In Vivo Evaluation of the Chronic Oral Toxicity of the Marine Toxin Palytoxin

Palytoxin (PLTX) is one of the most poisonous substances known to date and considered as an emergent toxin in Europe. Palytoxin binds to the Na+-K+ ATPase, converting the enzyme in a permeant cation channel. This toxin is known for causing human fatal intoxications associated with the consumption of contaminated fish and crustaceans such as crabs, groupers, mackerel, and parrotfish. Human intoxications by PLTX after consumption of contaminated fishery products are a serious health issue and can be fatal. Different reports have previously explored the acute oral toxicity of PLTX in mice. Although the presence of palytoxin in marine products is currently not regulated in Europe, the European Food Safety Authority expressed its opinion on PLTX and demanded assessment for chronic toxicity studies of this potent marine toxin. In this study, the chronic toxicity of palytoxin was evaluated after oral administration to mice by gavage during a 28-day period. After chronic exposure of mice to the toxin, a lethal dose 50 (LD50) of 0.44 µg/kg of PLTX and a No-Observed-Adverse-Effect Level (NOAEL) of 0.03 µg/kg for repeated daily oral administration of PLTX were determined. These results indicate a much higher chronic toxicity of PLTX and a lower NOAEL than that previously described in shorter treatment periods, pointing out the need to further reevaluate the levels of this compound in marine products.

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Toxicity Evaluation of Nanostructured Silica Orally Administered to Rats: Influence on Immune System Function

Nanomaterials ◽

10.3390/nano10112126 ◽

2020 ◽

Vol 10 (11) ◽

pp. 2126

Author(s):

Ivan V. Gmoshinski ◽

Vladimir A. Shipelin ◽

Antonina A. Shumakova ◽

Eleonora N. Trushina ◽

Oksana K. Mustafina ◽

...

Keyword(s):

Immune System ◽

Oral Toxicity ◽

Daily Consumption ◽

Immune System Function ◽

Tnf Α ◽

Adverse Effect Level ◽

Effect Level ◽

The Subject ◽

Nanostructured Silica

The experimental data on the oral toxicity of nanostructured amorphous silica (SiO2), widely used in food supplements, pharmaceuticals, and cosmetics, in terms of its in vivo effect on the immune system, are contradictory. Therefore, this study aimed to assess the rat’s immune function after SiO2 oral administration. In the first experiment, SiO2 was daily orally administered to Wistar rats for 92 days in doses of 0.1, 1.0, 10, and 100 mg/kg of body weight (bw). In the second 28-day experiment, SiO2 in a dose of 100 mg/kg bw was daily orally administered to rats parenterally immunized with the food allergen ovalbumin (OVA) for the reproduction of systemic anaphylaxis reaction. Together with integral indices, we assessed intestinal permeability to protein macromolecules; hematology; CD45RA+, CD3+, CD4+, CD8+, and CD161a+ cells; cytokines TNF-α, IL-6, and IL-10; and IgG to OVA. The results obtained showed that SiO2 has no effect on the severity of the anaphylactic reaction, but is capable inducing a toxic effect on the T-cell immune systems of rats. Estimated no observed adverse effect level NOAEL for SiO2 ranges up to 100 mg/kg bw in terms of its daily consumption for 1–3 months. Using SiO2 as a food additive should be the subject of regulation.

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Safety Evaluation of a Proprietary Food-Grade, Dried Fermentate Preparation of Saccharomyces cerevisiae

International Journal of Toxicology ◽

10.1177/1091581811425195 ◽

2012 ◽

Vol 31 (1) ◽

pp. 34-45 ◽

Cited By ~ 2

Author(s):

Alexander G. Schauss ◽

R. Glavits ◽

John Endres ◽

Gitte S. Jensen ◽

Amy Clewell

Keyword(s):

Saccharomyces Cerevisiae ◽

Clinical Symptoms ◽

Safety Evaluation ◽

In Vivo Studies ◽

Oral Toxicity ◽

Toxicity Studies ◽

Adverse Effect Level ◽

Effect Level

A safety evaluation was performed for EpiCor, a product produced by a proprietary fermentation process using Saccharomyces cerevisiae. Studies included the following assays: bacterial reverse mutation, mouse lymphoma cell mutagenicity, mitogenicity assay in human peripheral lymphocytes, and a cytochrome P450 ([CYP] CYP1A2 and CYP3A4) induction assessment as well as 14-day acute, 90-day subchronic, and 1-year chronic oral toxicity studies in rats. No evidence of genotoxicity or mitogenicity was seen in any of the in vitro or in vivo studies. The CYP assessment showed no interactions or inductions. No toxic clinical symptoms or histopathological lesions were observed in the acute, subchronic, or chronic oral toxicity studies in the rat. Results of the studies performed indicate that EpiCor does not possess genotoxic activity and has a low order of toxicity that is well tolerated when administered orally. The no observable adverse effect level (NOAEL) was 1500 mg/kg body weight (bw)/d for the 90-day study and 800 mg/kg bw/d for the 1 year study, for the highest doses tested.

