Prediction Of Chemical Toxicity Research Articles

Predicting Dose-Range Chemical Toxicity using Novel Hybrid Deep Machine-Learning Method.

Humans are exposed to thousands of chemicals, including environmental chemicals. Unfortunately, little is known about their potential toxicity, as determining the toxicity remains challenging due to the substantial resources required to assess a chemical in vivo. Here, we present a novel hybrid neural network (HNN) deep learning method, called HNN-Tox, to predict chemical toxicity at different doses. To develop a hybrid HNN-Tox method, we combined two neural network frameworks, the Convolutional Neural Network (CNN) and the multilayer perceptron (MLP)-type feed-forward neural network (FFNN). Combining the CNN and FCNN in the field of environmental chemical toxicity prediction is a novel approach. We developed several binary and multiclass classification models to assess dose-range chemical toxicity that is trained based on thousands of chemicals with known toxicity. The performance of the HNN-Tox was compared with other machine-learning methods, including Random Forest (RF), Bootstrap Aggregation (Bagging), and Adaptive Boosting (AdaBoost). We also analyzed the model performance dependency on varying features, descriptors, dataset size, route of exposure, and toxic dose. The HNN-Tox model, trained on 59,373 chemicals annotated with known LD50 and routes of exposure, maintained its predictive ability with an accuracy of 84.9% and 84.1%, even after reducing the descriptor size from 318 to 51, and the area under the ROC curve (AUC) was 0.89 and 0.88, respectively. Further, we validated the HNN-Tox with several external toxic chemical datasets on a large scale. The HNN-Tox performed optimally or better than the other machine-learning methods for diverse chemicals. This study is the first to report a large-scale prediction of dose-range chemical toxicity with varying features. The HNN-Tox has broad applicability in predicting toxicity for diverse chemicals and could serve as an alternative methodology approach to animal-based toxicity assessment.

Random forest algorithm-based accurate prediction of chemical toxicity to Tetrahymena pyriformis

The random forest (RF) algorithm, together with ten Dragon descriptors, was used to develop a quantitative structure–toxicity/activity relationship (QSTR/QSAR) model for a larger data set of 1792 chemical toxicity pIGC50 towards Tetrahymena pyriformis. The optimal RF (ntree =300 and mtry =3) model yielded root mean square (rms) errors of 0.261 for the training set (1434 chemicals) and 0.348 for the test set (358 chemicals). Compared with other QSTR models reported in the literature, the optimal RF model in this paper is more accurate. The feasibility of applying the RF algorithm to predict chemical toxicity pIGC50 towards Tetrahymena pyriformis has been verified.

In silico prediction of boiling point, octanol-water partition coefficient, and retention time index of polycyclic aromatic hydrocarbons through machine learning.

Polycyclic aromatic hydrocarbons (PAHs), a special class of persistent organic pollutants (POPs) with two or more aromatic rings, have received extensive attention owing to their carcinogenic, mutagenic, and teratogenic effects. Quantitative structure-property relationship (QSPR) is powerful chemometric method to correlate structural descriptors of PAHs with their physicochemical properties. In this manuscript, a QSPR study of PAHs was performed to predict their boiling point (bp), octanol-water partition coefficient (LogKow ), and retention time index (RI). In addition to traditional molecular descriptors, structural fingerprints play an important role in the correlation of the above properties. Three regression methods, partial least squares (PLS), multiple linear regression (MLR), and genetic function approximation (GFA), were used to establish QSPR models for each property of PAHs. The correlation coefficient (R2 test ) and root mean square error (RMSE) of best model were 0.980 and 24.39% (PLS), 0.979 and 35.80% (GFA), 0.926 and 22.90% (MLR) for bp, LogKow, and RI, respectively. The model proposed here can be used to estimate physicochemical properties and inform toxicity prediction of environmental chemicals.

SApredictor: An Expert System for Screening Chemicals Against Structural Alerts.

The rapid and accurate evaluation of chemical toxicity is of great significance for estimation of chemical safety. In the past decades, a great number of excellent computational models have been developed for chemical toxicity prediction. But most machine learning models tend to be “black box”, which bring about poor interpretability. In the present study, we focused on the identification and collection of structural alerts (SAs) responsible for a series of important toxicity endpoints. Then, we carried out effective storage of these structural alerts and developed a web-server named SApredictor (www.sapredictor.cn) for screening chemicals against structural alerts. People can quickly estimate the toxicity of chemicals with SApredictor, and the specific key substructures which cause the chemical toxicity will be intuitively displayed to provide valuable information for the structural optimization by medicinal chemists.

