Review
Medicine, Legal
P. Suresh Jayasekara, Sophie K. Skanchy, Marlene T. Kim, Govindaraj Kumaran, Benon E. Mugabe, Lauren E. Woodard, Jian Yang, Andrew J. Zych, Naomi L. Kruhlak
Summary: The ICH M7 (R1) guideline recommends the use of complementary (Q)SAR models to assess mutagenic potential of drug impurities, with expert knowledge playing a crucial role in overturning and resolving predictions, especially for low confidence predictions.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2021)
Article
Medicine, Legal
Alex N. Cayley, Robert S. Foster, Alessandro Brigo, Wolfgang Muster, Alyssa Musso, Michelle O. Kenyon, Patricia Parris, Angela T. White, Mirit Cohen-Ohana, Raphael Nudelman, Susanne Glowienke
Summary: This article examines the use of in silico tools to assess the mutagenic potential of impurities and proposes a standardized method of argumentation and assessment to improve the efficiency and consistency of expert review.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2023)
Review
Environmental Sciences
Keshav Goyal, Harsh Goel, Pritika Baranwal, Aman Dixit, Fahad Khan, Niraj Kumar Jha, Kavindra Kumar Kesari, Pratibha Pandey, Avanish Pandey, Mercilena Benjamin, Ankit Maurya, Vandana Yadav, Rana Suryauday Sinh, Pranay Tanwar, Tarun Kumar Upadhyay, Sandeep Mittan
Summary: Environmental mutagens have the potential to induce a wide range of mutations in humans and can lead to physiological, biochemical, and genetic modifications. The genotoxic effects on germ cells can have lasting impacts on health, and understanding the molecular mechanisms of physical and chemical mutagens is crucial for preventing DNA damage, carcinogenesis, and other disorders affecting human health. Various tests, such as the Ames test and Mutatox test, are important for detecting mutagenic factors in the environment and ongoing research is needed to further explore the impact of environmental mutagens on humans and animals.
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
(2022)
Article
Chemistry, Applied
Christopher J. Borths, Mark D. Argentine, John Donaubauer, Eric L. Elliott, Jared Evans, Timothy Talbot Kramer, Heewon Lee, Rodney Parsons, Jeffrey C. Roberts, Gregory W. Sluggett, Andrew Teasdale, Michael Urquhart, Ke Wang, Ping Zhuang
Summary: ICH M7 provides risk-based control options for managing mutagenic and potentially mutagenic impurities, with a preference for Option 4 due to its allowance of process knowledge utilization and reduction in analytical testing. Survey data indicates that the ability of a manufacturing process to purge impurities is a strong indicator of purity control.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)
Article
Chemistry, Applied
Natasha S. Murphy, Daniel C. O'Connor, Georgina C. Gavins, Lara James, Jonathan P. Lockett, James A. McManus, Gemma Packer, Rocio Lopez-Rodriguez, Samuel J. Webb, Michael J. Burns
Summary: Synthetic routes to drug products often introduce potentially mutagenic impurities (PMIs) that need to be controlled to safe levels. Current methods of identifying the formation risks of these impurities rely on manual assessment, which can be time-consuming and prone to oversight. In this study, an in silico risk assessment tool was developed to facilitate the identification of synthetic stages that introduce the risk of PMI formation.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Article
Toxicology
Jie Yin, Hairuo Wen, Hua Chen
Summary: Toxicity evaluation of main zopiclone impurities was conducted using forced degradation and high-performance liquid chromatography (HPLC) analysis. QSAR models were used to compare the toxicity, particularly the genotoxicity, of two main zopiclone degradation impurities. The results showed that 2-amino-5-chloropyridine had the highest toxicity in zebrafish embryo development. Recommendation was made to increase the control limit of this impurity in zopiclone materials and preparations to ensure safety and quality control.
JOURNAL OF APPLIED TOXICOLOGY
(2023)
Article
Engineering, Environmental
Elisabeth Cuervo Lumbaque, Diogo S. Ludtke, Dionysios D. Dionysiou, Vitor J. P. Vilar, Carla Sirtori
Summary: A tube-in-tube membrane photoreactor was proposed to enhance the efficiency of peroxydisulfate treatment, using UV-C radiation and TiO2P25 processes. Tests were conducted to analyze the removal of pharmaceuticals and identify transformation products, suggesting potential pathways of hydroxylation and other reactions.
