Journal articles: 'Toxicity testing – In vivo'

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Flint, Oliver P. "In Vitro Toxicity Testing: Purpose, Validation and Strategy." Alternatives to Laboratory Animals 18, no. 1_part_1 (1990): 11–18. http://dx.doi.org/10.1177/026119299001800103.1.

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The fullest potential for in vitro evaluation of toxicity will be realised in the context of the process of assessing the risk of human toxicity. This article is an attempt to clarify what contributions can be made by in vitro tests and what types of in vitro test can best be used. In vitro tests are clarified according to the type of biological endpoint evaluated, first into tests for general (‘basal’) cytotoxicity and, secondly, into tests for differentiated cell function. The role of each type of test is analysed and it is suggested that tests for general cytotoxicity, as opposed to differentiated function, are difficult to interpret in terms of in vivo toxicity. A general approach to evaluating in vitro tests is described, and a strategy for using these tests is proposed.

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Wang, Danlei, Maartje H. Rietdijk, Lenny Kamelia, Peter J. Boogaard, and Ivonne M. C. M. Rietjens. "Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro–in silico approach." Archives of Toxicology 95, no. 10 (2021): 3323–40. http://dx.doi.org/10.1007/s00204-021-03128-7.

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AbstractDevelopmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro–in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration–response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose–response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED50) amounted to 67 and 45 mg/kg bw being comparable to the ED50 derived from the in vivo dose–response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro–in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

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Noyes, Pamela D., Gloria R. Garcia, and Robert L. Tanguay. "Zebrafish as an in vivo model for sustainable chemical design." Green Chemistry 18, no. 24 (2016): 6410–30. http://dx.doi.org/10.1039/c6gc02061e.

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Heightened public awareness about the many thousands of chemicals in use and present as persistent contaminants in the environment has increased the demand for safer chemicals and more rigorous toxicity testing.

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Dorgelo, Folke O., Erik Biessen, and Gerrit M. Alink. "Are Cultured Neonatal Rat Heart Cells a Suitable Model for Predicting Acute and Chronic Toxicity In Vivo?" Alternatives to Laboratory Animals 14, no. 1 (1986): 14–22. http://dx.doi.org/10.1177/026119298601400104.

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Beating heart cells isolated from neonatal rats were used in an in vitro assay for testing the influence of chemical compounds on beating frequency. Half of the studied compounds had a no-effect level (NEL) in vivo based on changes in body weight or organ weight. Correlations were obtained between in vivo parameters such as LD50 values in acute toxicity studies and NELs in chronic toxicity studies, and in vitro parameters such as reduction in beating frequency and arrest of contraction. The in vitro parameters correlated well with in vivo LD50 values, but poorly with NELs in vivo.

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Kawada, Toshikatsu, Junya Kuroyanagi, Fumiyoshi Okazaki, et al. "An Integrative Evaluation Method for the Biological Safety of Down and Feather Materials." International Journal of Molecular Sciences 20, no. 6 (2019): 1434. http://dx.doi.org/10.3390/ijms20061434.

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Background: Down and feather materials have been commonly used and promoted as natural stuffing for warm clothing and bedding. These materials tend to become more allergenic as they become contaminated with microorganisms, in addition to being subjected to several kinds of chemical treatments. The biological or chemical contaminants in these materials pose a major risk to human health, to consumers and manufacturers alike. Here, we report the development of an integrative evaluation method for down and feather materials to assess bacterial contamination and in vivo toxicity. Methods: To assess bacterial contamination, we quantified 16S ribosomal RNA, performed culture tests, and established a conversion formula. To determine in vivo toxicity, we performed a zebrafish embryo toxicity testing (ZFET). Results: Washing the material appropriately decreases the actual number of bacteria in the down and feather samples; in addition, after washing, 16S rRNA sequencing revealed that the bacterial compositions were similar to those in rinse water. The ZFET results showed that even materials with low bacterial contamination showed high toxicity or high teratogenicity, probably because of the presence of unknown chemical additives. Conclusions: We established an integrative evaluation method for down and feather safety, based on bacterial contamination with in vivo toxicity testing.

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Garrod, Mathew, and David Yi San Chau. "An Overview of Tissue Engineering as an Alternative for Toxicity Assessment." Journal of Pharmacy & Pharmaceutical Sciences 19, no. 1 (2016): 31. http://dx.doi.org/10.18433/j35p6p.

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Tissue engineering is a multidisciplinary field that combines aspects of biology, material sciences, engineering and medicine - the ultimate goal being able to fabricate replacement tissues and/or organs for an ageing population. However, parallel to this milestone, is the exploitation of the biomimetic constructs as feasible alternatives to in vivo/ex vivo toxicity testing models due to their accurate representation of innate tissue and organs. Herein, we summarise a range of concepts within tissue engineering with a particular emphasis on biological material selection and implications to animal testing. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Combes, Robert, Christina Grindon, Mark T. D. Cronin, David W. Roberts, and John F. Garrod. "Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation." Alternatives to Laboratory Animals 36, no. 1 (2008): 45–63. http://dx.doi.org/10.1177/026119290803600107.

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Liverpool John Moores University and FRAME conducted a joint research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for acute systemic toxicity and toxicokinetic testing. The paper reviews in vitro tests based on basal cytotoxicity and target organ toxicity, along with QSAR models and expert systems available for this endpoint. The use of PBPK modelling for the prediction of ADME properties is also discussed. These tests are then incorporated into a decision-tree style, integrated testing strategy, which also includes the use of refined in vivo acute toxicity tests, as a last resort. The implementation of the strategy is intended to minimise the use of animals in the testing of acute systemic toxicity and toxicokinetics, whilst satisfying the scientific and logistical demands of the EU REACH legislation.

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Combes, Robert, Christina Grindon, Mark T. D. Cronin, David W. Roberts, and John F. Garrod. "Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation." Alternatives to Laboratory Animals 36, no. 1_suppl (2008): 91–109. http://dx.doi.org/10.1177/026119290803601s08.

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Liverpool John Moores University and FRAME conducted a joint research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for acute systemic toxicity and toxicokinetic testing. The paper reviews in vitro tests based on basal cytotoxicity and target organ toxicity, along with QSAR models and expert systems available for this endpoint. The use of PBPK modelling for the prediction of ADME properties is also discussed. These tests are then incorporated into a decision-tree style, integrated testing strategy, which also includes the use of refined in vivo acute toxicity tests, as a last resort. The implementation of the strategy is intended to minimise the use of animals in the testing of acute systemic toxicity and toxicokinetics, whilst satisfying the scientific and logistical demands of the EU REACH legislation.

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Gm, Subaiea, Aljofan M, Devadasu Vr, and Alshammari Tm. "ACUTE TOXICITY TESTING OF NEWLY DISCOVERED POTENTIAL ANTIHEPATITIS B VIRUS AGENTS OF PLANT ORIGIN." Asian Journal of Pharmaceutical and Clinical Research 10, no. 11 (2017): 210. http://dx.doi.org/10.22159/ajpcr.2017.v10i11.20717.

