Trust your gut: Establishing confidence in gastrointestinal models - An overview of the state of the science and contexts of use

Main Article Content

Susan Debad, David Allen, Omari Bandele, Colin Bishop, Michaela Blaylock, Paul Brown, Maureen K. Bunger, Julia Y. Co, Lynn Crosby, Amber B. Daniel, Steve S. Ferguson, Kevin Ford, Gonçalo Gamboa da Costa, Kristin H. Gilchrist, Matthew W. Grogg, Maureen Gwinn, Thomas Hartung , Simon P. Hogan, Ye Eun Jeong, George E. N. Kass, Elaina Kenyon, Nicole C. Kleinstreuer, Ville Kujala, Patrik Lundquist, Joanna Matheson, Shaun D. McCullough, Angela Melton-Celsa, Steven Musser, Ilung Oh, Oluwakemi B. Oyetade, Sarita U. Patil, Elijah J. Petersen, Nakissa Sadrieh, Christie M. Sayes, Benjamin S. Scruggs, Yu-Mei Tan, Bill Thelin, M. Tyler Nelson, José V. Tarazona, John F. Wambaugh, Jun-young Yang, Changwoo Yu, Suzanne Fitzpatrick
[show affiliations]

Abstract

The webinar series and workshop titled Trust Your Gut: Establishing Confidence in Gastrointestinal Models – An Overview of the State of the Science and Contexts of Use was co-organized by NICEATM, NIEHS, FDA, EPA, CPSC, DoD, and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) and hosted at the National Institutes of Health in Bethesda, MD, USA on October 11-12, 2023. New approach methods (NAMs) for assessing issues of gastrointestinal tract (GIT)-related toxicity offer promise in addressing some of the limitations associated with animal-based assessments. GIT NAMs vary in complexity, from two-dimensional monolayer cell line-based systems to sophisticated 3-dimensional organoid systems derived from human primary cells. Despite advances in GIT NAMs, challenges remain in fully replicating the complex interactions and processes occurring within the human GIT. Presentations and discussions addressed regulatory needs, challenges, and innovations in incorporating NAMs into risk assessment frameworks; explored the state of the science in using NAMs for evaluating systemic toxicity, understanding absorption and pharmacokinetics, evaluating GIT toxicity, and assessing potential allergenicity; and discussed strengths, limitations, and data gaps of GIT NAMs as well as steps needed to establish confidence in these models for use in the regulatory setting.


Plain language summary
Non-animal methods to assess whether chemicals may be toxic to the human digestive tract promise to complement or improve on animal-based methods. These approaches, which are based on human or animal cells and/or computer models, are faced with their own technical challenges and need to be shown to predict adverse effects in humans. Regulators are tasked with evaluating submitted data to best protect human health and the environment. A webinar series and workshop brought together scientists from academia, industry, military, and regulatory authorities from different countries to discuss how non-animal methods can be integrated into the risk assessment of drugs, food additives, dietary supplements, pesticides, and industrial chemicals for gastrointestinal toxicity.

Article Details

How to Cite
Debad, S. (2024) “Trust your gut: Establishing confidence in gastrointestinal models - An overview of the state of the science and contexts of use”, ALTEX - Alternatives to animal experimentation. doi: 10.14573/altex.2403261.
Section
Workshop Reports
References

Artursson, P., Palm, K. and Luthman, K. (2001). Caco-2 monolayers in experimental and theoretical predictions of drug transport. 1PII of original article: S0169-409X(96)00415-2. The article was originally published in Adv Drug Deliv Rev 22 (1996), 67-84.1. Adv Drug Del Rev 46, 27-43. doi:10.1016/S0169-409X(00)00128-9

Atkins, J. T., George, G. C., Hess, K. et al. (2020). Pre-clinical animal models are poor predictors of human toxicities in phase 1 oncology clinical trials. Br J Cancer 123, 1496-1501. doi:10.1038/s41416-020-01033-x

Avila, A. M., Bebenek, I., Bonzo, J. A. et al. (2020). An FDA/CDER perspective on nonclinical testing strategies: Classical toxicology approaches and new approach methodologies (NAMs). Regul Toxicol Pharmacol 114, 104662. doi:10.1016/j.yrtph.2020.104662

