Advances in selecting appropriate non-rodent species for regulatory toxicology research: Policy, ethical, and experimental considerations

Son, Yong Wook; Choi, Ha Ni; Hwan, Jeong; Kang, Byeong Cheol; Yun, Jun Won

doi:10.1016/j.yrtph.2020.104757

Cited by 18 publications

(10 citation statements)

References 126 publications

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“…24,25 Current regulatory guidelines usually require safety and tolerability data from two species: a rodent and a non-rodent, before administering potential new medicines to humans in the first clinical trials. 26,27 Dogs are the default non-rodent used in toxicology studies with multiple scientific advantages, including similarity in the organs and physiology, adequate background data and availability. 26,28 Rabbits are mostly used to evaluate reproductive and developmental toxicity as they are phylogenetically close to humans.…”

Section: Animal Experimentationmentioning

confidence: 99%

“…26,27 Dogs are the default non-rodent used in toxicology studies with multiple scientific advantages, including similarity in the organs and physiology, adequate background data and availability. 26,28 Rabbits are mostly used to evaluate reproductive and developmental toxicity as they are phylogenetically close to humans. 29 Moreover, they are relevant models for safety and pharmacology studies as their cardiovascular system has structural similarities with that of humans.…”

Section: Animal Experimentationmentioning

confidence: 99%

“…Minipigs effectively exhibit relevant similarity to humans: skin, cardiovascular system, gastrointestinal tract anatomy, and breeding habits. 26,30 Significant interspecies differences in metabolism exist that confound the direct extrapolation of data from laboratory animal species into man in the development of pharmaceuticals. 26,31 Non-human primates (NHPs), composed of monkeys and apes, are phylogenetically closer to humans than other species but involve high study costs associated with ethical issues.…”

Section: Animal Experimentationmentioning

confidence: 99%

“…26,30 Significant interspecies differences in metabolism exist that confound the direct extrapolation of data from laboratory animal species into man in the development of pharmaceuticals. 26,31 Non-human primates (NHPs), composed of monkeys and apes, are phylogenetically closer to humans than other species but involve high study costs associated with ethical issues. 32 Although animal models have significantly contributed to medical research, drug screening, and toxicity studies, they present two major disadvantages: significant interspecies differences with humans, and ethical considerations.…”

Section: Animal Experimentationmentioning

confidence: 99%

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Liver organ-on-chip models for toxicity studies and risk assessment

et al. 2022

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Section: Animal Experimentationmentioning

confidence: 99%

Section: Animal Experimentationmentioning

confidence: 99%

Section: Animal Experimentationmentioning

confidence: 99%

Section: Animal Experimentationmentioning

confidence: 99%

See 2 more Smart Citations

Liver organ-on-chip models for toxicity studies and risk assessment

et al. 2022

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“…Mice are an invaluable source of knowledge but are not always the most suitable means of translating new findings into clinical application. The shortcomings of the exclusive use of rodents in preclinical studies, for example, drug trials, are now widely recognized (1) and regulatory agencies around the world are requiring preclinical trial data from non-rodent species (2). As mammals, mice and humans share many fundamental similarities, but dissimilar protein interactions, physiology, and anatomy can lead to different disease phenotypes from similar genetic lesions (3).…”

Section: Introductionmentioning

confidence: 99%

The Missing Link: Cre Pigs for Cancer Research

et al. 2021

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The Cre/loxP system is a powerful tool for the generation of animal models with precise spatial and temporal gene expression. It has proven indispensable in the generation of cancer models with tissue specific expression of oncogenes or the inactivation of tumor suppressor genes. Consequently, Cre-transgenic mice have become an essential prerequisite in basic cancer research. While it is unlikely that pigs will ever replace mice in basic research they are already providing powerful complementary resources for translational studies. But, although conditionally targeted onco-pigs have been generated, no Cre-driver lines exist for any of the major human cancers. To model human pancreatic cancer in pigs, Cre-driver lines were generated by CRISPR/Cas9-mediated insertion of codon-improved Cre (iCre) into the porcine PTF1A gene, thus guaranteeing tissue and cell type specific function which was proven using dual fluorescent reporter pigs. The method used can easily be adapted for the generation of other porcine Cre-driver lines, providing a missing tool for modeling human cancers in large animals.

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The choice of ultra‐low attachment plates impacts primary human and primary canine hepatocyte spheroid formation, phenotypes, and function

Xing,

Kemas,

Mickols

et al. 2024

Biotechnology Journal

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Organotypic three‐dimensional liver spheroid cultures in which hepatic cells retain their molecular phenotype and functionality have emerged as powerful tools for preclinical drug development. In recent years a multitude of culture systems have been developed; however, a thorough side‐by‐side benchmarking of the different methods is lacking. Here, we compared the performance of ten different 96‐ and 384‐well microplate types to support spheroid formation and long‐term culture. Specifically, we evaluated differences in spheroid formation kinetics, viability, functionality, expression patterns, and their utility for hepatotoxicity assessments using primary human hepatocytes (PHH) and primary canine hepatocytes (PCH). All 96‐well plates enabled formation of PHH liver spheroids, albeit with differences between plates in spheroid size, geometry, and reproducibility. Performance of different 384‐wells was less consistent. Only 6/10 microplates supported the formation of PCH aggregates. Interestingly, even if PCH aggregates in these six microplates were more loosely packed than PHH spheroids, they maintained their function and were compatible with long‐term pharmacological and toxicological assays. Overall, Corning and Biofloat plates showed the best performance in the formation of both human and canine liver spheroids with highest viability, most physiologically relevant phenotypes, superior CYP activity and lowest coefficient of variation in toxicity assays. The presented data constitutes a valuable resource that demonstrates the impacts of current ultra‐low attachment plates on liver spheroid metrics and can guide evidence‐based plate selection. Combined, these results have important implications for the cross‐comparison of different studies and can facilitate the standardization and reproducibility of three‐dimensional liver culture experiments.

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Advances in selecting appropriate non-rodent species for regulatory toxicology research: Policy, ethical, and experimental considerations

Cited by 18 publications

References 126 publications

Liver organ-on-chip models for toxicity studies and risk assessment

Liver organ-on-chip models for toxicity studies and risk assessment

The Missing Link: Cre Pigs for Cancer Research

The choice of ultra‐low attachment plates impacts primary human and primary canine hepatocyte spheroid formation, phenotypes, and function

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