MOTIVATION:Chemical toxicity assessment is critical for drug development and environmental safety. Computational models have emerged as a promising alternative to animal testing and now play a significant role in efficiently evaluating new chemicals. To address the urgent need for user-friendly machine learning tools in computational toxicology, we developed ToxiVerse, a public web-based platform. RESULTS:ToxiVerse provides automatic chemical bioprofiling, curated toxicity datasets, and a predictive modeling interface designed for researchers who lack programming expertise. The platform comprises three integrated modules: (i) Bioprofiler, which provides chemical descriptors by combining chemical-bioactivity data from PubChem assays with a machine learning-based data gap-filling procedure; (ii) Database, which hosts ∼50 000 curated chemicals covering diverse toxicity endpoints; and (iii) Cheminformatics, which enables dataset upload, chemical curation, and automatic generation of quantitative structure-activity relationship models for toxicity prediction. AVAILABILITY:The tool is accessible at www.toxiverse.com, and source code is available at https://github.com/zhu-research-group/toxiverse.

High-throughput screening (HTS) programs have generated abundant data on numerous chemicals, supporting the discovery of toxicity mechanisms and advancing understanding of adverse outcome pathways (AOPs) in chemical toxicity. However, organizing and interpreting these data for predictive modeling remain challenging due to inconsistent repository formats, varied program objectives, heterogeneous assay targets, and differences in experimental protocols, including concentration ranges. To address these limitations, we developed a hierarchical mechanistic modeling framework that systematically structures and interprets concentration response HTS data. The model integrated curated data sets by mapping metadata from 455 PubChem assays to 216 protein targets and 103 biological pathways in WikiPathways. Assay-level concentration-response data were organized within a biologically layered hierarchy to construct AOP-based models. The resulting models generated pathway-level toxicity scores that quantified compound potency by integrating inferred protein activity and downstream pathway perturbations. In total, 103 pathways were statistically associated with five in vivo toxicity endpoints: acute systemic, maternal, developmental, human hepatotoxicity, and preclinical hepatotoxicity. This hierarchical framework leverages HTS metadata to predict diverse in vivo toxicity outcomes and enhance mechanistic interpretability of pathway-level effects. It links chemical bioactivity to adverse outcomes, providing a quantitative basis for compound ranking, potency assessment, and hazard prediction. Overall, this framework offers a structured, scalable method for integrating large bioactivity data sets into computational toxicology, supporting chemical risk assessment and early-stage drug discovery.

Chemical toxicity assessment is critical for drug development and environmental safety. Computational models have emerged as a promising alternative to animal testing and now play a significant role in efficiently evaluating new chemicals. To address the urgent need for providing user-friendly machine learning tools in computational toxicology, we developed ToxiVerse, a public web-based platform. It provides curated toxicity datasets, automatic chemical bioprofiling, and a predictive modeling interface designed for researchers who lack programming expertise. The platform comprises three integrated modules: (i) the Bioprofiler module, which provides chemical descriptors by combining chemical-bioactivity data from PubChem assay with a machine learning-based data gap-filling procedure; (ii) the Database module, which hosts around 50,000 curated unique chemicals covering diverse toxicity endpoints; and (iii) the Cheminformatics module, which allows users to upload their own datasets, use datasets from ToxiVerse, or retrieve existing data from PubChem; perform chemical curation; and automatically generate Quantitative Structure-Activity Relationship (QSAR) models to predict chemicals of interest. ToxiVerse enables researchers to carry out bioprofiling, access curated toxicity datasets, and evaluate chemical toxicity through machine learning-based modeling and prediction. The platform is supported by sample files and a detailed tutorial, and it is freely accessible at www.toxiverse.com.

Hepatotoxicity remains a leading cause of drug attrition and post-marketing withdrawal, resulting from diverse and complex toxicity mechanisms. Traditional in vitro models can only capture a limited subset of toxicity pathways, and animal studies face translational and ethical limitations. Regulatory agencies have therefore promoted new approach methodologies, including human-relevant assays, omics technologies, and computational models to improve predictive toxicology and support evidence-based decision-making. However, most machine learning models for hepatotoxicity either rely solely on chemical structure or operate as black boxes, limiting mechanistic interpretability and broader applicability. Here, we introduce the virtual toxicity network (vToxiNet), a biologically constrained deep learning framework that embeds systems toxicology knowledge directly into neural network architecture for interpretable hepatotoxicity prediction. vToxiNet integrates chemical descriptors, high-throughput assay responses, transcriptomic signatures, and Reactome pathway hierarchy to construct a virtual adverse outcome pathway network. Across cross-validation and multiple external validation datasets, vToxiNet demonstrates robust predictive performance and generalizes to previously unseen chemicals. Importantly, interpretation of vToxiNet enables gene and pathway-level attribution, supporting mechanism-informed hazard characterization and chemical prioritization. These results demonstrate that encoding biological hierarchy as architectural constraints enables both predictive accuracy and mechanistic insight, establishing a generalizable framework for modeling complex biological outcomes.

