Adverse Outcome Pathways: Will they deliver a superior alternative to animal
testing?
By Dr Gill Langley on behalf of The Lush Prize
Animal testing is resource-intensive in terms of money, time and animal use, posing financial andethical challenges. It is also highly fallible. Consequently it has become impossible to evaluate fully
all the chemicals being developed or already on the market1.
Research to replace animal testing with non-animal alternatives, such as in vitro, in chemico and in
silico approaches, has been underway for many years and has achieved considerable success.
However, faster progress could be made with a transparent and systematic framework that provides
an underlying rationale for developing and assessing non-animal models and tests, and reliablyinterpreting their data output. The Adverse Outcome Pathway (AOP) concept offers such aframework and, with it, the possibility of creating a genuinely 21st-century toxicology and risk
assessment strategy that is fit for purpose.
Since 2012, the Lush Prize has awarded a range of annual prizes to encourage the replacement ofanimal tests in chemical toxicology. The research-based Lush Prizes focus on human toxicity
pathways and 21st-century science. The Black Box Prize offers a £250,000 award, in any one year,
for a key breakthrough in AOP research and application. It was awarded2 for the first time in 2015,
to leading scientists involved in developing and validating replacement tests applicable to thehuman AOP for skin sensitisation.
Developed from a briefing on AOPs to help guide the Lush Prize programme, this paper:
1.
2.
3.
4.
5.
1.

describes the AOP concept and how it helps replace animal tests in chemical toxicology;
discusses recent progress with AOPs;
assesses the confidence of the toxicology and regulatory communities in the AOP concept;
introduces the possibility of AOPs being applied to medical research and drug discovery;
considers what next steps are needed to progress the AOP approach.
The AOP concept and replacing animal tests in chemical toxicology

An AOP is a conceptual construct that describes a sequence of linked events in a toxicity pathway.
The pathway starts at the molecular level and, via causal Key Events (KEs), progresses throughdifferent levels of biological organisation (i.e. cell, tissue, organ) to an adverse health outcome in an
individual or population3.
The first step in an AOP is the Molecular Initiating Event (MIE), when a chemical first interacts withan organism. The AOP links the MIE to an Adverse Outcome (AO, e.g. illness, death) via a definedseries of KEs that span the different scales of biological organisation. This progression throughdifferent biological levels is a notable feature of AOPs that distinguishes them from earlier toxicity
pathway and mechanistic concepts.
The skin sensitisation AOP was the first to receive endorsement by the Organisation for Economic
Co-operation and Development (OECD) and is illustrated in Figure 1.
1

Tollefsen	
  KE,	
  Scholz	
  S,	
  Cronin	
  MT	
  et	
  al.	  2014.	
  Applying	
  Adverse	
  Outcome	  Pathways	
  (AOPs)	
  to	
  support	
  Integrated	
  Approaches	
  to	
  Testing	
  and	  Assessment	
  (IATA).	
  Regul	  Toxicol	
  Pharmacol.	
  70(3):629-­‐640.	
  doi:	
  10.1016/j.yrtph.2014.09.009	
  2
	
  http://lushprize.org/2015-­‐prize/2015-­‐prize-­‐winners/	  3
	  Ankley	
  GT,	
  Bennett	
  RS,	  Erickson	
  RJ	
  et	
  al.	  (2010)	
  Adverse	
  outcome	  pathways:	
  a	
  conceptual	
  framework	
  to	
  support	
  ecotoxicology	  research	
  and	
  risk	  assessment.	
  Environ.	
  Toxicol.	
  Chem.	
  29:730-­‐741
Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize1

Figure 1. The skin sensitisation AOP: Covalent protein binding leading to skin sensitisation(human allergic contact dermatitis)

MIE

KE

KE

AO

(Credit NC3Rs, based on a diagram in: OECD. 2012. The adverse outcome pathway for skin sensitisation
initiated by covalent binding to proteins. OECD Series on Testing and Assessment No. 168. Part 1: Scientific
Evidence. ENV/JM/MONO(2012)10/PART1. Paris: OECD.)As there are many different toxicity pathways in humans, leading to numerous adverse outcomes,
there will be many thousands of AOPs. One adverse effect may be caused by one AOP or manydifferent ones, as toxicity pathways often overlap. KEs may be thus be related within and acrossdifferent AOPs. This requires a lot of research, analysis and theoretical calculations to cover all the
endpoints that are currently tested in animals. However, this also means that as more AOPs are
identified, knowledge will grow faster than linearly, probably in an exponential way, as each new
AOP is related to existing ones and so helps to build the bigger picture.
KE relationships (KERs) on different pathways and links between AOPs themselves will allow them
to be interlinked into networks. This can already be seen in the OECD’s AOP-Wiki: for example with
AOP 234 as shown in Figure 2, below.