In silico prediction of chemical aquatic toxicity by multiple machine learning and deep learning approaches.

Fish is one of the model animals used to evaluate the adverse effects of a chemical exposed to the ecosystem. However, its low throughput and relevantly high expense make it impossible to test all new chemicals in manufacture. Hence, using in silico models to prioritize compounds to be tested has been widely applied in environmental risk assessment and drug discovery. In this study, we constructed the local predictive models for four fish species, including bluegill sunfish, rainbow trout, fathead minnow, and sheepshead minnow, and the global models with all four fish data. A total of 1874 unique compounds with their labels, that is, toxic (LC50 < 10ppm) or nontoxic, were collected from ECOTOX and literature. Both conventional machine learning methods and the deep learning architecture, graph convolutional network (GCN), were used to build predictive models. The classification accuracy of the best local model for each fish species was higher than 0.83. For the global models, two strategies including consistency prediction and probability threshold were adopted to improve the predictive capability at the cost of limiting applicability domain. For 63% of compounds in domain, the accuracy was around 0.97. By comparison of the deep learning and machine learning methods, we found that the single-task GCN showed specific advantages in performance, and multitask GCN showed no advantages over the conventional machine learning methods. The data and models are available on GitHub (https://github.com/ChemPredict/ChemicalAquaticToxicity).

Critical features identification for chemical chronic toxicity based on mechanistic forecast models

Facing billions of tons of pollutants entering the ocean each year, aquatic toxicity is becoming a crucial endpoint for evaluating chemical adverse effects on ecosystems. Notably, huge amount of toxic chemicals at environmental relevant doses can cause potential adverse effects. However, chronic aquatic toxicity effects of chemicals are much scarcer, especially at population level. Rotifers are highly sensitive to toxicants even at chronic low-doses and their communities are usually considered as effective indicators for assessing the status of aquatic ecosystems. Therefore, the no observed effect concentration (NOEC) for population abundance of rotifers were selected as endpoints to develop machine learning models for the prediction of chemical aquatic chronic toxicity. In this study, forty-eight binary models were built by eight types of chemical descriptors combined with six machine learning algorithms. The best binary model was 1D & 2D molecular descriptors – random trees model (RT) with high balanced accuracy (BA) (0.83 for training and 0.83 for validation set), and Matthews correlation coefficient (MCC) (0.72 for training set and 0.67 for validation set). Moreover, the optimal model identified the primary factors (SpMAD_Dzp, AMW, MATS2v) and filtered out three high alerting substructures [c1cc(Cl)cc1, CNCO, CCOP(=S)(OCC)O] influencing the chronic aquatic toxicity. These results showed that the compounds with low molecular volume, high polarity and molecular weight could contribute to adverse effects on rotifers, facilitating the deeper understanding of chronic toxicity mechanisms. In addition, forecast models had better performances than the common models embedded into ECOSAR software. This study provided insights into structural features responsible for the toxicity of different groups of chemicals and thereby allowed for the rational design of green and safer alternatives.

Artificial Intelligence-Based Toxicity Prediction of Environmental Chemicals: Future Directions for Chemical Management Applications.

Recently, research on the development of artificial intelligence (AI)-based computational toxicology models that predict toxicity without the use of animal testing has emerged because of the rapid development of computer technology. Various computational toxicology techniques that predict toxicity based on the structure of chemical substances are gaining attention, including the quantitative structure-activity relationship. To understand the recent development of these models, we analyzed the databases, molecular descriptors, fingerprints, and algorithms considered in recent studies. Based on a selection of 96 papers published since 2014, we found that AI models have been developed to predict approximately 30 different toxicity end points using more than 20 toxicity databases. For model development, molecular access system and extended-connectivity fingerprints are the most commonly used molecular descriptors. The most used algorithm among the machine learning techniques is the random forest, while the most used algorithm among the deep learning techniques is a deep neural network. The use of AI technology in the development of toxicity prediction models is a new concept that will aid in achieving a scientific accord and meet regulatory applications. The comprehensive overview provided in this study will provide a useful guide for the further development and application of toxicity prediction models.

