Transcript Pathways in Category Formation - International QSAR Foundation

McKim Workshop on Strategic Approaches for
Reducing Data Redundancy in Cancer Assessment
Duluth, MN, USA
19 May, 2010
Goal & Problem
Categories
Mechanism, Modes, & Pathways
The Example of Skin Sensitization
 Adverse Outcome Pathways
 Critical Events & Integrated Testing Strategy
Summary
To place every discreet organic chemical in to
a category for every hazard endpoint of
interest.
Easy for data-rich acute effects.
Hard for data-sparse chronic effects.
With this in mind the concept of outcome
pathways is proposed.
There is discontinuity between chemical and
biological spaces (substances, which are
“similar” in molecule structure, are often
dissimilar in terms of their toxciity including the
ability to elicit a particular hazard endpoint, as
well as potency within that endpoint).
We often have difficulty in forming
toxicologically meaningful groups, especially for
elaborate hazard endpoints such as cancer.
 Provide a means of evaluating all members for common
toxicological behavior or consistent trends among data for an
endpoint (measured data on a few category members can be
used to estimate the missing values for one or more untested
member).
 Identification of a consistent pattern of toxic effects within a
category increases the confidence in the reliability of the
results for all.
 This is predicated on a priori binning the chemical in the
correct category.
 Category formation is a key topic of predictive toxicology.
The goal is to develop a TMC, which enables a
transparent, defensible assessment through
mechanistic comparisons without further
testing.
This shifts the emphasis to intrinsic chemical
activity and critical biological events and away
from statistical parameters, especially a fixation
on fit and predictivity.
Data for different in vivo endpoints differs so
several ways will be needed to form TMCs.
Are formed as a result of a common 1) chemical
reactivity mechanism, 2) biological mechanism, 3)
mode of toxic action (based on receptor, enzyme or
basic cellular processes), or 4) molecular similarity
When one moves from a common chemical
reactivity-based category to a receptor or common
cellular process-based category and even more so to
molecular similarity-based category confidence in
whether the chemical in question truly belongs to
the category diminishes
Toxicologically related to DNA- and protein-
binding.
Directly applicable to a limited number of
hazard endpoints where the Molecular
Initiating Event (MIE) is the rate limiting
factor in the in vivo effect.
Important but not the total answer to
forming TMCs.
In mammalian pharmacology and toxicology
literature the MechTA denotes the sequence of
events leading from the absorption of an
effective dose of a chemical to the specific
biological response in the target .
 Understanding a chemical’s MechTA requires
understanding the causality and temporal
relationships between the steps to a particular
toxic endpoint, as well as the steps that lead to
an effective dose at the biological target(s).
Meeting this definition of a MechTA requires
an exceptionally large amount of high quality
data, which only can be attained for a very
limited number of compounds.
This is currently out of reach for the vast
majority of industrial organic compounds.
One cannot impose the MechTA criteria to
forming TMCs and expect to make progress in
the near term.
Foundation can be traced to the studies of
McKim et al. (1987) and their fish acute toxicity
syndromes, which are represented by selected
biochemical and/or physiological effects of
exposure selected as key responses measured in
vivo from exposure to model chemicals.
Require less data than MechTA approach.
Successful in forming TMCs for acute aquatic
toxicity.
Designed to describe knowledge concerning
the linkages between chemical structure of
the target compound and the in vivo outcome
of regulatory interest.
The term adverse outcome pathway has been
selected so not to cause confusion with the
term “Toxicity Pathway” (United States
National Research Council in their document
entitled “Toxicity Testing in the Twenty-first
Century: A Vision and a Strategy”, 2007).
Facilitates the use of in silico, in
chemico, and in vitro (cellular, molecular,
and biochemical) endpoints in
forecasting in vivo effects.
Assimilates MIEs with measurements of
key biological process.
1. Haptenation; 2. Epidermal inflammation & LC activation; 3. LC migration; 4.
DC: T cell interaction; 5. T cell proliferation; 6. Increase in hapten-specific T cells;
7. Hapten re-exposure; 8. Acute inflammation; 9. T cell-mediated inflammation
Karlberg et al. Chem. Res.
Toxicol. 2008, 21, 53-69.
Events, which are:
Hypothesized in the pathway.
Essential to the induction of
the adverse outcome.
Measurable
A data generating and data gathering
exercise.
Largely focused on in silico, in chemico, and in
vitro endpoints.
Selected ITS endpoints must have biological
relevance to the hazard endpoint in question,
which is most transparent when linked to an
AOP.
Toxicants electrophile or chemicals converted
to a reactive metabolite.
Molecular site(s) of action are nucleophilic
sites (cysteine and lysine) in proteins.
MIE is covalent (irreversible) perturbation of
dermal proteins.
Biochemical paths are incompletely known,
but includes stimulation of selected cellular
responses (e.g., antioxidant-response
element).
EVENT
Protein binding
MEASUREMENT
in silico predictions from
structure
Chemical reactivity w/ SH
+ for TH1, - for TH2
Chemical reactivity w/ NH2
- for TH1, + for TH2
Keratinocyte stimulation of
Keap1-Nrf2-ARE cellular
Pathway
+ for TH1, - for TH2
Dendritic cell expression of IL4
- for TH1, + for TH2
Dendritic cell expression of IL8
+ for TH1, - for TH2
The sequence of events from chemical
structure through the MIE event to the in vivo
outcome.
Designed to avoid mixing data from multiple
mechanisms, which can cause the same in
vivo outcome.
An organizing principle for hazard
assessment, especially for elaborate
endpoints.
Describes a technique for grouping chemicals
based on both up-stream chemical and downstream biological processes.
Shifts emphasis from just intrinsic chemical
activity to chemical activity plus the cascade
of events that occur across the different levels
of biological organization.
Allows a shift from animal testing to
hypothesis testing.
Provides a basis for chemical extrapolation.
Provides for comparisons across level of
biological organization.
Provides for consideration of life form & life
stage at exposure.
Provides a basis for species extrapolation.
Molecular
Initiating
Event
Toxicant
Macro
-Molecular
Interactions
Chemical
Reactivity
Profiles
Receptor,
DNA,
Protein
Interactions
Biological Responses
Mechanistic
Profiling
Current OECD Toolbox
Molecular
Initiating
Event
Toxicant
Chemical
Reactivity
Profiles
Biological Responses
Macro
-Molecular
Interactions
Receptor,
DNA,
Protein
Interactions
Cellular
Organ
Gene
Activation
Protein
Production
Signal
Alteration
Organism
Population
Lethality
Altered
Function
Altered
Development
Sensitization
Structure
Birth Defect
Extinction
Reproductive
Impairment
Cancer
Mechanistic
Profiling
Cellular &
In Vitro Testing
In Vivo
Testing
ITS and Adverse Outcome Pathway