4	
  https://aopwiki.org/aops/23#network_view	
  Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize2

Figure 2. Network view of AOP 23 from the AOP-Wiki: Androgen receptor agonism leading to
reproductive dysfunction

The knowledge and understanding provided by AOPs have multiple applications that are expected
to contribute to better safety evaluation and to replacing animal tests (Figure 3).
Figure 3. Applications of AOPs in safety assessment and replacing animal tests(Credit NC3Rs)

Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize

3

These applications include:
•
•

•
•
•
•
•
•

improving evidence-based hazard and risk assessments
assisting the development of rational schemes (Integrated Approaches to Testing andAssessment, IATA) to assess hazard data from different tests, thereby maximising useful
information from minimal testing
increasing certainty of interpretation of existing as well as new information
improving ability to predict toxicity of one chemical from data on another (with less/no needfor testing), e.g. chemical read-across, structure/activity relationships
identifying data gaps to better target human-relevant researchaccelerating the development and validation of non-animal methods
providing a truly mechanistic basis for toxicity, allowing more computer predictions and fewer
animal tests
better and more rapid high-throughput screening for chemical prioritisation

It isn’t necessary to wait for all the AOPs to be in place before those benefits start to be seen (seesection 2, below). Even draft AOPs are useful, for example to assist in read-across. As each AOP isdeveloped, independently peer-reviewed and iteratively improved, via the literature and the AOP
Knowledge Base, it becomes reliable for and applicable to an expanding number of purposes.
These range from focusing future research and developing new non-animal tests, right through toregulatory decision-making (which would require the highest levels of evidence and confidence).
As the OECD says5:“Assessment of AOPs and evaluation of their suitability for application in different
regulatory contexts relies in part on (1) the confidence and precision with which the KEs
can be measured, (2) the level of confidence in the relationships between the KEs linked
in an AOP based on biological plausibility, empirical support for the KER andconsistency of supporting data and among different biological contexts, and (3) weight ofevidence for the overall hypothesised pathway, taking into account a number of
additional considerations”.
AOPs are more than just toxicity pathways. The AOP framework allows a new, systematic approachto collecting, organising and evaluating toxicity information. It enables toxic effects (adverse
outcomes) to be understood as processes, in contrast to animal testing which reveals toxic effects ina species but explains nothing about underlying mechanisms. AOPs support non-animal methods
by focusing on predicting adverse outcomes on the basis of the MIE and KEs, using mechanistic
data generated by in vitro, in chemico and in silico techniques.
The validation and regulatory use of alternatives, whether they be lung-on-a-chip, human stem cells,or high-throughput assays, depend on the AOP framework to support the regulatory relevance andapplication of these new methods. Regulators have said that with an AOP behind it, methods will be
more easily accepted as valid.
2.

Recent progress with AOPs

The AOP concept was first articulated in 20103 and by 2012 only two to three scientific papers per
year had referred to it. But by June 2017 the OECD had fully endorsed six AOPs, five of them with
relevance to human health, as shown below in Table 1. 18 other AOPs are now under review at theOECD, indicating they’re at a late stage in the endorsement process. These AOPs are for a range of5	  OECD.	
  2016.	
  Users'	
  Handbook	  supplement	  to	
  the	
  Guidance	
  Document	
  for	
  developing	
  and	
  assessing	  Adverse	
  Outcome	  Pathways,	
  OECD	
  Series	
  on	
  Adverse	
  Outcome	  Pathways,	
  No.	  1,	  OECD	
  Publishing,	
  Paris.	
  http://dx.doi.org/10.1787/5jlv1m9d1g32-­‐en	
  Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize4

toxic endpoints including embryo toxicity, epilepsy, learning and memory deficits, impaired fertility,
liver tumours and others.
The AOP-Wiki, the global online resource launched in 2014, where AOPs are entered, freely sharedand updated, already has a list of more than 241 AOPs6. These range from the simplest with only
two KEs; to complex pathways with KEs that also feature in 13 related AOPs – close to a network of
toxicity pathways.
Table 1. OECD-endorsed AOPs (July 2017)
AOP title and its
current/potential uses

AOP- Wikino.