Modern nanotechnology has generated numerous datasets from in vitro and in vivo studies on nanomaterials, with some available on nanoinformatics portals. However, these existing databases lack the digital data and tools suitable for machine learning studies. Here, we report a nanoinformatics platform that accurately annotates nanostructures into machine-readable data files and provides modeling toolkits. This platform, accessible to the public at https://vinas-toolbox.com/, has annotated nanostructures of 14 material types. The associated nanodescriptor data and assay test results are appropriate for modeling purposes. The modeling toolkits enable data standardization, data visualization, and machine learning model development to predict properties and bioactivities of new nanomaterials. Moreover, a library of virtual nanostructures with their predicted properties and bioactivities is available, directing the synthesis of new nanomaterials. This platform provides a data-driven computational modeling platform for the nanoscience community, significantly aiding in the development of safe and effective nanomaterials.

Computational modeling has emerged as a time-saving and cost-effective alternative to traditional animal testing for assessing chemicals for their potential hazards. However, few computational modeling studies for immunotoxicity were reported, with few models available for predicting toxicants due to the lack of training data and the complex mechanisms of immunotoxicity. In this study, we employed a data-driven quantitative structure-activity relationship (QSAR) modeling workflow to extensively enlarge the limited training data by revealing multiple targets involved in immunotoxicity. To this end, a probe data set of 6,341 chemicals was obtained from a high-throughput screening (HTS) assay testing for the activation of the aryl hydrocarbon receptor (AhR) signaling pathway, a key event leading to immunotoxicity. Searching this probe data set against PubChem yielded 3,183 assays with testing results for varying proportions of these 6,341 compounds. 100 assays were selected to develop QSAR models based on their correlations to AhR agonism. Twelve individual QSAR models were built for each assay using combinations of four machine-learning algorithms and three molecular fingerprints. 5-fold cross-validation of the resulting models showed good predictivity (average CCR = 0.73). A total of 20 assays were further selected based on QSAR model performance, and their resulting QSAR models showed good predictivity of potential immunotoxicants from external chemicals. This study provides a computational modeling strategy that can utilize large public toxicity data sets for modeling immunotoxicity and other toxicity endpoints, which have limited training data and complicated toxicity mechanisms.

Traditional methodologies for assessing chemical toxicity are expensive and time-consuming. Computational modeling approaches have emerged as low-cost alternatives, especially those used to develop quantitative structure-activity relationship (QSAR) models. However, conventional QSAR models have limited training data, leading to low predictivity for new compounds. We developed a data-driven modeling approach for constructing carcinogenicity-related models and used these models to identify potential new human carcinogens. To this goal, we used a probe carcinogen dataset from the US Environmental Protection Agency's Integrated Risk Information System (IRIS) to identify relevant PubChem bioassays. Responses of 25 PubChem assays were significantly relevant to carcinogenicity. Eight assays inferred carcinogenicity predictivity and were selected for QSAR model training. Using 5 machine learning algorithms and 3 types of chemical fingerprints, 15 QSAR models were developed for each PubChem assay dataset. These models showed acceptable predictivity during 5-fold cross-validation (average CCR = 0.71). Using our QSAR models, we can correctly predict and rank 342 IRIS compounds' carcinogenic potentials (PPV = 0.72). The models predicted potential new carcinogens, which were validated by a literature search. This study portends an automated technique that can be applied to prioritize potential toxicants using validated QSAR models based on extensive training sets from public data resources.

