Dosimetry in Risk Assessment and a bit More

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Dosimetry in Risk Assessment and a bit More
Mel Andersen McKim Conference QSAR and Aquatic
Toxicology Risk Assessment June 27-29, 2006
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Outline

• Key components in toxicological evaluations
• Where are we likely to go with PK and PD models
  and how might SAR methods be helpful
• Hand-off to Greg Lien

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Key Ideas in ToxicologyCSU 2000

• Mode of Action - more specifically Chemical Mode
  of Action
• Target Tissue Dosimetry
• Dose-Response/Risk Assessment

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What tools help us evaluate these
relationships? Pharmacokinetic models
calculate the tissue dose of active forms of the
toxic chemical for various doses, dose-routes,
and animal species Pharmacodynamic models
calculate the degree of response for any level of
tissue dose in different species for differing
exposure scenarios
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Physiologically Based Pharmacokinetic (PBPK)
Modeling
Air
Metabolic Constants Tissue Solubility Tissue
Volumes Blood and Air Flows Experimental System
Lung
Body
Tissue Concentration
X
Fat
X
X
X
X
X
X
Liver
X
Model Equations
Time
Define Realistic Model
Make Predictions
Collect Needed Data
Refine Model Structure
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Using PBPK models The Process 1987

• Identify toxic effects in animals and people
• Evaluate available data on mode(s) of action,
  metabolism, chemistry of compound, metabolites
  and related chemicals
• Describe potential mode(s) of action
• Propose relationship between response and tissue
  dose
• Develop a PBPK model to calculate tissue doses
• Estimate tissue dose during toxic exposures with
  PBPK model

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Mode of Action

• As in Clue, i.e., the butler in the pantry
  using the pipe wrench
• The reactive intermediate in the hepatocytes
  creating DNA-adducts
• The estrogenic compound binding the ER in the
  uterus to enhance cell proliferation.

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Extrapolations supported by these models

• High doses to low doses
• Dose route inhalation, oral, dermal
• Among species
• Across classes of chemicals
• Dosing scenarios
• in vitro to in vivo

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(No Transcript)
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McDougal et al., 1986. Toxicol. Appl.
Pharmacol.,85, 286-294.
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Improving Use of Dosimetry for Evaluating Health
Risks-ILSI/HESI
Research ElementsSupporting Health Evaluations
HUMAN BIOMONITORING
TOXICITY TESTING (std animal tstg)
b
a
Quantitative PK Methods
DOSIMETRY
d
c

• in vitro
• MOA STUDIES
• Gene tox
• Animal Alternatives

EPIDEMIOLOGY
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• Coverage of between 700 and 900 papers.
• Volatiles
• Persistent organics
• Drugs
• Inhaled Irritants
• Dioxin-like Compounds
• Metals
• Siloxanes, etc.

Get your copies at Wiley web-site hurry, dont
wait, they are going fast.
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Dosimetry Directions

• Develop parameter data bases for human PBPK
  models including improvements in QSAR approaches
  parameter estimation
• Expand suite of validated human PBPK models for
  biomonitoring research human studies issues
  here
• Extend quantiative approaches (experience) to
  study basic biological processes perturbed by
  chemical exposures

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Exposure----Dose-----Response Circa 1985
UNCERTAINTY
Exposure
Tissue Dose
Biologically Effective Dose
Early Responses
Late Responses
Pathology
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Perturbation of Biological Processes
Exposure Tissue Dose Biological interaction
Systems Inputs
Normal Biological Function
Impaired Function
Adaptation (Complex dose response relationships
thresholds Hormesis)
Disease Morbidity Mortality
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Conceptual model for cellular toxicity
Tissue Phase Reactions Cl2 HOCl
HCl
Ventilation
Dosimetry Inhaled Stressors
Adaptive State
Stressed State
Developed for Diesel Exhaust Particle (DEP)
toxicity referred to as hierarchical oxidative
stress (Andre Nel)
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Mechanistic Dose Response Models and Genomic Data
Dosimetry Inhaled Irritant
(3)
(1)
(2)
Adaptive State
Stressed State

• Use specific in vivo studies to develop a dose
  response model for activation of oxidative stress
  pathway following irritant exposures and
  differentiate dose regions that activate adaptive
  processes from those associated with inflammation
  and apoptosis (high concentrations)

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A model for oxidative stress in Pathway
Assist-automated model building and dose response
HOCl and Nrf2 and Keap-1
Dose-Responses
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Response Models Directions

• Focus on initial cellular responses and evaluate
  dose-response characteristics for these initial
  events mechanistically.for me these models focus
  on the chemical mode of action and accessible
  quantitative biology
• Develop data bases on cell response systems
  including dose response in a manner to enhance
  value for QSAR