Review
Pharmacology & Pharmacy
Abdallah Ladaycia, Brigitta Loretz, Catherine Passirani, Claus-Michael Lehr, Elise Lepeltier
Summary: Nanomedicine has attracted significant attention in cancer treatment and diagnosis studies, but only a few have successfully passed clinical trials. The human microbiota plays a crucial role in cancer development, and utilizing nanoparticles to modulate the microbiota may improve the translation of nanomedicine from preclinical to clinical trials. Co-culture models of bacteria and cancer cells, as well as animal cancer-microbiota models, offer a more representative tumor microenvironment for testing nanomedicine efficacy in cancer treatment. These models provide a closer representation of human cancer and may facilitate the transition from preclinical to clinical studies for nanomedicine efficacy.
ADVANCED DRUG DELIVERY REVIEWS
(2021)
Article
Engineering, Environmental
Matthew Schultz, Sophia Krause, Markus Brinkmann
Summary: In vitro biotransformation assays combined with IVIVE models have been proposed as an alternative to live fish bioconcentration studies. The hepatic clearances of five chemicals were investigated using an isolated perfused trout liver model, and the measured rates were compared to intrinsic clearances for validation of IVIVE models. The results show that current IVIVE methods can reliably predict in vivo clearance rates and indicate that discrepancies from measured bioconcentration factors might be driven by other processes.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2022)
Article
Biotechnology & Applied Microbiology
Jules Dichamp, Geraldine Celliere, Ahmed Ghallab, Reham Hassan, Noemie Boissier, Ute Hofmann, Joerg Reinders, Selahaddin Sezgin, Sebastian Zuehlke, Jan G. Hengstler, Dirk Drasdo
Summary: In this paper, the author explores extrapolation strategies for acetaminophen (APAP) based on mechanistic models and compares different model types. The research shows that a classical homogeneous compartment model can accurately predict in vivo toxicity from in vitro data. However, a spatial-temporal multiscale model, which integrates more experimental information, requires adjustments to achieve the same prediction, suggesting the importance of spatial compartmentalization.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2023)
Article
Pharmacology & Pharmacy
Karol Jaroch, Paulina Taczynska, Marta Czechowska, Joanna Bogusiewicz, Kamil Luczykowski, Katarzyna Burlikowska, Barbara Bojko
Summary: Solid phase microextraction (SPME) combined with high-resolution mass spectrometry was used to determine the metabolomic profile of mouse melanoma in different models. The multi-model approach allowed for time profile analysis and reduced the number of animals used, with the highest number of compounds detected in the in vitro 2D model.
JOURNAL OF PHARMACEUTICAL ANALYSIS
(2021)
Article
Chemistry, Multidisciplinary
Zhoumeng Lin, Santosh Aryal, Yi-Hsien Cheng, Andre J. Gesquiere
Summary: This review article critically evaluates existing studies on in vivo pharmacokinetic properties, in vitro cellular uptake and release kinetics, and whole-body physiologically based pharmacokinetic (PBPK) modeling studies of different nanomaterials (NMs). It discusses methods for simulating in vitro and in vivo dosimetry of NMs and shares perspectives on current challenges and future directions. The article proposes a Nano-IVIVE-PBPK framework for high-throughput screening of target dosimetry and potential toxicity of NMs.
Review
Pharmacology & Pharmacy
Leslie Z. Benet, Jasleen K. Sodhi
Summary: The study identifies misconceptions and poorly understood aspects of human clearance and IVIVE processes, suggesting that there is no theoretical basis for the success of IVIVE. It concludes that commonly employed clearance concepts and IVIVE approaches have limitations, and proposes recommendations for improving the IVIVE process.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Environmental Sciences
John W. W. Nichols, Patrick N. N. Fitzsimmons, Alex D. D. Hoffman, Kameron Wong
Summary: Computational models for predicting chemical bioaccumulation in fish often use an apparent first-order whole-body rate constant (k(B); d(-1)) to account for biotransformation. Estimating k(B) without exposing live animals is challenging. One possible method is to extrapolate in vitro intrinsic clearance (CLIN VITRO,INT) to the whole animal (in vitro-in vivo extrapolation, [IVIVE]). However, the accuracy of these predictions is difficult to assess due to uncertainties in extrapolation factors and fish mismatch between in vitro and in vivo experiments.
ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY
(2023)
Article
Immunology
Kata Horvati, Kinga Fodor, Bernadett Palyi, Judit Henczko, Gyula Balka, Gergo Gyulai, Eva Kiss, Beata Biri-Kovacs, Zsuzsanna Senoner, Szilvia Bosze
Summary: Tuberculosis is characterized by the ability of Mycobacterium tuberculosis to enter a dormant state within host cells, leading to long-term persistence and resistance to traditional antimicrobial drugs. Novel compounds or drug conjugates are needed to target the intracellular form of the bacteria. Experimental approaches combining in vitro and in vivo studies have been used to evaluate potential drug candidates, showing promise for the development of innovative anti-tuberculosis agents.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Computer Science, Interdisciplinary Applications
Suein Choi, Sungpil Han, So Jin Lee, Byunghee Lim, Soo Hyeon Bae, Seunghoon Han, Dong-Seok Yim
Summary: The article introduces a user-friendly open tool named Dall-phinAtoM for predicting human pharmacokinetics. The tool integrates references on PBPK and allometric methods and supports data integration, translation from animal to human, and prediction of concentration-time profiles.
COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE
(2022)
Article
Medicine, Research & Experimental
Sumit Arora, James Clarke, Eleftheria Tsakalozou, Priyanka Ghosh, Khondoker Alam, Jeffery E. Grice, Michael S. Roberts, Masoud Jamei, Sebastian Polak
Summary: This study developed a stepwise modeling workflow using IVPT data and PBPK modeling to describe the in vivo exposure of metronidazole in the stratum corneum following topical application of complex semisolid drug products. The optimized model accurately predicted metronidazole permeation profiles and provided an enhanced understanding of the impact of drug product attributes on in vitro skin permeation.
MOLECULAR PHARMACEUTICS
(2022)
Article
Pharmacology & Pharmacy
David E. Hines, Shannon Bell, Xiaoqing Chang, Kamel Mansouri, David Allen, Nicole Kleinstreuer
Summary: Traditional toxicology testing relies on in vivo methods, but there is growing interest in using in vitro and in silico methods to fill data gaps. In vitro to in vivo extrapolation (IVIVE) utilizes physiologically based pharmacokinetic (PBPK) models to estimate tissue-level chemical concentrations. However, the extensive data requirements of these models limit their routine use in in vitro testing.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Environmental Sciences
Marc A. A. Beal, Marc Audebert, Tara Barton-Maclaren, Hannah Battaion, Jeffrey C. C. Bemis, Xuefei Cao, Connie Chen, Stephen D. D. Dertinger, Roland Froetschl, Xiaoqing Guo, George Johnson, Giel Hendriks, Laure Khoury, Alexandra S. S. Long, Stefan Pfuhler, Raja S. S. Settivari, Shamika Wickramasuriya, Paul White
Summary: Genotoxicity assessment plays a crucial role in chemical development and evaluation. Traditional assays have limitations in hazard classification and quantifying toxicity. Novel high-throughput in vitro assays offer a powerful approach for potency ranking and risk assessment. In this study, the use of in vitro to in vivo extrapolation models demonstrated protective dose levels for 20 out of 31 chemicals, indicating the potential of this testing strategy in enhancing prioritization and risk assessment of genotoxic chemicals.
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
(2023)
Article
Medicine, Research & Experimental
Hong Yang, Ivy Xue, Qimei Gu, Peng Zou, Tao Zhang, Yanhui Lu, Jeffery Fisher, Doanh Tran
Summary: In this study, an IVIVE model was developed to predict the human milk/plasma drug concentration ratios, showing superior prediction accuracy compared to previous models. The model performed well in predicting passive diffusion drugs but had lower accuracy for P-gp substrates.
MOLECULAR PHARMACEUTICS
(2022)
Review
Pharmacology & Pharmacy
Claire Steinbronn, Xinning Yang, Jingjing Yu, Hristina Dimova, Shiew-Mei Huang, Isabelle Ragueneau-Majlessi, Nina Isoherranen
Summary: This study reviewed 120 new molecular entities approved between 2013 and 2018 and identified 15 metabolites with potential drug-drug interaction risk based on cytochrome P450 (CYP) inhibition experiments.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Engineering, Environmental
Kai Huang, Wei Zhou, Jie Fu, Qun Zhang, Yunhe Teng, Luyao Gu, Yilin Fu, Boyuan Hu, Yang Mei, Haiyan Zhang, Aiqian Zhang, Jianjie Fu, Guibin Jiang
Summary: This study establishes a quantitative in vitro to in vivo extrapolation method to quantify the effect of transthyretin (TTR)-binding chemicals on free thyroid hormones in human blood. The results show that exposure to TTR-binding chemicals can increase the levels of free thyroid hormones in the body, providing a new framework for risk assessment of endocrine-disrupting chemicals.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2023)
Article
Pharmacology & Pharmacy
Anthony W. Harrington, Changlu Liu, Naomi Phillips, Diane Nepomuceno, Chester Kuei, Joseph Chang, Weixuan Chen, Steven W. Sutton, Daniel O'Malley, Ly Pham, Xiang Yao, Siquan Sun, Pascal Bonaventure
Summary: The study suggests that oxysterols, including 24S-HC, could be physiological activators for GPR17, regulating oligodendrocyte progenitor cell differentiation and myelination through receptor activation.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Toxicology
Marina V. Evans, Thomas E. Moxon, Guoping Lian, Benjamin N. Deacon, Tao Chen, Linda D. Adams, Annabel Meade, John F. Wambaugh
Summary: This study investigates the applicability of the Potts-Guy equation in different human skin datasets and proposes an updated regression equation that combines mechanistic and structural activity relationships. The results show that the Potts-Guy equation is more applicable to experiments focused on the epidermis, while it performs poorly for dermatomed skin and full skin. The combination approach results in improved regression fit compared to the Potts-Guy approach alone.
