Comparison of In Vivo and In Vitro Toxicity Tests from Co-inertia Analysis

All new chemical entities synthesised in our laboratories have routinely been subjected to in vitro toxicity tests. Out of curiosity, we established a working hypothesis in which the in vitro data could be empirically transformed to predict the in vivo four-week standard maximum tolerated dose (MTD) studies in rats and dogs. As a first step to verifying this hypothesis, we report here the findings of an in vitro cytotoxicity study of 25 compounds randomly selected from our files, possessing a wide range of pharmacological activities and for which data from standard four-week MTD studies were available. Single blind in vitro toxicity studies in three carefully selected types of primary and cell line cultures were carried out. In vitro CT50 (concentration inducing 50% cell death) and CT100 (concentration inducing 100% cell death) values were obtained for each of the three cell types and, using empirical assumptions, these results were used to predict the MTD in vivo in the rat and dog. The actual in vivo threshold and toxic doses were obtained from the MTD study reports. The in vivo toxicity values predicted from the in vitro toxicity results with this series of 25 compounds showed a better than 80% correlation with the actual in vivo results obtained in the MTD studies. Whether or not in vitro cytotoxicity predictions are ultimately found to be directly and consistently related to the MTD in vivo for all pharmacological classes of compounds will require many additional studies, but it is hoped that these results will stimulate the necessary research effort required to answer this question.

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Characterization of Fibrous Wollastonite NYAD G in View of Its Use as Negative Standard for In Vitro Toxicity Tests

Minerals ◽

10.3390/min11121378 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1378

Author(s):

Dario Di Giuseppe ◽

Valentina Scognamiglio ◽

Daniele Malferrari ◽

Luca Nodari ◽

Luca Pasquali ◽

...

Keyword(s):

Biological Response ◽

Toxicity Tests ◽

In Vitro Toxicity ◽

In Vitro Tests ◽

In Vivo Models ◽

Mineral Fibre ◽

In Vivo Testing ◽

Positive Controls

Today, despite considerable efforts undertaken by the scientific community, the mechanisms of carcinogenesis of mineral fibres remain poorly understood. A crucial role in disclosing the mechanisms of action of mineral fibres is played by in vitro and in vivo models. Such models require experimental design based on negative and positive controls. Commonly used positive controls are amosite and crocidolite UICC standards, while negative controls have not been identified so far. The extensive characterisation and assessment of toxicity/pathogenicity potential carried out in this work indicate that the commercial fibrous wollastonite NYAD G may be considered as a negative standard control for biological and biomedical tests involving mineral fibres. Preliminary in vitro tests suggest that wollastonite NYAD G is not genotoxic. This material is nearly pure and is characterized by very long (46.6 µm), thick (3.74 µm) and non-biodurable fibres with a low content of metals. According to the fibre potential toxicity index (FPTI) model, wollastonite NYAD G is an inert mineral fibre that is expected to exert a low biological response during in vitro/in vivo testing.

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Metallic Elements (Cu, Zn, Ni and Mn) Toxicity Effects Determination on a Fresh Water Fish Cyprinus Carpio (Common Carp) Laboratory Acclimatized

Revista de Chimie ◽

10.37358/rc.17.8.5750 ◽

2017 ◽

Vol 68 (8) ◽

pp. 1711-1715

Author(s):

Stefania Gheorghe ◽

Gabriela Geanina Vasile ◽

Cristina Gligor ◽

Irina Eugenia Lucaciu ◽

Mihai Nita Lazar

Keyword(s):