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Objective: Our previous studies indicate that alkaloids could be developed as potential antihepatitis B agents. In the present study, we investigated the in vitro antihepatitis B virus (HBV) activity and in vivo acute oral toxicity of three isoquinoline alkaloids [-(-) Canadine, Corydadine, and Berberine] obtained from Fumaria and Corydalis species. The compounds were selected based on their therapeutic indexes calculated previously in vitro.Methods: The antiviral activity and cytotoxicity of selected isoquinoline alkaloids were evaluated in vitro in HepG2 cells. In vivo, acute oral toxicity was performed in female mice following the Organization for Economic Cooperation and Development test guideline-423 (acute toxicity class method).Results: The selected agents have shown high antiviral activity against HBV and low cytotoxicity in vitro. The results obtained from an acute oral toxicity study revealed that the LD50 of all the test compounds was >2000 mg/kg when administered orally to mice. All the tested compounds fall under the category 5 (unclassified) according to the Globally Harmonized System, with a LD50 value >2000 mg/kg when orally administered to mice.Conclusion: The results of the study revealed that OR-13 and MNAD can be studied further and can be developed as antihepatitis B drugs.

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Iñesta Vaquera, Francisco, Febe Ferro, Michael McMahon, Colin J. Henderson, and C. Roland Wolf. "Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies." F1000Research 11 (October 11, 2022): 1164. http://dx.doi.org/10.12688/f1000research.123077.1.

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Chemical risk assessment ensures protection from the toxic effects of drugs and manmade chemicals. To comply with regulatory guidance, studies in complex organisms are required, as well as mechanistic studies to establish the relevance of any toxicities observed to man. Although in vitro toxicity models are improving, in vivo studies remain central to this process. Such studies are invariably time-consuming and often involve large numbers of animals. New regulatory frameworks recommend the implementation of “smart” in vivo approaches to toxicity testing that can effectively assess safety for humans and comply with societal expectations for reduction in animal use. A major obstacle in reducing the animals required is the time-consuming and complexity of the pathological endpoints used as markers of toxicity. Such endpoints are prone to inter-animal variability, subjectivity and require harmonisation between testing sites. As a consequence, large numbers of animals per experimental group are required. To address this issue, we propose the implementation of sophisticated stress response reporter mice that we have developed. These reporter models provide early biomarkers of toxic potential in a highly reproducible manner at single-cell resolution, which can also be measured non-invasively and have been extensively validated in academic research as early biomarkers of stress responses for a wide range of chemicals at human-relevant exposures. In this report, we describe a new and previously generated models in our lab, provide the methodology required for their use and discuss how they have been used to inform on toxic risk. We propose our in vivo approach is more informative (refinement) and reduces the animal use (reduction) compared to traditional toxicity testing. These models could be incorporated into tiered toxicity testing and used in combination with in vitro assays to generate quantitative adverse outcome pathways and inform on toxic potential.

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Chrishtop, Vladimir V., Artur Y. Prilepskii, Varvara G. Nikonorova, and Vladimir A. Mironov. "Nanosafety vs. nanotoxicology: adequate animal models for testing in vivo toxicity of nanoparticles." Toxicology 462 (October 2021): 152952. http://dx.doi.org/10.1016/j.tox.2021.152952.

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Hengstler, Jan G., Rosemarie Marchan, and Marcel Leist. "Highlight report: towards the replacement of in vivo repeated dose systemic toxicity testing." Archives of Toxicology 86, no. 1 (2011): 13–15. http://dx.doi.org/10.1007/s00204-011-0798-7.

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Halle, Willi, Marlies Halder, Andrew Worth, and Elke Genschow. "The Registry of Cytotoxicity: Toxicity Testing in Cell Cultures to Predict Acute Toxicity (LD50) and to Reduce Testing in Animals." Alternatives to Laboratory Animals 31, no. 2 (2003): 89. http://dx.doi.org/10.1177/026119290303100204.

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This is a translation of a report on the Registry of Cytotoxicity (RC), originally published in German in 1998. The report presented an advanced in vitro method, which can significantly reduce the number of animals needed for the toxicity testing of a broad range of compounds/xenobiotics. With the RC method, it was possible to predict the oral or intravenous acute toxicity (LD50) — which is a regulatory requirement for newly developed pharmaceuticals and industrial and household chemicals — from the cytotoxicity data (mean IC50 = IC50X) obtained with mammalian cells. The RC method can be used before the in vivo test, and it does not pose any additional harm or suffering to laboratory animals. The RC method is of broad practical use: it can be applied, for example, in the pharmaceutical industry or the chemical industry in regulatory testing or in research. It is ready for validation, and could then be incorporated into OECD guidelines, thus reducing the total number of animals needed for regulatory toxicity testing. The RC method is based on the comparison of the IC50X values and the LD50 values by using linear regression analysis. With the RC method, it was possible to predict, within a predefined dose range, the acute oral LD50 for 252 of 347 xenobiotics, and the intravenous LD50 for rats and/or mice for 117 of 150 xenobiotics. Comparative studies showed that these results are highly reproducible.

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Zavala, Jose, Anastasia N. Freedman, John T. Szilagyi, et al. "New Approach Methods to Evaluate Health Risks of Air Pollutants: Critical Design Considerations for In Vitro Exposure Testing." International Journal of Environmental Research and Public Health 17, no. 6 (2020): 2124. http://dx.doi.org/10.3390/ijerph17062124.

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Air pollution consists of highly variable and complex mixtures recognized as major contributors to morbidity and mortality worldwide. The vast number of chemicals, coupled with limitations surrounding epidemiological and animal studies, has necessitated the development of new approach methods (NAMs) to evaluate air pollution toxicity. These alternative approaches include in vitro (cell-based) models, wherein toxicity of test atmospheres can be evaluated with increased efficiency compared to in vivo studies. In vitro exposure systems have recently been developed with the goal of evaluating air pollutant-induced toxicity; though the specific design parameters implemented in these NAMs-based studies remain in flux. This review aims to outline important design parameters to consider when using in vitro methods to evaluate air pollutant toxicity, with the goal of providing increased accuracy, reproducibility, and effectiveness when incorporating in vitro data into human health evaluations. This review is unique in that experimental considerations and lessons learned are provided, as gathered from first-hand experience developing and testing in vitro models coupled to exposure systems. Reviewed design aspects include cell models, cell exposure conditions, exposure chambers, and toxicity endpoints. Strategies are also discussed to incorporate in vitro findings into the context of in vivo toxicity and overall risk assessment.

