Safety evaluation of a proprietary food-grade, dried fermentate preparation of Saccharomyces cerevisiae.

PubMed

Schauss, Alexander G; Glavits, R; Endres, John; Jensen, Gitte S; Clewell, Amy

2012-01-01

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.

Determination of the Chronic Mammalian Toxicological Effects of TNT. Twenty-Six Week Subchronic Oral Toxicity Study of Trinitrotoluene (TNT) in the Beagle Dog.

DTIC Science & Technology

1983-06-01

41 +1 +1 .9 +9 +1 41 -4 o o 1.- I - - Cl C 103 .1 . 5 11 . +1 +1 +1 +1 -nIn 0 In (D 02 0 . 1 + 5 +1 +1 +1 +9 1 +1 +1 0 W 0 *Z to~ 1w 0 0 W I.-I .j I U...SPERFORMING ORG. REPORT NUMBERTwenty-Six Week Subchronic Oral Toxicity Study of 11 StdyNor Trinitrotoluene (TNT) in The Beagle On IL11 COSATRGAtd NoM. 5 ...in the present studya7 Unclassified TV - CL ASSI FIAINO THIS P AGC(Ht.M Dat Eteed Contract No., DAND17-79-C-9120 IITRI Project No. L6116 Study No. 5

A subchronic oral toxicity study of Salacia reticulata extract powder in rats.

PubMed

Oda, Yuriko; Yuasa, Atsuko; Ueda, Fumitaka; Kakinuma, Chihaya

2015-01-01

The safety of Salacia plant ( Salacia reticulata ) extract powder, which is used in Ayurvedic medical practices, was studied in a dose range-finding subchronic toxicity study in Crl:CD Sprague-Dawley rats. Male and female rats were randomly assigned to 4 treatment groups and were treated by oral gavage with 0, 10, 65, and 400 mg/kg body weight/day of the powder for 91 days. Body weight, food consumption, and clinical signs were assessed during the treatment period. Urinalysis, hematology, blood chemistry, and organ weights were determined one day after the final treatment. The animals were euthanized at the end of the treatment and were examined for necropsy and histopathological purposes. No adverse toxicity was observed in the Salacia powder-treated groups with a No Observed Adverse Effect Level of ≧400 mg/kg body weight/day in both male and female SD rats.

Acute and sub-chronic oral toxicity assessment of the aqueous extract leaves of Ficus glumosa Del. (Moraceae) in rodents.

PubMed

Ntchapda, Fidèle; Abakar, Djedouboum; Kom, Blaise; Nana, Paulin; Hamadjida, Adjia; Dimo, Théophile

2014-01-01

Ficus glumosa Del (Moraceae), a plant used in traditional medicine in Cameroon, Senegal, and East Africa for the treatment of edema, hemorrhoid, cardiovascular diseases especially hypertension. The present study evaluated the potential toxicity of the aqueous extract of the leaves of F.glumosa in acute and sub-chronic administration in rodents. Acute toxicity was evaluated on 3 months old mice of both sexes and weighing 20-30 g. A single dose (2-12 g/kg) of F. glumosa was administered orally to mice. Animal behavior, adverse effects, and mortality were determined for 14 days. In sub-chronic toxicity studied in both sexes of 9 weeks old rats and weighing 100-120 g at the start of the experiment, animals were treated orally with a daily dose of 300, 600 and 1200 mg/kg of the aqueous extract of the leaves of F. glumosa for 6 weeks. The body weight change, food, and water consumption, were determined throughout the experimental period, while the relative organ weights, the hematological and biochemical parameters of blood and urine, as well as the histology of tissues kidney and liver, were recorded at the end of the experiment. For acute treatment, no dose used induced critical behavioral changes or death. In sub-chronic treatment, daily oral administration of F. glumosa at the dose of 300, 600, and 1200 mg/kg resulted in a significant increase in body weight relative to food and water consumption in the last week of treatment. The relative organ weights were not affected by treatment. No hematological changes were observed except the significant increase in platelets. Aspartate aminotransferase, alanine transaminase, alkaline phosphatase, total protein, increased while the total cholesterol, triacylglycerol, conjugated bilirubin, and total bilirubin significantly decreased. Index of renal function showed a decrease of creatinine, urea, uric acid and Na(+), Cl(-) and Ca(2+), and inorganic phosphate. The histology of liver and kidney showed no significant alteration of tissue. These observations support the traditional use of F. glumosa in the treatment of hypertension. These results have shown that F. glumosa has a safety margin for therapeutic use.

Nonclinical Safety Assessment of Morus alba L. Fruits: Study of 90-D Toxicity in Sprague Dawley Rats and Genotoxicity in Salmonella.

PubMed

Chang, Bo Yoon; Kim, Seon Beom; Lee, Mi Kyeong; Park, Hyun; Kim, Sung Yeon

2016-05-01

Morus alba L. is a traditional herb with a long history of consumption, both as an edible fruit and as medicine. However, its safety evaluation has not yet been established. The objective of this study was to evaluate subchronic oral toxicity and genotoxicity of M. alba L. fruits (MFE). The subchronic toxicity after daily oral administration of MFE at 0, 40, 200, and 1000 mg/kg for 90 d was examined in Sprague Dawley (SD) rats. MFE administration did not lead to death, adverse effects, change in food and water consumption, and body weight gain. Significant toxic effects were not found within the parameters of organ weight, biochemical values, and hematological and urine analysis between the control and the MFE group. The genotoxicity of MFE was assayed by Ames test in Salmonella typhimurium strains TA98, TA102, and TA1535. No genotoxicity was found in all the tested strains. Thus in this study, a no-observed-adverse-effect level for MFE in 90 d repeated oral toxicity study in rats was determined to be greater than 1000 mg/kg regardless of gender. The results also suggested that MFE does not have a genotoxicity potential. © 2016 Institute of Food Technologists®

Acute and subchronic toxicological evaluation of Mequindox in Wistar rats.

PubMed

Ihsan, Awais; Wang, Xu; Huang, Xian-ju; Liu, Yu; Liu, Qin; Zhou, Wen; Yuan, Zong-hui

2010-01-01

We studied an acute and subchronic oral toxicity of Mequindox (MEQ), a quinoxaline 1,4-dioxide antimicrobial promoter, in Wistar rats according to OECD guidelines. For acute toxicity study, single doses of MEQ at 175, 550 and 2000 mg/kg b.w. were administered to rats by oral gavage. The calculated LD(50) was 550 mg/kg b.w. In subchronic study, rats were fed diets containing 0, 55, 110 or 275 mg MEQ/kg. There was a reduction in body weight of rats fed 275 mg MEQ/kg diet. At 90 days autopsy, a significant decrease in the kidney weight was observed in males while an increase in relative liver and adrenal weights were observed in females fed 275 mg MEQ/kg diet. There was a significant increased in alanineaminotransferase (ALT) and malondialdehyde (MDA) concentrations in males, superoxide dismutase (SOD) activities in females, and aspartateaminotransferase (AST) levels in serum of both genders fed 275 mg MEQ/kg diet. Other toxic effects of 275 mg MEQ/kg diet included significant decrease in sodium and significant increase in potassium concentrations in serum in both genders. We may conclude that MEQ can induce hepatic and adrenal histological changes as well as leaking of different serum constituents in Wistar rats. Copyright 2010 Elsevier Inc. All rights reserved.

NAPHTHALENE TOXICITY IN CD-1 MICE: GENERAL TOXICOLOGY AND IMMUNOTOXICOLOGY

EPA Science Inventory

The purpose of this study was to evaluate the acute and subchronic toxicity, and effects on immune function, of naphthalene (NAP) in random-bred CD-1 mice. The acute oral LD50 of this compound was 533 and 710 mg/kg in male and female mice, respectively. Fourteen- and ninety-day d...

Acute and subchronic toxicity of naturally weathered Exxon Valdez crude oil in mallards and ferrets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stubblefield, W.A.; Hancock, G.A.; Ford, W.H.

1995-11-01

The toxic properties of naturally weathered Exxon Valdez crude oil (WEVC) were assessed in a battery of acute and subchronic toxicity tests using mallards, Anas platyrhynchos, and European ferrets, Mustela putorius. Adult mallard acute oral toxicity study results indicated no mortalities or signs o toxicity, i.e., no-observed-adverse-effect level (NOAEL) and median lethal dose (LD50) > 5,000 mg/kg. Acute oral feeding and food avoidance tests with ducklings also indicated no toxicity (NOAEL and LC50 > 50,000 mg/kg diet) with no evidence of food avoidance (FAC50 > 20,000 mg/kg diet). No mortalities or toxic signs were noted in a 14-d feeding studymore » with adult birds at dietary concentrations up to 100,000 mg WEVC/kg diet. Among clinical and physiological end points evaluated, the only significant difference noted was an increase in liver: body weight ratios in the 100,000-mg WEVC/kg diet dose group. No differences in clinical chemistry or hematological parameters were noted, and there were no consistent differences in histological evaluations of organ tissues. Daily oral doses of up to 5,000 mg/kg of WEVC over 5 d resulted in minimal effects on ferrets. Increased serum albumin concentrations were observed in the 5,000-mg/kg dose group females and decreased spleen weights were noted in females of all WEVC treatment groups. No other significant observations were noted.« less