Failure of animal models to predict hepatotoxicity in humans has created a push to develop biological pathway-based alternatives, such as those that use in vitro assays. Public screening programs (e.g., ToxCast/Tox21 programs) have tested thousands of chemicals using in vitro high-throughput screening (HTS) assays. Developing pathway-based models for simple biological pathways, such as endocrine disruption, has proven successful, but development remains a challenge for complex toxicities like hepatotoxicity, due to the many biological events involved. To this goal, we aimed to develop a computational strategy for developing pathway-based models for complex toxicities. Using a database of 2171 chemicals with human hepatotoxicity classifications, we identified 157 out of 1600+ ToxCast/Tox21 HTS assays to be associated with human hepatotoxicity. Then, a computational framework was used to group these assays by biological target or mechanisms into 52 key event (KE) models of hepatotoxicity. KE model output is a KE score summarizing chemical potency against a hepatotoxicity-relevant biological target or mechanism. Grouping hepatotoxic chemicals based on the chemical structure revealed chemical classes with high KE scores plausibly informing their hepatotoxicity mechanisms. Using KE scores and supervised learning to predict in vivo hepatotoxicity, including toxicokinetic information, improved the predictive performance. This new approach can be a universal computational toxicology strategy for various chemical toxicity evaluations.

Traditional experimental approaches to evaluate hepatotoxicity are expensive and time-consuming. As an advanced framework of risk assessment, adverse outcome pathways (AOPs) describe the sequence of molecular and cellular events underlying chemical toxicities. We aimed to develop an AOP that can be used to predict hepatotoxicity by leveraging computational modeling and in vitro assays. We curated 869 compounds with known hepatotoxicity classifications as a modeling set and extracted assay data from PubChem. The antioxidant response element (ARE) assay, which quantifies transcriptional responses to oxidative stress, showed a high correlation to hepatotoxicity (PPV=0.82). Next, we developed quantitative structure-activity relationship (QSAR) models to predict ARE activation for compounds lacking testing results. Potential toxicity alerts were identified and used to construct a mechanistic hepatotoxicity model. For experimental validation, 16 compounds in the modeling set and 12 new compounds were selected and tested using an in-house ARE-luciferase assay in HepG2-C8 cells. The mechanistic model showed good hepatotoxicity predictivity (accuracy = 0.82) for these compounds. Potential false positive hepatotoxicity predictions by only using ARE results can be corrected by incorporating structural alerts and vice versa. This mechanistic model illustrates a potential toxicity pathway for hepatotoxicity, and this strategy can be expanded to develop predictive models for other complex toxicities.

Advances in high-throughput screening (HTS) revolutionized the environmental and health sciences data landscape. However, new compounds still need to be experimentally synthesized and tested to obtain HTS data, which will still be costly and time-consuming when a large set of new compounds need to be studied against many tests. Quantitative structure-activity relationship (QSAR) modeling is a standard method to fill data gaps for new compounds. The major challenge for many toxicologists, especially those with limited computational backgrounds, is efficiently developing optimized QSAR models for each assay with missing data for certain test compounds. This chapter aims to introduce a freely available and user-friendly QSAR modeling workflow, which trains and optimizes models using five algorithms without the need for a programming background.

High-throughput screening (HTS) techniques are increasingly being adopted by a variety of fields of toxicology. Notably, large-scale research efforts from government, industrial, and academic laboratories are screening millions of chemicals against a variety of biomolecular targets, producing an enormous amount of publicly available HTS assay data. These HTS assay data provide toxicologists important information on how chemicals interact with different biomolecular targets and provide illustrations of potential toxicity mechanisms. Open public data repositories, such as the National Institutes of Health's PubChem ( http://pubchem.ncbi.nlm.nih.gov ), were established to accept, store, and share HTS data. Through the PubChem website, users can rapidly obtain the PubChem assay results for compounds by using different chemical identifiers (including SMILES, InChIKey, IUPAC names, etc.). However, obtaining these data in a user-friendly format suitable for modeling and other informatics analysis (e.g., gathering PubChem data for hundreds or thousands of chemicals in a modeling friendly format) directly through the PubChem web portal is not feasible. This chapter aims to introduce two approaches to obtain the HTS assay results for large datasets of compounds from the PubChem portal. First, programmatic access via PubChem's PUG-REST web service using the Python programming language will be described. Second, most users, who lack programming skills, can directly obtain PubChem data for a large set of compounds by using the freely available Chemical In vitro-In vivo Profiling (CIIPro) portal ( http://www.ciipro.rutgers.edu ).