Linking electron ionization mass spectra of organic chemicals to toxicity endpoints through machine learning and experimentation

Quantitative structure-activity relationship (QSAR) modeling has been widely used to predict the potential harm of chemicals, in which the prediction heavily relies on the accurate annotation of chemical structures. However, it is difficult to determine the accurate structure of an unknown compound in many cases, such as in complex water environments. Here, we solved the above problem by linking electron ionization mass spectra (EI-MS) of organic chemicals to toxicity endpoints through various machine learning methods. The proposed method was verified by predicting 50% growth inhibition of Tetrahymena pyriformis (T. pyriformis) and liver toxicity. The optimal model performance obtained an R2 > 0.7 or balanced accuracy > 0.72 for both the training set and test set. External experimentation further verified the application potential of our proposed method in the toxicity prediction of unknown chemicals. Feature importance analysis allowed us to identify critical spectral features that were responsible for chemical-induced toxicity. Our approach has the potential for toxicity prediction in such fields that it is difficult to determine accurate chemical structures.

Data-Driven Machine Learning in Environmental Pollution: Gains and Problems.

The complexity and dynamics of the environment make it extremely difficult to directly predict and trace the temporal and spatial changes in pollution. In the past decade, the unprecedented accumulation of data, the development of high-performance computing power, and the rise of diverse machine learning (ML) methods provide new opportunities for environmental pollution research. The ML methodology has been used in satellite data processing to obtain ground-level concentrations of atmospheric pollutants, pollution source apportionment, and spatial distribution modeling of water pollutants. However, unlike the active practices of ML in chemical toxicity prediction, advanced algorithms such as deep neural networks in environmental process studies of pollutants are still deficient. In addition, over 40% of the environmental applications of ML go to air pollution, and its application range and acceptance in other aspects of environmental science remain to be increased. The use of ML methods to revolutionize environmental science and its problem-solving scenarios has its own challenges. Several issues should be taken into consideration, such as the tradeoff between model performance and interpretability, prerequisites of the machine learning model, model selection, and data sharing.

Extension of the Virtual Cell Based Assay from a 2-D to a 3-D Cell Culture Model.

Prediction of chemical toxicity is very useful in risk assessment. With the current paradigm shift towards the use of in vitro and in silico systems, we present herein a theoretical mathematical description of a quasi-diffusion process to predict chemical concentrations in 3-D spheroid cell cultures. By extending a 2-D Virtual Cell Based Assay (VCBA) model into a 3-D spheroid cell model, we assume that cells are arranged in a series of concentric layers within the sphere. We formulate the chemical quasi-diffusion process by simplifying the spheroid with respect to the number of cells in each layer. The system was calibrated and tested with acetaminophen (APAP). Simulated predictions of APAP toxicity were compared with empirical data from in vitro measurements by using a 3-D spheroid model. The results of this first attempt to extend the VCBA model are promising - they show that the VCBA model simulates close correlation between the influence of compound concentration and the viability of the HepaRG 3-D cell culture. The 3-D VCBA model provides a complement to current in vitro procedures to refine experimental setups, to fill data gaps and help in the interpretation of in vitro data for the purposes of risk assessment.

Use of Lhasa Limited Products for the In Silico Prediction of Drug Toxicity.

Lhasa Limited have had a role in the in silico prediction of drug and other chemical toxicity for over 30years. This role has always been multifaceted, both as a provider of predictive software such as Derek Nexus, and as an honest broker for the sharing of proprietary chemical and toxicity data. A changing regulatory environment and the drive for the Replacement, Reduction and Refinement (the 3Rs) of animal testing have led both to increased acceptance of in silico predictions and a desire for the sharing of data to reduce duplicate testing. The combination of these factors has led to Lhasa Limited providing a suite of products and coordinating numerous data-sharing consortia that do indeed facilitate a significant reduction in the testing burden that companies would otherwise be laboring under. Many of these products and consortia can be organized into workflows for specific regulatory use cases, and it is these that will be used to frame the narrative in this chapter.