Avila, A. M., Bebenek, I., Mendrick, D. L. et al. (2023). Gaps and challenges in nonclinical assessments of pharmaceuticals: An FDA/CDER perspective on considerations for development of new approach methodologies. Regul Toxicol Pharmacol 139, 105345. doi:10.1016/j.yrtph.2023.105345

Bein, A., Shin, W., Jalili-Firoozinezhad, S. et al. (2018). Microfluidic organ-on-a-chip models of human intestine. Cell Mol Gastroenterol Hepatol 5, 659-668. doi:10.1016/j.jcmgh.2017.12.010

Belair, D. G., Visconti, R. J., Hong, M. et al. (2020). Human ileal organoid model recapitulates clinical incidence of diarrhea associated with small molecule drugs. Toxicol In Vitro 68, 104928. doi:10.1016/j.tiv.2020.104928

Bell, S. M., Chang, X., Wambaugh, J. F. et al. (2018). In vitro to in vivo extrapolation for high throughput prioritization and decision making. Toxicol In Vitro 47, 213-227. doi:10.1016/j.tiv.2017.11.016

Blutt, S. E., Broughman, J. R., Zou, W. et al. (2017). Gastrointestinal microphysiological systems. Exp Biol Med (Maywood) 242, 1633-1642. doi:10.1177/1535370217710638

Bøgh, K. L., Van Bilsen, J., Głogowski, R. et al. (2016). Current challenges facing the assessment of the allergenic capacity of food allergens in animal models. Clin Transl Allergy 6, 21. doi:10.1186/s13601-016-0110-2

Bova, R. A., Lamont, A. C., Picou, T. J. et al. (2023). Shiga toxin (Stx) type 1a and Stx2a translocate through a three-layer intestinal model. Toxins 15, 207. doi:10.3390/toxins15030207

Calero-Medina, L., Jimenez-Casquet, M. J., Heras-Gonzalez, L. et al. (2023). Dietary exposure to endocrine disruptors in gut microbiota: A systematic review. Sci Total Environ 886, 163991. doi:10.1016/j.scitotenv.2023.163991

Cattaneo, I., Astuto, M. C., Binaglia, M. et al. (2023). Implementing new approach methodologies (NAMs) in food safety assessments: Strategic objectives and actions taken by the European Food Safety Authority. Trends Food Sci Technol 133, 277-290. doi:10.1016/j.tifs.2023.02.006

Chang, X., Tan, Y.-M., Allen, D. G. et al. (2022). IVIVE: Facilitating the use of in vitro toxicity data in risk assessment and decision making. Toxics 10, 232. doi:10.3390/toxics10050232

Chi, D. S., DeKruyff, R. H., Lerman, S. P. et al. (1982). Effect of histoincompatibility on migration of labeled bursa cells in the chicken. Transplantation 33, 377-381. doi:10.1097/00007890-198204000-00007

Chiu, K., Warner, G., Nowak, R. A. et al. (2020). The impact of environmental chemicals on the gut microbiome. Toxicol Sci 176, 253-284. doi:10.1093/toxsci/kfaa065

Co, J. Y., Klein, J. A., Kang, S. et al. (2023). Suspended hydrogel culture as a method to scale up intestinal organoids. Sci Rep 13, 10412. doi:10.1038/s41598-023-35657-9

Coecke, S., Pelkonen, O., Leite, S. B. et al. (2013). Toxicokinetics as a key to the integrated toxicity risk assessment based primarily on non-animal approaches. Toxicol In Vitro 27, 1570-1577. doi:10.1016/j.tiv.2012.06.012

Collins, F. S., Gray, G. M. and Bucher, J. R. (2008). Transforming environmental health protection. Science 319, 906-907. doi:10.1126/science.1154619

Conti, J., Sorio, C. and Melotti, P. (2022). Organoid technology and its role for theratyping applications in cystic fibrosis. Children (Basel) 10, 4. doi:10.3390/children10010004

Cook, D., Brown, D., Alexander, R. et al. (2014). Lessons learned from the fate of AstraZeneca’s drug pipeline: A five-dimensional framework. Nat Rev Drug Discov 13, 419-431. doi:10.1038/nrd4309

