Prediction of acute aquatic toxicity inTetrahymena pyriformis– ‘Eco-Derek’, a knowledge-based system approach^£

Abstract

A 'proof-of-concept' version of a software tool for making transparent predictions of acute aquatic toxicity has been developed. It is primarily limited to semi-quantitative predictions in one species, the ciliated protozoan, Tetrahymena pyriformis. A freely available system, 'Eco-Derek', was derived by adapting a well-established, knowledge-based structure-activity and reasoning platform (Derek for Windows, Lhasa Limited). The Derek reasoning code was modified to express potency rather than confidence. Structure-activity relationship (SAR) development utilised a curated version of a published dataset, supplemented with the CADASTER Challenge datasets. Forty-five structural alerts were produced. The dependence on log P was examined for each alert and entered into the system as qualitative reasoning rules specifying the predicted potency as Very Low, Low, Moderate, High or Very High. Evaluation studies showed: (a) moderate accuracy for the training set but low accuracy for an external test set; (b) non-linearity in the toxicity-log P relationship for chemicals without identified structural alerts; (c) insufficient differentiation of substituent effects in some of the reactivity-based structural alerts resulting in too few chemicals predicted with Very High toxicity; and (d) the need for additional structural alerts covering polar narcosis and less common reactive or metabolically activated chemical functionality.

In Silico Resources of Drug-Likeness as a Mirror: What Are We Lacking in Pesticide-Likeness?

“…In addition, we collected three models to predict the acute toxicity of pesticides. Payne et al derived a freely available model “Eco-Derek” to predict acute aquatic toxicity in Tetrahymena pyriformis. The predictive accuracy of this model for acute aquatic toxicity was between 0.673 and 0.803, determined by evaluating 1241 chemicals.…”

Prior Knowledge for Predictive Modeling: The Case of Acute Aquatic Toxicity

“…Compounds with double and triple bonds, such as vinyl/allyl group-containing chemicals, nitriles, propargyl alcohols, carbonyl-containing α,β-unsaturated chemicals, carbamates, and quinones, have often been examined separately, likely because of their reactive nature. 57 , 97 , 106 − 108 Despite the clear benefits of assigning compounds to certain chemical classes or MoAs, many researchers strive to develop “global” models 37 that were not limited by chemical class or MoA. 109 …”

“…Other chemical classes such as aliphatic alcohols, amines, amides, and acids were represented to a lesser extent, probably because their toxicity effects are instead studied in the context of a particular MoA. Compounds with double and triple bonds, such as vinyl/allyl group-containing chemicals, nitriles, propargyl alcohols, carbonyl-containing α,β-unsaturated chemicals, carbamates, and quinones, have often been examined separately, likely because of their reactive nature. ,,− Despite the clear benefits of assigning compounds to certain chemical classes or MoAs, many researchers strive to develop “global” models that were not limited by chemical class or MoA …”