Toxicological Evaluation of Lactase Derived from Recombinant Pichia pastoris

PubMed Central

Liu, Yifei; Chen, Delong; Luo, Yunbo; Huang, Kunlun; Zhang, Wei; Xu, Wentao

2014-01-01

A recombinant lactase was expressed in Pichia pastoris, resulting in enzymatic activity of 3600 U/mL in a 5 L fermenter. The lactase product was subjected to a series of toxicological tests to determine its safety for use as an enzyme preparation in the dairy industry. This recombinant lactase had the highest activity of all recombinant strains reported thus far. Acute oral toxicity, mutagenicity, genotoxic, and subchronic toxicity tests performed in rats and mice showed no death in any groups. The lethal dose 50% (LD50) based on the acute oral toxicity study is greater than 30 mL/kg body weight, which is in accordance with the 1500 L milk consumption of a 50 kg human daily. The lactase showed no mutagenic activity in the Ames test or a mouse sperm abnormality test at levels of up to 5 mg/plate and 1250 mg/kg body weight, respectively. It also showed no genetic toxicology in a bone marrow cell micronucleus test at levels of up to 1250 mg/kg body weight. A 90-day subchronic repeated toxicity study via the diet with lactase levels up to 1646 mg/kg (1000-fold greater than the mean human exposure) did not show any treatment-related significant toxicological effects on body weight, food consumption, organ weights, hematological and clinical chemistry, or histopathology compared to the control groups. This toxicological evaluation system is comprehensive and can be used in the safety evaluation of other enzyme preparations. The lactase showed no acute, mutagenic, genetic, or subchronic toxicity under our evaluation system. PMID:25184300

Safety profile and gender specific differences of a methanol extract of Eriosema laurentii (Leguminosae) in acute and subchronic (28 days) oral toxicity studies in Wistar rats.

PubMed

Ateba, Sylvin Benjamin; Simo, Rudy Valdès; Mbanya, Jean Claude; Krenn, Liselotte; Njamen, Dieudonné

2014-03-01

Despite widespread use of Eriosema laurentii De Wild (Leguminosae) in West and Central Africa as herbal medicine and food additive the toxicity of this plant is unknown. Therefore, we performed the safety evaluation of a methanol extract (AEL). In acute toxicity, single oral administration of 2000mg/kg AEL caused neither toxicological symptoms nor mortality and the LD50 was estimated >5000mg/kg. In the subchronic oral toxicity, AEL induced no phenotypical signs of toxicity during and after treatment. Only a delayed decrease of relative spleen weight in males at the highest dose of 400mg/kg occurred. High density lipoprotein (HDL) increased significantly in females at 200 and 400mg/kg. Non-persistent increases in alanine aminotransferase activity within normal ranges were noted at 200mg/kg in males and at all doses in females. In males, AEL induced a decrease of white blood cell count at 400mg/kg, whereas lymphocytes increased at 200 and 400mg/kg and granulocytes at 400mg/kg. In females, no differences in haematological parameters occurred. Neither differences in bilirubin, creatinine and total protein levels were observed nor histological alterations in organs. The results indicate a broad safety margin for AEL. Copyright © 2013 Elsevier Ltd. All rights reserved.

Toxicological evaluation of hydroethanolic extract of Helicteres sacarolha A. St.- Hil. et al.

PubMed

Balogun, Sikiru Olaitan; da Silva, Iberê Ferreira; Colodel, Edson Moleta; de Oliveira, Ruberlei Godinho; Ascêncio, Sérgio Donizeti; Martins, Domingos Tabajara de Oliveira

2014-11-18

Helicteres sacarolha, popularly known in Brazil as 'rosquinha', 'sacarolhas', 'semente-de-macaco', is widely distributed in different phytogeographic zones in Brazil. Preparations from its roots and leaves are employed in popular Brazilian medicine in the treatments of ailments such as peptic ulcer, hypertension among others. Cytotoxicity, acute oral and subchronic toxicity of the hydroethanolic extract of Helicteres sacrolha was investigated as well as the classes of phytochemical present in the extract. Hydroethanolic (70%) extract of Helicteres sacarolha (HEHs) was prepared by maceration. Potential cytotoxicity was evaluated in CHO-k1 cells. Acute administration of HEHs was done in mice as a single dose up to 5000mg/kg and subchronic oral toxicity study for 30 days in Wistar rats at daily oral doses of 0, 250 and 750mg/kg b.w. Clinical observations and toxicological related parameters were determined every 6 days. Blood was collected for biochemical and hematological analyses, while histological examinations were performed on selected organs. Selected secondary metabolites detected were quantified by UV-spectrophotometry and high performance liquid chromatography (HPLC). The extract was non-cytotoxic to CHO-k1 cells. In acute oral toxicity, there was no mortality or clinical alterations in the female mice, at all doses, except for the transient diarrhea observed at 5000mg/kg acute. Doses up to 2000mg/kg caused no mortality or treatment-related clinical manifestations in the male mice, but treatment-related alterations were however observed at 4000mg/kg, with mortalities recorded at 5000mg/kg. During the subchronic oral toxicity study, no mortality or treatment-related clinical signs were observed. Differences in relative organ weight, hematological parameters and histopathology observations between the treated and the control groups were considered not to be treatment-related. Spectrophotometric analysis revealed the presence of relatively high content of phenolics and flavonoids in HEHs. HPLC analysis confirmed the presence of the quantified compounds and demonstrated the presence of ellagic acid, morin and naringin. Our results confirmed that HEHs have a broad safety margin for therapeutic use. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Subchronic Toxicity Study in Rats of Two New Ethyl-Carbamates with Ixodicidal Activity

PubMed Central

Prado-Ochoa, María Guadalupe; Abrego-Reyes, Víctor Hugo; Velázquez-Sánchez, Ana María; Muñoz-Guzmán, Marco Antonio; Ramírez-Noguera, Patricia; Angeles, Enrique; Alba-Hurtado, Fernando

2014-01-01

Female and male Wistar rats were used to determine the subchronic oral toxicities of two new ethyl-carbamates with ixodicidal activities (ethyl-4-bromphenyl-carbamate and ethyl-4-chlorphenyl-carbamate). The evaluated carbamates were administered in the drinking water (12.5, 25 and 50 mg/kg/day) for 90 days. Exposure to the evaluated carbamates did not cause mortality or clinical signs and did not affect food consumption or weight gain. However, exposure to these carbamates produced alterations in water consumption, hematocrit, percentages of reticulocytes, plasma proteins, some biochemical parameters (aspartate aminotransferase, gamma-glutamyl transpeptidase, cholinesterase, and creatinine activities), thiobarbituric acid reactive substances, and the relative weight of the spleen. Histologically, slight pathological alterations were found in the liver that were consistent with the observed biochemical alterations. The nonobserved adverse effect levels (NOAELs) of the evaluated carbamates were 12.5 mg/kg/day for both the female and male rats. The low severity and reversibility of the majority of the observed alterations suggest that the evaluated carbamates have low subchronic toxicity. PMID:24818142

Acute and sub-chronic oral toxicity studies of erythritol in Beagle dogs.

PubMed

Eapen, Alex K; de Cock, Peter; Crincoli, Christine M; Means, Charlotte; Wismer, Tina; Pappas, Christopher

2017-07-01

Polyols, also known as sugar alcohols, are widely used in the formulation of tooth-friendly and reduced-calorie foods. Considering the significant health benefits of polyols in products formulated for human use, there is increased interest in evaluating potential uses in companion animal applications. Erythritol and xylitol are two polyols which are currently widely used in products ranging from reduced-sugar foods to personal care and cosmetics. Published studies have shown that both of these compounds are well-tolerated in rodents. Their toxicity profiles differ when comparing canine safety data. Doses of xylitol as low as 0.15 g/kg-BW in dogs can result in life-threatening hypoglycemia and acute liver failure, whereas erythritol is well-tolerated in dogs with reported No Adverse Effect Levels upwards of 5 g/kg-BW/day in repeat-dose studies. While pivotal studies substantiating the safe use of erythritol in humans have been published, there are limited published studies to support the safe use of erythritol in dogs. Here we present the results of an acute oral and a sub-chronic oral toxicity study in Beagle dogs. Given the potential health benefits of oral products formulated with erythritol and the data presented herein substantiating the safe use in dogs, erythritol can be safely used in products for canines. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sub-chronic Hepatotoxicity of Anacardium occidentale (Anacardiaceae) Inner Stem Bark Extract in Rats

PubMed Central

Okonkwo, T. J. N.; Okorie, O.; Okonta, J. M.; Okonkwo, C. J.

2010-01-01

The extracts of Anacardium occidentale have been used in the management of different cardiovascular disorders in Nigeria. These have necessitated the assessment of the toxicity of this plant extract in sub-chronic administration. The inner stem bark of Anacardium occidentale was extracted with 80 % methanol and quantitatively analysed for antinutrients and some heavy metals. The phytochemical compositions and acute toxicity of the extract were determined also. Toxicity profiles of the extract on some liver function parameters were evaluated following a sub-chronic oral administration at doses of 1.44 and 2.87 g/kg. The phytochemical screening of extract revealed the presence of high amount of tannins, moderate saponins and trace of free reducing sugars. The antinutrient levels were 5.75 % (tannins), 2.50 % (oxalates), 2.00 % (saponins), 0.25 % (phytate) and 0.03 % (cyanide). The quantity of iron detected from dried crude was 8.92 mg/100 g, while lead and cadmium were non-detectable. The extract had LD50of 2.154g/kg p.o. in mice. Sub-chronic administration of the extract significantly increased the serum levels of alanine aminotransaminase and aspartate aminotransaminase, which are indicative of liver damage. The serum levels of alkaline phosphatase and total protein of the treated animals were not significantly increased. The effects of sub-chronically administered extract on hepatocytes were minimal as the serum alkaline phosphatase; total bilirubin and total protein levels in treated animals were not significant (p< 0.05). Thus, sub-chronic administrations of Anacardium occidentale inner stem bark extract did not significantly (p< 0.05) depress the function of hepatocytes in Wistar rats. PMID:21188045

Subchronic toxicity, mutagenicity and allergenicity studies of a cultured dextrose food product.