For hazard identification, classification, and labeling purposes, animal testing guidelines are required by law to evaluate the developmental toxicity potential of new and existing chemical products. However, guideline developmental toxicity studies are costly, time-consuming, and require many laboratory animals. Computational modeling has emerged as a promising, animal-sparing, and cost-effective method for evaluating the developmental toxicity potential of chemicals, such as endocrine disruptors, without the use of animals. We aimed to develop a predictive and explainable computational model for developmental toxicants. To this end, a comprehensive dataset of 1244 chemicals with developmental toxicity classifications was curated from public repositories and literature sources. Data from 2140 toxicological high-throughput screening assays were extracted from PubChem and the ToxCast program for this dataset and combined with information about 834 chemical fragments to group assays based on their chemical-mechanistic relationships. This effort revealed two assay clusters containing 83 and 76 assays, respectively, with high positive predictive rates for developmental toxicants identified with animal testing guidelines (PPV = 72.4 and 77.3% during cross-validation). These two assay clusters can be used as developmental toxicity models and were applied to predict new chemicals for external validation. This study provides a new strategy for constructing alternative chemical developmental toxicity evaluations that can be replicated for other toxicity modeling studies.

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used. Here, we evaluated 226 secondary pharmacology profiles obtained from close to 90 unique sponsors. The results indicated that the most tested target in our set was the GABA benzodiazepine receptor (tested 168 times), the most hit target was adenosine 3 (hit 24 times), and the target with the highest hit percentage was the quinone reductase 2 (NQO2) receptor (hit 29% of the time). The overall results were largely consistent with those observed in previous publications. However, this study also identified the need for improvement in the submission process of secondary pharmacology studies by industry, which could enhance their utility for regulatory purpose. FDA-industry collaborative working groups will utilize this data to determine the best methods for regulatory submission of these studies and evaluate the need for a standard target panel.

The kidneys, heart and lungs are vital organ systems evaluated as part of acute or chronic toxicity assessments. New methodologies are being developed to predict these adverse effects based on in vitro and in silico approaches. This paper reviews the current state of the art in predicting these organ toxicities. It outlines the biological basis, processes and endpoints for kidney toxicity, pulmonary toxicity, respiratory irritation and sensitization as well as functional and structural cardiac toxicities. The review also covers current experimental approaches, including off-target panels from secondary pharmacology batteries. Current in silico approaches for prediction of these effects and mechanisms are described as well as obstacles to the use of in silico methods. Ultimately, a commonly accepted protocol for performing such assessment would be a valuable resource to expand the use of such approaches across different regulatory and industrial applications. However, a number of factors impede their widespread deployment including a lack of a comprehensive mechanistic understanding, limited in vitro testing approaches and limited in vivo databases suitable for modeling, a limited understanding of how to incorporate absorption, distribution, metabolism, and excretion (ADME) considerations into the overall process, a lack of in silico models designed to predict a safe dose and an accepted framework for organizing the key characteristics of these organ toxicants.

ABSTRACT Objectives Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research. Method A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library. Results Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone. Conclusions The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.

Tuberculosis is a global health dilemma. In 2016, the WHO reported 10.4 million incidences and 1.7 million deaths. The need to develop new treatments for those infected with Mycobacterium tuberculosis (Mtb) has led to many large-scale phenotypic screens and many thousands of new active compounds identified in vitro. However, with limited funding, efforts to discover new active molecules against Mtb needs to be more efficient. Several computational machine learning approaches have been shown to have good enrichment and hit rates. We have curated small molecule Mtb data and developed new models with a total of 18,886 molecules with activity cutoffs of 10 μM, 1 μM, and 100 nM. These data sets were used to evaluate different machine learning methods (including deep learning) and metrics and to generate predictions for additional molecules published in 2017. One Mtb model, a combined in vitro and in vivo data Bayesian model at a 100 nM activity yielded the following metrics for 5-fold cross validation: accuracy = 0.88, precision = 0.22, recall = 0.91, specificity = 0.88, kappa = 0.31, and MCC = 0.41. We have also curated an evaluation set (n = 153 compounds) published in 2017, and when used to test our model, it showed the comparable statistics (accuracy = 0.83, precision = 0.27, recall = 1.00, specificity = 0.81, kappa = 0.36, and MCC = 0.47). We have also compared these models with additional machine learning algorithms showing Bayesian machine learning models constructed with literature Mtb data generated by different laboratories generally were equivalent to or outperformed deep neural networks with external test sets. Finally, we have also compared our training and test sets to show they were suitably diverse and different in order to represent useful evaluation sets. Such Mtb machine learning models could help prioritize compounds for testing in vitro and in vivo.

