Beyond pharmaceuticals: Fit-for-purpose new approach methodologies for environmental cardiotoxicity testing

Articles

Agarwal, A., Goss, J. A., Cho, A. et al. (2013). Microfluidic heart on a chip for higher throughput pharmacological studies. Lab on a Chip 13, 3599-3608. doi:10.1039/c3lc50350j

Ahmed, R. E., Anzai, T., Chanthra, N. et al. (2020). A brief review of current maturation methods for human induced pluripotent stem cells-derived cardiomyocytes. Frontiers in Cell and Developmental Biology 8, 178. doi:10.3389/fcell.2020.00178

Åkesson, A., Donat-Vargas, C., Berglund, M. et al. (2019). Dietary exposure to polychlorinated biphenyls and risk of heart failure–a population-based prospective cohort study. Environment international 126, 1-6. doi:10.1016/j.envint.2019.01.069

Akins Jr, R. E., Rockwood, D., Robinson, K. G. et al. (2010). Three-dimensional culture alters primary cardiac cell phenotype. Tissue Engineering Part A 16, 629-641. doi:10.1089/ten.tea.2009.0458

Alhamdow, A., Lindh, C., Albin, M. et al. (2017). Early markers of cardiovascular disease are associated with occupational exposure to polycyclic aromatic hydrocarbons. Scientific reports 7, 1-11. doi:10.1038/s41598-017-09956-x

Alissa, E. M. and Ferns, G. A. (2011). Heavy metal poisoning and cardiovascular disease. Journal of Toxicology 2011, 870125. doi:10.1155/2011/870125

Ando, H., Yoshinaga, T., Yamamoto, W. et al. (2017). A new paradigm for drug-induced torsadogenic risk assessment using human ips cell-derived cardiomyocytes. Journal of Pharmacological and Toxicological Methods 84, 111-127. doi:10.1016/j.vascn.2016.12.003

Ankley, G. T., Bennett, R. S., Erickson, R. J. et al. (2010). Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environmental Toxicology and Chemistry: An International Journal 29, 730-741. doi:10.1002/etc.34

Archer, C. R., Sargeant, R., Basak, J. et al. (2018). Characterization and validation of a human 3d cardiac microtissue for the assessment of changes in cardiac pathology. Scientific reports 8, 1-15. doi:10.1038/s41598-018-28393-y

Bajaj, P., Schweller, R. M., Khademhosseini, A. et al. (2014). 3d biofabrication strategies for tissue engineering and regenerative medicine. Annual review of biomedical engineering 16, 247-276. doi:10.1146/annurev-bioeng-071813-105155

Baker, B. M. and Chen, C. S. (2012). Deconstructing the third dimension–how 3d culture microenvironments alter cellular cues. Journal of cell science 125, 3015-3024. doi:10.1242/jcs.079509

Balali-Mood, M., Naseri, K., Tahergorabi, Z. et al. (2021). Toxic mechanisms of five heavy metals: Mercury, lead, chromium, cadmium, and arsenic. Frontiers in pharmacology 12, doi:10.3389/fphar.2021.643972

Beauchamp, P., Moritz, W., Kelm, J. M. et al. (2015). Development and characterization of a scaffold-free 3d spheroid model of induced pluripotent stem cell-derived human cardiomyocytes. Tissue Engineering Part C: Methods 21, 852-861. doi:10.1089/ten.tec.2014.0376

Beauchamp, P., Jackson, C. B., Ozhathil, L. C. et al. (2020). 3d co-culture of hipsc-derived cardiomyocytes with cardiac fibroblasts improves tissue-like features of cardiac spheroids. Frontiers in molecular biosciences 7, 14. doi:10.3389/fmolb.2020.00014

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

Berg, E. L., Hsu, Y.-C. and Lee, J. A. (2014). Consideration of the cellular microenvironment: Physiologically relevant co-culture systems in drug discovery. Advanced drug delivery reviews 69, 190-204. doi:10.1016/j.addr.2014.01.013