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Chronic In Vivo Effects of Repeated Exposure to Low Oral Doses of Tetrodotoxin: Preliminary Evidence of Nephrotoxicity and Cardiotoxicity

Toxins ◽

10.3390/toxins11020096 ◽

2019 ◽

Vol 11 (2) ◽

pp. 96 ◽

Cited By ~ 6

Author(s):

Andrea Boente-Juncal ◽

Carmen Vale ◽

Manuel Cifuentes ◽

Paz Otero ◽

Mercedes Camiña ◽

...

Keyword(s):

Lethal Dose ◽

Preliminary Evidence ◽

Oral Toxicity ◽

Cardiac Tissues ◽

Marine Gastropods ◽

Urine Production ◽

Effect Level ◽

In Vivo Effects ◽

Oral Doses

Tetrodotoxin (TTX) is one of the most potent naturally occurring neurotoxins. InitiallyTTX was associated with human food intoxications in Japan, but nowadays, concerns about thehuman health risks posed by TTX have increased in Europe after the identification of the toxin infish, marine gastropods, and bivalves captured in European waters. Even when TTX monitoring isnot currently performed in Europe, an acute oral no observable effect level (NOAEL) of 75 μg/kghas been recently established but, to date, no studies evaluating the chronic oral toxicity of TTXhave been released, even when EFSA has highlighted the need for them. Thus, in this work, thechronic effects of low oral TTX doses (below the acute lethal dose 50) were evaluated followinginternationally adopted guidelines. The results presented here demonstrate that low oral doses ofTTX have deleterious effects on renal and cardiac tissues. Moreover, alterations in bloodbiochemistry parameters, urine production, and urinalysis data were already detected at the oraldose of 75 μg/kg after the 28 days exposure. Thus, the data presented here constitute an initialapproach for the chronic evaluation of the in vivo toxicity of tetrodotoxin after its ingestion throughcontaminated fishery products.

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Acute and Chronic Oral Toxicity of a Partially Purified Plaunotol Extract fromCroton stellatopilosusOhba

BioMed Research International ◽

10.1155/2013/303162 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Chatchai Chaotham ◽

Songpol Chivapat ◽

Anan Chaikitwattana ◽

Wanchai De-Eknamkul

Keyword(s):

Chronic Toxicity ◽

Clinical Symptoms ◽

Lethal Dose ◽

Blood Platelet ◽

Oral Toxicity ◽

Liver And Kidney ◽

High Doses ◽

Altered Liver ◽

Further Development

Plaunotol, an acyclic diterpenoid with highly effective antigastric ulcer properties, has been commercially isolated from leaves ofCroton stellatopilosusOhba. This Thai medicinal plant was traditionally used in the form of crude extracts, suggesting that it is possible to administer these plaunotol-containing extracts without toxicity. To confirm its safety, the oral toxicity of a partially purified plaunotol extract (PPE) was evaluatedin vivo. The PPE was simply prepared by 95% ethanol reflux extraction followed by hexane partition. The obtained extract was analyzed and found to contain 43% w/w of plaunotol and another compound, likely a fatty acid-plaunotol conjugate that is considered a major impurity. Oral administration of PPE to ICR mice and Wistar rats was conducted to evaluate acute and chronic toxicity of the plaunotol extract, respectively. The acute toxicity study demonstrated that PPE was practically nontoxic based on its high median lethal dose value (LD50=10.25 g/kg). The chronic toxicity studies also showed the absence of mortality and clinical symptoms in all rats treated with 11–1,100 mg/kg/day of PPE during a 6-month period. Histopathological and hematological analyses revealed that altered liver and kidney function and increased blood platelet number, but only at the high doses (550–1,100 mg/kg/day). These results suggest that PPE is potentially safe for further development as a therapeutic agent in humans.

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Acute and Subchronic Oral Toxicity of Oil Palm Puree in Sprague–Dawley Rats

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17103404 ◽

2020 ◽

Vol 17 (10) ◽

pp. 3404

Author(s):

Zaida Zainal ◽

Augustine Ong ◽

Choo Yuen May ◽

Sui Kiat Chang ◽

Afiqah Abdul Rahim ◽

...

