Ara case study 26 team l h pottenger m m moore e zeiger t zhou
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ARA Case Study #26 Team: L.H. Pottenger, M.M. Moore, E. Zeiger, T. Zhou PowerPoint PPT Presentation


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Assessment of Low-Dose Dose-Response Relationships (Non-linear or Linear) for Genotoxicity, Focused on Induction of Mutations & Clastogenic Effects. ARA Case Study #26 Team: L.H. Pottenger, M.M. Moore, E. Zeiger, T. Zhou. Disclaimer: this does not represent the views or policy of US FDA.

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ARA Case Study #26 Team: L.H. Pottenger, M.M. Moore, E. Zeiger, T. Zhou

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Ara case study 26 team l h pottenger m m moore e zeiger t zhou

Assessment of Low-Dose Dose-Response Relationships (Non-linear or Linear) for Genotoxicity, Focused on Induction of Mutations & Clastogenic Effects

ARA Case Study #26

Team:

L.H. Pottenger, M.M. Moore, E. Zeiger, T. Zhou

Disclaimer: this does not represent the views or policy of US FDA

ARA Workshop #2


Case study 26 g m

Case study #26-G/M

  • WHAT: Dose-response for genotoxic effects from DNA-reactive chemicals

  • WHY: Driver for risk assessment

  • HOW: Review published data vs. guidance on recommended data/approaches

  • Conclusions & Issues

ARA Workshop #2


What why low dose dose response for genotoxic effects

WHAT & WHYLow-Dose Dose-Response for Genotoxic Effects

  • Definitions:

    • Low-Dose: Range of human relevance (not MTD)

    • Mutation: Heritable change in genetic information (gene mutation; chromosomal event such as reciprocal translocation)

    • Included clastogenicity (micronucleus) data (not heritable)

    • Non-linear/threshold: Threshold is a subset of non-linear

    • Endogenous/Background for adducts & genotoxic effects

  • Genotoxic effects are a driver for decisions on cancer risk assessment dose-response models (mutagenic MOA)

  • Dose-response of key events is critical input into MOA analysis (mutation is early key event in mutagenic MOA)

  • Shape of dose-response for key events should be empirically defined with chemical-specific data, when available, and supported with hypothesis-driven theory

ARA Workshop #2


How our process

HOW: Our Process

  • Discussed possible criteria

    • Based on

      • Pottenger & Gollapudi, 2010

      • Swenberg et al., 2008

    • Several datasets preferred (different labs is best)

      • Adequate doses, replicates & controls; reproducible results

      • Preferably with dosimetry data

    • Apply dose-response modelling techniques

      • Statistical parameters to determine best fit

  • Selected & assigned candidate chemicals:

    • EO, EMS/ENU, MMS/MNU, Acrylamide/Glycidamide

  • Shared relevant publications

  • Developed chemical-specific appendices

  • Agreed general conclusions

  • Identified issues

ARA Workshop #2


Conceptual key events frameworks

Conceptual Key Events Frameworks

Mutation

Cancer

Pottenger & Gollapudi, 2010

Swenberg et al., 2008

ARA Workshop #2


Conclusions

Conclusions

  • Apparent linearity for biomarkers of exposure (hemoglobin & DNA adducts).

    • EMS(/ENU): Hb [& DNA adducts]

    • MMS(/MNU): DNA adducts based on 13C-MMS

    • EO: inadequate data; not clear if low-dose linear or not (14C-EO AMS data)

  • Clear, statistically supported evidence for low-dose non-linear/threshold dose-response for induction of mutations and clastogenicity for at least some DNA-reactive chemicals.

    • EMS: in vivo & in vitro statistical best fit for non-linear/threshold dose-response model

    • MMS/MNU: in vitro statistical best fit for non-linear/threshold dose-response model

ARA Workshop #2


Ems in vivo dosimetry

EMS in vivo dosimetry

Gocke and Muller, 2009

Apparent linearity for in vivo induction of protein (hemoglobin) [and DNA (N7-ethylG)] adducts by EMS

ARA Workshop #2


Ems in vivo clastogenicity

EMS in vivo clastogenicity

Gocke and Muller, 2009

Clear, statistically supported evidence for best fit of low-dose data on in vivo induction of clastogenicity by EMS to non-linear/threshold dose-response model.

ARA Workshop #2


Ems in vivo clastogenicity dosimetry

EMS in vivo clastogenicity & dosimetry

Gocke and Muller, 2009

Clear, evidence for low-dose non-linear/threshold dose-response for in vivo induction of clastogenicity by EMS, even at doses with increasing internal dose (Hb adducts).

ARA Workshop #2


Ems in vivo mutation

EMS in vivo mutation

Gocke and Muller, 2009

Clear, statistically supported evidence for low-dose non-linear/threshold dose-response for in vivo induction of mutation by EMS.

ARA Workshop #2


Issues

Issues

  • Current effort was a limited analysis of available data (with time & expertise constraints)

  • Develop hypothesis (theoretical underpinnings) to explain a non-linear/threshold dose-response for genotoxicity

  • Only a few examples evaluated statistically supported best fit of dose-response models.

    • Additional evaluation (i.e., statistical approaches to dose-modelling) should be considered

  • Additional examples/datasets are always useful

  • Eventually develop categories based on MOA/key events & hypothesis-driven theoretical understanding of MOA

ARA Workshop #2


Assessment of low dose dose response relationships non linear or linear for genotoxicity focused on induction of mutati

  • Questions?

ARA Workshop #2


Endogenous background dna adducts

Endogenous/Background DNA adducts

J. Swenberg,

personal communication

ARA Workshop #2


Ems in vivo mutation clastogenicity

EMS in vivo mutation & clastogenicity

Gocke and Muller, 2009

Clear, statistically supported evidence for low-dose non-linear/threshold

dose-response for induction of mutation and clastogenicity by EMS.

ARA Workshop #2


Mms and mnu in vitro mutation dosimetry

MMS and MNU in vitro mutation & dosimetry

Pottenger et al., 2009

ARA Workshop #2


Mms in vitro mutation dosimetry

MMS in vitro mutation & dosimetry

Swenberg et al., 2008; Doak et al., 2007

ARA Workshop #2


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