MIE

Adverse
OutcomeSpecies
data onwhich AOP
based
Mouse, rat,
hamster, fish

OECD
Projectno.

Alkylation of DNA in male premeiotic germ cells leading toheritable mutations
Likely future application to humans
Aromatase inhibition leading to
reproductive dysfunction (andpopulation decrease)
A high-confidence AOP suitable foruse in regulatory and risk
assessment applications for fish, &future applications for amphibians,
reptiles and birds (i.e.
ecotoxicology)
Binding of agonists to ionotropic
glutamate receptors in adult brain
causes excitotoxicity that mediates
neuronal cell death, contributing tolearning and memory impairment.
Can be used for in vitro assay
development allowing screening ofchemicals toxic to adult brain
Chronic binding of antagonist to Nmethyl-D-aspartate receptors(NMDARs) during brain
development induces impairment oflearning and memory abilities
Will assist development of new invitro assays to assess chemicals
that might impair children’s
cognitive function
Covalent Protein binding leading toSkin Sensitisation
Has supported the development ofmethods for assessing chemicalsensitisation hazard or potency inhumans without animal testing
Protein Alkylation leading to Liver
Fibrosis (caused by chemicals)Will aid
identification/selection/developmentof in vitro methods and chemical
read-across for untested

AOP no.
15

DNAalkylation

Offspring inherit
mutations via
father’s sperm

AOP no.
25

Aromatase
Inhibition

Reproductive
dysfunction

Fish

1.12

AOP no.
48

Glutamate
receptoragonism

Learning andmemoryimpairment

Human,
mouse, rat

1.23

AOP no.
13

N-methylD-aspartate
receptor
antagonism

Learning andmemoryimpairment

Human,
monkey, rat,
mouse

1.22

AOP no.
40

Covalent
binding ofprotein

Skin sensitisation

Human,mouse

1.1

AOP no.
38

Proteinalkylation

Liver fibrosis

Human, rat

1.14

1.11

6

	
  https://aopwiki.org/	  Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize

5chemicals, applicable to humans
Table 1 illustrates that AOPs for human health endpoints often include animal test data. This is partly because
for many toxicity endpoints, sufficient mechanistic human data has not been available. In the past there’s beenvery little biomonitoring of human populations to see how they’ve been affected by toxic exposures. However,newer research techniques such as genomic analysis in humans, as well as new human species-specific invitro and in silico studies, will increasingly confirm whether or not the animal data incorporated in AOPs proves
relevant for human health endpoints. If animal data is used in AOPs for human health endpoints, it is essentialthat it’s proved to be valid and is used critically.

