CATMoS: Collaborative Acute Toxicity Modeling Suite

Mansouri, Kamel; Karmaus, Agnes L.; Fitzpatrick, Jeremy; Patlewicz, Grace; Pradeep, Prachi; Alberga, Domenico; Alépée, Nathalie; Allen, Timothy E. H.; Allen, Dave; Alves, Vinicius M.; Andrade, Carolina Horta; Auernhammer, Tyler; Ballabio, Davide; Bell, Shannon; Benfenati, Emilio; Bhattacharya, Sudin; Bastos, Joyce V.; Boyd, Stephen A.; Brown, J.B.; Capuzzi, Stephen J.; Chushak, Yaroslav; Ciallella, Heather L; Clark, Alex M.; Consonni, Viviana; Daga, Pankaj; Ekins, Sean; Farag, Sherif; Fedorov, Maxim V.; Fourches, Denis; Gadaleta, Domenico; Gao, Feng; Gearhart, Jeffery M.; Goh, Garett; Goodman, Jonathan M.; Grisoni, Francesca; Grulke, Christopher M.; Hartung, Thomas; Hirn, Matthew; Karpov, Pavel; Korotcov, Alexandru; Lavado, Giovanna J.; Lawless, M.; Li, Xinhao; Luechtefeld, Thomas; Lunghini, Filippo; Mangiatordi, Giuseppe Felice; Marcou, Gilles; Marsh, Dan H.; Martin, Todd M.; Mauri, Andrea; Muratov, Eugene; Myatt, Glenn J.; Nguyễn, Ðắc-Trung; Nicolotti, Orazio; Note, Reine; Pande, Paritosh; Parks, Amanda K.; Peryea, Tyler; Polash, Ahsan Habib; Ralló, Robert; Roncaglioni, Alessandra; Rowlands, Craig; Ruíz, Patricia; Russo, Daniel P.; Sayed, Ahmed E; Sayre, Risa; Sheils, Timothy; Siegel, Charles; Silva, Arthur C.; Simeonov, Anton; Sosnin, Sergey; Southall, Noel; Strickland, Judy; Tang, Yun; Teppen, Brian J.; Tetko, Igor V.; Thomas, Dennis; Tkachenko, Valery; Todeschini, Roberto; Toma, Cosimo; Tripodi, Ignacio J.; Trisciuzzi, Daniela; Tropsha, Alexander; Varnek, Alexandre; Vuković, Kristijan; Wang, Zhongyu; Wang, Liguo; Waters, Katrina M.; Wedlake, Andrew J.; Wijeyesakere, Sanjeeva J.; Wilson, Dan; Xiao, Zijun; Yang, Hong-Chang; Zahoránszky-Kőhalmi, Gergely; Zakharov, Alexey; Zhang, Fagen F.; Zhang, Zhen; Zhao, Tongan; Zhu, Hao; Zorn, Kimberley M.; Casey, Warren; Kleinstreuer, Nicole

doi:10.1289/ehp8495

Cited by 66 publications

(51 citation statements)

References 81 publications

(46 reference statements)

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“…For example, 73% of the structural clusters containing at least one toxic chemical includes chemicals from at most two GHS categories. These findings are consistent with the previously published evaluations of the CATMoS model ( Mansouri et al, 2021 ) and the related QSAR efforts ( Alberga et al, 2019 ; Ballabio et al, 2019 ; Gadaleta et al, 2019 ). They also highlight the potential value of mechanism-based profilers ( Wijeyesakere et al, 2018 ; Wilson et al, 2018 ).…”

Section: Discussionsupporting

confidence: 93%

“…Of these, 2028 chemicals were classified as active and 1929 showed no activity. Comparison of the ToxCast activity assessment against a binary classification of toxicity ( Mansouri et al, 2021 ) showed a highly significant association ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…For this curation effort, the LD50 values represent the dose that is lethal for 50% of the animals in a rat acute oral toxicity study ( Karmaus et al, 2019 ). These data were collected from a variety of publicly available data sources, including, but not limited to ChemIDplus, the European Commission Joint Research Council’s Acutetoxbase, and OECD’s eChemPortal ( Kleinstreuer et al, 2018b ; NTP, 2018 ; Karmaus et al, 2019 ; Mansouri et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…Research supporting the use of existing data and in silico approaches to predict acute oral toxicity of mixtures has been successful as well ( Chushak et al, 2021 ; Hamm et al, 2021 ). Computational modeling was a key focus area ( Kleinstreuer et al, 2018b ) and a large international effort resulted in CATMoS ( Mansouri et al, 2021 ). The Department of Defense has begun implementation of the tiered testing paradigm recommended by the National Academy ( National Academies of Sciences, 2015 ; Sullivan et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Mapping Mechanistic Pathways of Acute Oral Systemic Toxicity Using Chemical Structure and Bioactivity Measurements