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Andersen, Knut-Jan, Erik Ilsø Christensen, and Hogne Vik. "Three-dimensional Growth of Renal Epithelial Cells in Vitro: A Tool in Toxicity Testing." Alternatives to Laboratory Animals 21, no. 2 (1993): 191–95. http://dx.doi.org/10.1177/026119299302100212.

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The tissue culture of multicellular spheroids from the renal epithelial cell line LLC-PK1 (proximal tubule) is described. This represents a biological system of intermediate complexity between renal tissue in vivo and simple monolayer cultures. The multicellular structures, which show many similarities to kidney tubules in vivo, including a vectorial water transport, should prove useful for studying the potential nephrotoxicity of drugs and chemicals in vitro. In addition, the propagation of renal epithelial cells as multicellular spheroids in serum-free culture may provide information on the release of specific biological parameters, which may be suppressed or masked in serum-supplemented media.

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Combes, Robert D. "Regulatory Genotoxicity Testing: A Critical Appraisal." Alternatives to Laboratory Animals 23, no. 3 (1995): 352–79. http://dx.doi.org/10.1177/026119299502300312.

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This review considers current approaches to regulatory genotoxicity testing, focusing on how the use of animals can be further replaced, reduced and refined. The complementary roles of in vitro and in vivo testing, and the justification for using animals, are discussed in detail. Recommendations are made for improvements and further work, in the light of the considerable current controversy surrounding the composition and deployment of testing strategies, and the interpretation of the data generated, particularly for carcinogenicity prediction. The major problems are the oversensitivity of in vitro tests and the insensitivity of in vivo assays. On the basis of an analysis of some published databases, it is concluded that there is insufficient support for using in vivo genotoxicity assays for screening. Also, it is questionable whether the scientific benefits of using such assays always outweigh the costs to the animals involved. The considerable efforts being made to harmonise in vivo protocols and to develop improved methods for detecting genotoxicity are discussed. It is recommended that more emphasis be placed on characterising genotoxins in vitro, especially for mechanisms of activity, to optimise the benefits of any confirmatory animal tests.. Also, regulatory agencies are urged to require better-designed and more-scientifically sound protocols, in which animal numbers are minimised and data interpretation, particularly that of negative results, is facilitated. Lastly, in the development and validation of transgenic rodent systems, emphasis should be placed on developing protocols in which other acute toxicity and metabolism endpoints can be measured simultaneously with in vivo mutagenesis, while minimising animal numbers.

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Trenin, Alexey S., Elena B. Isakova, Michael I. Treshchalin, et al. "Evaluation of New Antimicrobial Agents Based on tris(1H-Indol-3-yl)methylium Salts: Activity, Toxicity, Suppression of Experimental Sepsis in Mice." Pharmaceuticals 15, no. 2 (2022): 118. http://dx.doi.org/10.3390/ph15020118.

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The antimicrobial activity and toxicity of three novel synthetic antibacterial agents containing tris(1H-indol-3-yl)methylium fragment were studied in vitro and in vivo. All compounds in vitro revealed high activity (minimal inhibitory concentration (MIC) 0.13–1.0 µg/mL) against bacteria that were either sensitive or resistant to antibiotics, including multidrug-resistant clinical isolates. The derivatives combining high antimicrobial activity with relatively low cytotoxicity against human donor fibroblasts HPF-hTERT were subjected to further testing on mice. In vivo they revealed fairly good tolerance and relatively low toxicity. Acute toxicity was evaluated, and the main indicators of toxicity, including LD50 and LD10, were determined. A study of compounds in vivo showed their efficiency in the model of staphylococcal sepsis in mice. The efficiency of compounds may be due to the ability of indolylmethylium salts to form pores in the cytoplasmic membrane of microbial cells and thereby facilitate the penetration of molecules into the pathogen.

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Danzeisen, Ruth, David Lee Williams, Vanessa Viegas, Michael Dourson, Steven Verberckmoes, and Arne Burzlaff. "Bioelution, Bioavailability, and Toxicity of Cobalt Compounds Correlate." Toxicological Sciences 174, no. 2 (2020): 311–25. http://dx.doi.org/10.1093/toxsci/kfz249.

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Abstract Based on the wide use of cobalt substances in a range of important technologies, it has become important to predict the toxicological properties of new or lesser-studied substances as accurately as possible. We studied a group of 6 cobalt substances with inorganic ligands, which were tested for their bioaccessibility (surrogate measure of bioavailability) through in vitro bioelution in simulated gastric and intestinal fluids. Representatives of the group also underwent in vivo blood kinetics and mass balance tests, and both oral acute and repeated dose toxicity (RDT) testing. We were able to show a good correlation between high in vitro bioaccessibility with high in vivo bioavailability and subsequent high in vivo toxicity; consequently, low in vitro bioaccessibility correlated well with low in vivo bioavailability and low in vivo toxicity. In vitro bioelution in simulated gastric fluid was the most precise predictor of the difference in the oral RDT lowest observed adverse effect levels of 2 compounds representing the highly and poorly bioaccessible subset of substances. The 2 compounds cobalt dichloride hexahydrate and tricobalt tetraoxide differed by a factor of 440 in their in vitro bioaccessibility and by a factor of 310 in their RDT lowest observed adverse effect level. In summary, this set of studies shows that solubility, specifically in vitro bioelution in simulated gastric fluid, is a good, yet conservative, predictor of in vivo bioavailability and oral systemic toxicity of inorganic cobalt substances. Bioelution data are therefore an invaluable tool for grouping and read across of cobalt substances for hazard and risk assessment.

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Kiparissis, Yiannis, Parveen Akhtar, Peter V. Hodson, and R. Stephen Brown. "Partition-Controlled Delivery of Toxicants: A Novel In Vivo Approach for Embryo Toxicity Testing." Environmental Science & Technology 37, no. 10 (2003): 2262–66. http://dx.doi.org/10.1021/es026154r.

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Northup, Sharon J. "Perspectives on In Vitro Toxicity for Medical Devices." Journal of the American College of Toxicology 7, no. 4 (1988): 481–89. http://dx.doi.org/10.3109/10915818809019521.

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In vitro toxicity testing has found widespread application in its use for screening materials for medical devices. Cytotoxicity tests, which have been in use for nearly 20 years, have been validated for intralaboratory repeatability, interlaboratory reproducibility, and correlation with acute animal toxicity assays. The three primary cytotoxicity assays, i.e., direct contact, agar diffusion, and elution tests, allow a selection between assay and material characteristics. Mutagenicity assays have had limited application to materials testing because of the insoluble nature of the materials and the low level of extractable chemicals, which are generally below the sensitivity limit of these assays. In vitro blood compatibility tests for hemolysis and complement activation are used primarily for blood contacting materials in applications where there is a large surface area of material for ex vivo applications.

