Case-Studies of Dose-Dependent Transitions in Toxicology

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Overall Objectives

• Demonstrate the existence of new modalities of
  toxic tissue injury with increasing dose using a
  series of representative case examples.
• Examine the impact of dose-dependent transitions
  on the risk assessment process.
• Provide a forum for multi-sector discussion of
  data needs, experimental design, and principles
  for incorporating dose-dependent transitions into
  risk assessment decisions.

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Challenge

• The shape of the dose-response curve may be
  significantly affected by the existence of
  multiple mechanisms of toxicity. For example,
  critical, limiting steps in any given mechanistic
  pathway may become overwhelmed with increasing
  exposures, signaling the emergence of new
  modalities of toxic tissue injury at higher
  doses.

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Challenge (cont.)

• Chemical-specific case studies show that, as the
  dose of an agent increases, dose-dependent
  transitions such as receptor interactions,
  altered homeostasis, and saturation of
  pharmacokinetic and repair mechanisms can and do
  occur.

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Challenge (cont.)

• Determining which mechanisms are operative
  throughout the dose-response curve and examining
  the impact of these dose-dependent transitions in
  mechanisms of toxicity will have significant
  implications for interpretation of data sets for
  risk assessment.

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Basic Tenet

• The course from the point of exposure to
  expression of a biological response consists of a
  series of interrelated yet independent processes,
  each with its own set of finite kinetic
  characteristics.
• Saturation of any one of these active processes
  alters the course of the toxic response, which
  may be reflected in a deviation from a log-linear
  relationship as one explores the full
  dose-response curve.
• Deviations from linear dose-response
  relationships confound the extrapolation of
  experimental laboratory data to accurately
  predict human health outcomes

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Finite capacity

• Absorption
• Passive (dose-linear)
• Active
• Facilitated
• Distribution
• Serum binding
• Tissue transporters
• Uptake glycos
• Export ABC transporters

• Tissue storage
• Specific binding proteins fabp, GST, MT
• Non-specific storage depots lipid
• Excretion
• Filter
• Secrete organic anions
• Metabolic transformation
• Activation P450, MFO
• Detoxification conjugations, esterase
• Cofactor depletion conjugate base

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Finite capacity

• Dynamic -
• Receptor
• Finite number
• association/dissociation
• turnover/reactivation
• OPs, PPAR, ANS

• Target -
• Defense
• oxidative stress
• Repair
• DNA
• Replacement
• cell necrosis-stimulated proliferation

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Examples/Case Studies

• Metabolic activation/detoxification
• Acetaminophen
• Ethylene Glycol

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Acetaminophen Metabolic Disposition
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Acetaminophen protein adducts/ GSH depletion -
Time Course
(Mitchell et al.)
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Acetaminophen protein adducts/ GSH depletion -
Dose-dependence
(Mitchell et al.)
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APAP Binding fGSH
(Hinson et al.)
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Acetaminophen Metabolic Disposition
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P450-dependent Metabolic Disposition of
Acetaminophen
(Mitchell et al.)
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Acetaminophen
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Ethylene Glycol
(EG)
(GA)
Rate-limit
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EG GA Oxal
(Marshall, 1982)
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Ethylene Glycol
(EG)
(GA)
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Examples/Case StudiesAltered Repair/Replacement

• Propylene oxide

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O
Propylene Oxide
CH3
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Conclusions/concerns

• Documentation of dose-dependent transitions
• Dictated by saturation of specific kinetic steps
• Necessity to identify and characterize
  mechanisms

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Conclusions/concerns

• Key to applying to safety assessment is where
  transitions occur with respect to exptl dose and
  human dose
• Explore mechanisms at doses in range of the
  transitions

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Conclusions/concerns

• Dose extrapolations assume that in the absence of
  evidence to the contrary, similar transitions
  occur across species, gender, age (targets,
  metabolic profile, disposition, receptors,
  defense, repair, cell cycle kinetics)

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Conclusions/concerns

• Now that we recognize the existence of
  dose-dependent transitions in drug-induced
  toxicities, how do we go about applying the
  concept to reducing the uncertainty of safety
  assessment estimates?

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Proposed Definitions

• Transition - a change in the relationship of
  the response rate as a function of dose, which
  may be indicated as a change in the slope of the
  dose-response curve and reflects a change in key
  underlying kinetic and/or dynamic factors that
  influence the mechanism responsible for the
  observed toxicity.
• A transition usually occurs over a range of doses

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Importance/Relevance

• Transitions in the dose-response curve occur
  experimentally for a number of differentially-acti
  ng chemicals and should be factored into the risk
  assessment process to reduce uncertainty
• Risk assessments should be based on the best
  science consideration of dose-dependent
  transitions in the mechanism of toxicity is an
  example of integrating the best science.

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Origins

• Transitions may reflect either kinetic or dynamic
  determinants
• Importance of both PBPK and biologically-based
  modeling
• Identification of key determinant factor
  influencing that transition
• Identification of adaptive/compensatory responses
  in the respective species
• Essential elements (O2, Fe, Cu, Mn, Vit A)

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Importance/Relevance

• Identification of the transition phase in the
  dose-response relationship is critical to the
  effective extrapolation between species, gender,
  age, etc.
• Extrapolation beyond the tested dose-range
• Estimating margins with respect to exposure

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Dose-Selection

• Dose selection should emphasize the transition
  region of the dose-response curve.
• Current testing strategies likely will not
  capture transitions in the dose-response
  relationship.
• Key concern is where within the dose-response
  relationship the transition occurs with regard to
  other points, such as NOAEL

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Mechanism-based Biomarkers

• Characterization of the mechanism of toxicity in
  animals reveals useful biomarkers of response,
  which are essential to anticipating points of
  departure in the dose-response relationship for
  humans.
• Focus on endpoints that are linked to observed
  adverse effect and reliable in humans (bridging
  biomarkers).
• Opportunity to consider human data.

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Mechanism-based Biomarkers

• Assume that more molecular end-points yield a d/r
  curve to the left (more sensitive) of the actual
  whole animal toxic end-point
• A better understanding of molecular mechanisms
  will allow the integration of new approaches such
  as genomics, etc. in the R/A and R/C processes

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Interspecies Concordance

• If a dose-dependent transition is established for
  experimental species, the default assumption is
  that a similar transition occurs in humans.
• Unless there is evidence to the contrary, it is
  assumed that the same mechanisms of toxicity are
  operative in humans as in experimental species.

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Implementation

• Applying the concept of dose-dependent
  transitions in R/A requires a much better
  understanding of exposure cant be exclusively
  hazard-driven.
• Must provide incentives to generate the data

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Achieving Acceptance

• Acceptance is a far greater hurdle than
  conducting the scientific studies
• there is a critical need for communication to
  convince the risk managers of the value for
  change.

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Conclusion

• Risk assessments should be based on the best
  science consideration of dose-dependent
  transitions in the mechanism of toxicity is an
  example of integrating the best science.