Blanchette, A. D., Grimm, F. A., Dalaijamts, C. et al. (2019). Thorough qt/qtc in a dish: An in vitro human model that accurately predicts clinical concentration‐qtc relationships. Clinical Pharmacology & Therapeutics 105, 1175-1186. doi:10.1002/cpt.1259

Blanchette, A. D., Burnett, S. D., Grimm, F. A. et al. (2020). A bayesian method for population-wide cardiotoxicity hazard and risk characterization using an in vitro human model. Toxicological Sciences 178, 391-403. doi:10.1093/toxsci/kfaa151

Blanchette, A. D., Burnett, S. D., Rusyn, I. et al. (2022). A tiered approach to population-based in vitro testing for cardiotoxicity: Balancing estimates of potency and variability. Journal of Pharmacological and Toxicological Methods 107154. doi:10.1016/j.vascn.2022.107154

Blinova, K., Stohlman, J., Vicente, J. et al. (2017). Comprehensive translational assessment of human-induced pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias. Toxicological Sciences 155, 234-247. doi:10.1093/toxsci/kfw200

Blinova, K., Dang, Q., Millard, D. et al. (2018). International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell reports 24, 3582-3592. doi:10.1016/j.celrep.2018.08.079

Bowes, J., Brown, A. J., Hamon, J. et al. (2012). Reducing safety-related drug attrition: The use of in vitro pharmacological profiling. Nature reviews Drug discovery 11, 909-922. doi:10.1038/nrd3845

Burnett, S. D., Blanchette, A. D., Grimm, F. A. et al. (2019). Population-based toxicity screening in human induced pluripotent stem cell-derived cardiomyocytes. Toxicology and applied pharmacology 381, 114711. doi:10.1016/j.taap.2019.114711

Burnett, S. D., Blanchette, A. D., Chiu, W. A. et al. (2021a). Cardiotoxicity hazard and risk characterization of toxcast chemicals using human induced pluripotent stem cell-derived cardiomyocytes from multiple donors. Chemical Research in Toxicology 34, 2110-2124. doi:10.1021/acs.chemrestox.1c00203

Burnett, S. D., Blanchette, A. D., Chiu, W. A. et al. (2021b). Human induced pluripotent stem cell (ipsc)-derived cardiomyocytes as an in vitro model in toxicology: Strengths and weaknesses for hazard identification and risk characterization. Expert Opinion on Drug Metabolism & Toxicology 1-16. doi:10.1080/17425255.2021.1894122

Burridge, P. W., Li, Y. F., Matsa, E. et al. (2016). Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nature medicine 22, 547. doi:10.1038/nm.4087

Cai, S., Rao, X., Ye, J. et al. (2020). Relationship between urinary bisphenol a levels and cardiovascular diseases in the us adult population, 2003–2014. Ecotoxicology and Environmental Safety 192, 110300. doi:10.1016/j.ecoenv.2020.110300

Chaudhari, U., Nemade, H., Gaspar, J. A. et al. (2016). Micrornas as early toxicity signatures of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes. Archives of toxicology 90, 3087-3098. doi:10.1007/s00204-016-1668-0

Chaudhari, U., Nemade, H., Sureshkumar, P. et al. (2018). Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Archives of toxicology 92, 371-381. doi:10.1007/s00204-017-2065-z

Chen, I. Y., Matsa, E. and Wu, J. C. (2016). Induced pluripotent stem cells: At the heart of cardiovascular precision medicine. Nature Reviews Cardiology 13, 333. doi:10.1038/nrcardio.2016.36

Chen, Z., Lloyd, D., Zhou, Y.-H. et al. (2021). Risk characterization of environmental samples using in vitro bioactivity and polycyclic aromatic hydrocarbon concentrations data. Toxicological Sciences 179, 108-120. doi:10.1093/toxsci/kfaa166

Chiu, W. A. and Rusyn, I. (2018). Advancing chemical risk assessment decision-making with population variability data: Challenges and opportunities. Mammalian genome 29, 182-189. doi:10.1007/s00335-017-9731-6