Article
Chemistry, Multidisciplinary
Stefanie Lorenz, Ann-Kathrin Amsel, Neele Puhlmann, Marco Reich, Oliver Olsson, Klaus Kuemmerer
Summary: To prevent adverse effects of chemicals and pharmaceuticals in the environment, substances should be designed for full mineralization at the end of their life with the use of computational tools to reduce animal testing and chemical waste.
ACS SUSTAINABLE CHEMISTRY & ENGINEERING
(2021)
Review
Genetics & Heredity
Ayaka Furukawa, Satoshi Ono, Katsuya Yamada, Nao Torimoto, Mahoko Asayama, Shigeharu Muto
Summary: This study developed a shareable QSAR tool based on nitrenium ion stability and evaluated its prediction accuracy using in-house aromatic amine intermediates. The results showed that the tool has comparable performance to commercial QSAR tools and can provide quantitative indicators to support expert review. This local QSAR tool is useful for explaining the substituent effects on the mutagenicity of primary aromatic amines.
GENES AND ENVIRONMENT
(2022)
Article
Reproductive Biology
Geertje Lewin, Madeleine Joel, Birgit Peter, Manfred Lutzow
Summary: Safflower petals have been used traditionally in spice, tea blends, and medicine. Concerns have been raised regarding potential toxicity, but further evaluation showed no adverse effects on fertility, maternal health, or prenatal development.
REPRODUCTIVE TOXICOLOGY
(2021)
Article
Medicine, Legal
Kamila Gromek, William Hawkins, Zoe Dunn, Maciej Gawlik, Davide Ballabio
Summary: This study assessed and compared the predictions of various tools in predicting globally harmonized system and dangerous goods classifications based on lethal dose. The predictions showed good performance in identifying non-toxic compounds, which is useful for chemical classification, prioritizing toxicity assessments, and reducing animal use. However, the prediction of category-to-category was not ideal and could be improved by including expert review and read-across to similar substances.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Srinivas Nakka, Siva Krishna Muchakayala, Surendra Babu Manabolu Surya
Summary: Two potential genotoxic impurities were identified in the Molnupiravir synthetic routes. (Q)SAR methods were used to assess their genotoxicity and MRM technique was utilized for quantification. A validated UPLC-MS/MS method demonstrated excellent linearity and accuracy for the simultaneous quantification of the impurities and MOPR in drug substance and formulation dosage form.
RESULTS IN CHEMISTRY
(2023)
Article
Medicine, Legal
Joel Bercu, Melisa J. Masuda-Herrera, Alejandra Trejo-Martin, Catrin Hasselgren, Jean Lord, Jessica Graham, Matthew Schmitz, Lawrence Milchak, Colin Owens, Surya Hari Lal, Richard Marchese Robinson, Sarah Whalley, Phillip Bellion, Anna Vuorinen, Kamila Gromek, William A. Hawkins, Iris van de Gevel, Kathleen Vriens, Raymond Kemper, Russell Naven, Pierre Ferrer, Glenn J. Myatt
Summary: This study evaluated the accuracy and applicability of AOT in silico models provided by Leadscope software, demonstrating their reliability across different industrial sectors. Additionally, the importance of expert review and guidance on using these models to meet testing requirements, GHS classification/labelling, and transportation needs was emphasized.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Rita Schoeny, Kevin P. Cross, David M. DeMarini, Rosalie Elespuru, Atsushi Hakura, Dan D. Levy, Richard V. Williams, Errol Zeiger, Patricia A. Escobar, Jonathan R. Howe, Masayuki Kato, Jasmin Lott, Martha M. Moore, Stephanie Simon, Leon F. Stankowski, Kei-ichi Sugiyama, Bas-jan M. van der Leede
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
(2020)
Article
Medicine, Legal
Jae Wook Yoo, Naomi L. Kruhlak, Curran Landry, Kevin P. Cross, Alexander Sedykh, Lidiya Stavitskaya
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2020)
Article
Medicine, Legal
