Perspective on next steps for
application in practice
Alan R Boobis
Imperial College London
[email protected]
NC3Rs: Pathway-based approaches
across the biosciences
London
28th April, 2016
AOPs

An AOP is a sequence of events from the
exposure of an individual or population to a
chemical substance through a final adverse
(toxic) effect at the individual level (for human
health) or population level (for ecotoxicological
endpoints). The key events in an AOP should
be definable and make sense from a
physiological and biochemical perspective.
AOPs incorporate the toxicity pathway and
mode of action for an adverse effect.
AOP/MOA
Organ Effects
Molecular Initiating
Event
Exposure
Population
Cellular Effects
Individual
(Adverse Outcome)
ADME/TK
Adverse Outcome Pathway
Mode of Action
Key events (based on Bradford Hill considerations)
Level of confidence
Problem formulation
Qualitative
Product development


Prioritisation for risk management action




Quantitative
Indication of worst case effects for emergencies, etc, e.g.
during transport
Read across
Safety assessment


Ranking by potency
Grouping, for cumulative risk assessment
Classification and labelling


Screening to ‘de-risk’ compounds for further
development
e.g. Health-based guidance values
As part of risk assessment of compounds to which
people will be exposed, e.g. occupationally
Cost of false positive

Hazard ID
Hazard characterisation
Response
Assessment of key events
POD
Dose
MOE = POD/Exposure
Establishing fitness-for-purpose of
an AOP

Method performance characterization


Model predictive performance


Are methods for individual key events adequate
Confidence in determining the AOP using information on
key events
Utilization

Utility of AOP to address regulatory (or other) issue of
concern



Relevance
Extrapolation
Assessment context
AOP-Wiki status



As of 24 April, 2016
1 AOP endorsed by OECD
6 AOPs approved by EAGMST (Extended Advisory Group
on Molecular Screening and Toxicogenomics)




Under WNT (Working Group of the National Coordinators of the Test
Guidelines Programme) and TFHA (Task Force for Hazard
Assessment) Review
12 AOPs under review by EAGMST
84 under EAGMST development
15 under SAAOP (Society for the Advancement of Adverse
Outcome Pathways) development
Modified Bradford Hill
considerations

Concordance of dose-response relationships between key and end events

Dose-response relationships for key events would be compared with one another and
with those for endpoints of concern


Temporal association (time)


Key events and adverse outcomes would be evaluated to determine if they occur in
expected order
Consistency and specificity

Is the incidence of the toxic effect consistent with that for the key events?



Are the key events always observed at doses below or similar to those associated with the toxic
outcome?
i.e., Less than that for the key events?
Is the sequence of events reversible if dosing is stopped or a key event prevented?
Biological plausibility

Is the pattern of effects across species/strains/systems consistent with the hypothesized
mode of action?

Does the hypothesized mode of action make sense based on broader knowledge (e.g.,
biology, established mode of action)?
Not all adverse outcomes are
relevant to humans




Liver tumours induced in mice by
phenobarbital
Renal tumours in males rats
induced by D-limonene
Mammary tumours induced in
females rats by atrazine
Bladder tumours induced in rats by
sodium saccharin
Phenobarbital in mouse
Carcinoma of liver
Hence, not all AOPs are relevant to humans, even
those in rodents
MOA human relevance framework
Problem formulation
Key events
Mode of action
Assessment
specific data
generation
Critical data
gaps identified
Assessment
specific data
generation
Critical data
gaps identified
Hypothesized
mode of action
(key events)
based on Bradford
Hill considerations
Level of confidence
Qualitative and
quantitative human
concordance
Level of confidence
(Adverse)
effect
Implications for
safety assessment
(e.g. dose-response)
AOP and key events
Other factors
(e.g. lifestyle,
environment,
homeostasis)
Host characteristics (e.g.
lifestage, genetics)
Host characteristics (e.g.
lifestage, genetics)
•Cellular effects
•Organ effects
•Molecular
target
ADMT/TK
AOP
KEY EVENT [S]
MIE
•External dose
Other factors
(e.g. lifestyle,
environment,
homeostasis)
KEY EVENT[S]
Other factors
(e.g. lifestyle,
environment,
homeostasis)
Host characteristics (e.g.
lifestage, genetics)
•Adverse
outcome
(individual)
•Adverse
outcome
(population)
KEY EVENT[S]
Other factors
(e.g. lifestyle,
environment,
homeostasis)
Host characteristics (e.g.
lifestage, genetics)
Information necessary for hazard
characterization



Information on the toxicodynamic
response (AOP)
Toxicokinetics of the chemical of
interest
Chemical-specific dose-response
information relevant to human exposure
scenarios
Systems-based models
From DeWoksin (2007);
Schneider & Klabunde (2013)
Application in practice


AOPs are chemical-agnostic
Risk assessment is chemical-specific

Evidence that a given AOP will be engaged at human exposure
levels?






Human relevance?
Necessary key events?
Quantitative dose-response relationships
In vitro to in vivo extrapolation
Adequate coverage of possible AOPs without an unacceptably high
false positive rate
Learn by experience – need to provide confidence to risk
manager

Parallel assessments for a period of time?