Two recent AOP success stories
The skin sensitisation AOP (no. 40 in the AOP-Wiki, Table 1) was the first to be endorsed at OECDlevel and three non-animal tests based on KEs have been fully accepted for regulatory use in theOECD test guidelines7. Through its example, scientists and regulators are beginning to see how an
AOP can lead to an IATA that they can have confidence in.
Can we point to other breakthroughs yet? Let’s look at OECD-endorsed AOP 25, (see Table 1),
which deals with aromatase inhibition leading to reproductive dysfunction. The normal function ofaromatase is to convert testosterone to estradiol. Its inhibition by certain endocrine disrupterchemicals leads to reproductive dysfunction in female fish and consequent population crashes. The
AOP has seven KEs involving different biological levels of the reproductive system. A series ofcomputational simulation models, some of them reflecting dose/response aspects, have now beenaligned with the published AOP8. One of the computational models accounts for feedback andadaptation/compensation in the system, in order to simulate complex relationships among the KEs
as a function of dose and time.
The linked models could be used for quantitative risk assessment (i.e. understanding dose/response
relationships), with the initial input based upon the degree of inhibition of aromatase by a test
chemical, and a direct measurement of the MIE made using an in vitro test system. This is arelevant application of an AOP in the context of international endocrine disrupter screening andtesting programmes such as at the OECD and US Environmental Protection Agency. The approach
was recently used successfully to make quantitative predictions of fecundity of white sucker fish at asite impacted by a pulp and paper mill. The scientists who published this example in 2017 said8:“We argue that the systematic organization of knowledge into AOP frameworks caninform and help direct the design and development of computational prediction models
that can further enhance the utility of mechanistic and in silico data for chemical safetyassessment.”
Another success in the field of endocrine disrupter testing based on AOPs involves AOP 42 in the
AOP-Wiki, Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomesin Mammals, currently under review at the OECD. This AOP has already led to the development of
a high-throughput screening assay to detect potential thyroperoxidase inhibition, based on a KE9.
The new assay (so far not a replacement as it uses rat thyroid tissue in vitro) drastically reduces
animal use, requiring one-tenth of the rat thyroid protein used for the standard assay whilst also
giving dose/response information. It can be used to screen large numbers of chemicals as anintegral component of a tiered endocrine-disrupter screening approach. AOP 42 will also inform
quantitative structure/activity relationships and read-across models. It’s expected to lead to systems7	
  http://www.oecd-­‐ilibrary.org/environment/oecd-­‐guidelines-­‐for-­‐the-­‐testing-­‐of-­‐chemicals-­‐section-­‐4-­‐health-­‐effects_20745788	
  	
  Wittwehr	
  C,	
  Aladjov	
  H,	
  Ankley	
  G	
  et	
  al.	  2017.	
  How	  Adverse	
  Outcome	  Pathways	
  Can	  Aid	  the	  Development	
  and	
  Use	  of	
  Computational	
  Prediction	
  Models	
  for	
  Regulatory	
  Toxicology.	
  Toxicol	
  Sci.	
  155(2):326-­‐336.	
  doi:	
  10.1093/toxsci/kfw207	
  9
	
  Paul	
  KB,	
  Hedge	
  JM,	
  Rotroff	
  DM	
  et	
  al.	  2014.	
  Development	
  of	
  a	
  thyroperoxidase	
  inhibition	
  assay	
  for	
  high-­‐throughput	
  screening.	
  Chem.	
  Res.	
  Toxicol.	
  27(3):387-­‐99.	
  doi:	
  10.1021/tx400310w
8Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize

6biology (computational) models that quantitatively simulate and predict cognitive outcomes from invitro thyroperoxidase data.
Number of published papers on AOPs
Another way to look at progress is to assess the number of scientific papers published year by year
since the AOP concept was first described in 2010. PubMed was searched for published papers
containing the text words “adverse outcome pathway” and “adverse outcome pathways”. The
resulting Graph 1 shows exponential growth, suggesting that the AOP concept is gaining
widespread traction.
Graph 1. Scientific papers on AOPs published each year, 2010-2016

In a recent paper, Burden and colleagues wrote10:“It is clear that the well-considered use of AOPs has the potential to drive positive change intoxicology towards a reduced reliance on predictions made using vertebrate animal models
and on the measurement of apical toxicity endpoints per se. The concept itself, and thewidespread international uptake, is already stimulating the development of novel tools andscreening methods and driving real innovation within human toxicology and ecotoxicology.”
Now that there are several AOPs for some related pathways (e.g. in endocrine and reproductive
toxicity), people can begin to see how these pathways are becoming networks that have real
biological relevance. More tangible examples are in process, including IATA for carcinogenicity anddevelopmental toxicity that are in development by the OECD, the European Commission’s Joint
Research Centre and others.

10	
  Burden	
  N,	
  Sewell	  F,	
  Andersen	
  ME	
  et	
  al.	  2015.	
  Adverse	
  Outcome	  Pathways	
  can	
  drive	
  non-­‐animal	
  approaches	
  for	  safety	  assessment.	
  J	
  Appl	  Toxicol.	
  35(9):971-­‐975.	
  doi:	
  10.1002/jat.3165	
  Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize7

3.

Do the toxicology and regulatory communities have confidence in AOPs?