PubMed

Buard, A; Carlton, B D; Floch, F; Simon, G S

2003-05-01

MicroGARD(R) 200 is a fermented dextrose product used to extend food shelf-life by inhibiting spoilage due to Gram-negative bacteria, selected yeast and molds. The present studies were conducted to evaluate the safety of this food ingredient for determination of GRAS status. MicroGARD 200 was subjected to a bacterial reverse mutation assay, a subchronic oral toxicity study and an oral antigenicity study. It showed no evidence of mutagenic potential or toxicity in four strains of Salmonella typhimurium or in Escherichia coli strain WP2 uvrA with and without metabolic activation. MicroGARD 200 was orally administered to rats for 13 consecutive weeks at dietary concentrations of 0, 0.5, 2.0 or 5.0%. Water consumption and urinary excretion of sodium were slightly increased in both sexes at the high dose due to the sodium content of the test substance (about 6%). Increases in fasting glucose and decreased plasma creatinine were not accompanied by treatment-related histopathological changes and were within the normal range for historical controls. The potential antigenic properties of MicroGARD 200 were investigated via gavage in guinea pigs using an active systemic anaphylaxis (ASA) challenge [Annals of Allergy 67 (1991) 400; Allergy 49 (1994) 361]. There was no evidence of any anaphylactic sensitizing properties for MicroGARD 200.

Comparative biodistribution and safety profiling of olmesartan medoxomil oil-in-water oral nanoemulsion.

PubMed

Gorain, Bapi; Choudhury, Hira; Tekade, Rakesh Kumar; Karan, Saumen; Jaisankar, P; Pal, Tapan Kumar

2016-12-01

Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of less than 26%. Improvement of oral bioavailability with prolonged pharmacodynamics activity of olmesartan in Wistar rats had been approached by nanoemulsification strategy in our previous article [Colloid Surface B, 115, 2014: 286]. In continuation to that work, we herewith report the biodistribution behaviour and 28-day repeated dose sub-chronic toxicity of olmesartan medoxomil nanoemulsion in Wistar rats following oral administration. The levels of olmesartan in collected biological samples were estimated using our validated LC-MS/MS technique. Our biodistribution study showed significantly higher brain concentrations of olmesartan (0.290 ± 0.089 μg/mL, 0.333 ± 0.071 μg/mL and 0.217 ± 0.062 μg/mL at 0.5, 2.0 and 8.0 h post dosing, respectively) when administered orally as nanoemulsion formulation as compared to the aqueous suspension. In addition, the olmesartan nanoemulsion was found to be safe and non-toxic, as it neither produced any lethality nor remarkable haematological, biochemical and structural adverse effects as observed during the 28-days sub-chronic toxicity studies in experimental Wistar rats. It is herewith envisaged that the developed nanoemulsion formulation approach for the delivery of olmesartan medoxomil via oral route can further be explored in memory dysfunction and brain ischemia, for better brain penetration and improved clinical application in stroke patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Nephroprotective effect of bee honey and royal jelly against subchronic cisplatin toxicity in rats.

PubMed

Ibrahim, Abdelazim; Eldaim, Mabrouk A Abd; Abdel-Daim, Mohamed M

2016-08-01

Cisplatin is one of the most potent and effective chemotherapeutic agents. However, its antineoplastic use is limited due to its cumulative nephrotoxic side effects. Therefore, the present study was undertaken to examine the nephroprotective potential of dietary bee honey and royal jelly against subchronic cisplatin toxicity in rats. Male Wistar rats were randomly divided into controls, cisplatin-treated, bee honey-pretreated cisplatin-treated and royal jelly-pretreated cisplatin-treated groups. Bee honey and royal jelly were given orally at doses of 20 and 100 mg/kg, respectively. Subchronic toxicity was induced by cisplatin (1 mg/kg bw, ip), twice weekly for 10 weeks. Cisplatin treated animals revealed a significant increase in serum level of renal injury products (urea, creatinine and uric acid). Histopathologically, cisplatin produced pronounced tubulointerstitial injuries, upregulated the fibrogenic factors, α-smooth muscle actin (α-SMA) and transforming growth factor β1(TGF-β1), and downregulated the cell proliferation marker, bromodeoxyuridine (Brdu). Dietary bee honey and royal jelly normalized the elevated serum renal injury product biomarkers, improved the histopathologic changes, reduced the expression of α-SMA and TGF-β1 and increased the expression of Brdu. Therefore, it could be concluded that bee honey, and royal jelly could be used as dietary preventive natural products against subchronic cisplatin-induced renal injury.

A subchronic 90-day oral toxicity study of Origanum vulgare essential oil in rats.

PubMed

Llana-Ruiz-Cabello, M; Maisanaba, S; Puerto, M; Pichardo, S; Jos, A; Moyano, R; Cameán, A M

2017-03-01

Oregano essential oil (Origanum vulgare L. virens) (OEO) is being used in the food industry due to its useful properties to develop new active packaging systems. In this concern, the safety assessment of this natural extract is of great interest before being commercialized. The European Food Safety Authority requests different in vivo assays to ensure the safety of food contact materials. One of these studies is a 90 days repeated-dose oral assay in rodents. In the present work, 40 male and 40 female Wistar rats were orally exposed to 50, 100 and 200 mg/kg body weight (b.w.) OEO during 90 days following the OECD guideline 408. Data revealed no mortality and no treatment-related adverse effects of the OEO in food/water consumption, body weight, haematology, biochemistry, necropsy, organ weight and histopathology. These findings suggest that the oral no-observed-adverse-effect level (NOAEL) of this OEO is 200 mg/kg b.w. in Wistar rats, the highest dose tested. In conclusion, the use of this OEO in food packaging appears to be safe based on the lack of toxicity during the subchronic study at doses 330-fold higher than those expected to be in contact consumers in the worst scenario of exposure. Copyright © 2017 Elsevier Ltd. All rights reserved.

Toxicological investigations on the methanol sub-fraction of the seeds of Carica papaya as a male contraceptive in albino rats.

PubMed

Lohiya, Nirmal K; Manivannan, Boomi; Garg, Shipra

2006-10-01

Pre-clinical acute and sub-chronic toxicity studies of the methanol sub-fraction (MSF) of the seeds of Carica papaya, a putative male contraceptive, have been investigated in rats to evaluate safety of the test substance. A single oral dose of MSF at 2000 mg/kg body weight was studied over 14 days for acute toxicity, and daily oral doses of 50, 100, 250 and 500 mg/kg body weight were studied for 28- and 90-day periods for sub-chronic toxicity. Body weight, food and water intake and phenotypical toxicological symptoms were recorded daily. Sperm analysis, hematology, serum clinical biochemistry, libido and pathological examination of vital organs were recorded at the termination of the experimental periods. We observed no overt general toxicity in exposed animals. Food and water intake showed daily fluctuations within control limits. Sperm density showed a significant decrease in all 28- and 90-day repeated dose treated animals whereas total sperm motility inhibition was observed at 250 and 500 mg/kg dose levels at the 28-day time interval but in all dose groups at the 90-day interval. The preliminary results suggest the test substance may be a safe approach to male anti-fertility.

Fourteen-Day Subchronic Oral Toxicity Study of Nitroguanidine in Rats

DTIC Science & Technology

1988-06-01

Beckett , SGT Samuel S. Liu, BS, and SP4 Gary E. Mattison provided hematology support; SP4 Julius Harmon and Mary E. Lyons provided clinical...Count xlO6/^! xl03/|il White Blnod Cell Differential Neutro- Lympho- Eosino- Mono- phils cytes phils cytes % % % % 0 85D00308

Acute and subchronic oral toxicity studies in rats with nanoscale and pigment grade titanium dioxide particles.

PubMed

Warheit, D B; Brown, S C; Donner, E M

2015-10-01

Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO2) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO2 -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO2 test particles (d50 = 145 nm - 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO2 particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO2 test particles (d50 = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO2 particles (d50 = 73 nm by number) with doses up to 5000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD50 for the test substance was >5000 mg/kg bw. In summary, the results from these three toxicity studies - each with different TiO2 particulate-types, demonstrated an absence of adverse toxicological effects. Apart from reporting the findings of these three studies, this publication also focuses on additional critical issues associated with particle and nanotoxicology studies. First, describing the detailed methodology requirements and rigor upon which the standardized OECD 408 guideline subchronic oral toxicity studies are conducted. Moreover, an attempt is made to reconcile the complex issue of particle size distribution as it relates to measurements of nanoscale and pigment-grade TiO2 particles. Clearly this has been a confusing issue and often misrepresented in the media and the scientific literature. It is clear that the particle-size distribution for pigment-grade TiO2, contains a small ("tail") component of nanoscale particles (i.e., 21% by particle number and <1% by weight in the test material used in the 90-day study). However, this robust particle characterization finding should not be confused with mislabeling the test materials as exclusively in the nanoscale range. Moreover, based upon the findings presented herein, there appears to be no significant oral toxicity impact contributed by the nanoscale component of the TiO2 Test Material sample in the 90-day study. Finally, it seems reasonable to conclude that the study findings should be considered for read-across purposes to food-grade TiO2 particles (e.g., E171), as the physicochemical characteristics are quite similar. Copyright © 2015 Elsevier Ltd. All rights reserved.