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Grindon, Christina, Robert Combes, Mark T. D. Cronin, David W. Roberts, and John F. Garrod. "An Integrated Decision-tree Testing Strategy for Repeat Dose Toxicity with Respect to the Requirements of the EU REACH Legislation." Alternatives to Laboratory Animals 36, no. 1 (2008): 93–101. http://dx.doi.org/10.1177/026119290803600110.

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This paper presents some results of a joint research project conducted by FRAME and Liverpool John Moores University, and sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity end-points associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for repeat dose (sub-acute, sub-chronic and chronic) toxicity testing. It reviews the limited number of in silico and in vitro tests available for this endpoint, and outlines new technologies which could be used in the future, e.g. the use of biomarkers and the ‘omics’ technologies. An integrated testing strategy is proposed, which makes use of as much non-animal data as possible, before any essential in vivo studies are performed. Although none of the non-animal tests are currently undergoing validation, their results could help to reduce the number of animals required for testing for repeat dose toxicity.

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Grindon, Christina, Robert Combes, Mark T. D. Cronin, David W. Roberts, and John F. Garrod. "An Integrated Decision-tree Testing Strategy for Repeat Dose Toxicity with Respect to the Requirements of the EU REACH Legislation." Alternatives to Laboratory Animals 36, no. 1_suppl (2008): 139–47. http://dx.doi.org/10.1177/026119290803601s11.

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This paper presents some results of a joint research project conducted by FRAME and Liverpool John Moores University, and sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity end-points associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for repeat dose (sub-acute, sub-chronic and chronic) toxicity testing. It reviews the limited number of in silico and in vitro tests available for this endpoint, and outlines new technologies which could be used in the future, e.g. the use of biomarkers and the ‘omics’ technologies. An integrated testing strategy is proposed, which makes use of as much non-animal data as possible, before any essential in vivo studies are performed. Although none of the non-animal tests are currently undergoing validation, their results could help to reduce the number of animals required for testing for repeat dose toxicity.

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Franchini, Jessica L., John T. Propst, Gerald R. Comer, and Michael J. Yost. "Novel Tissue Engineered Tubular Heart Tissue forIn VitroPharmaceutical Toxicity Testing." Microscopy and Microanalysis 13, no. 4 (2007): 267–71. http://dx.doi.org/10.1017/s1431927607070663.

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A growing problem in cardiac drug toxicity has been blamed on the lack of adequate testing prior to authorization for prescription use. This study offers an effective alternative to the current method ofin vivopharmaceutical testing, which is time and cost prohibitive. We have accomplished this by developing the novel three-dimensional heart tube model. At the “heart” of our model lies our patented collagen scaffold that enables the cardiac myocytes to display anin vivo–like architecture. The cardiac myocytes were cocultured with the collagen tube for a period of 5 weeks, resulting in the heart tubes. Our heart tubes were treated with specific drugs (nifedipine, isoproterenol, and lidocaine) at varying concentrations. The percent of apoptotic cells was calculated based on observing the number of cells that labeled positive for caspase-3 via confocal microscopy. All three drugs exhibited negative effects at high concentrations in that the number of living cells decreased. Lidocaine showed an increase in apoptosis at concentrations of 75 μM and above. This may indicate that certain drugs have a minimum concentration level that must be reached before the cells experience apoptosis from the toxic levels.

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Bergström, Gunnar, Jonas Christoffersson, Kristin Schwanke, Robert Zweigerdt, and Carl-Fredrik Mandenius. "Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging." Lab on a Chip 15, no. 15 (2015): 3242–49. http://dx.doi.org/10.1039/c5lc00449g.

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Yankova, I., E. Ivanova, K. Todorova, et al. "Assessment of the toxicity and antiproliferative activity of hemocyanins from Helix lucorum, Helix aspersa and Rapana venosa." Bulgarian Chemical Communications Volume 53, Special Issue A (2021): 15–21. http://dx.doi.org/10.34049//bcc.53.a.0003.

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Hemocyanins (Hcs) are respiratory, oxygen-carrying metalloproteins that are freely dissolved in the hemolymph of many molluscs and arthropods. The interest in hemocyanins has grown significantly since it was found that they can be successfully used in immunotherapy of neoplastic diseases as non-specific or active stimulators of the immune system. The present study aims to assess the cytotoxicity, in vivo toxicity and antiproliferative activity of hemocyanins isolated from marine snail Rapana venosa (RvH), garden snails Helix lucorum (HlH) and Helix aspersa (HaH). For in vitro safety testing, 3T3 Neutral Red Uptake (NRU) test was used. The experiments for antiproliferative activity of the hemocyanins were performed by MTT assay on a panel of cell lines - a model of breast cancer. The in vivo toxicological assessment was performed by regular clinical examinations of hemocyanin-treated laboratory mice and histopathological analysis of hematoxylin/eosin stained preparations of parenchymal organs. The evaluation of the in vitro cytotoxicity showed that the tested hemocyanins does not induce toxic effects in nontumorigenic epithelial cell lines. In contrast, significant reduction of the viability of human breast carcinoma cell lines was found after treatment with high concentrations of hemocyanins. The in vivo experiments showed no signs of organ and systemic toxicity in the hemocyanin-treated animals. The presented data indicate that Hcs show a potential for development of novel anticancer therapeutics due to their beneficial properties, biosafety and lack of toxicity or side effects. Key words: hemocyanins (Hcs); cytotoxicity; antitumor activity; in vivo biosafety testing.

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Laternser, Sandra, Chiara Cianciolo Cosentino, Justyna M. Przystal, et al. "MODL-22. DEVELOPING A REAL-TIME PERSONALIZED DRUG TESTING PLATFORM FOR PEDIATRIC CNS CANCERS." Neuro-Oncology 22, Supplement_3 (2020): iii415. http://dx.doi.org/10.1093/neuonc/noaa222.595.

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Abstract INTRODUCTION The relatively small size of biopsied CNS tumors has presented a historical challenge for real-time drug screens. Moreover, in vivo assessment of drug response does not often benefit patients with aggressive gliomas given the relatively long time (&gt;8 months) of tumor engraftment in the classic mouse PDX models. Here, we aimed to develop an innovative real-time in vivo and in vitro drug screening platform capable of analyzing a minimal number (&lt;1E6) of cells obtained at biopsy. METHODS Existing primary cells were used to test 6 different culture platforms. The top platform was selected and used to expand tumor cells obtained of DMG biopsy. Tumor cells were validated using the minION sequencing platform. Single and combination drug (n=7) screens were performed. Effective drugs were further evaluated in zebrafish PDX and non-tumor bearing models to assess efficacy and toxicity, respectively. RESULTS A total of 8 biopsies were obtained. Successful cell expansion was achieved in 6/8 (75%) and a limited drug screen in 3/6 (50%) of cases. Single and combination drug (n=7) assays identified responder and non-responders to candidate drugs. Systemic toxicity of effective drugs was tested in non-tumor bearing zebrafish. Tumor cells were engrafted in zebrafish providing the opportunity for an in vivo screen. The entire process was completed within 21 days on average. CONCLUSIONS A novel platform was developed for rapid in vitro and in vivo drug screens of tumor cells obtained at biopsy. This platform will provide the opportunity to establish personalized therapy for heterogeneous cancers including DMGs.