In general, the AOP framework has been taken up by much of the toxicology community. This buyin represents the thinking that AOPs are the first real concept of how to replace animals with a nonanimal predictive toxicity system. The OECD is very much on board and resources are being
dedicated to the AOP-Wiki. The US National Institutes of Health (NIH), the EPA and to some extent
the Food and Drugs Administration (FDA) are active in the area: the EPA is working on AOPs andmaking updates to the Wiki. There’s growing interest/support in other countries like China, Korea
and Japan. There is very strong support for this kind of knowledge within the EU.
For example, an expert Panel of the European Food Safety Authority (EFSA) recently looked at data
linking pesticide exposure to childhood leukaemia and Parkinson’s disease, and developed some
AOPs. They concluded11:“The Panel supports the use of the AOP framework to scientifically and transparently
explore the biological plausibility of the association between pesticide exposure andhuman health outcomes, identify data gaps, define a tailored testing strategy andsuggests an AOP’s informed Integrated Approach for Testing and Assessment (IATA).”The NC3Rs recently surveyed academia, industry and regulators on the issue of AOPs12. Over 70%
of respondents indicated that they were comfortable using AOP terminology. 86% said it waspossible or likely they or their organisation would contribute to the OECD’s AOP programme. The
three key issues that would most encourage respondents to invest in AOP work were increased
confidence in the potential benefits; regulatory buy-in and increased funding.
The following list shows just some of the organisations and projects in Europe, North America andinternationally which are actively working on and supporting AOPs, through research, funding,holding workshops, organising training courses, developing and publishing AOPs, holding webinars,
and more.
Some organisations and projects (in Europe, North America and internationally) supporting
the AOP concept
American Chemistry Council
BioDetection Systems
Center for Alternatives to Animal Testing (US and EU)
Dow Chemical Company
Environment Canada
European Centre for Ecotoxicology and Toxicology of Chemicals
European Food Safety Authority
European Commission Directorate General Joint Research Centre
EU-ToxRisk
Evidence-based Toxicology
Human Toxicology Project Consortium
Humane Society International
Humane Society of the United States
International Life Sciences Institute - Health and Environmental Science Institute
Norwegian Institute for Water Research
Organisation for Economic Co-operation and Development (OECD)
11

	  EFSA	  Panel	  on	
  Plant	
  Protection	
  Products	
  and	  their	
  residues	
  (PPR).	
  2017.	
  Investigation	
  into	  experimental	
  toxicological	
  properties	  of	
  plant	
  protection	
  products	
  having	
  a	
  potential	
  link	  to	
  Parkinson’s	
  disease	
  and	
  childhood	  leukaemia.	
  EFSA	  Journal	
  15(3).	
  doi:	
  10.2903/j.efsa.2017.4691	
  12
	
  NC3Rs.	
  2016.	
  Adverse	
  Outcome	  Pathway	
  News.	
  Issue	
  4	
  December	
  2016Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize

8

People for the Ethical Treatment of Animals
Physicians Committee for Responsible Medicine
Proctor and Gamble
Society for the Advancement of Adverse Outcome Pathways
Society of Environmental Toxicology and ChemistrySociety of Toxicology
ToxCast
Toxicity Testing in the 21st Century (TT21C)
UK National Centre for the Three Rs
UnileverUS National Center for Advancing Translational Sciences
US National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological
Methods (NICEATM)
US Army Engineer Research and Development Center
US Environmental Protection Agency
US National Institutes of Health
WHO International Programme on Chemical Safety
4.

Will AOPs make an impact in medical research and drug discovery?

This is the next logical step and is an initiative being promoted by Humane Society International with
its BioMed21 project, which has now held three scientific workshops (in Brussels, Brazil and theUSA, the latter with US National Institutes of Health engagement). Senior regulatory and academic
scientists have participated in these and the first workshop has already been published13. Although
medical research is moving towards capturing mechanistic information about diseases – information
which could inform an AOP-like approach – the medical research community is not yet familiar
enough with the new concept. However, papers on this are starting to be published14,15,16, putting
the developmental stage of this field roughly equivalent to 2010-2011 for toxicology AOPs (Graph
1).
An important step would be to develop ‘disease research roadmaps’ that focus on human biologybased models13. This would involve a gap analysis to identify what human pathophysiologicalknowledge is currently lacking in each disease area, and whether we have the technologies andmodels to acquire it. The AOP concept provides a framework for assembling existing knowledge,
identifying those gaps and developing/adapting new techniques to fill them.
The obvious overlaps between toxicology AOPs and ‘disease AOPs’ will increasingly become
familiar to medical researchers. For example, an AOP for drug-induced cholestasis (liver disease) –strictly speaking a toxicology AOP – was published in 2013. However, this AOP is highly relevant
both to toxicology and liver disease research and illustrates the potential for the AOP concept toassist in understanding disease processes and identifying new drug targets.