Costa, J. and Ahluwalia, A. (2019). Advances and current challenges in intestinal in vitro model engineering: A digest. Front Bioeng Biotechnol 7, 144. doi:10.3389/fbioe.2019.00144

Cote, I., Andersen, M. E., Ankley, G. T. et al. (2016). The next generation of risk assessment multi-year study – Highlights of findings, applications to risk assessment, and future directions. Environ Health Perspect 124, 1671-1682. doi:10.1289/EHP233

Crevel, R. W. R., Baumert, J. L., Baka, A. et al. (2014). Development and evolution of risk assessment for food allergens. Food Chem Toxicol 67, 262-276. doi:10.1016/j.fct.2014.01.032

Croote, D., Darmanis, S., Nadeau, K. C. et al. (2018). High-affinity allergen-specific human antibodies cloned from single IgE B cell transcriptomes. Science 362, 1306-1309. doi:10.1126/science.aau2599

Croote, D., Wong, J. J. W., Pecalvel, C. et al. (2024). Widespread monoclonal IgE antibody convergence to an immunodominant, proanaphylactic Ara h 2 epitope in peanut allergy. J Allergy Clin Immunol 153, 182-192.e7. doi:10.1016/j.jaci.2023.08.035

Dahlgren, D., Roos, C., Sjögren, E. et al. (2015). Direct in vivo human intestinal permeability (Peff) determined with different clinical perfusion and intubation methods. J Pharm Sci 104, 2702-2726. doi:10.1002/jps.24258

De Castelbajac, T., Aiello, K., Arenas, C. G. et al. (2023). Innovative tools and methods for toxicity testing within PARC work package 5 on hazard assessment. Front Toxicol 5, 1216369. doi:10.3389/ftox.2023.1216369

Dearman, R. J., Basketter, D. A. and Kimber, I. (2013). Inter‐relationships between different classes of chemical allergens. J Appl Toxicol 33, 558-565. doi:10.1002/jat.1758

De Poel, E., Spelier, S., Hagemeijer, M. C. et al. (2023). FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes. J Cyst Fibros 22, 548-559. doi:10.1016/j.jcf.2023.03.004

DeLoid, G. M., Wang, Y., Kapronezai, K. et al. (2017). An integrated methodology for assessing the impact of food matrix and gastrointestinal effects on the biokinetics and cellular toxicity of ingested engineered nanomaterials. Part Fibre Toxicol 14, 40. doi:10.1186/s12989-017-0221-5

Drenckhahn, D. and Dermietzel, R. (1988). Organization of the actin filament cytoskeleton in the intestinal brush border: A quantitative and qualitative immunoelectron microscope study. J Cell Biol 107, 1037-1048. doi:10.1083/jcb.107.3.1037

Ede, J. D., Ong, K. J., Mulenos, M. R. et al. (2020). Physical, chemical, and toxicological characterization of sulfated cellulose nanocrystals for food-related applications using in vivo and in vitro strategies. Toxicol Res (Camb) 9, 808-822. doi:10.1093/toxres/tfaa082

EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) Products, Nutrition, null, Nda, A. et al. (2021). Guidance on the preparation and submission of an application for authorisation of a novel food in the context of Regulation (EU) 2015/2283 (Revision 1)2. EFSA J 19, e06555. doi:10.2903/j.efsa.2021.6555

EFSA Scientific Committee, More, S., Bampidis, V. et al. (2021a). Guidance on risk assessment of nanomaterials to be applied in the food and feed chain: Human and animal health. EFSA J 19, e06768. doi:10.2903/j.efsa.2021.6768

EFSA Scientific Committee, More, S. J., Bampidis, V. et al. (2021b). Guidance document on scientific criteria for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals. EFSA J 19, e07033. doi:10.2903/j.efsa.2021.7033

Falcón-Cano, G., Molina, C. and Cabrera-Pérez, M. Á. (2022). Reliable prediction of Caco-2 permeability by supervised recursive machine learning approaches. Pharmaceutics 14, 1998. doi:10.3390/pharmaceutics14101998