Clements, M. and Thomas, N. (2014). High-throughput multi-parameter profiling of electrophysiological drug effects in human embryonic stem cell derived cardiomyocytes using multi-electrode arrays. Toxicological Sciences 140, 445-461. doi:10.1093/toxsci/kfu084

Clements, M., Millar, V., Williams, A. S. et al. (2015). Bridging functional and structural cardiotoxicity assays using human embryonic stem cell-derived cardiomyocytes for a more comprehensive risk assessment. Toxicological Sciences 148, 241-260. doi:10.1093/toxsci/kfv180

Cosselman, K. E., Navas-Acien, A. and Kaufman, J. D. (2015). Environmental factors in cardiovascular disease. Nature Reviews Cardiology 12, 627-642. doi:10.1038/nrcardio.2015.152

Daneshian, M., Kamp, H., Hengstler, J. et al. (2016). Highlight report: Launch of a large integrated European in vitro toxicology project: EU-ToxRisk. Arch Toxicol 90, 1021–1024. doi:10.1007/s00204-016-1698-7

da Rocha, A. M., Creech, J., Thonn, E. et al. (2020). Detection of drug-induced torsades de pointes arrhythmia mechanisms using hipsc-cm syncytial monolayers in a high-throughput screening voltage sensitive dye assay. Toxicological Sciences 173, 402-415. doi:10.1093/toxsci/kfz235

Dix, D. J., Houck, K. A., Martin, M. T. et al. (2007). The toxcast program for prioritizing toxicity testing of environmental chemicals. Toxicological sciences 95, 5-12. doi:10.1093/toxsci/kfl103

Ferdinandy, P., Baczkó, I., Bencsik, P. et al. (2019). Definition of hidden drug cardiotoxicity: Paradigm change in cardiac safety testing and its clinical implications. European heart journal 40, 1771-1777. doi:10.1093/eurheartj/ehy365

Feric, N. T., Pallotta, I., Singh, R. et al. (2019). Engineered cardiac tissues generated in the biowire ii: A platform for human-based drug discovery. Toxicological Sciences 172, 89-97. doi:10.1093/toxsci/kfz168

Feyen, D. A., McKeithan, W. L., Bruyneel, A. A. et al. (2020). Metabolic maturation media improve physiological function of human ipsc-derived cardiomyocytes. Cell reports 32, 107925. doi:10.1016/j.celrep.2020.107925

Fischer, I., Milton, C. and Wallace, H. (2020). Toxicity testing is evolving! Toxicology Research 9, 67-80. doi:10.1093/toxres/tfaa011

Forsythe, S. D., Devarasetty, M., Shupe, T. et al. (2018). Environmental toxin screening using human-derived 3d bioengineered liver and cardiac organoids. Frontiers in public health 6, 103. doi:10.3389/fpubh.2018.00103

Frommeyer, G. and Eckardt, L. (2016). Drug-induced proarrhythmia: Risk factors and electrophysiological mechanisms. Nature Reviews Cardiology 13, 36-47. doi:10.1038/nrcardio.2015.110

Gao, X. and Wang, H.-S. (2014). Impact of bisphenol a on the cardiovascular system—epidemiological and experimental evidence and molecular mechanisms. International journal of environmental research and public health 11, 8399-8413. doi:10.3390/ijerph110808399

Garbern, J. C. and Lee, R. T. (2021). Mitochondria and metabolic transitions in cardiomyocytes: Lessons from development for stem cell-derived cardiomyocytes. Stem Cell Research & Therapy 12, 1-25. doi:10.1186/s13287-021-02252-6

Georgiadis, N., Tsarouhas, K., Tsitsimpikou, C. et al. (2018). Pesticides and cardiotoxicity. Where do we stand? Toxicology and applied pharmacology 353, 1-14. doi:10.1016/j.taap.2018.06.004

Gintant, G. (2011). An evaluation of herg current assay performance: Translating preclinical safety studies to clinical qt prolongation. Pharmacology & therapeutics 129, 109-119. doi:10.1016/j.pharmthera.2010.08.008

Gintant, G., Sager, P. T. and Stockbridge, N. (2016). Evolution of strategies to improve preclinical cardiac safety testing. Nature Reviews Drug Discovery 15, 457. doi:10.1038/nrd.2015.34