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Yah, Clarence S., and Geoffrey S. Simate. "Engineered nanoparticle bio-conjugates toxicity screening: The xCELLigence cells viability impact." BioImpacts 10, no. 3 (2020): 195–203. http://dx.doi.org/10.34172/bi.2020.24.

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Introduction: The vast diverse products and applications of engineered nanoparticle bio-conjugates (ENPBCs) are increasing, and thus flooding the-markets. However, the data to support risk estimates of ENPBC are limited. While it is important to assess the potential benefits, acceptability and uptake, it is equally important to understand where ENPBCs safety is and how to expand and affirm consumer security concerns. Methods: Online articles were extracted from 2013 to 2016 that pragmatically used xCELLigence real-time cell analysis (RTCA) technology to describe the in-vitro toxicity of ENPBCs. The xCELLigence is a +noninvasive in vitro toxicity monitoring process that mimics exact continuous cellular bio-responses in real-time settings. On the other hand, articles were also extracted from 2008 to 2016 describing the in vivo animal models toxicity of ENPBCs with regards to safety outcomes. Results: Out of 32 of the 121 (26.4%) articles identified from the literature, 23 (71.9%) met the in-vitro xCELLigence and 9(28.1%) complied with the in vivo animal model toxicity inclusion criteria. Of the 23 articles, 4 of them (17.4%) had no size estimation of ENPBCs. The xCELLigence technology provided information on cell interactions, viability, and proliferation process. Eighty-three (19/23) of the in vitro xCELLigence technology studies described ENPBCs as nontoxic or partially nontoxic materials. The in vivo animal model provided further toxicity information where 1(1/9) of the in vivo animal model studies indicated potential animal toxicity while the remaining results recommended ENPPCs as potential candidates for drug therapy though with limited information on toxicity. Conclusion: The results showed that the bioimpacts of ENPBCs either at the in vitro or at in vivo animal model levels are still limited due to insufficient information and data. To keep pace with ENPBCs biomedical products and applications, in vitro, in vivo assays, clinical trials and long-term impacts are needed to validate their usability and uptake. Besides, more real-time ENPBCs-cell impact analyses using xCELLigence are needed to provide significant data and information for further in vivo testing.

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Coccini, Teresa, Luigi Manzo, and Elisa Roda. "Safety Evaluation of Engineered Nanomaterials for Health Risk Assessment: An Experimental Tiered Testing Approach Using Pristine and Functionalized Carbon Nanotubes." ISRN Toxicology 2013 (April 17, 2013): 1–13. http://dx.doi.org/10.1155/2013/825427.

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Increasing application of engineered nanomaterials within occupational, environmental, and consumer settings has raised the levels of public concern regarding possible adverse effects on human health. We applied a tiered testing strategy including (i) a first in vitro stage to investigate general toxicity endpoints, followed by (ii) a focused in vivo experiment. Cytotoxicity of laboratory-made functionalized multiwalled carbon nanotubes (CNTs) (i.e., MW-COOH and MW-NH2), compared to pristine MWCNTs, carbon black, and silica, has been assessed in human A549 pneumocytes by MTT assay and calcein/propidium iodide (PI) staining. Purity and physicochemical properties of the test nanomaterials were also determined. Subsequently, pulmonary toxic effects were assessed in rats, 16 days after MWCNTs i.t. administration (1 mg/kg b.w.), investigating lung histopathology and monitoring several markers of lung toxicity, inflammation, and fibrosis. In vitro data: calcein/PI test indicated no cell viability loss after all CNTs treatment; MTT assay showed false positive cytotoxic response, occurring not dose dependently at exceedingly low CNT concentrations (1 μg/mL). In vivo results demonstrated a general pulmonary toxicity coupled with inflammatory response, without overt signs of fibrosis and granuloma formation, irrespective of nanotube functionalization. This multitiered approach contributed to clarifying the CNT toxicity mechanisms improving the overall understanding of the possible adverse outcomes resulting from CNT exposure.

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Cheli, F., C. Giromini, and A. Baldi. "Mycotoxin mechanisms of action and health impact: ‘in vitro’ or ‘in vivo’ tests, that is the question." World Mycotoxin Journal 8, no. 5 (2015): 573–89. http://dx.doi.org/10.3920/wmj2014.1864.

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The aim of this paper is to present examples of in vitro and in vivo tests for mycotoxin mechanisms of action and evaluation of health effects, with a focus on the gut environment and toxicity testing. In vivo investigations may provide information on the net effects of mycotoxins in whole animals, whereas in vitro models represent effective tools to perform simplified experiments under uniform and well-controlled conditions and a suitable alternative to in vivo animal testing providing insights not achievable with animal studies. The main limits of in vitro models are the lack of interactions with other cells and extracellular factors, lack of hormonal or immunological influences, and lack or different levels of in vitro expression of genes involved in the overall response to mycotoxins. The translation of in vitro data into meaningful in vivo effects remains an unsolved problem. The main issues to be considered are the mycotoxin concentration range in accordance with levels encountered in realistic situations, the identification of reliable biomarkers of mycotoxin toxicity, the measurement of the chronic toxicity, the evaluation of single- or multi-toxin challenge. The gastrointestinal wall is the first barrier preventing the entry of undesirable substances. The intestinal epithelium can be exposed to high concentrations of mycotoxins upon ingestion of contaminated food and the amount of mycotoxin consumed via food does not always reflect the amount available to exert toxic actions in a target organ. In vitro digestion models in combination with intestinal epithelial cells are powerful tools to screen and predict the in vivo bioavailability and digestibility of mycotoxins in contaminated food and correctly estimate health effects. In conclusion, in vitro and in vivo tests are complementary approaches for providing a more accurate picture of the health impact of mycotoxins and improved understanding and evaluation of relevant dietary exposure and risk scenarios.

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Macedo, Iara Tersia Freitas, Claudia Maria Leal Bevilaqua, Lorena Mayana Beserra de Oliveira, Ana Lourdes Fernandes Camurça-Vasconcelos, Luiz da Silva Vieira, and Sthenia dos Santos Albano Amóra. "Evaluation of Eucalyptus citriodora essential oil on goat gastrointestinal nematodes." Revista Brasileira de Parasitologia Veterinária 20, no. 3 (2011): 223–27. http://dx.doi.org/10.1590/s1984-29612011000300009.