Genotoxicity, acute and subchronic toxicity studies in rats of a rooster comb extract rich in sodium hyaluronate.

PubMed

Canut, Lourdes; Zapatero, Jorge; López, Sílvia; Torrent, Anna; Ruhí, Ramon; Vicente, Laura

2012-04-01

The toxicity of a rooster comb extract (IB0004) that contains mainly sodium hyaluronate was assessed in acute and subchronic studies and in a bacterial reverse mutation assay. In a single dose acute study, male and female rats were administered 2000 mg/kg body weight (bw) of the product and observed for 14 days. No mortality was recorded, thus it was considered that the minimum lethal dose for rats by oral route was greater than 2000 mg/kg bw. A 90-day subchronic study (5, 55 and 600 mg/kg bw/day, oral gavage) with 50 male and 50 female Wistar-Hannover rats produced no significant adverse effects on food consumption, body weight, mortality, clinical biochemistry, hematology, gross pathology, and histopathology. Although some differences were observed between the treated and control animals in body weight gain (%) and some hematological parameters, these changes were generally minor in nature and, are considered to be of no toxicological significance. The no-observable-adverse-effects level was established at 600 mg/kg bw/day. There was no evidence of mutagenic activity in Salmonella typhimurium TA98, TA100, TA1535 and TA1537 or in Escherichia coli WP2 uvra pkM101. In conclusion, the results from these safety studies support the safety of rooster comb extract IB0004 in food. Copyright © 2011 Elsevier Inc. All rights reserved.

Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticle-encapsulated aspirin and curcumin in combination with free sulforaphane in BALB/c mice

PubMed Central

Thakkar, Arvind; Chenreddy, Sushma; Thio, Astrid; Khamas, Wael; Wang, Jeffrey; Prabhu, Sunil

2016-01-01

Our previous studies have established the efficacy of chemopreventive regimens of aspirin and curcumin (CUR) encapsulated within solid lipid nanoparticles (SLNs) in combination with free sulforaphane (ACS combination) to prevent or delay the initiation and progression of pancreatic cancer, classified as one of the deadliest diseases with very low chances of survival upon diagnosis. Although toxicity of individual drugs and SLN has been studied previously, there are no studies in current literature that evaluate the potential toxicity of a combined regimen of ACS, especially when encapsulated within chitosan-SLNs (c-SLNs). Hence, objective of the current study was to investigate the potential toxic effects of ACS c-SLN combined chemopreventive regimens following acute (3 days), subacute (28 days), and subchronic (90 days) administrations by oral gavage in BALB/c mice. Mice were administered the following regimens: saline, blank c-SLN, low-dose ACS c-SLN (2+4.5+0.16 mg/kg), medium-dose ACS c-SLN (20+45+1.6 mg/kg), and high-dose ACS c-SLN (60+135+4.8 mg/kg). The potential toxicity was evaluated based on animal survival, body weight, hematology, blood chemistry, and organ histopathology. During 3-day, 28-day, and 90-day study periods, no animal deaths were observed. Treatment with ACS c-SLNs did not cause alteration in complete blood counts and blood chemistry data. Histopathological examination of various organ sections (pancreas, heart, liver, kidney, and brain) appeared normal. Based on the results of this study, no signs of toxicity in acute, subacute, and subchronic studies following oral administration of ACS c-SLNs were found indicating that the oral dosing regimens were safe at the levels tested for long-term administration to prevent the onset of pancreatic cancer. PMID:27499621

NINETY-DAY SUBCHRONIC STUDY OF THE TOXIC EFFECTS OF DICHLOROACETATE IN DOGS

EPA Science Inventory

Male and female juvenile Beagle dogs were dosed daily for 90 days with dichloroacetate. he compound was administered orally via gelatin capsule at doses of 0, 12.5, 39.5 and 72 mg/kg/day. ach dose group consisted of 5 males and 5 females. he dogs were observed clinically and bloo...

In vitro ovicidal and larvicidal activity of methanolic leaf extract of Manihot esculenta (cassava) on susceptible and resistant strains of Trichostrongylus colubriformis.

PubMed

Al-Rofaai, A; Rahman, W A; Sulaiman, S F; Yahaya, Z S

2012-11-23

This study aimed to represent the first report of the ovicidal and larvicidal activity of the methanolic leaf extract of Manihot esculenta (cassava) against eggs and larvae of susceptible and resistant strains of Trichostrongylus colubriformis. As well as, to determine the total tannin compounds, antioxidant activity and toxicity of the extract. The egg hatch test was used to evaluate ovicidal activity against unembryonated eggs, whereas larval feeding inhibition assay and MTT-formazan assay were used to evaluate larvicidal activity against first (L(1)) and infective (L(3)) larvae, respectively. The results showed no significant differences were detected between the sensitivities of susceptible and resistant strains of T. colubriformis to the extract. Eggs, L(1) and L(3) were significantly affected (P<0.001) compared with negative control, and L(1) were more sensitive than the eggs and L(3). The total tannin compounds were investigated using tannin quantification assay and determined by 254.44 TAE/mg. The antioxidant activity was evaluated using the DPPH radical scavenging assay and the median inhibition concentration (IC(50)) was determined by 2.638 mg/ml. Acute oral toxicity at dose of 5,000 mg/kg, and sub-chronic oral toxicity at 500 and 1,000 mg/kg of the extract were observed in male and female Sprague-Dawley (SD) rats. The acute oral toxicity revealed that the median lethal dose (LD(50)) of methanolic extract of cassava leaves on SD rats was greater than 5,000 mg/kg, whereas the sub-chronic oral toxicity did not show observed adverse effects at 500 and 1,000 mg/kg per day for 28 days. In conclusion, the methanolic extract of cassava leaves has direct ovicidal and larvicidal activity against T. colubriformis strains with a safety margin for animals, and it may be potentially utilized as a source of natural antioxidants. Copyright © 2012 Elsevier B.V. All rights reserved.

Development of an acceptable factor to estimate chronic end points from acute toxicity data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Venman, B.C.; Flaga, C.

1985-12-01

Acceptable daily intake (ADI) values are routinely developed for threshold toxicants from NOAELs determined from human or animal chronic or subchronic data. These NOAELs are then divided by appropriate uncertainty factors ranging from 10 to 1000 depending on the quality of the data. However, for the vast majority of chemicals used industrially, adequate toxicity data needed to use this process are not available. Thus, a procedure to estimate a chronic toxicity endpoint from acute toxicity data, such as an oral rat LD50, becomes necessary. An acute-to-chronic application factor of 0.0001 was developed, which when multiplied by an oral LD50 formore » an individual chemical, yields a surrogate chronic NOAEL. This figure can then be used to estimate an acceptable daily exposure for humans. The process used to estimate this application factor is detailed.« less

Subchronic toxicity, immunoregulation and anti-breast tumor effect of Nordamnacantal, an anthraquinone extracted from the stems of Morinda citrifolia L.

PubMed

Abu, Nadiah; Zamberi, Nur Rizi; Yeap, Swee Keong; Nordin, Noraini; Mohamad, Nurul Elyani; Romli, Muhammad Firdaus; Rasol, Nurulfazlina Edayah; Subramani, Tamilselvan; Ismail, Nor Hadiani; Alitheen, Noorjahan Banu

2018-01-27

Morinda citrifolia L. that was reported with immunomodulating and cytotoxic effects has been traditionally used to treat multiple illnesses including cancer. An anthraquinone derived from fruits of Morinda citrifolia L., nordamnacanthal, is a promising agent possessing several in vitro biological activities. However, the in vivo anti-tumor effects and the safety profile of nordamnacanthal are yet to be evaluated. In vitro cytotoxicity of nordamnacanthal was tested using MTT, cell cycle and Annexin V/PI assays on human MCF-7 and MDA-MB231 breast cancer cells. Mice were orally fed with nordamnacanthal daily for 28 days for oral subchronic toxicity study. Then, the in vivo anti-tumor effect was evaluated on 4T1 murine cancer cells-challenged mice. Changes of tumor size and immune parameters were evaluated on the untreated and nordamnacanthal treated mice. Nordamnacanthal was found to possess cytotoxic effects on MDA-MB231, MCF-7 and 4T1 cells in vitro. Moreover, based on the cell cycle and Annexin V results, nordamnacanthal managed to induce cell death in both MDA-MB231 and MCF-7 cells. Additionally, no mortality, signs of toxicity and changes of serum liver profile were observed in nordamnacanthal treated mice in the subchronic toxicity study. Furthermore, 50 mg/kg body weight of nordamncanthal successfully delayed the progression of 4T1 tumors in Balb/C mice after 28 days of treatment. Treatment with nordamnacanthal was also able to increase tumor immunity as evidenced by the immunophenotyping of the spleen and YAC-1 cytotoxicity assays. Nordamnacanthal managed to inhibit the growth and induce cell death in MDA-MB231 and MCF-7 cell lines in vitro and cease the tumor progression of 4T1 cells in vivo. Overall, nordamnacanthal holds interesting anti-cancer properties that can be further explored.