Gintant, G., Burridge, P., Gepstein, L. et al. (2019). Use of human induced pluripotent stem cell–derived cardiomyocytes in preclinical cancer drug cardiotoxicity testing: A scientific statement from the american heart association. Circulation research 125, e75-e92. doi:10.1161/RES.0000000000000291

Gomez-Garcia, M. J., Quesnel, E., Al-Attar, R. et al. (2021). Maturation of human pluripotent stem cell derived cardiomyocytes in vitro and in vivo. Seminars in Cell & Developmental Biology, Elsevier doi:10.1016/j.semcdb.2021.05.022

Grimm, F. A., Iwata, Y., Sirenko, O. et al. (2015). High-content assay multiplexing for toxicity screening in induced pluripotent stem cell-derived cardiomyocytes and hepatocytes. Assay and drug development technologies 13, 529-546. doi:10.1089/adt.2015.659

Grimm, F. A., Blanchette, A., House, J. S. et al. (2018). A human population-based organotypic in vitro model for cardiotoxicity screening. ALTEX 35, 441. doi:10.14573/altex.1805301

Grimm, F. A., Klaren, W. D., Li, X. et al. (2020). Cardiovascular effects of polychlorinated biphenyls and their major metabolites. Environmental health perspectives 128, 077008. doi:10.1289/EHP7030

Guo, L., Coyle, L., Abrams, R. M. et al. (2013). Refining the human ipsc-cardiomyocyte arrhythmic risk assessment model. toxicological sciences 136, 581-594. doi:10.1093/toxsci/kft205

Guth, B. D. (2007). Preclinical cardiovascular risk assessment in modern drug development. Toxicological Sciences 97, 4-20. doi:10.1093/toxsci/kfm026

Hann, M. M. and Oprea, T. I. (2004). Pursuing the leadlikeness concept in pharmaceutical research. Current Opinion in Chemical Biology 8, 255-263. doi:10.1016/j.cbpa.2004.04.003

Hartung, T., Luechtefeld, T., Maertens, A. et al. (2013). Food for thought… integrated testing strategies for safety assessments. Altex 30, 3. doi:10.14573/altex.2013.1.003

Horvath, P., Aulner, N., Bickle, M. et al. (2016). Screening out irrelevant cell-based models of disease. Nature Reviews Drug Discovery 15, 751-769. doi:10.1038/nrd.2016.175

Hsieh, N.-H., Chen, Z., Rusyn, I. et al. (2021). Risk characterization and probabilistic concentration–response modeling of complex environmental mixtures using new approach methodologies (nams) data from organotypic in vitro human stem cell assays. Environmental Health Perspectives 129, 017004. doi:10.1289/EHP7600

Huebsch, N., Loskill, P., Deveshwar, N. et al. (2016). Miniaturized ips-cell-derived cardiac muscles for physiologically relevant drug response analyses. Scientific reports 6, 24726. doi:10.1038/srep24726

ICCVAM (2018). A strategic roadmap for establishing new approaches to evaluate the safety of chemicals and medical products in the United States. National Toxicology Program Research Triangle Park, NC. doi:10.22427/NTP-ICCVAM-ROADMAP2018

ICH (2001). Safety pharmacology studies for human pharmaceuticals s7a. 36791-36792. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s7a-safety-pharmacology-studies-human-pharmaceuticals

ICH (2005). The non-clinical evaluation of the potential for delayed ventricular repolarization (qt interval prolongation) by human pharmaceuticals. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s7b-nonclinical-evaluation-potential-delayed-ventricular-repolarization-qt-interval-prolongation

Incardona, J. P. (2017). Molecular mechanisms of crude oil developmental toxicity in fish. Archives of environmental contamination and toxicology 73, 19-32. doi:10.1007/s00244-017-0381-1

Ingber, D. E. (2020). Is it time for reviewer 3 to request human organ chip experiments instead of animal validation studies? Advanced Science 7, 2002030. doi:10.1002/advs.202002030