Keyword(s):

Lethal Dose ◽

Pharmaceutical Formulations ◽

Toxicity Study ◽

Sprague Dawley ◽

Oral Toxicity ◽

Subchronic Toxicity ◽

Organ Weights ◽

Sprague Dawley Rats ◽

Adverse Effect Level ◽

Effect Level

Palm puree is rich in antioxidants and is produced via blending various proportions of mesocarp fibre and crude palm oil. The aim of this study was to assess the acute and subchronic toxicity of palm puree in male and female Sprague–Dawley rats. For the acute toxicity study, animals administered single palm-puree doses (2000 mg kg−1) by gavage were observed daily for 14 d. For the subchronic toxicity study, the rats were administered 500, 1000, or 2000 mg kg−1 palm puree daily for 28 d. We evaluated body and organ weights; performed haematological, biochemical, and histopathological analyses of blood and organ samples during and after treatment; and calculated the oral no-observed-adverse-effect level (NOAEL). The toxicity studies showed no signs of toxicity or mortality. The haematological, biochemical, and histopathological analyses and body and organ weights indicated no evidence of substantial toxicity at any dose of palm puree. The oral lethal dose and NOAEL for the palm puree were greater than 2000 mg kg−1 d−1 over 28 d. To the best of our knowledge, the present study is the first to confirm the safety of palm puree as a novel functional food. These encouraging results warrant further studies to elucidate its potential for pharmaceutical formulations.

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Ca2+ Imaging With Two-photon Microscopy to Detect the Disruption of Brain Function in Mice Administered With Neonicotinoid Insecticides

10.21203/rs.3.rs-484024/v1 ◽

2021 ◽

Author(s):

Anri Hirai ◽

Shouta Sugio ◽

Collins Nimako ◽

Shouta Nakayama ◽

Keisuke Kato ◽

...

Keyword(s):

Lethal Dose ◽

Neuronal Population ◽

Two Photon Microscopy ◽

Two Photon ◽

Adverse Effect Level ◽

Effect Level ◽

Highly Sensitive Detection ◽

Neonicotinoid Pesticides ◽

The Brain

Abstract Neonicotinoid pesticides are insecticides that are insecticides that reportedly have untargeted effects on bees and dragonflies causing a reduction in numbers. Neonicotinoids act as neuroreceptor modulators, and some studies have reported their association with neurodevelopmental disorders. However, the effect of neonicotinoids on the central nervous system has not yet been identified. Herein, we conducted in vivo Ca2+ imaging using a two-photon microscope to detect abnormal activity of neuronal circuits in the brain using a neonicotinoid. The oral administration of acetamiprid (ACE) (20 mg/kg body weight [bw]) in mature mice with a less than the no-observed-adverse-effect level (NOAEL) and a tenth or half of the median lethal dose (LD50) of nicotine (0.33 or 1.65 mg/kg bw, respectively), as a typical nAChRs agonist, increased anxiety-like behavior associated with altered activities of the neuronal population in the somatosensory cortex. Furthermore, we detected ACE and metabolites in the brain 1 h after ACE administration. The results suggested that in vivo Ca2+ imaging using a two-photon microscope enabled the highly sensitive detection of neurotoxicant-mediated brain disturbance of nerves.

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In Vivo Toxicity and the Antioxidant Activity of the Hot Water Extract of Glechoma Hederacea

10.21203/rs.3.rs-42365/v1 ◽

2020 ◽

Author(s):

Yun-Chin Chung ◽

Jiunn-Wang Liao ◽

Kuo-Yuan Li ◽

Jyun-Kai Jhan ◽

Su-Tze Chou

Keyword(s):

Adverse Effect ◽

Water Extract ◽

Hot Water ◽

Oral Toxicity ◽

Subacute Toxicity ◽

Hot Water Extract ◽

Adverse Effect Level ◽

Effect Level ◽

Glechoma Hederacea

Abstract Background Glechoma hederacea belongs to the Labiatae family and has many biological effects. Our previously in vitro studies, hot water extract of G. hederacea (HWG) possessed antioxidant and anti-inflammatory activities. Also, the Ames test indicated that HWG had no mutagenicity. However, the in vivo toxicity and antioxidant capacity have not been clearly demonstrated. Thus, this study was aimed to evaluate the antioxidant properties and the safety level of HWG by using animal models. Methods The genotoxicity were performed by micronucleus assays in mice. Acute oral toxicity and 28-day repeated feeding toxicity tests were performed via the oral gavage method for Sprague-Dawley (SD) rats. Furthermore, the effect of HWG on the oxidation–antioxidation equilibrium of male rats was also evaluated. Results HWG did not induce an increase in micronucleus ratios in vivo, no acute lethal effect at a maximum tested dose of 5.0 g HWG /kg bw was observed in rats. The 28-day oral toxicity study revealed the no observed adverse effect level (NOAEL) of HWG in rats was 1.0 g/kg bw. The HWG-treatment significantly elevated the vitamin C level and the SOD activity in heart, and increased the vitamin E concentrations in brain. The HWG-treatment maintained the balance of the glutathione level and the activities of catalase and glutathione peroxidase. Besides, the level of lipid peroxidation and plasma of total antioxidant status (TAS) showed that HWG-treated rats were not significantly changed compared with the control group. Conclusions HWG had no genotoxicity, and did not induce acute or subacute toxicity in SD rat. The level of no observed adverse effect level (NOAEL) of HWG rats was 1.0 g/kg bw for subacute toxicity study. HWG possessed antioxidant potential and reduced oxidative stress by improving the antioxidant system in animal.

