Table Of ContentBuilding a Prenatal
Developmental Toxicity Ontology
Special Rep o rt No. 19
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS
Building a Prenatal
Developmental Toxicity Ontology
Special Report No. 19
Brussels, August 2016
Building a Prenatal Developmental Toxicity Ontology
ECETOC Special Report No. 19
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ECETOC SR No. 19
Building a Prenatal Developmental Toxicity Ontology
Building a Prenatal Developmental Toxicity Ontology
Contents
SUMMARY 1
1. PREFACE 2
1.1 Definitions 2
2. INTRODUCTION 5
2.1 The value of ontologies 5
2.2 The need for a developmental toxicity ontology 6
2.3 Purpose of this report 6
3. AOP/ MOA ONTOLOGY CONCEPT DEFINED 8
4. RESOURCES FOR BUILDING A DEVELOPMENTAL TOXICITY ONTOLOGY 10
5. APPROACHES TO BUILDING AN AOP/ MOA ONTOLOGY 13
6. HOW CAN IT BE DONE? 14
6.1 Terminology 14
6.2 Specification 15
6.3 Ontology development 16
6.4 Informal ontologies 18
6.5 Natural Language Processing (NLP) 18
6.6 Gene Networks 20
7. CHALLENGES TO BUILDING AND APPLYING AN AOP/ MOA ONTOLOGY 24
7.1 Maternal factors 24
7.2 Potential MIEs and KEs for building AOPs and IATA for Developmental Toxicity 25
8. CASE STUDIES FOR AOP DEVELOPMENT 27
8.1 Role of Retinoic Acid during Embryogenesis 27
8.2 Retinoic Acid and Neural Tube Defects 29
8.3 Retinoic Acid and (hind) brain development 30
8.4 Conclusions on Case Studies on Retinoic Acid 32
9. USING TOXCAST TO DEVELOP AOPS 33
ABBREVIATIONS 36
BIBLIOGRAPHY 38
MEMBERS OF THE EXPERT GROUP 45
MEMBERS OF THE SCIENTIFIC COMMITTEE 46
ECETOC SR No. 19
Building a Prenatal Developmental Toxicity Ontology
SUMMARY
This report discusses the need for a systematic representation of knowledge about developmental toxicity
(i.e. an ontology) that would enable computer-based prediction of which chemicals are likely to induce
human developmental toxicity. The focus of the report is on ways of building a foundation for such an
ontology, based on knowledge of developmental biology and mode of action/adverse outcome pathways
(AOPs) in developmental toxicity. The ontology should include as much biology and signalling mechanism
pathway content that current science allows. It will be necessary to build a Resource Description
Framework (RDF) database to house not only the ontology but also the chemical data needed to assess
perturbations to developmental processes. In order to start, terminology and relationships from qualitative,
putative AOPs will need to be assembled. Ultimately, with the application of quantitative chemical bioassay
data, we will be able to populate quantitative, confirmed AOPs. The implementation of this ontology-
described database will also require consideration of the non-linearity of dynamic biological systems, the
influence of critical periods in development, and, ideally, the influence of maternal toxicity. This report
discusses some of the challenges in building a developmental toxicity ontology and RDF database. It also
discusses some of the currently available, web-based resources for building AOPs. Case studies on one of the
most well understood morphogens and developmental toxicants, retinoic acid, are presented as examples of
how such an ontology may be built up. The potential for the use of the rapidly expanding data in the ToxCast
program is also explored.
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Building a Prenatal Developmental Toxicity Ontology
1. PREFACE
1.1 Definitions
1
Adverse Outcome (AO) : A specialised type of key event (KE), measured at a level of organisation that
corresponds with an established protection goal and/or is functionally equivalent to an apical endpoint
measured as part of an accepted guideline test. Generally at the organ level or higher. Anchors the
“downstream” end of an adverse outcome pathway (AOP).
Adverse Outcome Pathway (AOP): A conceptual framework that organises existing knowledge concerning
biologically plausible, and empirically supported, links between molecular-level perturbation of a biological
1
system and an adverse outcome at a level of biological organisation of regulatory relevance. AOPs are
informed by, but independent of, the chemicals that may affect a pathway. An AOP is usually described as a
linear sequence of key events, starting from a molecular initiating event, followed by various key
intermediate events, as compensatory mechanisms and feedback loops are overcome, linked by defined
key-event relationships, and ending with an adverse outcome. Thus, an AOP encompasses increasing levels
of complexity from the molecular initiating event, via the biochemical, cellular, tissue and organ levels to the
adverse outcome at the entire organism or population level (see Figure 1).