Catrin Hasselgren, Joel Bercu, Alex Cayley, Kevin Cross, Susanne Glowienke, Naomi Kruhlak, Wolfgang Muster, John Nicolette, M. Vijayaraj Reddy, Roustem Saiakhov, Krista Dobo
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2020)
Article
Medicine, Legal
Candice Johnson, Ernst Ahlberg, Lennart T. Anger, Lisa Beilke, Romualdo Benigni, Joel Bercu, Sol Bobst, David Bower, Alessandro Brigo, Sarah Campbell, Mark T. D. Cronini, Ian Crooks, Kevin P. Cross, Tatyana Doktorova, Thomas Exner, David Faulkner, Ian M. Fearon, Markus Fehr, Shayne C. Gad, Veronique Gervais, Amanda Giddings, Susanne Glowienke, Barry Hardy, Catrin Hasselgren, Jedd Hillegass, Robert Jolly, Eckart Krupp, Liat Lomnitski, Jason Magby, Jordi Mestres, Lawrence Milchak, Scott Miller, Wolfgang Muster, Louise Neilson, Rahul Parakhia, Alexis Parentys, Patricia Parris, Alexandre Paulino, Ana Theresa Paulino, David W. Roberts, Harald Schlecker, Reinhard Stidl, Diana Suarez-Rodrigez, David T. Szabo, Raymond R. Tice, Daniel Urbisch, Anna Vuorinen, Brian Wall, Thibaud Weiler, Angela T. White, Jessica Whritenour, Joerg Wichard, David Woolley, Craig Zwickl, Glenn J. Myatt
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2020)
Article
Medicine, Legal
Joel P. Bercu, Melisa Masuda-Herrera, George Johnson, Andreas Czich, Susanne Glowienke, Michelle Kenyon, Rob Thomas, David J. Ponting, Angela White, Kevin Cross, Fernanda Waechter, Maria Augusta C. Rodrigues
Summary: The ICH M7 framework provides a method to evaluate potential carcinogenic risk to patients, and controlling impurities like N-nitrosamines is demonstrated to be effective for patient safety.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2021)
Article
Toxicology
Arianna Bassan, Vinicius M. Alves, Alexander Amberg, Lennart T. Anger, Lisa Beilke, Andreas Bender, Autumn Bernal, Mark T. D. Cronin, Jui-Hua Hsieh, Candice Johnson, Raymond Kemper, Moiz Mumtaz, Louise Neilson, Manuela Pavan, Amy Pointon, Julia Pletz, Patricia Ruiz, Daniel P. Russo, Yogesh Sabnis, Reena Sandhu, Markus Schaefer, Lidiya Stavitskaya, David T. Szabo, Jean-Pierre Valentin, David Woolley, Craig Zwickl, Glenn J. Myatt
Summary: Current methodologies are being developed to predict kidney, heart, and lung toxicities based on in vitro and in silico approaches, but face obstacles such as a lack of comprehensive mechanistic understanding, limited in vitro testing approaches, and limited in vivo databases suitable for modeling.
COMPUTATIONAL TOXICOLOGY
(2021)
Article
Toxicology
Arianna Bassan, Vinicius M. Alves, Alexander Amberg, Lennart T. Anger, Scott Auerbach, Lisa Beilke, Andreas Bender, Mark T. D. Cronin, Kevin P. Cross, Jui-Hua Hsieh, Nigel Greene, Raymond Kemper, Marlene T. Kim, Moiz Mumtaz, Tobias Noeske, Manuela Pavan, Julia Pletz, Daniel P. Russo, Yogesh Sabnis, Markus Schaefer, David T. Szabo, Jean-Pierre Valentin, Joerg Wichard, Dominic Williams, David Woolley, Craig Zwickl, Glenn J. Myatt
Summary: Hepatotoxicity is a common adverse effect observed from exposure to xenobiotics, particularly in pharmaceutical research where it can lead to drug withdrawals, clinical failures, and discontinuation of drug candidates. More sustainable and informative methods for assessing hepatotoxicity are critically needed.
COMPUTATIONAL TOXICOLOGY
(2021)
Article
Toxicology
Kevin M. Crofton, Arianna Bassan, Mamta Behl, Yaroslav G. Chushak, Ellen Fritsche, Jeffery M. Gearhart, Mary Sue Marty, Moiz Mumtaz, Manuela Pavan, Patricia Ruiz, Magdalini Sachana, Rajamani Selvam, Timothy J. Shafer, Lidiya Stavitskaya, David T. Szabo, Steven T. Szabo, Raymond R. Tice, Dan Wilson, David Woolley, Glenn J. Myatt
Summary: Neurotoxicology focuses on studying the adverse effects of exposure to chemical, biological, or physical agents on the nervous system, and there is a need for alternative methods to assess these effects. The research emphasizes on using computer-assisted methods to predict neurotoxicity based on chemical structure, which must be integrated with experimental information to ensure transparency and consistency in assessments.