Safety assessment of aqueous extract from leaf Smallanthus sonchifolius and its main active lactone, enhydrin.

PubMed

Barcellona, Carolina Serra; Cabrera, Wilfredo Marcelino; Honoré, Stella Maris; Mercado, María Inés; Sánchez, Sara Serafina; Genta, Susana Beatriz

2012-11-21

Leaves of Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson (yacon) have been used since pre-Columbian times in the Andean region to prepare medicinal herbal tea with beneficial health properties. However, there are still disagreements about the safe use. This work was carried out to evaluate the toxicity profile of both, 10% decoction of yacon leaves and their major active lactone, enhydrin. In vitro cytotoxicity assays were performed with Hep-G2, COS1, CHO-K1 and Vero cell lines using a test of metabolic competence based upon assessment of mitochondrial performance. In vivo toxicity study was performed in adult Wistar rats. In the acute oral toxicity each group of rats was orally given a single dose of 10% decoction or enhydrin. General condition, behavior and mortality were recorded for up to 14 days post treatment. In subchronic toxicity studies, both products were given orally for 90 days to rats. Body weight and food intakes were observed weekly. Hematological, clinical chemistry parameters and organ weight were determined in all animals at the end of the experimental period. Cell viability decreased in a concentration dependent fashion when cells were incubated with 2-200 μg of 10% decoction and 0.015-7.5 μg of enhydrin. In acute study in rats, there were no deaths or signs of toxicity observed after oral administration of single doses of 10% decoction or enhydrin at any dose level up to the highest dose tested (14.0 g/kg and 0.32 g/kg, respectively). In subchronic studies in rats, both products administered orally for 90 days at daily doses of 0.07, 0.14 and 0.28 g 10% decoction/kg and 0.4, 0.8 and 8.0 mg enhydrin/kg, did not caused haematological, biochemical and histological alterations. The results presented in this paper lead us to the conclusion that the use of 10% decoction and enhydrin is safe in rat at doses in which it is demonstrated the hypoglycaemic effect. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Characterisation and toxicological assessment of Neutral Methacrylate Copolymer for GRAS evaluation.

PubMed

Eisele, Johanna; Haynes, Geoff; Kreuzer, Knut; Rosamilia, Tiana

2013-12-01

Neutral Methacrylate Copolymer is a fully polymerised copolymer used in the pharmaceutical industry to permit pH-independent delayed release of active ingredients from oral dosage forms. This function has potential use with food supplements and this article describes available information on the safety of the substance. Oral administration of radiolabelled copolymer to rats resulted in the detection of chemically unchanged copolymer in the faeces, with negligible absorption. Safety studies revealed no adverse toxicity following repeated administration at doses of up to 2000 mg/kg bw/d in a sub-chronic study in rats or 250 mg/kg bw/d in a sub-chronic study in dogs. No reproductive toxicity occurred at up to 2000 mg/kg bw/d in rats or rabbits. The substance shows no evidence of genotoxicity, has low acute toxicity and no irritation or sensitisation potential. An ADI value of 20 mg/kg bw was concluded from two alternative approaches. Daily exposure from use in dietary supplements is estimated as up to 10.0 mg/kg bw in adults and 13.3 mg/kg bw in children. There would therefore appear to be no safety concerns under the intended conditions of use. The information provided is intended to support an evaluation that the substance may be "generally recognized as safe" (GRAS). Copyright © 2013 Elsevier Inc. All rights reserved.

Aqueous extract of Senecio candicans DC induce liver and kidney damage in a sub-chronic oral toxicity study in Wistar rats.

PubMed

Lakshmanan, Hariprasath; Raman, Jegadeesh; Pandian, Arjun; Kuppamuthu, Kumaresan; Nanjian, Raaman; Sabaratam, Vikineswary; Naidu, Murali

2016-08-01

Senecio candicans DC. (Asteraceae) is used as a remedy for gastric ulcer and stomach pain in the Nilgiris, district, Tamil Nadu. The present investigation was carried out to evaluate the sub-chronic toxicity of an aqueous extract of Senecio candicans (AESC) plant in Wistar albino rats. The study was conducted in consideration of the OECD 408 study design (Repeated Dose 90-Day Oral Toxicity Study in Rodents) and the extract was administered via gavage at doses of 250, 500 or 750 mg/kg body weight per day for 90-days. Hematological, biochemical parameters were determined on days 0, 30, 60 and 90 of administration. Animals were euthanized after 90 d treatment and its liver and kidney sections were taken for histological study. The results of sub-chronic study showed significant increase (P < 0.05) in serum uric acid, creatinine, aspartate transaminase (AST) and alanine transaminase (ALP) levels. Histological examination of liver showed mild mononuclear infiltration in the portal trait, enlarged nucleus around the central vein and mild loss of hepatocyte architecture in rats treated with 750 mg/kg of AESC. Histological examination of kidney showed focal interstitial fibrosis, crowding of glomeruli and mild hydropic change with hypercellular glomeruli in rats treated with 750 mg/kg of AESC. However, no remarkable histoarchitectural change in hepatocytes and glomeruli were observed in rats treated with lower concentrations (250 and 500 mg/kg b.w.) of AESC compared to control group animals. The no-observed adverse effect level (NOAEL) of AESC in the present study was 500 mg/kg b.w. Signs of toxic effects are evident from the current study. Although AESC contains low concentrations of PA, findings from this study suggest that regular consumers of herbal remedies derived from this plant may develop kidney and liver toxicity. Further studies on the isolation and characterization of PAs are necessary to determine the safe dose level of the extract for therapeutic use in traditional medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

Dose and time-dependent sub-chronic toxicity study of hydroethanolic leaf extract of Flabellaria paniculata Cav. (Malpighiaceae) in rodents

PubMed Central

Akindele, Abidemi J.; Adeneye, Adejuwon A.; Salau, Oluwole S.; Sofidiya, Margaret O.; Benebo, Adokiye S.

2014-01-01

Flabellaria paniculata Cav. (Malpighiaceae) is a climbing shrub, the preparations of which are used in the treatment of wounds and ulcers in Nigeria and Ghana. This study investigated the sub-chronic toxicity profile of the hydroethanolic leaf extract of F. paniculata (HLE-FP). HLE-FP was administered p.o. (20, 100, and 500 mg/kg) for 30 and 60 days to different groups of rats. Control animals received 10 ml/kg distilled water. In the group of animals for reversibility study, HLE-FP administration ceased on the 60th day and animals were monitored for a further 15 days. Results showed that oral treatment with HLE-FP for 30 days caused significant (p < 0.05) reductions in weight gain pattern compared to control. These changes were sustained with 60 days treatment. However, no significant (p > 0.05) differences in relative organ weights between control and treatment groups were observed. HLE-FP-treated rats showed significant (p < 0.05) increases in Hb, PCV and RBC on day 30 and significant (p < 0.05) increases in MCV and MCH indices on day 60 compared to control. There were significant (p < 0.05) elevations in serum K+, urea and creatinine compared to control. The liver function tests showed slight but non-significant alterations in relevant parameters when compared to control. Biochemical findings were supported by histopathological observations of vital organs including the kidney and liver. Toxicities observed in respect of kidney function were irreversible at 15 days of stoppage of treatment. In the acute toxicity study, HLE-FP given p.o. caused no lethality at 5000 mg/kg but behavioral manifestations like restlessness, generalized body tremor, feed, and water refusal were observed. The i.p. LD50 was estimated to be 2951.2 mg/kg. Findings in this study showed that HLE-FP is relatively non-toxic on acute exposure and generally safe on sub-chronic administration, but could be deleterious on the kidneys on prolonged oral exposure at a high dose. Thus, caution should be exercised with its long-term usage. PMID:24795634

Ninety-Day Oral Toxicity Assessment of an Alternative Biopolymer for Controlled Release Drug Delivery Systems Obtained from Cassava Starch Acetate.

PubMed

Jesus, Douglas Rossi; Barbosa, Lorena Neris; Prando, Thiago Bruno Lima; Martins, Leonardo Franco; Gasparotto, Francielli; Guedes, Karla Moraes Rocha; Dragunski, Douglas Cardoso; Lourenço, Emerson Luiz Botelho; Dalsenter, Paulo Roberto; Gasparotto Junior, Arquimedes

2015-01-01

The large consumption of biodegradable films from cassava starch acetate (FCSA) as ingredients in food and pharmaceutical products requires the assessment of the possible toxicity of these products. The aim of this study was to investigate the toxicity of biodegradable film from cassava starch acetate after oral exposure of Wistar rats for 90 days. The amount of food consumed and the body weight were weekly monitored. Blood and urine samples were obtained for the assessment of serum parameters and renal function. Histopathological analyses in target organs were also performed. No evidence of clinical toxicity in hematological, biochemical, or renal parameters in the FCSA-treated animals was found. In addition, relative organ weight and histopathological evaluations did not differ between groups treated with FCSA and control. Data obtained suggest that the subchronic exposure to FCSA does not cause obvious signs of toxicity in Wistar rats, indicating possible safety of this biofilm.