Judson, R., Richard, A., Dix, D. J. et al. (2009). The toxicity data landscape for environmental chemicals. Environmental health perspectives 117, 685-695. doi:10.1289/ehp.0800168

Kleensang, A., Maertens, A., Rosenberg, M. et al. (2014). T4 workshop report: Pathways of toxicity. Altex 31, 53. doi:10.14573/altex.1309261

Kofron, C., Kim, T. Y., Munarin, F. et al. (2021). A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3d cardiac microtissues. Scientific Reports 11, 1-16. doi:10.1038/s41598-021-89478-9

Krewski, D., Acosta Jr, D., Andersen, M. et al. (2010). Toxicity testing in the 21st century: A vision and a strategy. Journal of Toxicology and Environmental Health, Part B 13, 51-138. doi:10.1080/10937404.2010.483176

Krishna, S., Berridge, B. and Kleinstreuer, N. (2020). High-throughput screening to identify chemical cardiotoxic potential. Chemical Research in Toxicology 34, 566-583. doi:10.1021/acs.chemrestox.0c00382

Krishna, S., Borrel, A., Huang, R. et al. (2022). High-throughput chemical screening and structure-based models to predict herg inhibition. Biology 11, 209. doi:10.3390/biology11020209

Lee-Montiel, F. T., Laemmle, A., Dumont, L. et al. (2020). Integrated hipsc-based liver and heart microphysiological systems predict unsafe drug-drug interaction. bioRxiv doi:10.1101/2020.05.24.112771

Lee, E. K., Kurokawa, Y. K., Tu, R. et al. (2015). Machine learning plus optical flow: A simple and sensitive method to detect cardioactive drugs. Scientific reports 5, 1-12. doi:10.1038/srep11817

Lind, L., Araujo, J. A., Barchowsky, A. et al. (2021). Key characteristics of cardiovascular toxicants. Environmental health perspectives 129, 095001. doi:10.1289/EHP9321

Lind, Y. S., Lind, P. M., Salihovic, S. et al. (2013). Circulating levels of persistent organic pollutants (pops) are associated with left ventricular systolic and diastolic dysfunction in the elderly. Environmental research 123, 39-45. doi:10.1016/j.envres.2013.02.007

Lipinski, C. A., Lombardo, F., Dominy, B. W. et al. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews 23, 3-25. doi:10.1016/S0169-409X(96)00423-1

Luo, Y.-S., Chen, Z., Blanchette, A. D. et al. (2021). Relationships between constituents of energy drinks and beating parameters in human induced pluripotent stem cell (ipsc)-derived cardiomyocytes. Food and Chemical Toxicology 149, 111979. doi:10.1016/j.fct.2021.111979

Magdy, T., Schuldt, A. J., Wu, J. C. et al. (2018). Human induced pluripotent stem cell (hipsc)-derived cells to assess drug cardiotoxicity: Opportunities and problems. Annual review of pharmacology and toxicology 58, 83-103. doi:10.1146/annurev-pharmtox-010617-053110

Marris, C., Kompella, S. N., Miller, M. et al. (2020). Polyaromatic hydrocarbons in pollution: A heart‐breaking matter. The Journal of physiology 598, 227-247. doi:10.1113/JP278885

Marx, U., Akabane, T., Andersson, T. B. et al. (2020). Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development. Alternatives to Animal Experimentation: ALTEX 37, 365-394. doi:10.14573/altex.2001241

Mathur, A., Loskill, P., Shao, K. et al. (2015). Human ipsc-based cardiac microphysiological system for drug screening applications. Scientific reports 5, 8883. doi:10.1038/srep08883

Meek, M., Boobis, A., Cote, I. et al. (2014). New developments in the evolution and application of the who/ipcs framework on mode of action/species concordance analysis. Journal of Applied Toxicology 34, 1-18. doi:10.1002/jat.2949

Mercola, M., Colas, A. and Willems, E. (2013). Induced pluripotent stem cells in cardiovascular drug discovery. Circulation research 112, 534-548. doi:10.1161/CIRCRESAHA.111.250266