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Phytotherapy may be an alternative strategy for controlling gastrointestinal parasites. This study evaluated the anthelmintic efficacy of Eucalyptus citriodora essential oil (EcEO). The in vitro effects of EcEO were determined through testing the inhibition of egg hatching and larval development of Haemonchus contortus. EcEO was subjected to acute toxicity testing on mice, orally and intraperitoneally. The in vivo effects of EcEO were determined by the fecal egg count reduction test (FECRT) in goats infected with gastrointestinal nematodes. The results showed that 5.3 mg.mL-1 EcEO inhibited egg hatching by 98.8% and 10.6 mg.mL-1 EcEO inhibited H. contortus larval development by 99.71%. The lethal doses for 50% of the mice were 4153 and 622.8 mg.kg-1, for acute toxicity orally and intraperitoneally. In the FECRT, the efficacy of EcEO and ivermectin was 66.25 and 79.16% respectively, on goat gastrointestinal nematodes eight days after treatment. EcEO showed in vitro and in vivo anthelmintic activity.

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Faria, João, Sabbir Ahmed, Karin G. F. Gerritsen, Silvia M. Mihaila, and Rosalinde Masereeuw. "Kidney-based in vitro models for drug-induced toxicity testing." Archives of Toxicology 93, no. 12 (2019): 3397–418. http://dx.doi.org/10.1007/s00204-019-02598-0.

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Abstract The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs’ microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and response to environmental signals. Cell polarity is dependent on communication between cells, which includes paracrine and autocrine signals, as well as biomechanic and chemotactic processes. These processes all influence kidney cell proliferation, migration, and differentiation. For drug disposition studies, this microenvironment is essential for prediction of toxic responses. This review provides an overview of drug-induced injuries to the kidney, details on relevant and translational biomarkers, and advances in 3D cultures of human renal cells, including organoids and kidney-on-a-chip platforms.

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Newman, L. M., R. L. Giacobbe, L.-J. Fu, and E. M. Johnson. "Developmental Toxicity Evaluation of Several Cosmetic Ingredients in the Hydra Assay." Journal of the American College of Toxicology 9, no. 3 (1990): 361–65. http://dx.doi.org/10.3109/10915819009078745.

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The developmental toxicity hazard potential of six cosmetic products was determined in the in vitro Hydra assay. These studies were conducted to supplement available toxicological information and provide an indication of the priority of these compounds for higher level (in vivo) developmental toxicity testing. All but one ingredient, potassium sorbate, was predicted by the assay to be generally equally or more toxic to adults than to embryos and, therefore, to be low-priority chemicals for more elaborate tests. In contrast, assay results suggest that potassium sorbate is a prime candidate for higher-level animal developmental toxicology testing. The endpoints for this in vitro prescreen were ‘set’ some years ago to avoid false negatives as much as possible, but approximately 7% false positives result. Therefore, it is premature to consider sorbate as being uniquely hazardous to in utero development until this is established by testing in pregnant laboratory mammals.

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Kohonen, Pekka, Emilio Benfenati, David Bower, et al. "The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing." Molecular Informatics 32, no. 1 (2013): 47–63. http://dx.doi.org/10.1002/minf.201200114.

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Piatek, Magdalena, Gerard Sheehan, and Kevin Kavanagh. "Galleria mellonella: The Versatile Host for Drug Discovery, In Vivo Toxicity Testing and Characterising Host-Pathogen Interactions." Antibiotics 10, no. 12 (2021): 1545. http://dx.doi.org/10.3390/antibiotics10121545.

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Larvae of the greater wax moth, Galleria mellonella, are a convenient in vivo model for assessing the activity and toxicity of antimicrobial agents and for studying the immune response to pathogens and provide results similar to those from mammals. G. mellonella larvae are now widely used in academia and industry and their use can assist in the identification and evaluation of novel antimicrobial agents. Galleria larvae are inexpensive to purchase and house, easy to inoculate, generate results within 24–48 h and their use is not restricted by legal or ethical considerations. This review will highlight how Galleria larvae can be used to assess the efficacy of novel antimicrobial therapies (photodynamic therapy, phage therapy, metal-based drugs, triazole-amino acid hybrids) and for determining the in vivo toxicity of compounds (e.g., food preservatives, ionic liquids) and/or solvents (polysorbate 80). In addition, the disease development processes are associated with a variety of pathogens (e.g., Staphylococcus aureus, Listeria monocytogenes, Aspergillus fumigatus, Madurella mycotomatis) in mammals are also present in Galleria larvae thus providing a simple in vivo model for characterising disease progression. The use of Galleria larvae offers many advantages and can lead to an acceleration in the development of novel antimicrobials and may be a prerequisite to mammalian testing.

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Combes, Robert, Christina Grindon, Mark T. D. Cronin, David W. Roberts, and John F. Garrod. "Integrated Decision-tree Testing Strategies for Mutagenicity and Carcinogenicity with Respect to the Requirements of the EU REACH Legislation." Alternatives to Laboratory Animals 36, no. 1_suppl (2008): 43–63. http://dx.doi.org/10.1177/026119290803601s05.

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Liverpool John Moores University and FRAME recently conducted a research project sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for using alternative methods (both in vitro and in silico) for mutagenicity (genotoxicity) and carcinogenicity testing — two toxicity endpoints, which, together with reproductive toxicity, are of pivotal importance for the REACH system. The manuscript critically discusses well-established testing approaches, and in particular, the requirement for short-term in vivo tests for confirming positive mutagenicity, and the need for the rodent bioassay for detecting non-genotoxic carcinogens. Recently-proposed testing strategies focusing on non-animal approaches are also considered, and our own testing scheme is presented and supported with background information. This scheme makes maximum use of pre-existing data, computer ( in silico) and in vitro methods, with weight-of-evidence assessments at each major stage. The need for the improvement of in vitro methods, to reduce the generation of false-positive results, is also discussed. Lastly, ways in which reduction and refinement measures can be used are also considered, and some recommendations are made for future research to facilitate the implementation of the proposed testing scheme.

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Deglmann, C. J., R. Metzger, M. Stickel, S. Hoerrlein, F. W. Schildberg, and H. G. Koebe. "A New Bioassay Including a Small Scale Hepatocyte Bioreactor for Hepato-Mediated Toxicity Testing in a Target Cell Line." International Journal of Artificial Organs 25, no. 10 (2002): 975–84. http://dx.doi.org/10.1177/039139880202501012.