Federer, C., Yoo, M. and Tan, A. C. (2016). Big data mining and adverse event pattern analysis in clinical drug trials. Assay Drug Dev Technol 14, 557-566. doi:10.1089/adt.2016.742

Fedi, A., Vitale, C., Ponschin, G. et al. (2021). In vitro models replicating the human intestinal epithelium for absorption and metabolism studies: A systematic review. J Control Release 335, 247-268. doi:10.1016/j.jconrel.2021.05.028

Fenwick, N., Griffin, G. and Gauthier, C. (2009). The welfare of animals used in science: How the “Three Rs” ethic guides improvements. Can Vet J 50, 523-530.

Fogh, J., Fogh, J. M. and Orfeo, T. (1977). One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice23. J Natl Cancer Inst 59, 221-226. doi:10.1093/jnci/59.1.221

Gelberg, H. (2018). Pathophysiological mechanisms of gastrointestinal toxicity. In Comprehensive Toxicology (139-178). Elsevier. doi:10.1016/B978-0-12-801238-3.10923-7

Gibb, M., Pradhan, S. H., Mulenos, M. R. et al. (2021). Characterization of a human in vitro intestinal model for the hazard assessment of nanomaterials used in cancer immunotherapy. Appl Sci 11, 2113. doi:10.3390/app11052113

Gustafsson, J. K., Davis, J. E., Rappai, T. et al. (2021). Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis. Elife 10, e67292. doi:10.7554/eLife.67292

Hoffmann, S., Aiassa, E., Angrish, M., et al. (2022). Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks. ALTEX 39, 499-518. doi:10.14573/altex.2202141

Hoh, R. A., Joshi, S. A., Lee, J.-Y. et al. (2020). Origins and clonal convergence of gastrointestinal IgE+ B cells in human peanut allergy. Sci Immunol 5, eaay4209. doi:10.1126/sciimmunol.aay4209

Holmes, A., Rudd, J., Tattersall, F. et al. (2009). Opportunities for the replacement of animals in the study of nausea and vomiting. Br J Pharmacol 157, 865-880. doi:10.1111/j.1476-5381.2009.00176.x

Honda, G, Kenyon, E. M., Davidson-Fritz, S. et al. (2024). Impact of gut permeability on estimation of oral bioavailability for chemicals in commerce and the environment. Toxicol In Vitro, submitted.

Jamei, M., Marciniak, S., Feng, K. et al. (2009). The Simcyp® population-based ADME simulator. Expert Opin Drug Metab Toxicol 5, 211-223. doi:10.1517/17425250802691074

Kang, T. and Kim, H. (2016). Farewell to animal testing: Innovations on human intestinal microphysiological systems. Micromachines 7, 107. doi:10.3390/mi7070107

Kim, M. T., Sedykh, A., Chakravarti, S. K. et al. (2014). Critical evaluation of human oral bioavailability for pharmaceutical drugs by using various cheminformatics approaches. Pharm Res 31, 1002-1014. doi:10.1007/s11095-013-1222-1

Kavlock, R. J., Bahadori, T., Barton-Maclaren, T. S. et al. (2018). Accelerating the pace of chemical risk assessment. Chem Res Toxicol 31, 287-290. doi:10.1021/acs.chemrestox.7b00339

Kazemi, S., Danisman, E. and Epstein, M. M. (2023). Animal models for the study of food allergies. Curr Protoc 3, e685. doi:10.1002/cpz1.685

Kleinstreuer, N. C., Karmaus, A. L., Mansouri, K. et al. (2018). Predictive models for acute oral systemic toxicity: A workshop to bridge the gap from research to regulation. Comput Toxicol 8, 21-24. doi:10.1016/j.comtox.2018.08.002

Kopec, A. K., Yokokawa, R., Khan, N. et al. (2021). Microphysiological systems in early stage drug development: Perspectives on current applications and future impact. J Toxicol Sci 46, 99-114. doi:10.2131/jts.46.99

Krewski, D., Andersen, M. E., Tyshenko, M. G. et al. (2020). Toxicity testing in the 21st century: Progress in the past decade and future perspectives. Arch Toxicol 94, 1-58. doi:10.1007/s00204-019-02613-4

