Considerations for Improving High to Low Dose Extrapolation

1
Considerations for Improving High to Low Dose
Extrapolation

• Lauren Zeise
• US EPA BOSC presentation
• February 2, 2005

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Considerations for improvements in

• Non-cancer dose response
• Cancer risk assessment
• Modeling and characterization processes

3
Non-cancer dose response characterization issues

• Single number characterizes entire dose response
  relationship
• No risk estimation and low dose prediction
• Threshold dose response nearly always assumed
• Background exposure not typically considered

4
RfD from typical experiment Adjusted NOAEL or
Benchmark Dose
NOAEL
BMD
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Low dose risk estimation Probabilistic RfD
method

• Adjustment uncertainty factors are probability
  distributions
• Human non-cancer dose response is a dose vs. risk
  function
• RfD is dose at a de minimis risk level
• Uncertainty in RfD estimated

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Construction of probabilistic dose response
ED01 Distribution
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US EPA Dioxin Risk Assessment Recognition of
background

• Recognizes background exposures
• Does not establish RfD
• Characterizes the margin of exposure
• exposure inducing 1 risk
• human background exposure level

Nursing Infant
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Background Exposures
Risk
Axis translation
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Non-carcinogenic effects where threshold not
apparent
...recent epidemiological studies ... suggest
that there is no threshold concentration for O3,
Pb, and PM

• Lead
• PM
• Ozone
• Methylmercury
• Arsenic
• Benzene

National Research Council, 2004
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Cancer Dose Response
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Creating tools to translate biological data on
variability into mathematical models of human
cancer risk

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Combining models of human variability and cancer
13
Total risk when agent causes cancer at multiple
sites
Needed Tools to calculate lower bounds on e.g.
ED01 and ED10
Dimethoxybenzidine
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Rodent Bioassays Dosing Periods and Critical
Windows
Standard Assay
conception
birth
3 years
2 years
6 wks
8 wks
15
Tumors of nervous system in rats treated with
N-ethylnitrosourea (ENU) at different ages (Naito
et al., 1981)
Total nerve tumors
Birth
McDonald, 2002
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Background exposures, non-linear carcinogens,
incomplete carcinogens
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Probabilistic RfD compared to EPA standard cancer
assessment

• Non-cancer Prob RfD
• Threshold model
• Individual thresholds vary Variable
  susceptibility addressed
• Background exposures ignored
• Uncertainty expressed as probability distribution

• Cancer
• Non-threshold model
• Variability in susceptibility not addressed
• Assumes background important
• Full uncertainty in estimates typically not
  modeled

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Harmonization of cancer and non-cancer approaches

• Limitations in both approaches
• Expand existing approaches to more optimal
  harmonized approach? Explore new approaches?
• Address background, human variability, and
  uncertainty
• Incorporate qualitative measures of uncertainty
• Some possible critical features chemical
  persistence, subtlety of effect, complexity of
  toxicological process

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Terminology

• Uncertainty Variability
• NOAEL NOEL
• Uncertainty Factor Adjustment Factor
• Non-linear Linear Low dose linear

Supralinear
Sublinear
Low Dose Linear
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Mechanistic models and pharmacokinetic model
adjustments for high to low dose extrapolation
Model series of differential equations
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Developments for pharmaco- kinetic and dynamic
models

• Site specificity assumption
• Model and parameter uncertainty characterization
  (e.g., hierarchical Bayesian approach)
• Statistical evaluation
• Overall model validation
• Expert review

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Risk Management Considerations

• Dose response so that risk characterizations
  adequately inform decision making
• Support routine decision making (e.g.,
  permitting)
• Support decision making broad in scope

National Research Council, 1996