Incorporating Biology into the Dose-Response Assessment of Nuclear - - PowerPoint PPT Presentation

Incorporating Biology into the Dose-Response Assessment of Nuclear Receptor Agonists

Created by: Melvin Andersen The Hamner Institute Presented by: Douglas C. Wolf

• U. S. Environmental Protection Agency

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Major Goals of the Nuclear Receptors Workshop

Establish a mode of action (MOA) for NR-mediated rodent liver tumors

• Phenobarbital for CAR/PXR; DEHP (and clofibrate) for PPARα; TCDD

for AHR

• Applied the IPCS Framework for Human Relevance and the modified Hill

Criteria applied to MOA (IPCS and EPA MOA Framework) General Charge Questions

• 1. Is a minimum threshold of ligand necessary for activation to stimulate

downstream responses including gene expression?

• 2. Is a minimum threshold of receptor ligand required for any toxicological

responses?

• 3. Is linear low‐dose modeling of receptor ligands appropriate, based on the

underlying science of nuclear receptor signaling biology, and if not, provide insights into more appropriate low‐dose modeling approaches?

3.) Can human relevance of the MOA be reasonably excluded on the basis of fundamental quantitative differences? Are there any quantitative differences in the key events such that default values for uncertainty factors for species or individual differences could be modified?

Relevant or Unknown Human Relevance Not Relevant in Humans

2.) Can human relevance of the MOA be reasonably excluded on the basis of fundamental qualitative differences? Yes No

Human Relevance Framework

Not Sufficient Sufficient 1.) Is the weight of evidence sufficient to establish the mode of action? Yes No

Boobis et al., 2006

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• Key Event: Empirically observable causal precursor step to the

adverse outcome that is a necessary element of the mode of

• action. Required for the MOA but may not be sufficient to induce the

adverse outcome alone.

• Associative Event: Biological processes that are not causal and

necessary key events but are reliable indicators or markers for key

• events. Can be used as markers for a key event or as indicators of

exposure.

• Modulating Factor: Biological responses that are not necessary to

induce the adverse outcome, but could modulate the dose-response behavior or probability of inducing one or more key events or the adverse outcome.

Using Hill Criteria to Determine Key Events for Mouse Liver Tumor MOA

Quantitative Dose-Response Modeling

Nuclear Receptor Molecular Interactions Transcription and Translation Change in Enzyme Activity

• r Protein Function

Change in Cell, Tissue, or Organ Function

Ligand Binding Partner Protein(s) Co-Regulatory Proteins mRNA (RT-PCR, genomics) Protein Formation Histopathology Clinical Changes CYPs ROS

Dose-Response/Temporality Concordance Table AHR

Table 1: Dose Response, Temporality Concordance

Species Concordance, Human Relevance Table, AHR

Dose-Response/Temporality Concordance Table CAR/PXR

Species Concordance/Human Relevance Table CAR/PXR

Dose-Response/Temporality Concordance Table PPARα

Species Concordance/Human Relevance Table PPARα

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Summary

AHR: The AHR expert panel, for the first time in an expert panel format, rigorously applied the MOA framework and agreed on a mode of action. CAR/PXR: The CAR expert panel identified the relevant data and rigorously applied the MOA and HRF with emphasis on the qualitative and quantitative aspects of human relevance. PPARα: The PPAR α expert panel built upon previous applications of the framework using significant new data that allowed for refinement of the key event descriptions and updated considerations related to human relevance. Each panel identified key data needs and suggested improvements for application of the MOA/HRF. A series of manuscripts will be forthcoming on the results of this workshop.