Kulkarni, D. H., Gustafsson, J. K., Knoop, K. A. et al. (2020). Goblet cell associated antigen passages support the induction and maintenance of oral tolerance. Mucosal Immunol 13, 271-282. doi:10.1038/s41385-019-0240-7

Lee, B., Moon, K. M. and Kim, C. Y. (2018). Tight junction in the intestinal epithelium: Its association with diseases and regulation by phytochemicals. J Immunol Res 2018, 2645465. doi:10.1155/2018/2645465

Licari, A., Votto, M., D’Auria, E. et al. (2020). Eosinophilic gastrointestinal diseases in children: A practical review. Curr Pediatr Rev 16, 106-114. doi:10.2174/1573396315666191022154432

Lopez-Escalera, S. and Wellejus, A. (2022). Evaluation of Caco-2 and human intestinal epithelial cells as in vitro models of colonic and small intestinal integrity. Biochem Biophys Rep 31, 101314. doi:10.1016/j.bbrep.2022.101314

Manatakis, D. V., VanDevender, A. and Manolakos, E. S. (2021). An information-theoretic approach for measuring the distance of organ tissue samples using their transcriptomic signatures P. Luigi Martelli (ed.). Bioinformatics 36, 5194-5204. doi:10.1093/bioinformatics/btaa654

Mansouri, K., Karmaus, A. L., Fitzpatrick, J. et al. (2021). CATMoS: Collaborative acute toxicity modeling suite. Environ Health Perspect 129, 47013. doi:10.1289/EHP8495

Marrero, D., Pujol-Vila, F., Vera, D. et al. (2021). Gut-on-a-chip: Mimicking and monitoring the human intestine. Biosens Bioelectron 181, 113156. doi:10.1016/j.bios.2021.113156

Marshall, L. J., Bailey, J., Cassotta, M. et al. (2023). Poor translatability of biomedical research using animals – A narrative review. Altern Lab Anim 51, 102-135. doi:10.1177/02611929231157756

Martin, O. V. (2023). Synergistic effects of chemical mixtures: How frequent is rare? Current Opinion in Toxicology 36, 100424. doi:10.1016/j.cotox.2023.100424

Martin-Folgar, R., González-Caballero, M. C., Torres-Ruiz, M. et al. (2024). Molecular effects of polystyrene nanoplastics on human neural stem cells. PLoS One 19, e0295816. doi:10.1371/journal.pone.0295816

Marx-Stoelting, P., Rivière, G., Luijten, M. et al. (2023). A walk in the PARC: Developing and implementing 21st century chemical risk assessment in Europe. Arch Toxicol 97, 893-908. doi:10.1007/s00204-022-03435-7

McDole, J. R., Wheeler, L. W., McDonald, K. G. et al. (2012). Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345-349. doi:10.1038/nature10863

Mestas, J. and Hughes, C. C. W. (2004). Of mice and not men: Differences between mouse and human immunology. J Immunol 172, 2731-2738. doi:10.4049/jimmunol.172.5.2731

Min, J., Keswani, T., LaHood, N. A. et al. (2024). Design of an Ara h 2 hypoallergen from conformational epitopes. Clin Exp Allergy 54, 46-55. doi:10.1111/cea.14433

Minekus, M., Alminger, M., Alvito, P. et al. (2014). A standardised static in vitro digestion method suitable for food – An international consensus. Food Funct 5, 1113-1124. doi:10.1039/c3fo60702j

Monticello, T. M., Jones, T. W., Dambach, D. M. et al. (2017). Current nonclinical testing paradigm enables safe entry to first-in-human clinical trials: The IQ consortium nonclinical to clinical translational database. Toxicol Appl Pharmacol 334, 100-109. doi:10.1016/j.taap.2017.09.006

Musther, H., Olivares-Morales, A., Hatley, O. J. D. et al. (2014). Animal versus human oral drug bioavailability: Do they correlate? Eur J Pharm Sci 57, 280-291. doi:10.1016/j.ejps.2013.08.018

NRC – National Research Council. (1983). Risk Assessment in the Federal Government: Managing the Process. Washington, D.C.: National Academies Press. doi:10.17226/366