Background: This meta analysis seeks to investigate the association between HPV and p16 status with overall survival in laryngeal and hypopharyngeal carcinoma. Methods: Medline, Scopus, EMBASE, and the Cochrane Library were used to identify studies for inclusion. Abstracts that discussed HPV/p16 status and prognosis in laryngeal or hypopharyngeal carcinoma were included. Next, full text articles were screened and included based upon a checklist established a priori. Pooled hazard ratios for overall survival were generated using a random effects model. RevMan 5.3, Meta Essentials, and OpenMeta[Analyst] were used for statistical analysis. Results: Thirteen studies published between 2014 and 2019 with sample sizes ranging from 31 to 9,656 were selected for inclusion in this meta analysis. The pooled data demonstrated that p16 status was not significantly associated with OS in either laryngeal or hypopharyngeal carcinoma with HRs of 1.03 (95% CI: 0.73, 1.45; p = 0.88) and 1.02 (95% CI: 0.55, 1.86; p = 0.96), respectively. The pooled data showed that HPV status was predictive of OS in laryngeal cancer with 0.63 (95% CI: 0.41, 0.97; p = 0.03). Conclusions: Our results suggest that p16-positivity does not provide a survival benefit in LC and HPC. This is in contrast to studies in the oropharynx, where p16 status is a standard proxy for HPV infection and HPV infection is associated with improved prognosis.

ADVERTISEMENT RETURN TO ISSUEPREVAddition and Correct...Addition and CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to "Comparing and Validating Machine Learning Models for Mycobacterium tuberculosis Drug Discovery"Thomas LaneThomas LaneMore by Thomas Lane, Daniel P. RussoDaniel P. RussoMore by Daniel P. Russo, Kimberley M. ZornKimberley M. ZornMore by Kimberley M. Zorn, Alex M. ClarkAlex M. ClarkMore by Alex M. Clark, Alexandru KorotcovAlexandru KorotcovMore by Alexandru Korotcov, Valery TkachenkoValery TkachenkoMore by Valery Tkachenko, Robert C. ReynoldsRobert C. ReynoldsMore by Robert C. Reynolds, Alexander L. PerrymanAlexander L. PerrymanMore by Alexander L. Perryman, Joel S. FreundlichJoel S. FreundlichMore by Joel S. Freundlich, and Sean Ekins*Sean EkinsMore by Sean Ekinshttps://orcid.org/0000-0002-5691-5790Cite this: Mol. Pharmaceutics 2021, 18, 7, 2833Publication Date (Web):June 17, 2021Publication History Published online17 June 2021Published inissue 5 July 2021https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.1c00428https://doi.org/10.1021/acs.molpharmaceut.1c00428correctionACS PublicationsCopyright © 2021 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views843Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (415 KB) Get e-AlertscloseSUBJECTS:Bacteria,Drug discovery,Graduate education,Machine learning,Therapeutics Get e-Alerts

Traditional experimental testing to identify endocrine disruptors that enhance estrogenic signaling relies on expensive and labor-intensive experiments. We sought to design a knowledge-based deep neural network (k-DNN) approach to reveal and organize public high-throughput screening data for compounds with nuclear estrogen receptor α and β (ERα and ERβ) binding potentials. The target activity was rodent uterotrophic bioactivity driven by ERα/ERβ activations. After training, the resultant network successfully inferred critical relationships among ERα/ERβ target bioassays, shown as weights of 6521 edges between 1071 neurons. The resultant network uses an adverse outcome pathway (AOP) framework to mimic the signaling pathway initiated by ERα and identify compounds that mimic endogenous estrogens (i.e., estrogen mimetics). The k-DNN can predict estrogen mimetics by activating neurons representing several events in the ERα/ERβ signaling pathway. Therefore, this virtual pathway model, starting from a compound's chemistry initiating ERα activation and ending with rodent uterotrophic bioactivity, can efficiently and accurately prioritize new estrogen mimetics (AUC = 0.864-0.927). This k-DNN method is a potential universal computational toxicology strategy to utilize public high-throughput screening data to characterize hazards and prioritize potentially toxic compounds.

BACKGROUND:Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES:The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS:An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS:The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION:CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495.