Dataset Information

Transitioning the Generalised Read-Across approach (GenRA) to quantitative predictions: A case study using acute oral toxicity data.

ABSTRACT: Read-across approaches continue to evolve as does their utility in the field of risk assessment. Previously we presented our generalised read-across (GenRA) approach (Shah et al., 2016), which utilises chemical descriptor and/or in vitro bioactivity data to make read-across predictions on the basis of the similarity weighted average of nearest neighbours. The current public version of GenRA predicts 574 apical outcomes as a binary call from repeat dose toxicity studies available in ToxRefDB (Helman et al., 2019). Here we investigated the application of GenRA to quantitative values, specifically using a large dataset of rat oral acute LD50 toxicity data (LD50 values for 7011 discrete chemicals) that had been collected under the auspices of the ICCVAM acute toxicity workgroup (ATWG). GenRA LD50 predictions were made based on the following criteria - chemicals were characterised by Morgan chemical fingerprints with a minimum similarity threshold of 0.5 and a maximum of 10 nearest neighbours over the entire dataset. An R² value of 0.61 and RMSE of 0.58 was achieved based on these parameters. Monte Carlo cross validation was then used to estimate confidence in the R². Cross validated R² values were found to fall in the range of 0.47 to 0.62. However, when evaluating GenRA locally to clusters of mechanistically or structurally-similar chemicals, average R² values improved up to 0.91. GenRA can be extended to make reasonable quantitative predictions of acute oral rodent toxicity with improved performance exhibited for specific local domains.

SUBMITTER: Helman G

PROVIDER: S-EPMC7898163 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Transitioning the Generalised Read-Across approach (GenRA) to quantitative predictions: A case study using acute oral toxicity data.

Helman George G Shah Imran I Patlewicz Grace G

Computational toxicology (Amsterdam, Netherlands) 20191101 November 2019

Read-across approaches continue to evolve as does their utility in the field of risk assessment. Previously we presented our generalised read-across (GenRA) approach (Shah et al., 2016), which utilises chemical descriptor and/or <i>in vitro</i> bioactivity data to make read-across predictions on the basis of the similarity weighted average of nearest neighbours. The current public version of GenRA predicts 574 apical outcomes as a binary call from repeat dose toxicity studies available in ToxRef ...[more]

PMID: 33623834

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Project description:Read-across is a useful data gap filling technique used within category and analogue approaches in regulatory hazard and risk assessment. Recently we developed an algorithmic, approach called Generalised Read-Across (GenRA) (Shah et al., 2016) which makes read-across predictions of toxicity effects using a similarity weighted average of source analogues characterised by their chemical and/or bioactivity descriptors. A default GenRA approach (termed baseline GenRA) relies on identifying 10 source analogues relative to a target substance that are structurally similar based on Morgan chemical fingerprints and computing an activity score to estimate presence or absence of in vivo toxicity. This current study investigated the impact that similarity in bioavailability plays in altering the local neighbourhood of source analogues as well as read-across performance relative to baseline GenRA using physicochemical property information as a surrogate for bioavailability. Two approaches were evaluated: 1) a filtering approach which restricted structurally related analogues based on their physicochemical properties; and 2) a search expansion approach which included additional analogues based on a combined structural and physicochemical similarity index. Filtering minimally improved performance, and was very dependent on the similarity threshold selected. The search expansion approach performed at least as well as the baseline GenRA, and showed up to a 9% improvement in read-across performance for at least 10 of the 50 organs considered. We summarise the overall impact that physicochemical information plays on GenRA performance, illustrate the improvement for a specific case study substance and describe how to select the most appropriate physicochemical similarity threshold to achieve optimal read-across performance depending on the toxicity effect and chemical of interest. The analyses show that physicochemical property information does result in a modest (up to 9% increase) improvement in structural based read-across predictions.

Project description:The Analog Identification Methodology (AIM) was developed over 20 years ago to identify analogues to support read-across at the US Environmental Protection Agency. However, the current public version of the standalone tool, released in 2012, is no longer usable on Windows operating systems supported by Microsoft. Additionally, the structural logic for analogue selection is based on older, customised Simplified molecular-input-line-entry system (SMILES)-type features that are incompatible with modern cheminformatics tools. Given these limitations, a case study was undertaken to explore a more transparent, extensible method of implementing the AIM fragments using Chemical Subgraphs and Reactions Mark-up Language (CSRML). A CSRML file was developed to codify the original AIM fragments, and the extent to which AIM fragments were faithfully replicated was assessed using the AIM Database. The overall mean performance of the CSRML-AIM across all fragments in terms of sensitivity, specificity, and Jaccard similarity was 89.5%, 99.9%, and 82.2%, respectively. Comparing the AIM fragments with public ToxPrints using a large set of ~25,000 substances of regulatory interest to EPA found them to be dissimilar, with an average maximum Jaccard score of 0.24 for AIM and 0.29 for ToxPrint fingerprints. Both fragment sets were then used as inputs in the automated read-across approach, Generalised Read-Across (GenRA), to evaluate the quality of fit in predicting rat acute oral toxicity LD50 values with the coefficient of determination (R2) and root mean squared error (RMSE). The performance of AIM fragments was R2=0.434 and RMSE=0.663 whereas that of ToxPrints was R2=0.477 and RMSE=0.638. A bootstrap resampling using 100 iterations found the mean and the 95th confidence interval of R2 to be 0.349 [0.319, 0.379] for AIM fragments and 0.377 [0.338, 0.412] for ToxPrints. Although AIM and ToxPrints performed similarly in predicting LD50, they differed in their performance at a local level, revealing that their features can offer complementary insights.

Dataset Information

Transitioning the Generalised Read-Across approach (GenRA) to quantitative predictions: A case study using acute oral toxicity data.

Publications

Transitioning the Generalised Read-Across approach (GenRA) to quantitative predictions: A case study using acute oral toxicity data.

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