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New approaches for in vitro testing of hepato-mediated toxicity are undertaken to offer alternatives to in vivo animal testing. The described bioassay for hepato-mediated toxicity testing is based on a small scale hepatocyte-bioreactor with pig hepatocytes connected to a silicon sensor based microphysiometer system for monitoring of the extracellular acidification rate (EAR) of cells and the microphysiometer alone. EAR represents the metabolic activity of tested cells (hepatocytes and ZR 751 cells) under the influence of perfused media, compared to controls, which were set to 100%. Cyclophosphamide (CYCL), whose cytostatic effect is dependent on CYP 450 biotransformation was used as a model substrate. CYCL showed decrease of EAR in hepatocytes, but not in ZR 751 cells. Bioreactor supernatant including CYCL was pumped into the microphysiometer and EARs of the target ZR 751 cell line were recorded. After 7 h of bioreactor supernatant perfusion the ZR 751 cell line showed an EAR decrease of 18.68% ± 10.18, as compared to controls (bioreactor supernatant from the identical set-up without CYCL). Thus the presented model of hepato-activated toxicity showed an EAR decrease in the ZR 751 cell line that reflected the toxic activation of CYCL by the bioreactor. This new bioassay serves as an example of future applications for hepatocyte bioreactors in automated toxicity testing devices, e.g. in preclinical drug studies or evaluation of hepato-mediated toxicity, not depending on cell destruction or further assays.

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Marques, Mariana, João Nunes, Bárbara Ustymenko, et al. "cEpiderm, a Canine Skin Analog Suitable for In Vivo Testing Replacement." BioChem 2, no. 4 (2022): 215–20. http://dx.doi.org/10.3390/biochem2040015.

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Skin is one of the organs most tested for toxicity and safety evaluation during the process of drug research and development and in the past has usually been performed in vivo using animals. Over the last few years, non-animal alternatives have been developed and validated epidermis models for human and rat skin are already available. Our goal was to develop a histotypical canine skin analog, suitable for non-animal biocompatibility and biosafety assessment. Canine keratinocytes were seeded in an air-lift culture using an adapted version of the CELLnTEC protocol. Corrosion and irritation protocols were adapted from human EpiSkinTM. For histological analysis, sample biopsies were fixed in neutral-buffered formalin, and paraffin slices were routinely processed and stained with hematoxylin and eosin. A canine multilayer and stratified epidermal-like tissue (cEpiderm), confirmed by histological analysis, was obtained. The cEpiderm tissue exhibited normal morphological and functional characteristics of epidermis, namely impermeability and an adequate response to stressors. The cEpiderm is a promising canine skin model for non-animal safety testing of veterinary pharmaceuticals and/or cosmetics, significantly contributing to reducing undesirable in vivo approaches. cEpiderm is therefore a valid canine skin model and may be made commercially available either as a service or as a product.

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Tao, Ye, Jixue Yang, Zhao Ma, et al. "The Vigabatrin Induced Retinal Toxicity is Associated with Photopic Exposure and Taurine Deficiency: An In Vivo Study." Cellular Physiology and Biochemistry 40, no. 5 (2016): 831–46. http://dx.doi.org/10.1159/000453143.

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Background/Aims: Retinal toxicity is one of the most commonly discussed and concerning adverse effects of vigabatrin (VGB). The present study explored the relationship between the VGB elicited retinal toxicity, photopic exposure, and taurine deficiency, aiming at screening for risk factors to minimize the adverse effects of VGB. Methods: The effects of VGB on function and morphology of mouse retinas were examined via a series of in vivo tests, including electroretinography (ERG), Spectral domain optical coherence tomography (SD-OCT), and optokinetic testing. Moreover, VGB-treated mice were in addition treated with taurine to verify possible protective effects against retinal toxicity. Results: A close relationship between VGB induced retinal toxicity and light exposure was observed. The VGB-treated mice which were reared in darkness preserved better visual function and retinal architectures as verified by the optokinetic tests, OCT and ERG examinations. The retinal taurine level of the VBG-treated mice which were exposed to light were significantly lower than that of the VBG mice reared in darkness. Furthermore, several in vivo evidence provided by our research confirmed that the VGB induced morphological and functional impairments could be partially alleviated by taurine treatment. The present study showed the retinal toxicity of VGB by in vivo measurements. Conclusion: The VGB induced retinal toxicity is closely associated with photopic exposure and taurine deficiency. Patients who are taking VGB might benefit from minimization of light exposure and dietetic taurine supplements.

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Dix, David J. "Abstracts." International Journal of Toxicology 27, no. 6 (2008): 405. http://dx.doi.org/10.1080/10915810802571781.

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The U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), and National Institutes of Health (NIH) Chemical Genomics Center (NCGC) have complementary research programs designed to improve chemical toxicity evaluations by developing high throughput screening (HTS) methods that evaluate the impact of environmental chemicals on key toxicity pathways. These federal partners are coordinating an extension of the EPA’s ToxCast program, the NTP’s HTS initiative, and the NCGC’s Molecular Libraries Initiative into a collaborative research program focused on identifying toxicity pathways and developing in vitro assays to characterize the ability of chemicals to perturb those pathways. The goal is to develop new paradigm for high throughput toxicity testing that collects mechanistic and quantitative data from in vitro assays measuring chemical modulation of biological processes involved in the progression to toxicity. As toxicity pathways are identified, the in vitro assays can be optimized for comparison to in vivo animal studies, and for predicting effects in humans. Subsequent computational modeling of toxicity pathway responses and appropriate chemical dosimetry will need to be developed to make these predictions relevant for human health risk assessment. This work was reviewed by EPA and approved for publication but does not necessarily reflect official Agency policy. Index Terms: Toxicogenomics, High Throughput Screening/Testing, EPA ToxCast, Chemical Risk Assessment

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Yogev, Sivan, Ayelet Shabtay-Orbach, Abraham Nyska, and Boaz Mizrahi. "Local Toxicity of Topically Administrated Thermoresponsive Systems: In Vitro Studies with In Vivo Correlation." Toxicologic Pathology 47, no. 3 (2018): 426–32. http://dx.doi.org/10.1177/0192623318810199.

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Thermoresponsive materials have the ability to respond to a small change in temperature—a property that makes them useful in a wide range of applications and medical devices. Although very promising, there is only little conclusive data about the cytotoxicity and tissue toxicity of these materials. This work studied the biocompatibility of three Food and Drug Administration approved thermoresponsive polymers: poly( N-isopropyl acrylamide), poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) tri-block copolymer, and poly(lactic acid-co-glycolic acid) and poly(ethylene glycol) tri-block copolymer. Fibroblast NIH 3T3 and HaCaT keratinocyte cells were used for the cytotoxicity testing and a mouse model for the in vivo evaluation. In vivo results generally showed similar trends as the results seen in vitro, with all tested materials presenting a satisfactory biocompatibility in vivo. pNIPAM, however, showed the highest toxicity both in vitro and in vivo, which was explained by the release of harmful monomers and impurities. More data focusing on the biocompatibility of novel thermoresponsive biomaterials will facilitate the use of existing and future medical devices.

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Cordelli, Eugenia, Margherita Bignami, and Francesca Pacchierotti. "Comet assay: a versatile but complex tool in genotoxicity testing." Toxicology Research 10, no. 1 (2021): 68–78. http://dx.doi.org/10.1093/toxres/tfaa093.

