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Implications of Linear Low-Dose Extrapolation for Noncancer Risk Assessment

Implications of Linear Low-Dose Extrapolation for Noncancer Risk Assessment. Oliver Kroner, Lynne Haber, Rick Hertzberg TERA. **This case study is a characterization of the method, and is not intended as endorsement or opposition of linear extrapolation.

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Implications of Linear Low-Dose Extrapolation for Noncancer Risk Assessment

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  1. Implications of Linear Low-Dose Extrapolation for Noncancer Risk Assessment Oliver Kroner, Lynne Haber, Rick Hertzberg TERA

  2. **This case study is a characterization of the method, and is not intended as endorsement or opposition of linear extrapolation. Method 1: extend a straight line from the chosen BMDL adjusted to the human equivalent dose or concentration (HED or HEC). Method 2: linearize HED(C) dose-response data using probit transformation in logarithmic space. Fit regression line to the data and extend to the low-dose

  3. Method 1: Linear extrapolation from BMD Response Animal BMD Human Equivalent Dose UFS UFD UFA 0.1 Dose

  4. Results • Strengths: • simplicity • Provides Risk Specific Dose at any level of exposure • Weaknesses: • Risk estimates produced were highly conservative compared to current RfC/RfD methods • No consideration of biological understanding

  5. Panel Comments • Possibly useful for screening level assessment or priority setting, but should not be construed as accurate estimate of risk • Requested exploration of non-cancer linear extrapolation in log-dose, probit space

  6. Probit Transformation • Linearizes biological data • requires quantal population data • To allow graphing in log space, response rates were converted to Excess Risk [added risk(d) = P(d) - P(0)] for each dose group • a dataset of at least three test doses above the control From Casarett & Doull 2009

  7. Method 2: Linear extrapolation in Log-Dose, Probit Space Probit Response Animal Data Human Equivalent Dose 5 UFS UFD UFA Log Dose

  8. Summary of Results

  9. Conclusions • Simple • Provides estimate of risk at any level of exposure But, • Limited Applicability: • Restrictive data requirements permitted the use of four of the 25 chemicals considered • Inconsistent Results: • Risk estimates at the RfD/RfCranged from 1 x 10-12 (1,3-dichloropropene) to 0.5 (nitrobenzene).

  10. Extra Slides

  11. Areas of Uncertainty to Consider in Noncancer Dose Response Assessment Sub-chronic Animal Chronic Human Chronic Animal Response Reproductive UFL UFS 0.1 UFD PBPK UFH UFA Dose

  12. Calculation of Human Equivalence Dose or Concentration • Method 1 Benchmark Dose 95% Lower-bound confidence limit (BMDL) Uncertainty Factors: UFS, UFA, and UFD • Method 2Benchmark Dose (BMD) Uncertainty Factors: UFS, UFA, and UFD • Method 3.Benchmark Dose (BMD) Uncertainty Factors: geometric means of the UFS, UFA, and UFD • Method 4. Benchmark Dose (BMD) Uncertainty Factors: geometric mean of the UFA

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