One Hundred Eighty Day Subchronic Oral Toxicity Study of Pyridostigmine Bromide in Rats. Volume 1

DTIC Science & Technology

1990-06-01

has proposed a treatment regimen incorporating prophylaxis with a reversible cholinesterase inhibitor and, following nerve agent exposure, antidotal...would accomplish two goals: the oxime would abate the inhibition induced by the reversible cholinesterase inhibitor prophylaxis, and the atropine will...cholinesterase inhibitor as the pretreatment component of a therapeutic regimen that would include antidotal therapy with 2-PAM chloride and atropine. A

Subchronic and Genetic Safety Assessment of a New Medicinal Dendrobium Species: Dendrobium Taiseed Tosnobile in Rats

PubMed Central

Yang, Li-Chan; Liao, Jiunn-Wang; Wen, Chi-Luan

2018-01-01

Dendrobium Taiseed Tosnobile is a new species of herba dendrobii (Shi-Hu) that was developed by crossbreeding D. tosaense and D. nobile. Its pharmacological activity and active component have been reported, but its subchronic toxicity and genetic safety have not yet been investigated. This study assessed the 90-day oral toxicity and genetic safety of the aqueous extracts of D. Taiseed Tosnobile (DTTE) in male and female Sprague-Dawley (SD) rats. Eighty rats were divided into four groups, each consisting of ten male and ten female rats. DTTE was given orally to rats at 800, 1600, or 2400 mg/kg for 90 consecutive days, and distilled water was used for the control group. Genotoxicity studies were performed using a bacterial reverse mutation assay and in vivo mammalian cell micronucleus test in ICR mice and analyzed using flow cytometry. Throughout the study period, no abnormal changes were observed in clinical signs and body weight or on ophthalmological examinations. Additionally, no significant differences were found in urinalysis, hematology, and serum biochemistry parameters between the treatment and control groups. Necropsy and histopathological examination indicated no treatment-related changes. Based on results, the no-observed-adverse-effect level of DTTE is greater than 2400 mg/kg in SD rats. PMID:29541145

Evaluation of the systemic toxicity and mutagenicity of OLIGOPIN®, procyanidolic oligomers (OPC) extracted from French Maritime Pine Bark extract.

PubMed

Segal, L; Penman, M G; Piriou, Y

2018-01-01

The potential systemic toxicity of Oligopin®, a French Maritime Pine Bark extract (FMPBE) rich in procyanidolic oligomers, was evaluated in an acute oral limit test and a 90-day repeated dose oral toxicity study with Sprague Dawley rats. The potential mutagenicity was assessed in a bacterial reverse mutation assay and in vitro mammalian chromosome aberration assay with human lymphocytes. The results indicate that Oligopin® was nongenotoxic in both bacterial and human cell assays, was not acutely toxic via oral administration at up to 2000 mg/kg and was well tolerated following 90 days of oral administration to SD rats, with a no observed adverse effect level of 1000 mg/kg/day. The lack of significant adverse systemic effects in the 90 day study is concordant with findings from several human clinical trials. The acute toxicity and mutagenicity data are consistent with data reported by AFSSA in a summary of FMPBE safety, in which a NOAEL of 100 mg/kg/day was established. In contrast, the NOAEL derived from the 90-day study with Oligopin® was 1000 mg/kg/day, suggesting that it is less systemically toxic than other FMPBE previously evaluated in subchronic studies, and comparable to proanthocyanidins extracted from grape seeds, which are widely used as nutritional supplement ingredients.

The Subchronic Oral Toxicity of 2,4-Dinitroanisole (DNAN) in Rats

DTIC Science & Technology

2012-06-01

Harlan, Teklad; ALPHA-dri® is a registered trademark with Shepard Specialty Papers.) A total of four male and four female rats not placed on study...registered trademark with Shepard Specialty Papers.) Ten males and ten females were distributed into four treatment groups and a vehicle control group...If significant differences were observed, then a Mann~Whitney test was conducted to compare pairs of treatment groups. SPSS® 16.0 ( Chicago

The toxicology and safety of apple polyphenol extract.

PubMed

Shoji, T; Akazome, Y; Kanda, T; Ikeda, M

2004-06-01

Apple polyphenol extract has strong antioxidant activity and various physiological functions, and is used in Japan as a food additive and nutritional supplements. Here, we tested the consumption safety of Applephenon, which is a polyphenol extract produced from unripe apples. The Ames test without S9 mixture revealed that Applephenon, had slight mutagenicity at a high concentration of 2500 microg/plate; however, both chromosomal aberration test and the micronucleus test found no significant mutagenicity. Furthermore, an acute oral-toxicity test, and a 90-day subchronic-toxicity test showed no significant hematological, clinical, chemical, histopathological, or urinary effects at a dose of 2000 mg/kg. These results confirm that Applephenon is safe and no toxic at average dietary level.

Absence of subchronic oral toxicity and genotoxicity of rice koji with Aspergillus terreus.

PubMed

Yun, Jun-Won; Kim, Seung-Hyun; Kim, Yun-Soon; You, Ji-Ran; Cho, Eun-Young; Yoon, Jung-Hee; Kwon, Euna; Lee, Sang Ju; Kim, Seong Pil; Seo, Jae Hoon; In, Jae Pyung; Ahn, Jae Hun; Jang, Ja-June; Park, Jin-Sung; Che, Jeong-Hwan; Kang, Byeong-Cheol

2017-10-01

Koji products have been considered as an effective fermented food consumed in East Asia with many health benefits. Particularly, rice koji with Aspergillus terreus (RAT) has been reported to be able to prevent hyperlipidemia and hepatic steatosis through regulating cholesterol synthesis. Despite its biological activities, there is a lack of comprehensive information to give an assurance of its safety. Therefore, the objective of this study was to perform a series of toxicological studies (repeated dose oral toxicity and genotoxicity) according to test guidelines published by the Organization for Economic Cooperation and Development. Along with acute toxicity study using rats and beagle dogs, a 13-week toxicity study revealed no clear RAT-related toxic changes, including body weight, mortality, hematology, serum biochemistry, organ weight, and histopathology after oral administration at doses of 500, 1000, and 2000 mg/kg BW. The no-observed-adverse-effect level of RAT was considered to be more than 2000 mg/kg BW/day in rats of both genders. In addition, potential genotoxicity was evaluated using a standard battery of tests (Ames test, chromosome aberration assay, and micronucleus assay) which revealed that RAT showed no genotoxicity. Accordingly, these results suggest that RAT is a safe and non-toxic functional food for human consumption at proper dose. Copyright © 2017. Published by Elsevier Inc.

Intestinal lymphangiectasis and lipidosis in rats following subchronic exposure to indole-3-carbinol via oral gavage.

PubMed

Boyle, Michael C; Crabbs, Torrie A; Wyde, Michael E; Painter, J Todd; Hill, Georgette D; Malarkey, David E; Lieuallen, Warren G; Nyska, Abraham

2012-06-01

To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged ≤300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with ≥150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged ≤250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present.

Evaluation of cytotoxic effects and acute and chronic toxicity of aqueous extract of the seeds of Calycotome villosa (Poiret) Link (subsp. intermedia) in rodents.

PubMed

Lyoussi, Badiaa; Cherkaoui Tangi, Khadija; Morel, Nicole; Haddad, Mohamed; Quetin-Leclercq, Joelle

2018-01-01

The present investigation was carried out to evaluate the safety of an aqueous extract of the seeds of Calycotome villosa (Poiret) Link (subsp. intermedia) by determining its cytotoxicity and potential toxicity after acute and sub-chronic administration in rodents. Cytotoxic activity was tested in cancer and non-cancer cell lines HeLa, Mel-5, HL-60 and 3T3. Acute toxicity tests were carried out in mice by a single oral administration of Calycotome seed-extract (0 - 12 g/kg) as well as intraperitoneal doses of 0 - 5 g/kg. Sub-chronic studies were conducted in Wistar rats by administration of oral daily doses for up to 90 days. Changes in body and vital organ weights, mortality, haematology, clinical biochemistry and histologic morphology were evaluated. The lyophilized aqueous extract of C. villosa exhibited a low cytotoxicity in all cell lines tested with an IC 50 > 100 µg/ml. In the acute study in mice, intra-peritoneal administration caused dose-dependent adverse effects and mortality with an LD 50 of 4.06 ± 0.01 g/kg. In the chronic tests, neither mortality nor visible signs of lethality was seen in rats. Even AST and ALT were not affected while a significant decrease in serum glucose levels, at 300 and 600 mg/kg was detected. Histopathological examination of the kidney and liver did not show any alteration or inflammation at the end of treatment. In conclusion, the aqueous extract of C. villosa seed appeared to be non-toxic and did not produce mortality or clinically significant changes in the haematological and biochemical parameters in rats.

Oral subchronic toxicity evaluation of a novel antitumor agent 25-methoxydammarane-3, 12, 20-triol from Panax notoginseng in Sprague-Dawley rats.