Cyprinus Carpio ◽

Aquatic Organisms ◽

Control Fish ◽

Toxicity Tests ◽

Fresh Water Fish ◽

Metallic Elements ◽

Mn Toxicity ◽

Vitro Effect

Metallic elements copper (Cu), zinc (Zn), nickel (Ni) and manganese (Mn) are some of the most commonly found in water and sediment samples collected from the Danube - Danube Delta. These elements are important as essential micronutrients, being normally present at low concentrations in biological organisms, but in high concentrations they become toxic with immediate and delayed effects. The role of this metals is still controversial, that�s why bioconcentration potential is so important. In this non-clinical study, we tested in vitro effect of heavy metals on carp, Cyprinus carpio, reproducing in vivo presence of Cu, Zn, Ni and Mn in the Romanian�s surface water. The toxicity tests were performed according to OECD 203 by detecting the average (50%) lethal concentration - LC50 on aquatic organisms (freshwater fish) at 96h. The results pointed out that, copper value for LC 50 at 96h was estimated as 3.4 mg/L (concentrations tested in the range of 0.1 - 4.75 mg/L). Zinc value for LC 50 at 96h was estimated as 20.8 mg/L (concentrations tested in the range of 0.028 � 29.6 mg/L). Nickel value for LC 50 at 96h was estimated as 40.1 mg/L (concentrations tested in the range of 0.008 - 84.5 mg/L). For manganese the mortality effects has recorded at LC 50 at 96h at estimated value higher than 53 mg/L (concentrations tested in the range of 0.04 - 53.9 mg/L). The accuracy of the testing metals concentration was insured by the screening of the dilution water, as well as food and control fish, acclimated in laboratory conditions.

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In Vivo and In Vitro Toxicity Evaluation of Polyprenols Extracted from Ginkgo biloba L. Leaves

Molecules ◽

10.3390/molecules201219839 ◽

2015 ◽

Vol 20 (12) ◽

pp. 22257-22271 ◽

Cited By ~ 7

Author(s):

Cheng-Zhang Wang ◽

Jiao-Jiao Yuan ◽

Wen-Jun Li ◽

Hong-Yu Zhang ◽

Jian-Zhong Ye

Keyword(s):

Ginkgo Biloba ◽

In Vitro Toxicity ◽

Toxicity Evaluation

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Integration of in vitro neurotoxicity data with biokinetic modelling for the estimation of in vivo neurotoxicity

Human & Experimental Toxicology ◽

10.1177/0960327106072994 ◽

2007 ◽

Vol 26 (4) ◽

pp. 333-338 ◽

Cited By ~ 47

Author(s):

Anna Forsby ◽

Bas Blaauboer

Keyword(s):

Exposure Period ◽

Cellular Protein ◽

In Vitro Toxicity ◽

Target Tissue ◽

Receptor Function ◽

Human Neuroblastoma ◽

Protein Levels ◽

Effective Doses

Risk assessment of neurotoxicity is mainly based on in vivo exposure, followed by tests on behaviour, physiology and pathology. In this study, an attempt to estimate lowest observed neurotoxic doses after single or repeated dose exposure was performed. Differentiated human neuroblastoma SH-SY5Y cells were exposed to acrylamide, lindane, parathion, paraoxon, phenytoin, diazepam or caffeine for 72 hours. The effects on protein synthesis and intracellular free Ca2+concentration were studied as physiological endpoints. Voltage operated Ca2 +channel function, acetylcholine receptor function and neurite degenerative effects were investigated as neurospecific endpoints for excitability, cholinergic signal transduction and axonopathy, respectively. The general cytotoxicity, determined as the total cellular protein levels after the 72 hours exposure period, was used for comparison to the specific endpoints and for estimation of acute lethality. The lowest concentration that induced 20% effect (EC 20) obtained for each compound, was used as a surrogate for the lowest neurotoxic level (LOEL) at the target site in vivo. The LOELs were integrated with data on adsorption, distribution, metabolism and excretion of the compounds in physiologically-based biokinetic (PBBK) models of the rat and the lowest observed effective doses (LOEDs) were estimated for the test compounds. A good correlation was observed between the estimated LOEDs and experimental LOEDs found in literature for rat for all test compounds, except for diazepam. However, when using in vitro data from the literature on diazepam's effect on gamma-amino butyric acid (GABA)A receptor function for the estimation of LOED, the correlation between the estimated and experimental LOEDs was improved from a 10 000-fold to a 10-fold difference. Our results indicate that it is possible to estimate LOEDs by integrating in vitro toxicity data as surrogates for lowest observed target tissue levels with PBBK models, provided that some knowledge about toxic mechanisms is known. Human & Experimental Toxicology (2007) 26, 333—338

