1 Toxicity Pathways to Assessment Endpoints P. Schmieder, S. Bradbury, G. Veith, J. McKim Toxicity Pathway • A concept; a way of depicting a chain of events starting with a molecular initiating event (site of chemical –biological interaction) and ending with an adverse effect manifested in an individual, or higher level – population, community, ecosystem • May include a biochemical/signaling pathway, but goes beyond, to at least hypothesize how something observed at one level of biological organization is linked to response manifested at another level. • Chemical similarity is defined in the context of biological similarity – “Similar” chemicals, by definition, invoke the same toxicity pathway (within a specified biological model) – QSARs are developed for “similar” chemicals from a known or hypothesized “mode/mechanism” of action; hypothesis is tested to refine the models • QSAR requires a well-defined biological system WHAT: WHY:
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1
Toxicity Pathways to Assessment Endpoints
P. Schmieder, S. Bradbury, G. Veith, J. McKim
Toxicity Pathway
• A concept; a way of depicting a chain of events starting with a molecular initiating event (site of chemical –biological interaction) and ending with an adverse effect manifested in an individual, or higher level – population, community, ecosystem
• May include a biochemical/signaling pathway, but goes beyond, to at least hypothesize how something observed at one level of biological organization is linked to response manifested at another level.
• Chemical similarity is defined in the context of biological similarity
– “Similar” chemicals, by definition, invoke the same toxicity pathway (within a specified biological model)
– QSARs are developed for “similar” chemicals from a known or hypothesized “mode/mechanism” of action; hypothesis is tested torefine the models
• QSAR requires a well-defined biological system
WHAT:
WHY:
2
Effects of toxicants occur at different levels of biological
organization. Toxic effects are best known and understood at
the cell and organ level, while the ecosystem and community
level are least understood although most relevant.
(Haux and Forlin, 1988)
Productivity
Energy Flow
Population CellOrganIndividual
Understanding
Relevance
CommunityEcosystem
Contaminant
dynamics in
microcosms
Chronic
toxicity
Reproduction
Growth
Acute toxicity
Lethal
Sublethal
Respiration
Osmoregulation
Structural
changes
Induction
TOXIC
CHEMICAL
Toxicity Pathway Uses
• Assess knowledge gaps - what we know and what we don’t know about a chemical’s toxicity (toxicodynamics)
• Assess the plausibility that a series of events are linked, i.e., degree of connectedness; – degree of specificity/certainty needed depends upon intended use
• prioritization for further testing – correlation; “good” hypothesis?• quantitative RA - confirm cause and effect?
• Pinpoint molecular initiating event for chemical extrapolation– QSAR – can be based on in vivo endpt if system is simple enough,
e.g., fish acute/chronic for narcotic chemicals where applied chem concis directly related to chemical activity in blood and further to the whole organism effect
– Measurements closer to molecular initiating event will be more definitive for QSAR but some degree of relevance should be established (Linkage across levels of biological organization)
• Basis for species extrapolation
• Shifting RA paradigm - predict most likely tox pathways for a chemical to pinpoint most appropriate testing
3
Well-Defined Biological System(Know what you know and what you don’t know)
• Metabolism– Is the system used for collection of empirical data
capable of xenobiotic metabolism?
– Is what you’re measuring due to parent chemical or a metabolite?
• Kinetics– What do you understand about the chemical kinetics
within the system?
– Is the chemical in solution• Bound and unavailable
• Loss to hydrolysis
Measure chemical form and concentration in your system
-2 0 2 4 6-8
-6
-4
-2
0
Log P
Lo
g F
ah
ea
d M
inn
ow
Mo
lar
To
xic
ity (
1/L
C5
0)
4
-2 0 2 4 6 8
Log P
-10
-8
-6
-4
-2
0
Lo
g F
ath
ea
d M
ola
r T
ox
icit
y (
1L
C5
0)
Fathead Minnow Acute Toxicity Database
Narcosis I
Narcosis IINarcosis III
Uncoupler
Sorting Modes of Action
(Toxicity Pathways)
Fish Acute Toxicity Syndromes
- respiratory/cardiovascular responses (RBT)
Behavioral observations (FHM)
Mixture studies (FHM)
5
Nonpolar Narcotic Toxicants
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4 5 6
Log P
Lo
g M
ola
r C
on
ce
ntr
ati
on
LC50-96hr MATC-30 day Water Solubility
Assigning ChemToxicol. Similarity
for QSAR
Xenobiotic
MembranePartitioning
Ion Gradient
Interruption
Failed ATP
Production
-Decreased Respiration
-Decreased Circulation
-Faulty Osmoregulation
Delineating Toxicity Pathways Across Levels of Biological Organization:
Acute Nonpolar Narcosis
Toxicological
Understanding
Risk Assessment
Relevance
In vivo Assays
MOLECULARTARGETS/RESPONSES
TISSUE/ORGAN SYSTEM PHYSIOLOGYINDIVIDUAL
Lethality
6
-2 0 2 4 6 8
Log P
-8
-6
-4
-2
0
2
Log M
ola
r C
oncentr
ation
Water SolubilityLC50-96hrMATC-30 day
LC50-96hr
MATC-30 day
Uncoupling Toxicants
Assigning ChemToxicol. Similarity
for QSAR
Xenobiotic
Chemical
Partitioning
Membrane
Proteins/
Ion Channels
-Increased Respiration
-Increased O2 Consumption
-Decreased O2 Utilization
Delineating Toxicity Pathways Across Levels of Biological Organization:
Acute Uncoupling of Oxidative Phosphorylation
Toxicological
Understanding
Risk Assessment
Relevance
In vivo Assays
MOLECULARTARGETS
TISSUE/ORGAN SYSTEM PHYSIOLOGYINDIVIDUAL
Lethality
7
Reactive Toxicants
-8
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4 5 6
Log P
Lo
g M
ola
r C
on
ce
ntr
ati
on
LC50-96hr MATC-30 day Water Solubility
Sorting Modes of Action
(Toxicity Pathways)
Fish Acute Toxicity Syndromes
- respiratory/cardiovascular responses (RBT)
Behavioral observations (FHM)
Mixture studies (FHM)
Biochemical responses – in vitro
8
Effects of toxicants occur at different levels of biological
organization. Toxic effects are best known and understood at
the cell and organ level, while the ecosystem and community
level are least understood although most relevant.
(Haux and Forlin, 1988)
Productivity
Energy Flow
Population CellOrganIndividual
Understanding
Relevance
CommunityEcosystem
Contaminant
dynamics in
microcosms
Chronic
toxicity
Reproduction
Growth
Acute toxicity
Lethal
Sublethal
Respiration
Osmoregulation
Structural
changes
Induction
TOXIC
CHEMICAL
Assigning ChemToxicol. Similarity
for QSAR
Xenobiotic
Binding to cytoskeletalcomponents
-Redox cycling- SH Arylation
GSH OxidationPrSH OxidationROS Production
Decr. Energy ChgDisrupt Cytoskel.
(MT;IF);Blebbing
Altered Cell SignalingCell Death
Liver Toxicity
Multiple Organ
System
Toxicities/Disease
Defining Toxicity Pathways Across Levels of Biological Organization:
3. Explore Correlations/Pathways to Downstream Effects4. Explore QSARs to Predict Initiating Event from Structure
QSARQSAR Systems Systems
BiologyBiology
Delineation of Toxicity PathwaysDelineation of Toxicity PathwaysLinkages Across Levels of Biological OrganizationLinkages Across Levels of Biological Organization