PubMed

Li, Wei; Zhang, Xiangrong; Xin, Yanfei; Xuan, Yaoxian; Liu, Jinping; Li, Pingya; Zhao, Yuqing

2016-06-01

Panax notoginseng and its main active ingredients ginsenosides have long been used as medicines and food additives in China. Comparing with the extensive uses and active researches of P. notoginseng and its products, the side effect and probable toxicity were rare. 25-Methoxydammarane-3,12,20-triol (25-OCH3-PPD), a novel dammarane-type triterpene sapogenin that was first isolated from the extract of P. notoginseng, was proven to have strong antitumor activities against prostate cancer, breast cancer and lung cancer. The aim of the present study was to investigate the potential subchronic toxicity of 25-OCH3-PPD after it was repeatedly orally administered to Sprague-Dawley rats (5/sex/group/each time-point) at dose levels of 0, 150, 300 or 600 mg/kg/day for 13 weeks and 4-week recovery. No mortality and treatment-related toxicity effects were observed as a result of the administration of 25-OCH3-PPD at any dose level (150, 300 and 600 mg/kg) for 92 consecutive days. Although there were some statistical changes, such as increased weights in female rats and decreased organ weights and coefficients of the liver, spleen, kidney, and adrenal gland compared with the control group at the corresponding time, the autopsy and histopathological examination of the target organs did not show any abnormal responses. As a result, 25-OCH3-PPD was well tolerated by SD rat at doses of up to 600 mg/kg and that it is a potential candidate for therapeutic use. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute and sub-chronic toxicity studies of honokiol microemulsion.

PubMed

Zhang, Qianqian; Li, Jianguo; Zhang, Wei; An, Quan; Wen, Jianhua; Wang, Aiping; Jin, Hongtao; Chen, Shizhong

2015-04-01

The purpose of this study was to investigate the acute and sub-chronic toxicity of honokiol microemulsion. In the acute toxicity tests, the mice were intravenously injected graded doses of honokiol microemulsion and were observed for toxic symptoms and mortality daily for 14 days. In the sub-chronic toxicity study, rats were injected honokiol microemulsion at doses of 100, 500, 2500 μg/kg body weight (BW) for 30 days. After 30 days treatment and 14 days recovery, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity tests, the estimated median lethal dosage (LD50) was 50.5mg/kg body weight in mice. In the sub-chronic toxicity tests, the non-toxic reaction dose was 500 μg/kg body weight. In each treatment group, degeneration or/and necrosis in vascular endothelial cells and structure change of vessel wall can be observed in the injection site (cauda vein) of a few animals while there were no changes in the vessels of other organs. The overall findings of this study indicate that the honokiol microemulsion is non-toxic up to 500 μg/kg body weight, and it has irritation to the vascular of the injection site which should be paid attention to in clinical medication. Copyright © 2015. Published by Elsevier Inc.

Acute and subchronic toxicities of QX100626, a 5-HT4 receptor agonist, in rodents and Beagle dogs.

PubMed

Zhang, Xiaofang; Yuan, Bojun; Mao, Yu; Dai, Xiaoyu; Zhang, Xiaodong; Lu, Guocai

2014-10-01

Serotonin 5-hydroxytryptamine 4(5-HT4) receptor agonists have been widely prescribed as a prokinetics drug for patients with gastro-esophageal reflux disease and functional dyspepsia. QX100626, one of the 5-HT4 receptor agonists, has been studied as a promising agent for this clinical use. The objective of the present study was to identify possible target organs of toxicity and propose a non-toxic dose of QX100626 for clinical usage. After single lethal dose oral and intravenous testing in rodents, some signs indicative of adverse CNS effects were observed. The minimum toxic dose of QX100626 for a single oral administration for dogs was 90.0mg/kgb.w., and the severe toxic dose was more than 300mg/kgb.w. The No Observed Adverse Effect Level (NOAEL) of QX100626 by daily oral administration for rats and dogs was 20mg/kg and 10mg/kg, respectively, whereas the minimum toxic dosages were 67 and 30mg/kg, respectively. All of the adverse effects suggested that kidney, digestive tract, as well as nervous, hematological, and respiratory systems might be the target organs of toxicity for humans induced by QX100626. The compound could be a safe alternative to other existing prokinetic agents for the treatment of functional bowel disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

In vivo anti-psoriatic activity, biodistribution, sub-acute and sub-chronic toxicity studies of orally administered methotrexate loaded chitin nanogel in comparison with methotrexate tablet.

PubMed

Panonnummal, Rajitha; Jayakumar, R; Anjaneyan, Gopikrishnan; Sabitha, M

2018-04-15

The anti-psoriatic efficacy of orally administered methotrexate loaded chitin nanogel (MCNG) was evaluated (two doses- 2.715 mg/kg and 5.143 mg/kg) and compared against orally administered methotrexate tablet MTX (5.143 mg/kg). MCNG at both dose levels of 2.715 mg/kg and 5.143 mg/kg exhibited significant anti-psoriatic activity which is very much comparable with MTX, caused normalization of histological features and inflammatory score associated with induced psoriasis. Biodistribution studies revealed the presence of drug in serum and in vital organs at all the three cases with highest amount in MCNG at 5.143 mg/kg dose, followed by MTX tablet and are lowest in MCNG at 2.715 mg/kg dose. MCNG at the highest dose of 5.143 mg/kg caused liver, lung and kidney toxicities on sub acute toxicity studies and MTX tablet was found to be toxic on liver and lung on sub chronic toxicity studies. MCNG 2.715 mg/kg was found to be safe on both sub acute and sub chronic administrations, suggesting that it can provide sufficient serum and tissue level of methotrexate necessary to clear psoriatic lesions, without inducing systemic toxicity and expected to be a better alternative for orally administered conventional methotrexate tablet for patients who need systemic medications for psoriasis. Copyright © 2018. Published by Elsevier B.V.

Fourteen-Day Subchronic Oral Toxicity Study of 4-Nitrophenyl Methyl (Phenyl) Phosphinate in Male and Female Rats.

DTIC Science & Technology

1982-09-01

gavage for 14 days. Neb±rops les and histological examinations were performed on all animals. Urinalysis, standard hematological measurements and an...activity. The only compound related effects found in the histological examinations were gross changes in the digestive system in one or more male rats at...rats (1/2, 1/4, 1/8, and 1/16 of the LD^) were used. Rats were dosed daily by gastric gavage for 14 dayg. Necropsies and histological examinations gire

A 90-day subchronic toxicity study of neem oil, a Azadirachta indica oil, in mice.

PubMed

Wang, C; Cao, M; Shi, D-X; Yin, Z-Q; Jia, R-Y; Wang, K-Y; Geng, Y; Wang, Y; Yao, X-P; Yang, Z-R; Zhao, J

2013-09-01

To determine the no-observed-adverse-effect level (NOAEL) of exposure and target organs of neem oil for establishing safety criteria for human exposure, the subchronic toxicity study with neem oil in mice was evaluated. The mice (10 per sex for each dose) was orally administered with neem oil with the doses of 0 (to serve as a control), 177, 533 and 1600 mg/kg/day for 90 days. After the treatment period, observation of reversibility or persistence of any toxic effects, mice were continuously fed without treatment for the following 30 days. During the two test periods, the serum biochemistry, organ weight and histopathology were examined. The results showed that the serum biochemistry and organ coefficient in experimental groups had no statistical difference compared with those of the control group. At the 90th day, the histopathological examinations showed that the 1600 mg/kg/day dose of neem oil had varying degrees of damage on each organ except heart, uterus and ovarian. After 30-day recovery, the degree of lesions to the tissues was lessened or even restored. The NOAEL of neem oil was 177 mg/kg/day for mice and the target organs of neem oil were determined to be testicle, liver and kidneys.

Pharmacological assay of Cordia verbenacea V: oral and topical anti-inflammatory activity, analgesic effect and fetus toxicity of a crude leaf extract.

PubMed

Sertié, J A A; Woisky, R G; Wiezel, G; Rodrigues, M

2005-05-01

Cordia verbenacea D.C. (Borraginaceae) is a perennial bush plant that grows widely along the southeastern coast of Brazil. Its leaves have been used in folk medicine for their anti-ulcer, anti-inflammatory and cicatrizing activities. We have already described the anti-inflammatory properties of C. verbenacea and its low toxicity in different acute animal models. In the present study, we investigated the anti-inflammatory activity in sub-chronic animal models of a crude leaf lyophilized extract when administered by oral route or topically applied, and concomitantly, its analgesic potency and toxicity to the fetus. Topical administration of the extract inhibited nystatin-induced edema proportionally to the doses used, and this effect at a dose of 4.56 mg/kg body wt. was similar to that observed with 6.0 mg/kg body wt. of naproxen. In miconazole-induced edema, the leaf extract at a dose of 1.24 mg/kg body wt., orally administered, has a very similar effect as compared to nimezulide (2.5 mg/kg body wt.) and dexamethasone (0.2 mg/kg body wt.). At an oral dose of 2.48 mg/kg body wt. the extract showed a very low analgesic effect, and total absence of fetus toxicity at doses of less than 7.44 mg/kg body wt.

Final safety assessment of thiodipropionic acid and its dialkyl esters as used in cosmetics.

PubMed

Diamante, Catherine; Fiume, Monice Zondlo; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Alan Andersen, F

2010-07-01

Dilauryl thiodipropionate (DLTDP), dicetyl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, and ditridecyl thiodipropionate are dialkyl esters of their respective alcohols and thiodipropionic acid (TDPA) used in cosmetics. Ingested DLTDP was excreted in the urine as TDPA. Single-dose acute oral and parenteral studies and subchronic and chronic repeated dose oral studies did not suggest significant toxicity. Neither DLTDP nor TDPA was irritating to animal skin or eyes and they were not sensitizers. TDPA was neither a teratogen nor a reproductive toxicant. Genotoxicity studies were negative for TDPA and DLTDP. Clinical testing demonstrated some evidence of irritation but no sensitization or photosensitization. The Cosmetic Ingredient Review Expert Panel considered that the data from DLTDP reasonably may be extrapolated to the other dialkyl esters and concluded that these ingredients were safe for use in cosmetic products that are formulated to be nonirritating.

