk Characterizations
3.4      Risk Characterization Choices and Risk Exaggeration
3.5      A Better Approach to Cancer Risk Characterization
3.6      Overview of Background, Motivation, and Statistical Methods for Margin-of-Exposure Characterizations of Cancer Risks
           3.6.1    Importance of Dose
           3.6.2    Dose-Response Modeling
           3.6.3    Dose-Response Models
           3.6.4    Maximum Likelihood Estimation
           3.6.5    Multistage Model
           3.6.6    Example of Fitted Multistage Model
           3.6.7    Potency
           3.6.8    Linearized Multistage Model
           3.6.9    Overstatement of Risks by the Linearized Multistage Model
           3.6.10  Adverse Impacts of the Variability in the Magnitude of the Bias in the Linearized Multistage Model's Overstatement of Risks
           3.6.11  Non-Responsiveness of the Linearized Multistage Model to Data
           3.6.12  Ranking Relative Risks
           3.6.13  Added Risk versus Extra Risk
           3.6.14  Need for a Better Dose-Response Characterization
           3.6.15  Better Dose-Response Characterization
           3.6.16  Benchmark Doses
           3.6.17  Responsiveness of Benchmark Doses Data Versus the Relative Non-Responsiveness of the Regulatory Upper-Bound Potency Q1* based on the Linearized Multistage Model
           3.6.18  Recommended Dose-Response Characterization
           3.6.19  Margin-of-Exposure Characterizations
           3.6.20  Conclusion
           3.6.21 Figures 1 to 16
3.7      Innovative Risk Assessment
3.8      Components of High-to-Low-Dose Extrapolation and Dose-Response Modeling
3.9      Probabilistic Exposure Assessment
3.10    Aggregate Risk Assessment
3.11    Cumulative Risk Assessment
3.12    Example Activities