et al. 2022

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Regulatory agencies around the world have committed to reducing or eliminating animal testing for establishing chemical safety. Adverse outcome pathways can facilitate replacement by providing a mechanistic framework for identifying the appropriate non-animal methods and connecting them to apical adverse outcomes. This study separated 11,992 chemicals with curated rat oral acute toxicity information into clusters of structurally similar compounds. Each cluster was then assigned one or more ToxCast/Tox21 assays by looking for the minimum number of assays required to record at least one positive hit call below cytotoxicity for all acutely toxic chemicals in the cluster. When structural information is used to select assays for testing, none of the chemicals required more than four assays and 98% required two assays or less. Both the structure-based clusters and activity from the associated assays were significantly associated with the GHS toxicity classification of the chemicals, which suggests that a combination of bioactivity and structural information could be as reproducible as traditional in vivo studies. Predictivity is improved when the in vitro assay directly corresponds to the mechanism of toxicity, but many indirect assays showed promise as well. Given the lower cost of in vitro testing, a small assay battery including both general cytotoxicity assays and two or more orthogonal assays targeting the toxicological mechanism could be used to improve performance further. This approach illustrates the promise of combining existing in silico approaches, such as the Collaborative Acute Toxicity Modeling Suite (CATMoS), with structure-based bioactivity information as part of an efficient tiered testing strategy that can reduce or eliminate animal testing for acute oral toxicity.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mapping Mechanistic Pathways of Acute Oral Systemic Toxicity Using Chemical Structure and Bioactivity Measurements

et al. 2022

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“…The acute oral toxicity data set was retrieved from the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) workshop for the Collaborative Acute Toxicity Modeling Suite (CATMoS) project that our team was part of ( ICCVAM 2019 ; Kleinstreuer et al. 2018 ; Mansouri et al. 2021 ).…”

Section: Methodsmentioning

confidence: 99%

STopTox: An in Silico Alternative to Animal Testing for Acute Systemic and Topical Toxicity

Borba

Alves

Braga³

et al. 2022

Environ Health Perspect

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Occupational Toxicology in the Pharmaceutical Industry

Dolan

Bercu

Graham³

et al. 2023

Patty's Toxicology

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Much of the activity in the pharmaceutical industry has its origins in the fine chemicals industry of the late nineteenth century. At that time, advances in chemistry and medicine led to the manufacture of pharmacologically active small molecules to produce desirable biological effects to treat diseases and illnesses at relatively low doses. Advances in biology and chemistry in the past quarter century have led to an increase in innovation resulting in a variety of novel modalities, especially recombinant proteins, antibody‐drug conjugates, cell and gene therapies, peptides and polypeptides, oligonucleotides, and vaccines. The roles and responsibilities of occupational toxicologists in the pharmaceutical industry have expanded dramatically in the twenty‐first century, commensurate with the changing regulatory requirements and treatment modalities. The occupational toxicologists' roles have become increasingly multidisciplinary and the scope of their involvement has expanded to encompass diverse aspects of worker safety as well as patient safety, and to include involvement throughout a molecule's development, from early development through postcommercialization.

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CATMoS: Collaborative Acute Toxicity Modeling Suite

Cited by 66 publications

References 81 publications

Mapping Mechanistic Pathways of Acute Oral Systemic Toxicity Using Chemical Structure and Bioactivity Measurements

Mapping Mechanistic Pathways of Acute Oral Systemic Toxicity Using Chemical Structure and Bioactivity Measurements

STopTox: An in Silico Alternative to Animal Testing for Acute Systemic and Topical Toxicity

Occupational Toxicology in the Pharmaceutical Industry

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