&EPA www.epa.gov/research science in ACTION INNOVATIVE RESEARCH FOR A SUSTAINABLE FUTURE Estimation of Toxicity Using the Toxicity Estimation Software Tool (TEST) Problem Tens of thousands of chemicals are currently in commerce, and hundreds more are introduced every year. Since experimental measurements of toxicity are extremely time consuming and expensive, it is imperative that alternative methods to estimate toxicity are developed. Solution Quantitative Structure- Activity/Property Relationship (QSAR) models can be used to estimate toxicity from molecular structure (the atoms from which a molecule is built and the particular way the atoms are linked together). To make use of these models, EPA scientists developed the Toxicity Estimation Software Tool (TEST). TEST is a freely available program that allows users to easily estimate toxicity from molecular structure. Endpoints TEST estimates toxicity values for a variety of toxicity endpoints including: • Acute aquatic toxicity • Acute mammalian toxicity • Bioaccumulation factor • Developmental toxicity • Mutagenicity TEST can estimate physical properties including: • Boiling point • Density • Water solubility • Thermal conductivity T.E.S.T (Toxicity Estimation Software Tool) File Edit Help 3Ti -1 c H 0 N P 1 S F Cl Br 1 Sh As CH H,C < Molecule ID: [333-41-S | Endrjoint: [Fathead minnow LCSO (96 hr) [r] Method: [Consensus Q Relax fragment constraint Calct (Above) Structure entry with TEST TEST can provide toxicity values for the WAste Reduction Algorithm (WAR). WAR is used to evaluate the environmental friendliess of chemical process designs.1 TEST can provide toxicity and physical property values for the PARIS II (Program for Assisting the Replacement of Industrial Solvents) methodology.2 PARIS II is used to find more environmentally friendly replacements for industrial solvents. QSAR Methodology QSARs are mathematical models used to predict measures of toxicity from physical characteristics of the structure of chemicals (known as molecular descriptors). Examples of molecular descriptors include connectivity indices and molecular fragment counts (such as the number of hydroxyl groups attached to aromatic rings). TEST utilizes a consensus approach to make toxicity predictions. In the consensus approach, predictions are made using the average of the predictions from several different QSAR methods including hierarchical clustering and group contribution based methods.3 The QSAR models were developed using a pool of more than 800 descriptors. Predictions from each QSAR methodology are subject to a series of constraints that ensure each predicted value represents an U.S. Environmental Protection Agency Office of Research and Development EPA600-F11019 July 2011 ------- interpolation rather than an extrapolation. Model Validation The QSAR models were validated by randomly dividing the data sets into training and prediction sets. The results from the validation exercises (along with the data sets) are provided with the software. The prediction statistics typically exceed those from other QSAR software packages for the same endpoints. TEST Results TEST provides the prediction results using a series of web pages so the calculation details are completely transparent. References 1. Comp. Chem. Eng., 1999, 23 1477-1491. I.Ind. Eng. Chem. Res., 2002, 41, 5867-5877. 3. Toxicol. Mech. Method, 2008,18, 251-266. Contacts Todd Martin, Ph.D., Office of Research & Development, 513-569-7682, martin.toddfgiepa.gov Douglas Young, Ph.D., Office of Research & Development, 513-569- 7624, young.douglasfatepa. gov (Below) Results from TEST Toxicity prediction results for 333-41-5 for Consensus method Prediction results Endpoint Fathead minnow LC^o (96 hr) -Log(mol'L) Fathead minnow LCso (96 hr) mg/L Experimental value CAS: 333-41-5 Semite: ECOTOX 4.81 4.70 Predicted value* 5.20 1.91 4Note: the test chemical was present in the external test set. Individual Predictions Method Hierarchical clustering Single model Group contribution FDA Nearest neighbor Pnedk ted value -Log(mol/L) 5.39 4.92 4.84 4.89 5.9(5 U.S. Environmental Protection Agency Office of Research and Development Recycled/ recyclable Printed with vegetable-based ink on paper mat consists of a minimum of 50% post-consumer fiber content processed chlorine free EPA600/R-12/015 July 2011 ------- |