The use of a harmonised and internationally accepted nomenclature for developmental toxicity is a requirement for all database operations. Such a nomenclature would offer a comprehensive description of adverse developmental outcomes from traditional animal testing.
A harmonised terminology effort was undertaken through a series of “Workshops on the Terminology in Developmental Toxicology” to eliminate ambiguities and inconsistencies within the terminology and to establish working definitions for malformations and variations (Wise et al., 1997; Chahoud et al., 1999; Solecki et al. 2001, 2003; Makris et al., 2009; Solecki et al. 2013, 2015). Adaptations for a better use in computerised systems were made by dividing a teratological diagnosis into a localisation term and an observation term, by eliminating topographical descriptions from the apical endpoints and adding a hierarchical structure for the anatomical localisations, based on observational modes (External, Skeletal, SoftTissue). The USEPA’s Toxicity Reference Database (ToxRefDB) slightly enhanced the annotation system, joining 895 terms from the harmonised nomenclature (version 1) with standardised terms from the OECD-OPPTS vocabulary to generate a thesaurus of 982 non-redundant terms (Knudsen et al., 2009). In the enhanced system, ‘description’ annotates the particular apical endpoint condition or phenotype (observation) and ‘target’ annotates coarse regional anatomy (localisation). The website for this DevTox nomenclature, together with other potential sources of terminology for developmental toxicology, is listed in Table 3.
Table 3: Literature and Data Sources
|Scientific literature sources|
|Gene Ontology (GO) project||http://www.geneontology.org/|
|Edinburgh Mouse Atlas Gene Expression (EMAGE) database||http://www.emouseatlas.org/emage/|
|Mammalian Phenotype Ontology (MPO) Browser||http://www.informatics.jax.org/|
|Zebrafish Model Organism Database||http://zfin.org/cgi-bin|
|Online Mendelian Inheritance in Man (OMIM) database||http://www.ncbi.nlm.nih.gov/omim/|
|Potential sources of terminology and data to address developmental toxicology|
|DevTox – a public website for internationally harmonised terms||http://www.DevTox.org|
|USEPA Toxicology Reference Database housing reference in vivo animal toxicology data for the ToxCast research program||http://www.epa.gov/ncct/toxrefdb/|
There are several limitations with the DevTox vocabulary that need to be considered for an AOP-based approach. One is that it is observational rather than embryological. For example, hypospadias is mapped to ‘trunk’. This coarse parent, although technically correct – the perineum, is not informative of the underlying biology leading to the defect. Hypospadias should rather be annotated as genitourinary (system), urethra (tissue), and penis (location). The latter triad maps an informative relationship between embryology and defect. A second caveat is that common conditions are missing. For example, the term coloboma appears as ‘ocular coloboma’ and ‘palpebral coloboma’. The former misses a more specific diagnosis localised to the iris, retina, or choroid. Since DevTox adaptations made for computability divide a diagnosis into localisation and observation terms, while eliminating topographical descriptions, ‘retinal coloboma’ does not appear in the lexicon despite being the most common coloboma. Also, the DevTox terminology does not consider larger syndromes. For example, the CHARGE syndrome (Colobomas, Heart defects, Atresia of the choanae in the nasal structures, Retarded growth and mental development or CNS abnormalities, Genital hypoplasia in males, and Ear anomalies and/or deafness). The hierarchical relationship of these malformations in the DevTox lexicon identifies a need for a stronger developmental ontology.