JOURNAL OF APPLIED TOXICOLOGY
(2023)
Article
Environmental Sciences
Risa R. Sayre, R. Woodrow Setzer, Marc L. Serre, John F. Wambaugh
Summary: This study evaluates the impact of data curation and statistical practices on surface water concentration of organic chemicals, and proposes a method for ranking potential risks. The results show a wide range of organic chemical concentrations across the United States and identify chemicals that may pose higher environmental risks.
JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY
(2023)
Article
Environmental Sciences
Kristin M. Eccles, Agnes L. Karmaus, Nicole C. Kleinstreuer, Fred Parham, Cynthia Rider, John F. Wambaugh, Kyle P. Messier
Summary: This study establishes a workflow to assess the joint action of 41 modeled ambient chemical exposures by integrating human exposures and hazard data. It exemplifies the proof-of-concept using CYP1A1 mRNA up-regulation and uses multiple modeling methods to estimate the joint effect of the chemical mixture on activity levels. A Monte Carlo uncertainty analysis is performed to quantify the influence of each parameter on the combined effects.
SCIENCE OF THE TOTAL ENVIRONMENT
(2023)
Article
Environmental Sciences
Daniel E. Dawson, Christopher Lau, Prachi Pradeep, Risa R. Sayre, Richard S. Judson, Rogelio Tornero-Velez, John F. Wambaugh
Summary: In this study, a random forest method was used to model the t(1/2) of PFAS across four species and eleven compounds. A classification model for t(1/2) was developed, and the t(1/2) of 3890 compounds was predicted. This model provides a basis for tentative extrapolation and prioritization.
Article
Toxicology
Fabrice A. Muller, Marianna Stamou, Felix H. Englert, Ole Frenzel, Sabine Diedrich, Laura Suter-Dick, John F. Wambaugh, Shana J. Sturla
Summary: In this study, a combination of in vitro and in silico models were used to identify chemicals that may induce lipid accumulation and hepatotoxicity. High-content imaging was used to quantify cellular markers in chemically exposed human liver cells, and extrapolation of human oral equivalent doses was performed using computational models. Known steatosis-inducing chemicals as well as food-related chemicals were characterized, and orotic acid was confirmed to induce hepatotoxicity.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Chemistry, Medicinal
Marci Smeltz, John F. Wambaugh, Barbara A. Wetmore
Summary: New approaches using in vitro screening and in silico approaches, rely on in vitro toxicokinetic (TK) data to evaluate chemical substances. The evaluation of 71 PFAS compounds was conducted to understand their plasma protein binding (PPB) by ultracentrifugation with liquid chromatography-mass spectrometry analysis. Results showed that over half of the PFAS compounds had PPB exceeding 99.5%, and binding was lower for longer carbon chain length PFCAs. Bayesian modeling was used to provide uncertainty bounds for incorporation into TK modeling. This evaluation greatly expands our current knowledge and will aid in PFAS NAM development.
CHEMICAL RESEARCH IN TOXICOLOGY
(2023)
Article
Environmental Sciences
Stephanie L. Smith-Roe, Carol D. Swartz, Asma Rashid, Nicholas C. Christy, Jamie E. Sly, Xiaoqing Chang, Nisha S. Sipes, Keith R. Shockley, Shawn F. Harris, Sandra J. McBride, Gary J. Larson, Bradley J. Collins, Esra Mutlu, Kristine L. Witt
Summary: Glyphosate, the most widely used herbicide, is not found to be toxic, but the toxicity may be related to other components in the formulations.