13	
  Langley	
  GR,	
  Adcock	
  IM,	  Busquet	
  F	
  et	
  al.	  2017.	
  Towards	
  a	
  21st-­‐century	
  roadmap	
  for	
  biomedical	
  research	
  and	
  drug	  discovery:	
  consensus	
  report	
  and	  recommendations.	
  Drug	  Discov	
  Today.	
  22(2):327-­‐339.	
  doi:	
  10.1016/j.drudis.2016.10.011	
  14
	
  Langley	
  GR.	  2014.	
  Considering	
  a	
  new	  paradigm	
  for	
  Alzheimer's	
  disease	
  research.	
  Drug	  Discov	
  Today.	
  19(8):1114-­‐24.	
  doi:	  10.1016/j.drudis.2014.03.013.	
  Epub	
  2014	
  Mar	
  21	
  
15
	
  Pistollato	
  F,	
  Ohayon	  EL,	
  Lam	  A,	  et	
  al.	  2016.	
  Alzheimer	
  disease	
  research	
  in	
  the	
  21st	  century:	
  past	  and	
  current	
  failures,	
  new	
  perspectives	
  and	
  funding	
  priorities.	
  Oncotarget.	
  7(26):38999-­‐39016.	
  doi:	
  10.18632/oncotarget.9175	
  16
	
  Langley	
  G,	
  Austin	
  CP,	  Balapure	
  AK	
  et	
  al.	  2015.	
  Lessons	
  from	  Toxicology:	
  Developing	
  a	
  21st-­‐Century	
  Paradigm	
  for	
  Medical	
  Research.	
  Environ	  Health	
  Perspect.	
  123(11):A268-­‐A272.	
  doi:	
  10.1289/ehp.1510345
Langley, G. (2017). Adverse Outcome Pathways: Will they deliver a superior alternative to animal testing? Lush Prize

95.

What next steps are needed to progress the AOP approach?

The ideal goal for the AOP concept is that it should facilitate the complete replacement of animal
testing with advanced, non-animal approaches. While we’re still a long way from that, there areclear directions that can be taken to bring this goal closer.
Views were solicited internationally from scientists and regulators as to the challenges that must be
addressed to realise the full potential of the AOP framework in research and regulatory decisionmaking17. The main issues identified were AOP networks; quantitative AOPs; collaboration on andcommunication of AOP knowledge; AOP discovery and development; chemical and cross-species
extrapolation; exposure/toxicokinetics considerations; and AOP applications.
There are some very practical questions relevant to the use of AOPs in a regulatory context thatmust be answered, including10: What are the weight-of-evidence considerations necessary before
an AOP can be accepted? Could an AOP based solely on in vitro or computational data be
acceptable as a basis for chemical risk assessments?
None of these challenges needs prove impossible to overcome: some are already being addressed,
although others will be difficult. There are often precedents that can be adapted from related fields.
One example is the proposed scientific confidence framework for evaluating AOPs for specifictoxicology and regulatory purposes18. This recent proposal was based on a similar confidence
framework developed for a prediction model for high-throughput screening for endocrine endpoints.
In this way, developments in toxicology – and in medical research and drug development – interact
and influence each other, aided by increased multi-disciplinary collaboration.
The traction already gained by the AOP concept is impressive. It could be that this is the stepchange that toxicology has needed to make it truly fit for the 21st century.
--------------------------------

Acknowledgements
Thanks to Troy Seidle, Gilly Stoddart, Kristie Sullivan and Kate Willett for their input.

17	
  LaLone	  CA,	
  Ankley	
  GT,	  Belanger	
  SE	
  et	
  al.	  2017.	
  Advancing	
  the	
  adverse	
  outcome	  pathway	
  framework	
  -­‐	  An	
  international	
  horizon	
  scanning	
  approach.	
  Environ	
  Toxicol	
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