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Solubility and ADMET profiles of short oligomers of lactic acid

ADMET & DMPK ◽

10.5599/admet.843 ◽

2020 ◽

Cited By ~ 1

Author(s):

Daniela Dascălu ◽

Diana Larisa Roman ◽

Madalina Filip ◽

Alecu Aurel Ciorsac ◽

Vasile Ostafe ◽

...

Keyword(s):

Molecular Weight ◽

Glucocorticoid Receptors ◽

Degradation Products ◽

Organic Anion ◽

Toxicity Tests ◽

Medical Applications ◽

Eye Injuries ◽

Toxicological Effects

<p class="ADMETkeywordsheading">Polylactic acid (PLA) is a polymer with an increased potential to be used in different medical applications, including tissue engineering and drug-carries. The use of PLA in medical applications implies the evaluation of the human organism's response to the polymer inserting and to its degradation products. Consequently, within this study, we have investigated the solubility and ADMET profiles of the short oligomers (having the molecular weight lower than 3000 Da) resulting in degradation products of PLA. There is a linear decrease of the molar solubility of investigated oligomers with molecular weight. The results that are obtained also reveal that short oligomers of PLA have promising pharmacological profiles and limited toxicological effects on humans. These oligomers are predicted as potential inhibitors of the organic anion transporting peptides OATP1B1 and OATP1B3, they present minor probability to affect the androgen and glucocorticoid receptors, have a weak potential of hepatotoxicity, and may produce eye injuries. These outcomes may be used to guide or to supplement in vitro and/or in vivo toxicity tests such as to enhance the biodegradation properties of the biopolymer.</p>

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A study on Dowager Cixi’s Yanling-Yishou-Dan of Qing Dynasty in a Japanese laboratory of biochemistry and molecular biology in 1990s: An attempt for TCM modernization

Traditional Medicine and Modern Medicine ◽

10.1142/s2575900020500135 ◽

2021 ◽

pp. 1-21

Author(s):

Jiankang Liu

Keyword(s):

Qing Dynasty ◽

Brain Homogenate ◽

Modern Technology ◽

Toxicity Tests ◽

Brain Functions ◽

Great Progress ◽

Theoretical Evidence ◽

The Brain

Traditional Chinese Medicine (TCM) modernization has been proposed for many years, but the progress is still slow due to both ideological and technical obstacles. When I went to Japan in 1989, I found Japan has made a great progress on TCM by using modern technology. Therefore, I have studied a fine extract prepared from medicinal herbs (renamed Yi-Zhi-Yi-Shou, YZYS), a prescription of Dowager Cixi’s Yanling-Yishou-Dan of Qing Dynasty, with the current drug investigation strategies. I examined its antioxidant activity both in vitro and in vivo. The in-vitro studies found that YZYS possesses strong antioxidant capacity, such as scavenging various kinds of free radicals, and inhibits free radical-induced peroxidation of brain homogenate, microsomes, mitochondria, amino acids, deoxyribose and DNA. The in-vivo study with immobilization-induced emotional stress in rats, showed that YZYS effectively inhibits stress-induced stomach ulcers and oxidative damage in plasma and the brain. In addition, YZYS is shown to be non-toxic in both acute and chronic toxicity tests. These studies demonstrate that YZYS is a potent natural antioxidant and offer theoretical evidence for the beneficial effect of YZYS on health and brain functions, and that TCM prescriptions can be studied scientifically as modern medical drugs.

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