TOXTREE: TOXIC HAZARD ESTIMATION BY A DECISION TREE APPROACH - THE FIRST SEVEN YEARS Nina Jeliazkova (a), Silvia Lapenna (b), Andrew Worth (b) a) Ideaconsult Ltd, Sofia , Bulgaria e-mail: jeliazkova.nina@gmail.com b) European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy Toxtree is a flexible and user-friendly open-source application that predicts various kinds of toxic effects, mostly by applying structural alerts, arranged in a decision tree fashion. Toxtree was initially commissioned by the European Commission’s Joint Research Centre (JRC) and the first version (v. 1.0) was released in 2005. It implemented the Cramer structural rules for estimating the threshold of toxicological concern. During the following years, more than 10 major releases have been made available, and the number of plug-ins had risen from one to fifteen. Toxtree was designed with flexible capabilities for future extensions, providing a core platform, implementing the user interface and common functionalities as input and output, and standardized Java interfaces for the prediction modules (or plug-ins). This architecture allows the development of prediction modules to concentrate on the model specifics, and facilitates the collaboration of independent developers. Toxtree modules have been developed by the JRC in collaboration with various consultants, in particular Ideaconsult Ltd (Sofia, Bulgaria), who also maintain the core as an open source (GPL license) project at http://toxtree.sf.net. key feature of Toxtree is the transparent reporting of the rationale underlying each prediction. This is supported by keeping track of the path through the decision tree and reporting the result of applying the rules. Since version 2.1.0 (2010), Toxtree supports structural alerts highlighting. Some of the prediction modules also use descriptor calculation procedures and QSAR models. The SMARTCyp plugin was extended in 2011 to enable metabolite predictions, in addition to predicting sites of metabolism. While the earlier versions supported only input by SMILES and common chemical file formats, since version 2.2.0 (2010), Toxtree accepts InChI and chemical names as input. Version 2.5.0 (2011) introduced a chemical identifier lookup via remote OpenTox web service. Besides being used as downloadable standalone application, Toxtree was reported to be embedded in various workflow systems and exposed as a web service as early as 2007. Since 2010, Toxtree has been available as an OpenTox API compatible web service and also embedded in the online application ToxPredict. We report validation statistics for several plug-ins, as well as predicted class distribution statistics for several endpoints, based on the application of Toxtree to large scale public datasets.

1. TOXTREE:
TOXIC HAZARD ESTIMATION BY DECISION TREE APPROACH
Nina Jeliazkova a, Silvia Lapennab, Andrew Worthb
a) Ideaconsult Ltd, 4 A. Kanchev str., Sofia 1000, Bulgaria, jeliazkova.nina@gmail.com
b) European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy
Toxtree citations
• Toxtree is a flexible and user-friendly open-source application [1]. 70
• Places chemicals into categories and predicts various kinds of toxic effect, 60
50
mostly by applying structural alerts, arranged in a decision tree fashion. 40
30
• Available at http://toxtree.sourceforge.net 20
10
• Initially commissioned by the European Commission’s Joint Research Centre. 0
2006 2007 2008 2009 2010 2011 2012
• The first version (v. 1.0) was released in 2005. It implemented the Toxtree usage map
Cramer structural rules for estimating the threshold of toxicological concern. Toxtree citations
• More than 10 major releases since 2005. 70
60
• Input: SDF, MOL, SMILES, XLS, CSV, CML, structure diagram editor (since v. 1.0), 50
InChI, chemical names (since 2.2.0), chemical identifier lookup via remote OpenTox
40
30
web service (since 2.5.0). 20
10
• The latest version Toxtree 2.5.1 includes 15 prediction modules: 0
2006 2007 2008 2009 2010 2011 2012
• Cramer rules & Cramer rules with extensions
• Verhaar scheme
• Modified Verhaar scheme for predicting toxicity mode of action
• Skin irritation (BfR rules) and Eye irritation (BfR rules)
• Benigni / Bossa rule base for mutagenicity and carcinogenicity
• START biodegradation and persistence
• Structural alerts for identification of Michael acceptors;
• Structural alerts for skin sensitization
• Kroes Threshold of Toxicological Concern Decision tree
• SMARTCyp - Cytochrome P450-Mediated Drug Metabolism and
metabolites prediction;
• Structural alerts for the in vivo micronucleus assay in rodents (ISSMIC)
• Structural alerts for Functional Group Identification (ISSFUNC)
• Structural alerts for protein binding
A key feature of Toxtree is the transparent reporting of the rationale underlying
each prediction. This is supported by keeping track of the path through the
decision tree and reporting the result of applying the rules. Since version 2.1.0
(2010), Toxtree supports structural alerts highlighting.
Some of the prediction modules also use descriptor calculation procedures and
QSAR models. The SMARTCyp plugin was extended in 2011 to enable metabolite
predictions, in addition to predicting sites of metabolism.
Besides being used as downloadable standalone application, Toxtree was reported
to be embedded in various workflow systems and exposed as a web service as
early as 2007. Since 2010, Toxtree has been available as an OpenTox API
compatible web service and also embedded in the online application
http://toxpredict.org .
Application to publicly available datasets
Chemical structures and data from various sources have been imported into the
Ambit database [2,3] and made available via the OpenTox REST API interface.
Toxtree modules are available as OpenTox API compliant models.
For developers ECHA Preregistration list Plant Protection Products
• Designed with flexible capabilities for future extensions.
• Provides a core platform, implementing the user interface and
common functionalities as input and output, and standardized Java
interfaces for the prediction modules.
• This architecture allows the development of prediction modules to
concentrate on the model specifics, and facilitates the collaboration of
independent developers.
• Toxtree modules have been developed by the JRC in collaboration with
various consultants.
• You could develop the next toxicity prediction module!
Structural alerts for acyl Verhaar scheme for Structural alerts for acyl Verhaar scheme for
Cramer rules transfer agents toxicity mode of action Cramer rules transfer agents toxicity mode of action
Frequently Asked Questions:
http://toxtree.sourceforge.net/faq.html#K2
Q: How to run Toxtree predictions from (Java) code and embed Toxtree
into my software?
A1: Java standalone example
• Toxtree and CDK dependencies are available via Apache Maven
repository. Example code available.
A2: REST web service - via OpenTox API
http://opentox.org/dev/apis/api-1.2 Structural alerts for the
• Toxtree modules are available as OpenTox REST API web services. The in vivo micronucleus
example assumes your dataset is uploaded to an OpenTox dataset START biodegradation assay in rodents
service. The dataset service accepts common chemical data formats
for upload via HTTP POST calls.
References
[1] Patlewicz G, Jeliazkova N, Safford RJ, Worth AP, Aleksiev B. (2008) An evaluation of the implementation of the Cramer classification scheme
in the Toxtree software. SAR QSAR Environ Res. ;19(5-6):495-524.
[2] Jeliazkova N., Jeliazkov V. AMBIT RESTful web services: an implementation of the OpenTox application programming interface, Journal of
Cheminformatics 2011, 3:18, doi:10.1186/1758-2946-3-18.
[3] OpenTox D3.4 Report on Final Database http://opentox.org/data/documents/development/opentoxreports/opentoxreportd34