Case-Studies of Dose-Dependent Transitions in Toxicology by gjy28315

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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.
                 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.
            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.
            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.
Saturable and/or     Examples
Inducible
Kinetic and
Dynamic Stages

Absorption           (via GI tract or respiratory
                     tract – passive vs. active)

Distribution         protein binding, active
                     transporters

Elimination          renal organic anion transport

Chemical
transformation

   activation          butadiene
   detoxification      vinyl chloride,
     enzyme             methylene chloride,
      saturation         vinylidene chloride
     cofactor           (glutathione depletion),
      depletion          ethylene glycol
                         (developmental tox)
Saturable and/or Inducible      Examples
Kinetic and Dynamic
Stages

Receptor interaction               PPAR

   affinity constants,            Progesterone,
    saturation                      hydroxyflutamide


Repair/reversal (DNA repair,    vinyl chloride
receptor activation, protein
synthesis, cell replacement)

Altered homeostasis             propylene oxide, formaldehyde,
(induction, metabolic switch,   vinyl acetate
cell proliferation)             Mn, Zinc
                     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
                  Finite capacity
• Absorption               • Tissue storage
   – Passive (dose-linear)    – Specific binding proteins
                                [fabp, GST, MT]
   – Active                   – Non-specific storage
   – Facilitated                depots [lipid]

                           • Excretion
• Distribution                – Filter
   – Serum binding            – Secrete [organic anions]
   – Tissue transporters
      • Uptake [glycos]    • Metabolic transformation
                             – Activation [P450, MFO]
      • Export [ABC          – Detoxification
        transporters]            [conjugations, esterase]
                              – Cofactor depletion
                                 [conjugate base]
                     Finite capacity

• Dynamic -                      • Target -
   – Receptor                       – Defense
      • Finite number                  • [oxidative stress]
      • association/dissociation    – Repair
      • turnover/reactivation          • [DNA]
   – [OP’s, PPAR, ANS]              – Replacement
                                       • [cell necrosis-
                                         stimulated proliferation]
   Examples/Case Studies

Metabolic activation/detoxification

        [Acetaminophen]
        [Ethylene Glycol]
Acetaminophen Metabolic Disposition
Acetaminophen protein adducts/
 GSH depletion - Time Course




                        (Mitchell et al.)
 Acetaminophen protein adducts/
GSH depletion - Dose-dependence




                        (Mitchell et al.)
APAP Binding = f[GSH]




               (Hinson et al.)
Acetaminophen Metabolic Disposition
 P450-dependent Metabolic
Disposition of Acetaminophen




                        (Mitchell et al.)
Acetaminophen
       Ethylene Glycol

                       (EG)



(GA)


          Rate-limit
EG   GA   Oxal
                 (Marshall, 1982)
        Ethylene Glycol

                   (EG)

 High dose
(GA)




                Low dose
  Examples/Case Studies:
Altered Repair/Replacement


     [Propylene oxide]
Propylene Oxide
                  O
                      CH3
                                                                                     Zn-induced


Risk of Adverse Pregnancy Outcome
                                                 IUGR                                Cu Deficiency

                                        Terata                                                Zn toxicosis




                                                                Normal

                                                               A.E. or Acute Phase

                                                               Hyperzincemia




                                    0            10      20         30         40             50             60
                                                        Dietary Zinc Intake (mg/day)
                     Conclusions/concerns

        % response



                                          Saturation of activation


                            Saturation of detox, defense, repair


                               dose

1. Documentation of dose-dependent transitions
   a. Dictated by saturation of specific kinetic steps
      i. Necessity to identify and characterize mechanisms
                      Conclusions/concerns

         % response



                                           Typical lab animal doses



                             Typical human doses


                                dose

2. Key to applying to safety assessment is where transitions occur
   with respect to expt’l dose and human dose
   a. Explore mechanisms at doses in range of the transitions
                        Conclusions/concerns

           % response




                                    dose
3. 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)
                        Conclusions/concerns

           % response




                                   dose
4. 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?
         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
             Importance/Relevance

 Transitions in the dose-response curve occur
  experimentally for a number of differentially-acting
  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‟.
                       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)
           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
              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
       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.
     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
     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.
             Implementation


 Applying the concept of dose-dependent
  transitions in R/A requires a much better
  understanding of exposure – can’t be
  exclusively hazard-driven.

 Must provide incentives to generate the data
        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.
                  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’.

								
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