Meyer, T., Tiburcy, M. and Zimmermann, W.-H. (2019). Cardiac macrotissues-on-a-plate models for phenotypic drug screens. Advanced Drug Delivery Reviews 140, 93-100. doi:10.1016/j.addr.2019.03.002

Mikryukov, A. A., Mazine, A., Wei, B. et al. (2021). Bmp10 signaling promotes the development of endocardial cells from human pluripotent stem cell-derived cardiovascular progenitors. Cell Stem Cell 28, 96-111. e117. doi:10.1016/j.stem.2020.10.003

Mironov, V., Trusk, T., Kasyanov, V. et al. (2009). Biofabrication: A 21st century manufacturing paradigm. Biofabrication 1, 022001. doi:10.1088/1758-5082/1/2/022001

Moffat, J. G., Vincent, F., Lee, J. A. et al. (2017). Opportunities and challenges in phenotypic drug discovery: An industry perspective. Nature reviews Drug discovery 16, 531-543. doi:10.1038/nrd.2017.111

National Research Council (2007). Toxicity testing in the 21st century: A vision and a strategy. Vol. The National Academies Press. doi:10.17226/11970

Nerbonne, J. M., Nichols, C. G., Schwarz, T. L. et al. (2001). Genetic manipulation of cardiac k+ channel function in mice: What have we learned, and where do we go from here? Circulation research 89, 944-956. doi:10.1161/hh2301.100349

Nunes, S. S., Miklas, J. W., Liu, J. et al. (2013). Biowire: A platform for maturation of human pluripotent stem cell–derived cardiomyocytes. Nature methods 10, 781-787. doi:10.1038/nmeth.2524

O'Hara, T. and Rudy, Y. (2012). Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species. American Journal of Physiology-Heart and Circulatory Physiology 302, H1023-H1030. doi:10.1152/ajpheart.00785.2011

Olson, H., Betton, G., Robinson, D. et al. (2000). Concordance of the toxicity of pharmaceuticals in humans and in animals. Regulatory Toxicology and Pharmacology 32, 56-67. doi:10.1006/rtph.2000.1399

Ong, C. S., Fukunishi, T., Zhang, H. et al. (2017). Biomaterial-free three-dimensional bioprinting of cardiac tissue using human induced pluripotent stem cell derived cardiomyocytes. Scientific reports 7, 1-11. doi:10.1038/s41598-017-05018-4

Parish, S. T., Aschner, M., Casey, W. et al. (2020). An evaluation framework for new approach methodologies (nams) for human health safety assessment. Regulatory Toxicology and Pharmacology 112, 104592. doi:10.1016/j.yrtph.2020.104592

Pauluhn, J. (2005). Overview of inhalation exposure techniques: Strengths and weaknesses. Experimental and Toxicologic Pathology 57, 111-128. doi:10.1016/j.etp.2005.05.014

Pfeiffer-Kaushik, E. R., Smith, G. L., Cai, B. et al. (2019). Electrophysiological characterization of drug response in hsc-derived cardiomyocytes using voltage-sensitive optical platforms. Journal of pharmacological and toxicological methods 99, 106612. doi:10.1016/j.vascn.2019.106612

Pointon, A., Pilling, J., Dorval, T. et al. (2017). From the cover: High-throughput imaging of cardiac microtissues for the assessment of cardiac contraction during drug discovery. Toxicological Sciences 155, 444-457. doi:10.1093/toxsci/kfw227

Polonchuk, L., Chabria, M., Badi, L. et al. (2017). Cardiac spheroids as promising in vitro models to study the human heart microenvironment. Scientific reports 7, 1-12. doi:10.1038/s41598-017-06385-8

Priest, B., Bell, I. M. and Garcia, M. (2008). Role of herg potassium channel assays in drug development. Channels 2, 87-93. doi:10.4161/chan.2.2.6004

Protze, S. I., Lee, J. H. and Keller, G. M. (2019). Human pluripotent stem cell-derived cardiovascular cells: From developmental biology to therapeutic applications. Cell Stem Cell 25, 311-327. doi:10.1016/j.stem.2019.07.010