Nelson, M. T., Charbonneau, M. R., Coia, H. G. et al. (2021). Characterization of an engineered live bacterial therapeutic for the treatment of phenylketonuria in a human gut-on-a-chip. Nat Commun 12, 2805. doi:10.1038/s41467-021-23072-5

Nelson, M. T., Coia, H. G., Holt, C. et al. (2023). Evaluation of human performance aiding live synthetically engineered bacteria in a gut-on-a-chip. ACS Biomater Sci Eng 9, 5136-5150. doi:10.1021/acsbiomaterials.2c00774

Newberry, R. D. and Hogan, S. P. (2021). Intestinal epithelial cells in tolerance and allergy to dietary antigens. J Allergy Clin Immunol 147, 45-48. doi:10.1016/j.jaci.2020.10.030

Noah, T. K., Lee, J.-B., Brown, C. A. et al. (2021). Thermoneutrality alters gastrointestinal antigen passage patterning and predisposes to oral antigen sensitization in mice. Front Immunol 12, 636198. doi:10.3389/fimmu.2021.636198

Ölander, M., Wiśniewski, J. R., Matsson, P. et al. (2016). The proteome of filter-grown Caco-2 cells with a focus on proteins involved in drug disposition. J Pharm Sci 105, 817-827. doi:10.1016/j.xphs.2015.10.030

O’Reilly, M., Mellotte, G., Ryan, B. et al. (2020). Gastrointestinal side effects of cancer treatments. Ther Adv Chronic Dis 11, 204062232097035. doi:10.1177/2040622320970354

Pali-Schöll, I., Verhoeckx, K., Mafra, I. et al. (2019). Allergenic and novel food proteins: State of the art and challenges in the allergenicity assessment. Trends Food Sci Technol 84, 45-48. doi:10.1016/j.tifs.2018.03.007

Pallocca, G. and Leist, M. (2021). RISK HUNT 3R. ALTEX 38.4, 690-691.

Patil, S. U., Ogunniyi, A. O., Calatroni, A. et al. (2015). Peanut oral immunotherapy transiently expands circulating Ara h 2-specific B cells with a homologous repertoire in unrelated subjects. J Allergy Clin Immunol 136, 125-134.e12. doi:10.1016/j.jaci.2015.03.026

Peters, M. F., Choy, A. L., Pin, C. et al. (2020). Developing in vitro assays to transform gastrointestinal safety assessment: Potential for microphysiological systems. Lab Chip 20, 1177-1190. doi:10.1039/C9LC01107B

Petersen, E. J., Nguyen, A., Brown, J., et al. (2021). Characteristics to consider when selecting a positive control material for an in vitro assay. ALTEX 38, 365-376. doi:10.14573/altex.2102111

Petersen, E. J., Ceger, P., Allen, D. G., et al. (2022). U.S. Federal Agency interests and key considerations for new approach methodologies for nanomaterials. ALTEX 39, 183-206. doi:10.14573/altex.2105041

Petersen, E. J., Elliott, J. T., Gordon, J., et al. (2023). Technical framework for enabling high-quality measurements in new approach methodologies (NAMs). ALTEX 40, 174-186. doi:10.14573/altex.2205081

Pirmohamed, M. (2023). Pharmacogenomics: Current status and future perspectives. Nat Rev Genet 24, 350-362. doi:10.1038/s41576-022-00572-8

Pradhan, S. H., Mulenos, M. R., Steele, L. R. et al. (2020). Physical, chemical, and toxicological characterization of fibrillated forms of cellulose using an in vitro gastrointestinal digestion and co-culture model. Toxicol Res (Camb) 9, 290-301. doi:10.1093/toxres/tfaa026.