Chemical toxicity prediction based on semi-supervised learning and graph convolutional neural network

As safety is one of the most important properties of drugs, chemical toxicology prediction has received increasing attentions in the drug discovery research. Traditionally, researchers rely on in vitro and in vivo experiments to test the toxicity of chemical compounds. However, not only are these experiments time consuming and costly, but experiments that involve animal testing are increasingly subject to ethical concerns. While traditional machine learning (ML) methods have been used in the field with some success, the limited availability of annotated toxicity data is the major hurdle for further improving model performance. Inspired by the success of semi-supervised learning (SSL) algorithms, we propose a Graph Convolution Neural Network (GCN) to predict chemical toxicity and trained the network by the Mean Teacher (MT) SSL algorithm. Using the Tox21 data, our optimal SSL-GCN models for predicting the twelve toxicological endpoints achieve an average ROC-AUC score of 0.757 in the test set, which is a 6% improvement over GCN models trained by supervised learning and conventional ML methods. Our SSL-GCN models also exhibit superior performance when compared to models constructed using the built-in DeepChem ML methods. This study demonstrates that SSL can increase the prediction power of models by learning from unannotated data. The optimal unannotated to annotated data ratio ranges between 1:1 and 4:1. This study demonstrates the success of SSL in chemical toxicity prediction; the same technique is expected to be beneficial to other chemical property prediction tasks by utilizing existing large chemical databases. Our optimal model SSL-GCN is hosted on an online server accessible through: https://app.cbbio.online/ssl-gcn/home.

Prediction of chemical reproductive toxicity to aquatic species using a machine learning model: An application in an ecological risk assessment of the Yangtze River, China

The endocrine disrupting chemicals (EDCs) have been at the forefront of environmental issues for over 20 years and are a principle factor considered in every ecological risk assessment, but this kind of risk assessment faces difficulties. The expense, time cost of in vivo tests, and lack of toxicity data are key limiting factors for the ability to conduct ecological risk assessments of EDCs to aquatic species. In this study, a machine learning model named the support vector machine (SVM) was used to predict the reproductive toxicity of EDCs, and the performance of the models was evaluated. The results showed that the SVM model provided more accurate toxicity prediction data compared with the interspecies correlation estimation (ICE) model developed by previous study to predict the reproductive toxicity. The application of the predicted toxicity data was an important supplement to the observed data for the ecological risk assessment of EDCs in the Yangtze River, where estrogens and phenolic compounds have been found at some sampling sites in the middle and lower reaches. The results showed that the ecological risk of estrone, 17β-estradiol, and ethinyl estradiol were significant. This study revealed the application potential of machine learning models for the prediction of reproductive toxicity effects of EDCs. This can provide reliable alternative toxicity data for the ecological risk assessments of EDCs.

Identification of Alkaloid Compounds Arborinine and Graveoline from Ruta angustifolia (L.) Pers for their Antifungal Potential against Isocitrate lyase (ICL1) gene of Candida albicans

Candida albicans has been reported globally as the most widespread pathogenic species contributing candidiasis from superficial to systemic infections in immunocompromised individuals. Their metabolic adaptation depends on glyoxylate cycle to survive in nutrient-limited host. The long term usage of fungistatic drugs and the lack of cidal drugs frequently result in strains that could resist commonly used antifungals and display multidrug resistance (MDR). In search of potential therapeutic intervention and novel fungicidals, we have explored a plant alkaloids, namely arborinine and graveoline for its antifungal potential. Alkaloids belongs to Rutaceae family have been reported with numerous antimicrobial activities. In this study, we aimed to isolate and identify the antifungal active alkaloids of R. angustifolia and assess antifungal effect targeting C. albicans isocitrate lyase (ICL) gene which regulates isocitrate lyase, key enzyme in glyoxylate cycle contributing to the virulence potential of C. albicans. Alkaloids were extracted by bioassay guided isolation technique which further identified by TLC profile and compared with the standard through HPLC and NMR analysis. The antifungal activities of the extracted alkaloids were quantified by means of MIC (Minimum Inhibitory Concentration). The gene expression of the targeted gene upon treatment was analysed using RT-qPCR and western blot. Additionally, this study looked at the drug-likeness and potential toxicity effect of the active alkaloid compounds in silico analysis. Spectroscopic analysis showed that the isolated active alkaloids were characterized as acridone, furoquinoline, 4-quinolone known as arborinine and graveoline. Results showed that each compound significantly inhibited the growth of C. albicans at the dose of 250 to 500µg/mL which confirm its antifungal activity. Each alkaloid was found to successfully downregulate the expression of both ICL1 gene CaIcl1 protein. Finally, ADMET analysis suggests a good prediction of chemical properties, namely absorption, distribution, metabolism, excretion and toxicity (ADMET) that will contribute in drug discovery and development later on.