Prüss-Ustün, A. and Corvalán, C. F. (2006). Preventing disease through healthy environments: Towards an estimate of the environmental burden of disease. Vol. World Health Organization. https://apps.who.int/iris/handle/10665/43457

Rampoldi, A., Singh, M., Wu, Q. et al. (2019). Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicological Sciences 169, 280-292. doi:10.1093/toxsci/kfz038

Ravenscroft, S. M., Pointon, A., Williams, A. W. et al. (2016). Cardiac non-myocyte cells show enhanced pharmacological function suggestive of contractile maturity in stem cell derived cardiomyocyte microtissues. Toxicological Sciences 152, 99-112. doi:10.1093/toxsci/kfw069

Richards, D. J., Li, Y., Kerr, C. M. et al. (2020). Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity. Nature Biomedical Engineering 4, 446-462. doi:10.1038/s41551-020-0539-4

Sallam, K., Li, Y., Sager, P. T. et al. (2015). Finding the rhythm of sudden cardiac death: New opportunities using induced pluripotent stem cell–derived cardiomyocytes. Circulation research 116, 1989-2004. doi:10.1161/CIRCRESAHA.116.304494

Sarazan, R. D., Mittelstadt, S., Guth, B. et al. (2011). Cardiovascular function in nonclinical drug safety assessment: Current issues and opportunities. International Journal of Toxicology 30, 272-286. doi:10.1177/1091581811398963

Sauve-Ciencewicki, A., Davis, K. P., McDonald, J. et al. (2019). A simple problem formulation framework to create the right solution to the right problem. Regulatory Toxicology and Pharmacology 101, 187-193. doi:10.1016/j.yrtph.2018.11.015

Schaaf, S., Shibamiya, A., Mewe, M. et al. (2011). Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology. PloS one 6, e26397. doi:10.1371/journal.pone.0026397

Schmid, C., Abi-Gerges, N., Leitner, M. G. et al. (2021). Ion channel expression and electrophysiology of singular human (primary and induced pluripotent stem cell-derived) cardiomyocytes. Cells 10, 3370. doi:10.3390/cells10123370

Scuderi, G. J. and Butcher, J. (2017). Naturally engineered maturation of cardiomyocytes. Frontiers in cell and developmental biology 5, 50. doi:10.3389/fcell.2017.00050

Sevim, Ç., Doğan, E. and Comakli, S. (2020). Cardiovascular disease and toxic metals. Current Opinion in Toxicology 19, 88-92. doi:10.1016/j.cotox.2020.01.004

Sharma, A., Burridge, P. W., McKeithan, W. L. et al. (2017). High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Science translational medicine 9, doi:10.1126/scitranslmed.aaf2584

Sirenko, O., Cromwell, E. F., Crittenden, C. et al. (2013). Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity. Toxicology and applied pharmacology 273, 500-507. doi:10.1016/j.taap.2013.09.017

Sirenko, O., Grimm, F. A., Ryan, K. R. et al. (2017). In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model. Toxicology and applied pharmacology 322, 60-74. doi:10.1016/j.taap.2017.02.020

Skardal, A., Murphy, S. V., Devarasetty, M. et al. (2017). Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform. Scientific reports 7, 1-16. doi:10.1038/s41598-017-08879-x

Skardal, A., Aleman, J., Forsythe, S. et al. (2020). Drug compound screening in single and integrated multi-organoid body-on-a-chip systems. Biofabrication 12, 025017. doi:10.1088/1758-5090/ab6d36

Swinney, D. (2013). Phenotypic vs. Target‐based drug discovery for first‐in‐class medicines. Clinical Pharmacology & Therapeutics 93, 299-301. doi:10.1038/clpt.2012.236

Swinney, D. C. and Anthony, J. (2011). How were new medicines discovered? Nature reviews Drug discovery 10, 507-519. doi:10.1038/nrd3480

Takasuna, K., Asakura, K., Araki, S. et al. (2017). Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of csahi heart initiative. Journal of pharmacological and toxicological methods 83, 42-54. doi:10.1016/j.vascn.2016.09.004