Price, G. and Patel, D. A. (2024). Drug bioavailability. In StatPearls. Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK557852/ (accessed 02.06.2024)

Punt, A., Louisse, J., Pinckaers, N. et al. (2022). Predictive performance of next generation physiologically based kinetic (PBK) model predictions in rats based on in vitro and in silico input data. Toxicol Sci 186, 18-28. doi:10.1093/toxsci/kfab150

Qureshi, Z. P., Seoane‐Vazquez, E., Rodriguez‐Monguio, R. et al. (2011). Market withdrawal of new molecular entities approved in the United States from 1980 to 2009. Pharmacoepidemiology and Drug 20, 772-777. doi:10.1002/pds.2155

Richard, A. M., Judson, R. S., Houck, K. A. et al. (2016). ToxCast chemical landscape: Paving the road to 21st century toxicology. Chem Res Toxicol 29, 1225-1251. doi:10.1021/acs.chemrestox.6b00135

Rotroff, D. M., Wetmore, B. A., Dix, D. J. et al. (2010). Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117, 348-358. doi:10.1093/toxsci/kfq220

Sayes, C. M., Reed, K. L. and Warheit, D. B. (2007). Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Scie 97, 163-180. doi:10.1093/toxsci/kfm018

Tarazona, J. V., Cattaneo, I., Niemann, L. et al. (2022). A tiered approach for assessing individual and combined risk of pyrethroids using human biomonitoring data. Toxics 10, 451. doi:10.3390/toxics10080451

Thomas, R. S., Philbert, M. A., Auerbach, S. S. et al. (2013). Incorporating new technologies into toxicity testing and risk assessment: Moving from 21st century vision to a data-driven framework. Toxicol Sci 136, 4-18. doi:10.1093/toxsci/kft178

Thompson, C. L., Fu, S., Knight, M. M. et al. (2020). Mechanical stimulation: A crucial element of organ-on-chip models. Front Bioeng Biotechnol 8, 602646. doi:10.3389/fbioe.2020.602646

Tsaioun, K. (2016). Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods. ALTEX 33, 343-358. doi:10.14573/altex.1610101

Turner, J. (2023). Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment. ALTEX 40, 519-533. doi:10.14573/altex.2212081

Valiei, A., Aminian-Dehkordi, J. and Mofrad, M. R. K. (2023). Gut-on-a-chip models for dissecting the gut microbiology and physiology. APL Bioeng 7, 011502. doi:10.1063/5.0126541

Van Norman, G. A. (2019). Limitations of animal studies for predicting toxicity in clinical trials: Is it time to rethink our current approach? JACC Basic Transl Sci 4, 845-854. doi:10.1016/j.jacbts.2019.10.008

Ventola, C. L. (2013). Role of pharmacogenomic biomarkers in predicting and improving drug response: Part 1: The clinical significance of pharmacogenetic variants. P T 38, 545-560.

Wambaugh, J. F., Hughes, M. F., Ring, C. L. et al. (2018). Evaluating in vitro-in vivo extrapolation of toxicokinetics. Toxicol Sci 163, 152-169. doi:10.1093/toxsci/kfy020

Wambaugh, J. F., Wetmore, B. A., Ring, C. L. et al. (2019). Assessing toxicokinetic uncertainty and variability in risk prioritization. Toxicol Sci 172, 235-251. doi:10.1093/toxsci/kfz205

Wang, H., Brown, P. C., Chow, E. C. Y. et al. (2021). 3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration. Clin Transl Sci 14, 1659-1680. doi:10.1111/cts.13066

Wetmore, B. A., Wambaugh, J. F., Ferguson, S. S. et al. (2012). Integration of dosimetry, exposure, and high-throughput screening data in chemical toxicity assessment. Toxicol Sci 125, 157-174. doi:10.1093/toxsci/kfr254

Wetmore, B. A., Wambaugh, J. F., Allen, B. et al. (2015). Incorporating high-throughput exposure predictions with dosimetry-adjusted in vitro bioactivity to inform chemical toxicity testing. Toxicol Sci 148, 121-136. doi:10.1093/toxsci/kfv171

Xiang, Y., Wen, H., Yu, Y. et al. (2020). Gut-on-chip: Recreating human intestine in vitro. J Tissue Eng 11, 204173142096531. doi:10.1177/2041731420965318

Yim, D.-S., Choi, S. and Bae, S. H. (2020). Predicting human pharmacokinetics from preclinical data: Absorption. Transl Clin Pharmacol 28, 126. doi:10.12793/tcp.2020.28.e14

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