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Computational Modeling to Predict Human Toxicity
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Janet Moser, Douglas. R. Sommerville, George. R. Famini
In 2007, the National Research Council (NRC) released a report, Toxicity Testing in the 21st Century: A Vision and a Strategy (National Research Council, 2007), that set forth a vision and implementation strategy to create a major shift away from traditional toxicity testing by incorporating recent advances in systems biology, epigenetics, toxicogenomics, bioinformatics, and computational toxicology. In vitro methodology was proposed as the principal approach for all routine toxicity testing, using cells, cell lines, or cellular components, preferably of human origin, to evaluate cellular responses in toxicity pathway assays using high-throughput tests. Computational systems biology models would be created for expected dose–response relationships for each of the toxicity pathway assays, and in vitro to in vivo extrapolation would rely on pharmacokinetic models to predict the human response (Andersen and Krewski, 2009).
Hazard Characterization and Dose–Response Assessment
Published in Ted W. Simon, Environmental Risk Assessment, 2019
The prediction models used for screening, hazard identification, or hazard characterization of in vitro data are slowly maturing. In 2012, when the predictive performance of more than 600 in vitro assays was examined across 60 in vivo endpoints using 84 different statistical classification methods and compared to the predictions based solely on chemical descriptors, the predictive power of the in vitro assays was no better than that of the chemical descriptors.333 The first author of this paper was Dr. Rusty Thomas, who worked at the Hamner Institute for many years until EPA wisely offered him the job of leading the National Center for Computational Toxicology. This group at EPA has partnered with the National Toxicology Program, the National Center for Advancing Translational Science, and the Food and Drug Administration to address five distinct areas of focus: developing alternative test systems that are predictive of human toxicity and dose response;addressing the technical limitations of the current in vitro test systems;curating and characterizing extant in vivo toxicity studies;establishing scientific confidence in the in vitro test systems;refinement of in vitro-to-in vivo extrapolation and the understanding of in vitro disposition.334,335Twenty-first-century toxicology presents an exciting era for toxicologists, risk assessors, and researchers. Programs such as the EPA’s ToxCast™ are laudable in that they demonstrate just how new technologies can be exploited to address the challenges of risk assessment. However, the new challenges are establishing credible validation/evaluation methods and understanding of the strengths and limitations for specific uses.
Comparative cytotoxicity induced by parabens and their halogenated byproducts in human and fish cell lines
Published in Drug and Chemical Toxicology, 2023
Ashley L. Ball, Megan E. Solan, Marco E. Franco, Ramon Lavado
It is well known that in vitro to in vivo extrapolation is challenging and the use of in vitro-derived data on its own can lead to misinterpretation at the in vivo level. However, cell-based bioassays can help inform subsequent evaluations and support better experimental designs. As shown in our study, the cytotoxic effects of parabens are in line with more comprehensive risk assessments suggesting that parent parabens pose a low risk to organisms in aquatic environments, yet the halogenated parabens are likely to induce more severe effects, as they have been predicted to act as estrogen antagonists (Sasaki and Terasaki 2018) and have been shown to induce AhR activity (Gouukon et al.2020). The data reported in this study support follow-up studies examining the mechanism of toxicity in fish cells and a closer look at the potential bioactivation of the metabolite 4-HBA due to its high reported concentrations in the literature. Further evaluations should also be considered to explore the brominated parabens outside of the commercially available products to determine if they pose a safety risk to aquatic organisms and ecosystems with reported low cytotoxicity values.
Cannabinoids and drug metabolizing enzymes: potential for drug-drug interactions and implications for drug safety and efficacy
Published in Expert Review of Clinical Pharmacology, 2022
Keti Bardhi, Shelby Coates, Christy J.W. Watson, Philip Lazarus
Very few of the in vitro studies performed to date have performed static modeling or dynamic modeling to further investigate the potential for in vivo DDI between the pharmaceutics and cannabinoids. Earlier studies did not perform these static models, nor did they account for the non-specific binding of the cannabinoids in their experimental systems and adjust their IC50 and Ki values accordingly. Of those studies that have performed in vitro to in vivo extrapolation (IVIVE), all of them have been static modeling. Nasrin et al. [74] found that CBD exhibited the greatest potential for in vivo DDI, with it showing an inhibitory effect for 7 of the major CYPs (1A2, 3A4, 2B6, 2C9, 2C19, 2D6, and 2E1). They also found that THC and 11-OH-THC have the potential for in vivo DDI for CYPs 2C19, 2C9, and 1A2, and CYPs 2B6 and 2C9, respectively [74]. Similarly, Bansal et al. [147] found that CBD and THC have the potential to cause in vivo DDI with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 and CYPs 1A2, 2C9, and 3A4, respectively. In a follow-up study, the authors considered time-dependent inhibition, and found that CBD and THC had the potential for in vivo DDI with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, and CYPs 1A2, 2C9, and 3A4, respectively [148].
An integrative translational framework for chemical induced neurotoxicity – a systematic review
Published in Critical Reviews in Toxicology, 2020
Deepika Deepika, Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
However, some gaps exist in this framework like dose variation in animal, human and in vitro studies, limited data availability, species to species variation, extrapolation of results from adult to mother and children, human brain complexity, etc. Data availability for chemicals on different compartments of human brain region is one of the major challenges for developing and validating the in silico models needed for an integrated approach. Another challenge is translation of different dose of chemicals and their short time exposure used for in vitro and to in vivo which do not reflect the real-life scenario for the toxicity of chemicals (Zhang et al. 2019). Lack of data for different age groups and complex brain anatomy and physiology also poses a major challenge for predicting neurotoxicity. However, risk from these gaps can be minimized by further utilizing other tools available in the integrated modeling in which output of experiment data can be used as initial input for in silico models. For instance, data obtained from in vitro can be used in the predictive chemistry approach (read across) for predicting the hazard of neurotoxic chemicals where endpoint data is lacking by linking to structurally similar chemicals (Roncaglioni et al. 2013). Quantitative in vitro to in vivo extrapolation can be used to accurately link concentration of chemicals that induce in vitro response to in vivo exposure levels (Yoon et al. 2012). Combination of in silico and in vitro parameters with PBPK and QIVIVE can be used to predict the human exposure conditions that would produce the toxic concentration inside brain regions (Yoon et al. 2012).