Biologicallymotivated approaches to extrapolation from high to low doses and the advent of systems b

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Biologically-motivated approaches to
extrapolation from high to low doses and the
advent of systems biology The road to
toxicological safety assessment

• Rory B. Conolly, Sc.D.
• Center for Computational Systems Biology
• Human Health Assessment
• CIIT Centers for Health Research
• rconolly_at_ciit.org
• U.S. EPA Board of Scientific Counselors Risk
  Assessment Workshop, National Academy of Sciences
  Auditorium, Washington, DC, February 2-3, 2005.

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Outline

• Toxicity and dose-response
• Priorities Toxicity or safety?
• Toxicological safety assessment
• Summary and conclusions

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Typical high dose rodent data what do they tell
us?
Response
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Not much!
Response
?
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Possibilities
Response
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Possibilities
Response
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Possibilities
Response
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Possibilities
Response
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Historical perspective

• In the distant past
• (1970s and earlier)
• A level of comfort with the use of high dose data
  to imply human health risk
• Expedient
• Limited knowledge of mechanisms

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Historical perspective (II)

• Then,
• 1970s, Gehring et al.,
• vinyl chloride
• 1980s, Andersen et al.,
• PBPK modeling, styrene, methylene chloride
• U.S. EPA cancer guidelines
• Etc., etc.

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Today

• Widespread recognition that chemical-specific
  high-to-low dose extrapolation may differ from
  default approaches.
• Concern that some high dose mechanisms may not be
  relevant.
• Need to protect the public health.
• Need to avoid unnecessary loss of access to
  useful materials.
• Need to do good science in support of human
  health risk assessment.

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What are our priorities?

• Study of poisons?
• Effects and mechanisms regardless of dose
• Evaluation of chemical safety?
• Dose-response in the region of actual or
  predicted exposure levels.
• Given limited resources, where do we focus our
  efforts?

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Partition the problem into manageable parts
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Is safety assessment a practicable alternative?

• Three key elements
• Exposure
• Need data or predictions
• Biologically-based dosimetry models
• PBPK, CFD
• Systems biology
• Opportunity to understand, at the molecular
  level, the transition from normal biology to
  frank toxicity

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Tissue dosimetry is the front end to a
pharmacodynamic model
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CFD simulation of nasal airflow(Kimbell et. al)
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Systems biology
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Levels of biological organization

• Populations
• Organisms
• Tissues
• Cells
• Organelles
• Molecules

Mechanistic
Descriptive
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Levels of biological organization

• Populations
• Organisms
• Tissues
• Cells
• Organelles
• Molecules

(systems)
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Approach

• Initial pathway identification
• Static map
• Existing data
• New data
• Computational modeling
• Dynamic behavior
• Iterate with data collection

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Data
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Omics

• Genomics
• Proteomics
• Metabonomics
• parts list of the biological machine

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Robots
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ATM curated Pathway from Pathway Assist
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Computational systems biology

• Organize and integrate data
• Study dynamic behavior
• Analysis
• Are model predictions consistent with existing
  data?
• Predictions
• Suggest new experiments
• Ability to predict data before it is collected is
  a good test of the model

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Example

• Skin irritation
• MAPK, IL-1a, and NF-kB computational modules
• High throughput overexpression data to
  characterize IL-1a MAPK interaction with
  respect to NF-kB

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Skin Irritation
Chemical
Dead cells
Epidermis
Tissue damage
(keratinocytes)
Tissue damage
Dermis
Nerve Endings
A cascade of inflammatory responses (cytokines)
(fibroblasts)
Blood vessels

• Study on the dose response of the skin cells to
  inflammatory cytokines contributes to
  quantitative assessment of skin irritation

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Modular Composition of IL-1 Signaling
IL-1
Extracellular
IL-1R
Intracellular
IL-1 specific top module
Secondary messenger
MAPK
Others
Constitutive downstream NF-kB module
NF-kB
IL-6, etc.
Transcriptional factors
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NF-kB Module Simulation

• Parameters from existing NF-kB model (Hoffmann et
  al., 2002) and refined to fit experimental data
  in literature

IkB
_

NF-kB
Concentration (mM)
Time (hrs)
Add constant input signal
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The IBNF-B Signaling Module Temporal Control
and Selective Gene Activation Alexander Hoffmann,
Andre Levchenko, Martin L. Scott, David
Baltimore Science 2981241 1245, 2002
6 hr
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MAPK intracellular signaling cascades
http//www.weizmann.ac.il/Biology/open_day/book/ro
ny_seger.pdf
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MAPK time-course and bifurcation after a short
pulse of PDGF
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IL-1 MAPK crosstalk and NFkB activation
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Gain-of-function screen
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Model prediction
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Normal variation ? frank toxicity

• Populations
• Organisms
• Tissues
• Cells
• Organelles
• Molecules

Functional changes
Structural changes
Changes in network topology
Stable perturbations
Transient perturbations
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Paybacks

• Relevant toxicology
• Better understanding of what we mean by toxic
• Perspective on chemical trespass
• Resources used efficiently
• Science-based dose-response assessment

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Summary

• Toxicity or safety?
• Toxicological safety assessment
• Exposure
• Delivered dose
• Systems biology
• Paybacks

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Acknowledgements

• CIIT Centers for Health Research
• Rusty Thomas
• Maggie Zhao
• Qiang Zhang
• Mel Andersen
• Purdue
• Yanan Zheng
• Wright State University
• Jim McDougal
• Funding
• DOE
• ACC

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End