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Abstract The comet assay is a versatile method for measuring DNA strand breaks in individual cells. It can also be applied to cells isolated from treated animals. In this review, we highlight advantages and limitations of this in vivo comet assay in a regulatory context. Modified versions of the standard protocol detect oxidized DNA bases and may be used to reveal sites of DNA base loss, DNA interstrand crosslinks, and the extent of DNA damage induced indirectly by reactive oxygen species elicited by chemical-induced oxidative stress. The assay is, however, at best semi-quantitative, and we discuss possible approaches to improving DNA damage quantitation and highlight the necessity of optimizing protocol standardization to enhance the comparability of results between laboratories. As a genotoxicity test in vivo, the in vivo comet assay has the advantage over the better established micronucleus erythrocyte test that it can be applied to any organ, including those that are specific targets of chemical carcinogens or those that are the first sites of contact of ingested or inhaled mutagens. We illustrate this by examples of its use in risk assessment for the food contaminants ochratoxin and furan. We suggest that improved quantitation is required to reveal the full potential of the comet assay and enhance its role in the battery of in vivo approaches to characterize the mechanisms of toxicity and carcinogenicity of chemicals and to aid the determination of safe human exposure limits.

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Smith, M. A., C. L. Morton, H. Carol, et al. "Pediatric Preclinical Testing Program (PPTP) testing of the CENP-E inhibitor GSK923295A." Journal of Clinical Oncology 27, no. 15_suppl (2009): 10015. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10015.

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10015 Background: GSK923295A is a small molecule inhibitor of centromere-associated protein E (CENP-E), a mitotic kinesin that is required for metaphase chromosome alignment and integration of mitotic spindle mechanics with mitotic checkpoint signaling. An initial phase I clinical trial in adults is ongoing. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n = 27) and in vivo panel of xenografts (n = 60) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). GSK923295A was tested in vitro at concentrations from 1.0 nM to 10.0 μM (96 hour exposure) and was tested in vivo using a daily × 3 for 2 weeks schedule, repeated at day 21. GSK923295A was administered IP at a dose of 125 mg/kg. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a time to event measure based on the median event-free survival (EFS); and 3) a treated to control (T/C) tumor volume measure. Results: GSK923295A demonstrated potent in vitro activity against the PPTP cell line panel with a median IC50 of 27 nM (range 12 nM to > 10 μM). 35 of 37 solid tumor xenograft models were evaluable. GSK923295A induced significant differences in EFS distribution compared to controls in 32 of 35 evaluable models. Objective responses were noted in 13 of 35 xenografts, including 9 with maintained complete responses (MCR), 3 with complete response (CR), and 1 with partial response (PR). Three of 5 Ewing sarcoma xenografts achieved MCR or CR, as did 2 of 3 rhabdoid tumor, and 2 of 5 rhabdomyosarcoma models. For the neuroblastoma panel, the best response was progressive disease (PD) with growth delay compared to controls (PD2 response), which was observed in 5 of 6 xenografts. GSK923295A showed activity against the ALL panel, but unexplained toxicity (generally on or after day 21) precluded formal analysis. Conclusions: GSK923295A has substantial in vitro and in vivo activity against the PPTP's preclinical models. The observed high level of preclinical activity for GSK923295A will need to be evaluated in the context of systemic exposures achieved in the xenograft models and those achievable in humans at tolerable doses. (Supported by NCI NO1CM42216) [Table: see text]

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Ortiz-Andrade, Rolffy, Jesús Alfredo Araujo-León, Amanda Sánchez-Recillas, et al. "Toxicological Screening of Four Bioactive Citroflavonoids: In Vitro, In Vivo, and In Silico Approaches." Molecules 25, no. 24 (2020): 5959. http://dx.doi.org/10.3390/molecules25245959.

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Many studies describe different pharmacological effects of flavonoids on experimental animals and humans. Nevertheless, few ones are confirming the safety of these compounds for therapeutic purposes. This study aimed to investigate the preclinical safety of naringenin, naringin, hesperidin, and quercetin by in vivo, in vitro, and in silico approaches. For this, an MTT-based cytotoxicity assay in VERO and MDCK cell lines was performed. In addition, acute toxicity was evaluated on Wistar rats by OECD Guidelines for the Testing of Chemicals (Test No. 423: Acute Oral Toxicity-Class Method). Furthermore, we used the ACD/Tox Suite to predict toxicological parameters such as hERG channel blockade, CYP450 inhibition, and acute toxicity in animals. The results showed that quercetin was slightly more cytotoxic on cell lines (IC50 of 219.44 ± 7.22 mM and 465.41 ± 7.44 mM, respectively) than the other citroflavonoids. All flavonoids exhibited an LD50 value > 2000 mg/kg, which classifies them as low-risk substances as OECD guidelines established. Similarly, predicted LD50 was LD50 > 300 to 2000 mg/kg for all flavonoids as acute toxicity assay estimated. Data suggests that all these flavonoids did not show significant toxicological effects, and they were classified as low-risk, useful substances for drug development.

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Ahari, Hamed, Bahareh ‎. Nowruzi, Amir Ali Anvar, and Samaneh Jafari Porzani. "The Toxicity Testing of Cyanobacterial Toxins In vivo and In vitro by Mouse Bioassay: A Review." Mini-Reviews in Medicinal Chemistry 22, no. 8 (2022): 1131–51. http://dx.doi.org/10.2174/1389557521666211101162030.

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: Different biological methods based on bioactivity are available to detect cyanotoxins, including neurotoxicity, immunological interactions, hepatotoxicity, cytotoxicity, and enzymatic activity. The mouse bioassay is the first test employed in laboratory cultures, cell extracts, and water bloom materials to detect toxins. It is also used as a traditional method to estimate the LD50. Concerning the ease of access and low cost, it is the most common method for this purpose. In this method, a sample is injected intraperitoneally into adult mice, and accordingly, they are assayed and monitored for about 24 hours for toxic symptoms. The toxin can be detected using this method from minutes to a few hours; its type, e.g., hepatotoxin, neurotoxin, etc., can also be determined. However, this method is nonspecific, fails to detect low amounts, and cannot distinguish between homologues. Although the mouse bioassay is gradually replaced with new chemical and immunological methods, it is still the main technique to detect the bioactivity and efficacy of cyanotoxins using LD50 determined based on the survival time of animals exposed to the toxin. In addition, some countries oppose animal use in toxicity studies. However, high cost, ethical considerations, low-sensitivity, non-specificity, and prolonged processes persuade researchers to employ chemical and functional analysis techniques. The qualitative and quantitative analyses, as well as high specificity and sensitivity, are among the advantages of cytotoxicity tests to investigate cyanotoxins. The present study aimed at reviewing the results obtained from in vitro and in vivo investigations of the mouse bioassay to detect cyanotoxins, including microcystins, cylindrospermopsin, saxitoxins, etc.

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Journal articles on the topic 'Toxicity testing – In vivo'

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