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Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50) and No Observed Adverse Effect Level (NOAEL)

Toxins ◽

10.3390/toxins9030075 ◽

2017 ◽

Vol 9 (3) ◽

pp. 75 ◽

Cited By ~ 18

Author(s):

Paula Abal ◽

M. Louzao ◽

Alvaro Antelo ◽

Mercedes Alvarez ◽

Eva Cagide ◽

...

Keyword(s):

Adverse Effect ◽

Lethal Dose ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Adverse Effect Level ◽

Effect Level

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Safety Assessment of Bacillus licheniformis Me1 Isolated from Milk for Probiotic Application

International Journal of Toxicology ◽

10.1177/1091581812443388 ◽

2012 ◽

Vol 31 (3) ◽

pp. 228-237 ◽

Cited By ~ 16

Author(s):

Vadakedath Nithya ◽

Serva P. Muthukumar ◽

Prakash M. Halami

Keyword(s):

Bacillus Licheniformis ◽

Safety Assessment ◽

Micronucleus Assay ◽

Toxicity Study ◽

Oral Toxicity ◽

Ocular Lesions ◽

Industry Applications ◽

Adverse Effect Level ◽

Effect Level

In this study, an in vivo toxicological safety assessment of Bacillus licheniformis Me1, a native isolate from milk, was performed. An acute toxicity study in male albino Wistar rats demonstrated no treatment-related illness or mortality. A 90-day subchronic oral toxicity study using 2 doses (1.1 × 1010 and 1.1 × 1011 colony-forming unit [CFU]/kg body weight [BW], respectively) failed to show dose-dependent illness or mortality. Moreover, neither significant differences in serum biochemical and hematological analyses nor histopathological changes in organs or tissues were found when compared to the control groups. The no-observed-adverse-effect level (NOAEL) was found to be greater than 1.1 × 1011 CFU/kg BW. The in vivo micronucleus assay in mice did not reveal any signs of genotoxic effect at any of the doses tested. Furthermore, dermal and acute eye irritation tests conducted in rabbits showed no edema or erythema and ocular lesions. These results suggest that B licheniformis Me1 can be considered safe for food industry applications.

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A New Symmetrical Thiazolidinedione Derivative: In Silico Design, Synthesis, and In Vivo Evaluation on a Streptozotocin- Induced Rat Model of Diabetes

Processes ◽

10.3390/pr9081294 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1294

Author(s):

Samuel Álvarez-Almazán ◽

Gabriel Navarrete-Vázquez ◽

Itzia Irene Padilla-Martínez ◽

José Correa-Basurto ◽

Diana Alemán-González-Duhart ◽

...

Keyword(s):

Rat Model ◽

In Silico ◽

Female Rats ◽

Therapeutic Effects ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

In Vivo Evaluation ◽

Docking Simulations ◽

Ppar Γ

By activating PPAR-γ, thiazolidinediones normalize glucose levels in animal models of type 2 diabetes and in patients with this pathology. The aim of the present study was to analyze 219 new derivatives in silico and select the best for synthesis, to be evaluated for acute oral toxicity in female rats and for control of diabetes-related parameters in a rat model of streptozotocin-induced diabetes. The best compound was chosen based on pharmacokinetic, pharmacodynamic, and toxicological parameters obtained in silico and binding orientation observed by docking simulations on PPAR-γ. Compound 1G was synthesized by a quick and easy Knoevenagel condensation. Acute oral toxicity was found at a dose greater than 2000 mg/Kg. Compound 1G apparently produces therapeutic effects similar to those of pioglitazone, decreasing glycaemia and triglyceride levels in diabetic animals, without liver damage. Moreover, it did not cause a significant weight gain and tended to reduce polydipsia and polyphagia, while diminishing systemic inflammation related to TNF-α and IL-6. It lowered the level of endogenous antioxidant molecules such as reduced glutathione and glutathione reductase. In conclusion, 1G may be a candidate for further testing as an euglycemic agent capable of preventing the complications of diabetes.

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