Special Report 19


A number of groups have developed ontologies for human development as well as genetic and other developmental abnormalities. Portals for biological ontologies and for toxicological or adverse effects, as well as those based on the developmental effects of specific chemicals are available. In parallel with the development of ontologies, some of them specific to developmental toxicity, there have been considerable advances in determining mechanisms/MOAs for adverse effects on developmental outcomes, including in some cases associated toxicological information on the causative chemical, and the compilation of this information into publicly accessible repositories (See Table 1).

Table 1: Summary of some publicly available resources on ontologies of human and animal development and information on developmental effects and developmental toxicants

Ontologies for Human Development include:
Uberon (Mungall et al., 2012) Primarily based on anatomical relationships
EHDAA2 (Bard, 2012)
Gene Ontology (GO; http://geneontology.org/)
AmiGO 2 from University of Berkeley (http://amigo2.berkeleybop.org/amigo),
National Library of Medicine MeSH headings (2015)
Human Phenotype Ontology (http://www.human-phenotype-ontology.org/)
Ontology for Biomedical Investigations (http://purl.bioontology.org/ontology/OBI). Links information on several aspects, including function and pathology
Existing ontologies on genetic and other developmental abnormalities include:
OMIM (Online Mendelian Inheritance in Man; http://omim.org/)
GWAS Central (http://www.gwascentral.org/phenotypes/tree)
Portals for biological ontologies, including aspects of development
The Open Biological and Biomedical Ontologies (http://www.obofoundry.org/)
BioPortal (http://bioportal.bioontology.org/)
Ontologies for toxicological or adverse effects, that include developmental effects
MEDDRA (Medical Dictionary for Regulatory Activities)


International Classification of Diseases (http://www.cdc.gov/nchs/icd.htm) Currently in transition to the 10th revision
Ontologies based on the developmental effects of specific chemicals



Also hosts associated toxicological information on the causative chemicals
DevTox initiative in Germany (http://www.devtox.org/index.htm) Also hosts associated toxicological information on the causative chemicals
OECD QSAR Toolbox (Reproductive/developmental toxicity ontology, http://www.qsartoolbox.org/ontologies)



Efforts are underway to construct a comprehensive toxicological ontology (OpenToxipedia OntologyBrowser, http://www.opentoxipedia.org/index.php/Special:OntologyBrowser) but as yet the section on developmental toxicity has to be started.
Additional databases of toxicological information on developmental effects (amongst others)
RepDose (http://fraunhofer-repdose.de/repdose/)
ECHA (http://echa.europa.eu/information-on-chemicals)

OECD eChemPortal (http://www.echemportal.org)

Background information on design and conduct of developmental toxicity studies in the rat and rabbit
Leroy and Allais , 2013
Allais and Reynaud, 2013
Barrow, 2013
Data generated using non-animal methods is being compiled into publicly accessible databases
US EPA ToxCast (http://epa.gov/ncct/toxcast/data.html)
European Bioinformatics Institute Chemical Entities of Biological Interest (http://www.ebi.ac.uk/chebi/)
The OECD QSAR Toolbox (http://www.qsartoolbox.org/)
Open TG-GATEs (http://toxico.nibio.go.jp/english/index.html)
Comparative Toxicogenomics Database (http://ctdbase.org/)
Chemical Effects in Biological Systems (http://www.niehs.nih.gov/research/resources/databases/cebs/index.cfm)
Data from the DiXa project (http://www.dixa-fp7.eu/)
DrugMatrix (https://ntp.niehs.nih.gov/drugmatrix/index.html)
PubChem (https://pubchem.ncbi.nlm.nih.gov/)

Following work by the WHO International Programme on Chemical Safety on MOA (WHO, 2007), the OECD commenced an activity to map AOPs for the adverse effects of chemicals in humans and other species, particularly those of ecotoxicological relevance. A key action was to establish a public repository (AOP wiki) of established and proposed AOPs (see Table 2). The intention is to cover all toxicological effects, including developmental toxicity. At present, the AOP wiki contains only a relatively limited number of AOPs, and very few of these are on mammalian development. The expectation is that the wealth of information being generated on the biological and toxicological effects of chemicals using non-animal methods will provide the substrate and impetus to develop a far greater number of AOPs, particularly when linked with the adverse outcome data available in some of the databases listed in Table 1.

A number of efforts are now underway to integrate this information into adverse outcome or toxicity pathways for developmental effects. For example, Knudsen et al. (2009), Kleinstreuer et al. (2011) and Sipes et al. (2011) have utilised data from high-throughput screening to develop predictive algorithms for a number of adverse effects on prenatal development. Others such as Robinson et al. (2010, 2013) and van Dartel et al. (2011) have investigated the use of toxicogenomics data for this purpose. Bal-Price et al. (2015) have reported on putative AOPs for developmental neurotoxicity. Some aspects of these approaches were discussed at a workshop of the Neurobehavioral Teratology Society[1] in 2009 (Bushnell et al., 2010). In very few instances were AOPs, as defined by the OECD, elaborated for any of the effects in question. One example where this was the specific focus of the study can be found in the work of Zhang et al. (2014) from the Hamner Institute.

A number of websites provide information on effects of chemicals on signalling pathways and other biological processes that might be relevant to AOPs (Table 2).

[1] Now renamed Developmental Neurotoxicology Society.

Table 2: AOP resources

AOP databases
OECD resource for AOPs of chemicals in humans and other species (http://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm).
OECD AOP wiki (public AOP knowledge base) https://aopkb.org/aopwiki/index.php/Main_Page).
Effects of chemicals on biological processes relevant to AOPs
NIH LINCS project http://www.lincsproject.org/)
Connectivity Map from the Broad Institute https://www.broadinstitute.org/cmap/),


Despite the considerable work being undertaken in all of these areas, there is no single source of information providing a comprehensive ontology of developmental toxicity linked to the MIEs and AOPs responsible for these effects.