In silico prediction of chemical respiratory toxicity via machine learning

Chemical respiratory toxicity usually causes serious harms to human body, so it is necessary to identify drugs or compounds with potential respiratory toxicity in early drug discovery stage. In this study, we collected 2,529 compounds from public databases and literature, and used six machine learning methods together with nine types of molecular fingerprints to construct a series of binary classification models for prediction of chemical respiratory toxicity. The accuracy of the best performing model was 0.869 for test set, and 0.933 for external validation set. Meanwhile, we defined the applicability domain of the models based on molecular similarity. We also identified the structural alerts about chemical respiratory toxicity through information gain and substructure frequency analysis, which could be used to elucidate their mechanisms and optimize the structures with less toxicity. Our study would be very helpful for prediction of chemical respiratory toxicity in early stage of drug discovery and environmental risk assessment.

In silico prediction of chemical acute contact toxicity on honey bees via machine learning methods

In recent years, the decline of honey bees and the collapse of bee colonies have caught the attention of ecologists, and the use of pesticides is one of the main reasons for the decline. Therefore, ecological risk assessment of pesticides is essential and necessary. In silico tools, such as QSAR models can play an important role in predicting physicochemical and biological properties of chemicals. In this study, a total of 54 classification models were developed by combination of 6 machine learning methods along with 9 kinds of molecular fingerprints based on the experimental honey bees acute contact toxicity data (LD50) of 676 structurally diverse pesticides. The best model proposed was SVM algorithm combined with CDK extended fingerprint. The analysis of the applicability domain of the model successfully excluded some extreme molecules. Additionally, 9 structural alerts about honey bees acute contact toxicity were identified by information gain and substructure frequency analysis.

TOP: A deep mixture representation learning method for boosting molecular toxicity prediction.

At the early stages of the drug discovery, molecule toxicity prediction is crucial to excluding drug candidates that are likely to fail in clinical trials. In this paper, we presented a novel molecular representation method and developed a corresponding deep learning-based framework called TOP (the abbreviation of TOxicity Prediction). TOP integrates specifically designed data preprocessing methods, an RNN based on bidirectional gated recurrent unit (BiGRU), and fully connected neural networks for end-to-end molecular representation learning and chemical toxicity prediction. TOP can automatically learn a mixed molecular representation from not only SMILES contextual information that describes the molecule structure, but also physiochemical properties. Therefore, TOP can overcome the drawbacks of existing methods that use either of them, thus greatly promotes toxicity prediction accuracy. We conducted extensive experiments over 14 classic toxicity prediction tasks on three different benchmark datasets, including balanced and imbalanced ones. The results show that, with the help of the novel molecular representation method, TOP significantly outperforms not only three baseline machine learning methods, but also five state-of-the-art methods.

In silico prediction of toxicity and its applications for chemicals at work.

Objective and methodsThis study reviewed the concept of in silico prediction of chemical toxicity for prevention of occupational cancer and future prospects in workers’ health. In this review, a new approach to determine the credibility of in silico predictions with raw data is explored, and the method of determining the confidence level of evaluation based on the credibility of data is discussed. I searched various papers and books related to the in silico prediction of chemical toxicity and carcinogenicity. The intention was to utilize the most recent reports after 2015 regarding in silico prediction.Results and conclusionThe application of in silico methods is increasing with the prediction of toxic risks to human and the environment. The various toxic effects of industrial chemicals have triggered the recognition of the importance of using a combination of in silico models in the risk assessments. In silico occupational exposure models, industrial accidents, and occupational cancers are effectively managed and chemicals evaluated. It is important to identify and manage hazardous substances proactively through the rigorous evaluation of chemicals.

Prediction of Chemical Toxicity for Drug Design Using AIRS Algorithms and Hybrid Classifiers

Prediction of Chemical Toxicity for Drug Design Using AIRS Algorithms and Hybrid Classifiers

Prediction of chemical toxicity to Tetrahymena pyriformis with four-descriptor models.

A quantitative structure-toxicity relationship (QSTR) model based on four descriptors was successfully developed for 1163 chemical toxicants against Tetrahymena pyriformis by applying general regression neural network (GRNN). The training set consisting of 600 organic compounds was used to train GRNN models that were evaluated with the test set of 563 compounds. For the optimal GRNN model, the training set possesses the coefficient of determination R2 of 0.86 and root mean square (rms) error of 0.41, and the test set has R2 of 0.80 and rms of 0.41. Investigated results indicate that the optimal GRNN model is accurate, although the GRNN model has only four descriptor and more samples in the test set.