COMPUTATIONAL TOXICOLOGY
(2022)
Editorial Material
Toxicology
Kevin P. Cross, Candice Johnson, Glenn J. Myatt
COMPUTATIONAL TOXICOLOGY
(2022)
Article
Medicine, Legal
Alejandra Trejo-Martin, Joel P. Bercu, Andrew Thresher, Rachael E. Tennant, Robert F. Thomas, Kevin Cross, Andreas Czich, Kerstin Waese, John J. Nicolette, Joel Murray, Paul Sonders, Alison Kondratiuk, Jennifer R. Cheung, Dean Thomas, Anthony Lynch, James Harvey, Susanne Glowienke, Laura Custer, Patricia A. Escobar
Summary: The Ames test showed high sensitivity in predicting the carcinogenic hazards of N-nitrosamines (NAs) in pharmaceuticals, regardless of different experimental conditions.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Sadegh Faramarzi, Marlene T. T. Kim, Donna A. A. Volpe, Kevin P. P. Cross, Suman Chakravarti, Lidiya Stavitskaya
Summary: Two statistical-based quantitative structure-activity relationship (QSAR) models were developed in this study to predict drug permeability across the blood-brain barrier (BBB). By using in vivo data and cross-validation, these models showed good performance in sensitivity and negative predictivity, making them a useful tool to reduce the use of experimental animals.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Medicine, General & Internal
Kimberly Chiu, Rebecca Racz, Keith Burkhart, Jeffry Florian, Kevin Ford, M. Iveth Garcia, Robert M. M. Geiger, Kristina E. E. Howard, Paula L. L. Hyland, Omnia A. A. Ismaiel, Naomi L. L. Kruhlak, Zhihua Li, Murali K. K. Matta, Kristin W. W. Prentice, Aanchal Shah, Lidiya Stavitskaya, Donna A. A. Volpe, James L. L. Weaver, Wendy W. W. Wu, Rodney Rouse, David G. G. Strauss
Summary: The U.S. FDA's Division of Applied Regulatory Science (DARS) incorporates new science into drug reviews and addresses regulatory and public health issues. By forming interdisciplinary teams, DARS conducts critical research to provide answers and solutions to scientific questions and regulatory challenges. This article reviews DARS-led research projects and highlights its impactful work.
FRONTIERS IN MEDICINE
(2023)
Article
Chemistry, Medicinal
Paween Mahinthichaichan, Ruibin Liu, Quynh N. Vo, Christopher R. Ellis, Lidiya Stavitskaya, Jana Shen
Summary: In 2021, the nation witnessed a record high of opioid overdose deaths, primarily due to synthetic opioids such as fentanyl. Understanding the residence time of opioids is crucial for evaluating the effectiveness of naloxone, a FDA-approved reversal agent. This study estimated the residence times of various fentanyl and morphine analogs and compared them with recent measurements of opioid kinetic properties and naloxone inhibitory constants. Microscopic simulations provided insights into the binding mechanism and molecular determinants of dissociation kinetics for fentanyl analogs, leading to the development of a machine learning approach for analyzing the kinetic impact of fentanyl's substituents.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Medicine, Legal
Fiona Sewell, Ian Ragan, Graham Horgan, David Andrew, Thomas Holmes, Irene Manou, Boris P. Mueller, Tim Rowan, Barbara G. Schmitt, Marco Corvaro
Summary: There are currently three test guidelines for acute oral toxicity studies, but the subjectivity of one guideline may be hindering its wider use. In order to address this, the NC3Rs and EPAA collaborated to analyze historical data and provide recommendations on the recognition of 'evident toxicity'.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2024)
Article
Medicine, Legal
Michael DeVito, Bas Bokkers, Majorie B. M. van Duursen, Karin van Ede, Mark Feeley, Elsa Antunes Fernandes Gaspar, Laurie Haws, Sean Kennedy, Richard E. Peterson, Ron Hoogenboom, Keiko Nohara, Kim Petersen, Cynthia Rider, Martin Rose, Stephen Safe, Dieter Schrenk, Matthew W. Wheeler, Daniele S. Wikoff, Bin Zhao, Martin van den Berg
Summary: In October 2022, the World Health Organization reevaluated the toxic equivalency factors (TEFs) for chlorinated dioxin-like compounds in a panel convened in Lisbon. This effort utilized an updated database, Bayesian dose response modeling, and meta-analysis to derive Best-Estimate TEFs. Applying these new TEFs may result in lower total toxic equivalents for dioxin-like chemicals.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2024)