Apical Endpoint: Traditional, directly measured, adverse whole-organism outcomes of exposure in in vivo
tests. In this context, generally death, reproductive failure, or developmental dysfunction.
Developmental Toxicity Ontology (DTO): This is an application ontology built for the specific purposes of
organising existing information about modes of action of developmental toxicants and their relationships
with adverse outcomes.
Integrated Approaches to Testing and Assessment (IATA): A structured approach that strategically
integrates and weights all relevant data to inform regulatory decisions regarding potential hazard and/or risk
and/or the need for further targeted testing and therefore optimising and potentially reducing the number
2
of tests that need to be conducted.
1
Key Event (KE) : A measurable change in biological state that is essential, but not necessarily sufficient, for
the progression from a defined biological perturbation toward a specific adverse outcome. KEs are
represented as nodes in an AOP diagram or AOP network and provide verifiability to an AOP description.
1
Taken from Villeneuve et al. (2014a,b). Adverse Outcome Pathway (AOP) Development I: Strategies and Principles, Toxicological Sciences 142:312-
320 and/or the OECD (2013b), Users’ Handbook Supplement to the Guidance Document for Developing and Assessing AOPs (ENV/JM/MONO(2013)6.
2
Working definition taken from OECD (2015). Report of the workshop on a framework for the development and use of integrated approaches to
testing and assessment Series on Testing and Assessment No. 215. ENV/JM/MONO(2015)22, 22 July 2015.
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Building a Prenatal Developmental Toxicity Ontology
1
Key Event Relationship (KER) : A scientifically-based relationship between a pair of KEs, identifying one as
upstream and the other as downstream. It facilitates inference or extrapolation of the state of the
downstream KE from the known, measured or predicted, state of the upstream KE.
1
Molecular Initiating Event (MIE) : A specialised type of KE, defined as the point where a chemical directly
interacts with a biomolecule within an organism to create a perturbation that starts the AOP – as such, by
definition, it occurs at the molecular level. Anchors the “upstream” end of an AOP.
Mode Of Action (MOA): A biologically plausible sequence of key events leading to an observed effect
supported by robust experimental observations and mechanistic data. A mode of action describes key
cytological and biochemical events—that is, those that are both measurable and necessary to the
3
observed effect—in a logical framework . A mode of action starts with the molecular initiating event. Unlike
AOP, it does not (usually) include consideration of exposure or effects at higher levels than the individual
(see Figure 1).
Ontology: An ontology is an organised representation of a domain of knowledge consisting of concepts and
information, generally referred to as classes, and relationships between classes. Ontologies are useful in
organising information into a structure that makes the information more understandable and facilitates
hypothesis generation.
Resource Description Framework (RDF): An infrastructure for storing information, usually in triplestore or
RDF triple format. The relationships in an RDF are organised and described by an ontology. The ontologies
themselves can be stored in an RDF.
Toxicity pathway: Perturbation of a normal biochemical pathway from the molecular initiating event to the
cellular effect (see Figure 1).
3
Boobis AR, Cohen SM, Dellarco V, McGregor D, Meek ME, Vickers C, Willcocks D, Farland W (2006). IPCS framework for analyzing the relevance of a
cancer mode of action for humans. Crit Rev Toxicol 36:781–792.
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Building a Prenatal Developmental Toxicity Ontology
Figure 1: Schematic representation of the concept of the Adverse Outcome Pathway showing relationship to Mode of Action and Toxicity Pathway. (adapted from OECD (2013a)
Guidance Document on Developing and Assessing Adverse Outcome Pathways, ENV/JM/MONO(2013)6 )
Chemical Molecular
Cellular Organ Organism Population
Structure Initiating
Reponses Responses responses Responses
& Event
Properties
<-----Toxicity Pathway------>
<---------------- Mode of Action ------------------>
<-------------------------------- Adverse Outcome Pathway -------------------------------------->
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