Teuschler, L., Klaunig, J., Carney, E. et al. (2002). Support of science-based decisions concerning the evaluation of the toxicology of mixtures: A new beginning. Regulatory Toxicology and Pharmacology 36, 34-39. doi:10.1006/rtph.2002.1570

Törnqvist, E., Annas, A., Granath, B. et al. (2014). Strategic focus on 3r principles reveals major reductions in the use of animals in pharmaceutical toxicity testing. PloS one 9, e101638. doi:10.1371/journal.pone.0101638

Truskey, G. A. (2018). Human microphysiological systems and organoids as in vitro models for toxicological studies. Frontiers in public health 6, 185. doi:10.3389/fpubh.2018.00185

Ulmer, B. M., Stoehr, A., Schulze, M. L. et al. (2018). Contractile work contributes to maturation of energy metabolism in hipsc-derived cardiomyocytes. Stem Cell Reports 10, 834-847. doi:10.1016/j.stemcr.2018.01.039

Verheijen, M., Schrooders, Y., Gmuender, H. et al. (2018). Bringing in vitro analysis closer to in vivo: Studying doxorubicin toxicity and associated mechanisms in 3d human microtissues with pbpk-based dose modelling. Toxicology letters 294, 184-192. doi:10.1016/j.toxlet.2018.05.029

Vincent, F., Loria, P., Pregel, M. et al. (2015). Developing predictive assays: The phenotypic screening “rule of 3”. Science translational medicine 7, 293ps215-293ps215. doi:10.1126/scitranslmed.aab1201

Virani, S. S., Alonso, A., Benjamin, E. J. et al. (2020). Heart disease and stroke statistics—2020 update: A report from the american heart association. Circulation 141, E139-E596. doi:10.1161/CIR.0000000000000757

Wambaugh, J. F., Wetmore, B. A., Pearce, R. et al. (2015). Toxicokinetic triage for environmental chemicals. Toxicological Sciences 147, 55-67. doi:10.1093/toxsci/kfv118

Wetmore, B. A., Wambaugh, J. F., Ferguson, S. S. et al. (2013). Relative impact of incorporating pharmacokinetics on predicting in vivo hazard and mode of action from high-throughput in vitro toxicity assays. toxicological sciences 132, 327-346. doi:10.1093/toxsci/kft012

Wetmore, B. A. (2015). Quantitative in vitro-to-in vivo extrapolation in a high-throughput environment. Toxicology 332, 94-101. doi:10.1016/j.tox.2014.05.012

Witty, A. D., Mihic, A., Tam, R. Y. et al. (2014). Generation of the epicardial lineage from human pluripotent stem cells. Nature biotechnology 32, 1026-1035. doi:10.1038/nbt.3002

Wu, L., Rajamani, S., Li, H. et al. (2009). Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late na+ current in the heart. American Journal of Physiology-Heart and Circulatory Physiology 297, H1048-H1057. doi:10.1152/ajpheart.00467.2009

Yang, F. and Massey, I. Y. (2019). Exposure routes and health effects of heavy metals on children. Biometals 32, 563-573. doi:10.1007/s10534-019-00193-5

Zhang, S., Zhou, Z., Gong, Q. et al. (1999). Mechanism of block and identification of the verapamil binding domain to herg potassium channels. Circulation Research 84, 989-998. doi:10.1161/01.res.84.9.989

Zhao, Y., Rafatian, N., Wang, E. Y. et al. (2020). Towards chamber specific heart-on-a-chip for drug testing applications. Advanced Drug Delivery Reviews 165-166, 60-76. doi:10.1016/j.addr.2019.12.002

Zink, D., Chuah, J. K. C. and Ying, J. Y. (2020). Assessing toxicity with human cell-based in vitro methods. Trends in Molecular Medicine 26, 570-582. doi:10.1016/j.molmed.2020.01.008

Zuppinger, C. (2019). 3d cardiac cell culture: A critical review of current technologies and applications. Frontiers in cardiovascular medicine 6, 87. doi:10.3389/fcvm.2019.00087