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
(2023)
Article
Engineering, Environmental
Jeffrey M. Minucci, S. Thomas Purucker, Kristin K. Isaacs, John F. Wambaugh, Katherine A. Phillips
Summary: A high-throughput, data-driven approach using a Bayesian hierarchical model has been developed to estimate occupational exposure by predicting the distribution of workplace air concentrations based on industry type and the physicochemical properties of a substance. This model outperforms a null model in predicting substance detection and concentration, achieving 75.9% classification accuracy and a RMSE of 1.00 log10 mg m-3. It can also be used to predict air concentration distributions for new substances and improve occupational exposure consideration in risk-based chemical prioritization efforts.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2023)
Article
Environmental Sciences
Kristin K. Isaacs, Jonathan T. Wall, Katie Paul Friedman, Jill A. Franzosa, Helen Goeden, Antony J. Williams, Kathie L. Dionisio, Jason C. Lambert, Monica Linnenbrink, Amar Singh, John F. Wambaugh, Alexander R. Bogdan, Christopher Greene
Summary: The Minnesota Department of Health has partnered with the U.S. Environmental Protection Agency to develop an automated workflow for screening potential drinking water contaminants. This workflow utilizes multiple data sources and quantitative algorithms to quickly evaluate the toxicity and exposure potential of chemicals, allowing for efficient prioritization of further assessments. This workflow is a valuable tool for resource-saving, expanding screening capabilities, and selecting candidates for contaminant assessment programs.
JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Jo Nyffeler, Clinton Willis, Felix R. Harris, M. J. Foster, Bryant Chambers, Megan Culbreth, Richard E. Brockway, Sarah Davidson -Fritz, Daniel Dawson, Imran Shah, Katie Paul Friedman, Dan Chang, Logan J. Everett, John F. Wambaugh, Grace Patlewicz, Joshua A. Harrill
Summary: 'Cell Painting' is an imaging-based high-throughput phenotypic profiling method that uses fluorescent labeling of cultured cells to visualize subcellular structures and quantify morphological changes in response to chemicals. This cost-effective bioactivity screening method allows for rapid hazard assessment of thousands of chemicals by detecting effects associated with various molecular mechanisms in an untargeted manner.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2023)
Article
Cell Biology
Hua-Rong Lu, Manabu Seo, Mohamed Kreir, Tetsuya Tanaka, Rie Yamoto, Cristina Altrocchi, Karel van Ammel, Fetene Tekle, Ly Pham, Xiang Yao, Ard Teisman, David J. Gallacher
Summary: Drug-induced seizure risk is a significant safety concern in drug development, leading to increased costs and delays. This study investigated the use of fluorescent dyes to measure changes in calcium oscillations in hiPSC-derived neurons co-cultured with primary astrocytes in 2D and 3D forms as a potential indicator of seizure risk. The results showed high accuracy in identifying drugs with seizure risk using this approach in 2D cultures compared to 3D cultures.
Article
Biochemistry & Molecular Biology
Dieter Van de Sande, Mohammadreza Ghasemi, Taylor Watters, Francis Burton, Ly Pham, Cristina Altrocchi, David J. Gallacher, Huarong Lu, Godfrey Smith
Summary: This study found that human induced pluripotent stem cell-derived cardiomyocytes treated to enhance structural maturity are superior to mature ventricular cardiomyocytes in detecting drug-induced changes. The electrophysiological and contractility measurements showed similar results in two different experimental settings, but with slight differences in contraction amplitude, which may be explained by differences in cell-to-matrix adhesion. These findings suggest that both types of 2D culture containing structural matured hiPSC-CMs are equally effective in detecting drug-induced electrophysiological effects in functional safety studies.
Article
Environmental Sciences
Anna Kreutz, Matthew S. S. Clifton, W. Matthew Henderson, Marci G. G. Smeltz, Matthew Phillips, John F. F. Wambaugh, Barbara A. A. Wetmore
Summary: Concerns about PFAS have risen due to increased knowledge about their presence, persistence, and potential to accumulate in the environment. This study evaluated the toxicokinetic properties of 73 PFAS, providing critical information about their binding, clearance, and potential transformation products. The results highlight the high binding capacity of these PFAS in plasma and their ability to undergo metabolism and abiotic loss. Understanding these factors is important for assessing the environmental fate of PFAS.
Article
Toxicology
Matthew Boyce, Kristin A. A. Favela, Jessica A. A. Bonzo, Alex Chao, Lucina E. E. Lizarraga, Laura R. R. Moody, Elizabeth O. O. Owens, Grace Patlewicz, Imran Shah, Jon R. R. Sobus, Russell S. S. Thomas, Antony J. J. Williams, Alice Yau, John F. F. Wambaugh
Summary: Understanding the metabolic fate of xenobiotic substances is important for assessing their health risks and identifying associated metabolites. Non-targeted analysis using high-resolution LCMS has become a popular method for characterizing metabolites of poorly studied or novel substances. In this study, suspect screening analysis using LCMS was evaluated for xenobiotic chemical metabolism. Thirty-three diverse chemicals were incubated with primary hepatocytes and analyzed using LCMS. Predictive tools were used to generate suspect screening lists of potential metabolites for each compound. The workflow was applied to several test chemicals, resulting in the identification of known and potential novel metabolites. This study demonstrates that suspect screening analysis can be a valuable tool for rapidly identifying and characterizing metabolites of xenobiotic chemicals.
FRONTIERS IN TOXICOLOGY
(2023)