ara case study 26 team l h pottenger m m moore e zeiger t zhou
Download
Skip this Video
Download Presentation
ARA Case Study #26 Team: L.H. Pottenger, M.M. Moore, E. Zeiger, T. Zhou

Loading in 2 Seconds...

play fullscreen
1 / 16

Assessment of Low-Dose Dose-Response Relationships Non-linear or Linear for Genotoxicity, Focused on Induction of Mutati - PowerPoint PPT Presentation


  • 137 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Assessment of Low-Dose Dose-Response Relationships Non-linear or Linear for Genotoxicity, Focused on Induction of Mutati' - gunnar


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
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

slide12
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

ad