The para isomer of dinitrobenzene disrupts redox homeostasis in liver and kidney of male wistar rats.

PubMed

Sangodele, Janet Olayemi; Olaleye, Mary Tolulope; Monsees, Thomas K; Akinmoladun, Afolabi Clement

2017-07-01

Para - Dinitrobenzene (p -DNB) is one of the isomers of dinitrobenzene which have been detected as environmental toxicants. Skin irritation and organ toxicities are likely for industrial workers exposed to p -DNB. This study evaluated the effect of sub-chronic exposure of rats to p -DNB on cellular redox balance, hepatic and renal integrity. Forty eight male Wistar rats weighing 160-180 g were administered 50, 75, 1000 and 2000 mg/kg b.wt (body weight) of p -DNB or an equivalent volume of vehicle (control) orally and topically for 14 days. After the period of treatment, the activities of kidney and liver catalase (CAT), alkaline phosphatase (ALP) and superoxide dismutase (SOD) as well as extent of renal and hepatic lipid peroxidation (LPO) were determined. Serum ALP activity and plasma urea concentration were also evaluated. Compared with control animals, p -DNB -administered rats showed decrease in the body and relative kidney and liver weights as well as increased renal and hepatic hydrogen peroxide and lipid peroxidation levels accompanied by decreased superoxide dismutase and catalase activities. However, p -DNB caused a significant increase in plasma urea concentration and serum, liver and kidney ALP activities relative to control. In addition, p -DNB caused periportal infiltration, severe macro vesicular steatosis and hepatic necrosis in the liver. Our findings show that sub-chronic oral and sub-dermal administration of p -DNB may produce hepato-nephrotoxicity through oxidative stress.

Toxicological assessment of nattokinase derived from Bacillus subtilis var. natto.

PubMed

Lampe, Bradley J; English, J Caroline

2016-02-01

Subtilisin NAT, commonly known as "nattokinase," is a fibrinolytic enzyme produced by the bacterial strain B. subtilis var. natto, which plays a central role in the fermentation of soybeans into the popular Japanese food natto. Recent studies have reported on the potential anticoagulatory and antihypertensive effects of nattokinase administration in humans, with no indication of adverse effects. To evaluate the safety of nattokinase in a more comprehensive manner, several GLP-compliant studies in rodents and human volunteers have been conducted with the enzyme product, NSK-SD (Japan Bio Science Laboratory Co., Ltd., Japan). Nattokinase was non-mutagenic and non-clastogenic in vitro, and no adverse effects were observed in 28-day and 90-day subchronic toxicity studies conducted in Sprague-Dawley rats at doses up to 167 mg/kg-day and 1000 mg/kg-day, respectively. Mice inoculated with 7.55 × 10(8) CFU of the enzyme-producing bacterial strain showed no signs of toxicity or residual tissue concentrations of viable bacteria. Additionally consumption of 10 mg/kg-day nattokinase for 4 weeks was well tolerated in healthy human volunteers. These findings suggest that the oral consumption of nattokinase is of low toxicological concern. The 90-day oral subchronic NOAEL for nattokinase in male and female Sprague-Dawley rats is 1000 mg/kg-day, the highest dose tested. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

In vitro and in vivo Safety Evaluation of NephureTM

PubMed Central

Cowley, Helena; Yan, Qin; Koetzner, Lee; Dolan, Laurie; Nordwald, Erik; Cowley, Aaron B.

2017-01-01

NephureTM is a proprietary oxalate decarboxylase (OxDC) enzyme being developed as a food ingredient. In this study, the safety of NephureTM was evaluated in a bacterial mutagenicity assay and in a sub-chronic (13-week) oral toxicity study in rats. NephureTM did not show any mutagenic properties in the mutagenicity assay. In the 13-week sub-chronic oral toxicity study in which 10 Sprague Dawley rats per sex were administered 0, 118, 235 and 475 mg/kg bw/day (8260, 16450 and 33,250 Units/kg bw/day, respectively) of NephureTM by gavage, male and female rats did not show any test article-related clinical observations or effects on body weight, body weight gain, food consumption, food efficiency, ophthalmology, functional observational battery parameters or motor activity. Furthermore, there were no changes in coagulation, clinical chemistry, urinalysis or hematology parameters, macroscopic/microscopic findings or organ weights that could be attributed to the test article. Based on these results, NephureTM was not mutagenic and the no-adverse-effect level (NOAEL) in the 13-week study was determined to be 475 mg/kg bw/day (33,250 Units/kg bw/day). Evaluation of the estimated consumption of NephureTM, generation of the metabolite formate, and the current safety studies resulted in a conclusion of a tolerable upper limit of 3450 Units of OxDC activity/day (57.5 Units activity/kg bw/day), when NephureTM is added to food to decrease dietary oxalate. PMID:28322893

Acute and Cumulative Effects of Unmodified 50-nm Nano-ZnO on Mice.

PubMed

Kong, Tao; Zhang, Shu-Hui; Zhang, Ji-Liang; Hao, Xue-Qin; Yang, Fan; Zhang, Cai; Yang, Zi-Jun; Zhang, Meng-Yu; Wang, Jie

2018-01-02

Nanometer zinc oxide (nano-ZnO) is widely used in diverse industrial and agricultural fields. Due to the extensive contact humans have with these particles, it is crucial to understand the potential effects that nano-ZnO have on human health. Currently, information related to the toxicity and mechanisms of nano-ZnO is limited. The aim of the present study was to investigate acute and cumulative toxic effects of 50-nm unmodified ZnO in mice. This investigation will seek to establish median lethal dose (LD50), a cumulative coefficient, and target organs. The acute and cumulative toxicity was investigated by Karber's method and via a dose-increasing method, respectively. During the experiment, clinical signs, mortality, body weights, hematology, serum biochemistry, gross pathology, organ weight, and histopathology were examined. The LD50 was 5177-mg/kg·bw; the 95% confidence limits for the LD50 were 5116-5238-mg/kg·bw. It could be concluded that the liver, kidney, lung, and gastrointestinal tract were target organs for the 50-nm nano-ZnO acute oral treatment. The cumulative coefficient (K) was 1.9 which indicated that the cumulative toxicity was apparent. The results also indicated that the liver, kidney, lung, and pancrea were target organs for 50-nm nano-ZnO cumulative oral exposure and might be target organs for subchronic and chronic toxicity of oral administered 50-nm ZnO.

A 90-day subchronic study of rats fed lean pork from genetically modified pigs with muscle-specific expression of recombinant follistatin.

PubMed

Zou, Shiying; Tang, Min; He, Xiaoyun; Cao, Yuan; Zhao, Jie; Xu, Wentao; Liang, Zhihong; Huang, Kunlun

2015-11-01

Because cardiovascular disease incidence has rapidly increased in recent years, people are choosing relatively healthier diets with low animal fat. A transgenic pig with low fat and a high percentage of lean meat was created in 2011; this pig overexpresses the follistatin (FST) gene. To evaluate the safety of lean pork derived from genetically modified (GM) pigs, a subchronic oral toxicity study was conducted using Sprague-Dawley rats. GM pork and non-GM pork were incorporated into the diet at levels of 3.75%, 7.5%, and 15% (w/w), and the main nutrients of the various diets were subsequently balanced. The safety of GM pork was assessed by comparison of the toxicology response variables in Sprague-Dawley rats consuming diets containing GM pork with those consuming non-GM pork. No treatment-related adverse or toxic effects were observed based on an examination of the daily clinical signs, body weight, food consumption, hematology, serum biochemistry, and organ weight or based on gross and histopathological examination. The results demonstrate that GM pork is as safe for consumption as conventional pork. Copyright © 2015 Elsevier Inc. All rights reserved.

Hepatotoxicity and subchronic toxicity tests of Morinda citrifolia (noni) fruit.

PubMed

West, Brett J; Su, Chen X; Jensen, C Jarakae

2009-10-01

Morinda citrifolia (noni) fruit juice has been approved as a safe food in many nations. A few cases of hepatitis in people who had been drinking noni juice have been reported, even though no causal link could be established between the liver injury and ingestion of the juice. To more fully evaluate the hepatotoxic potential of noni fruit juice, in vitro hepatotoxicity tests were conducted in human liver cells, HepG2 cell line. A subchronic oral toxicity test of noni fruit was also performed in Sprague-Dawley (SD) rats to provide benchmark data for understanding the safety of noni juice, without the potential confounding variables associated with many commercial noni juice products. Freeze-dried filtered noni fruit puree did not decrease HepG2 cell viability or induce neutral lipid accumulation and phospholipidosis. There were no histopathological changes or evidence of dose-responses in hematological and clinical chemistry measurements, including liver function tests. The no-observed-adverse-effect level (NOAEL) for freeze-dried noni fruit puree is greater than 6.86 g/kg body weight, equivalent to approximately 90 ml of noni fruit juice/kg. These findings corroborate previous conclusions that consumption of noni fruit juice is unlikely to induce adverse liver effects.

Comparative Analysis of the Relationship between Trichloroethylene Metabolism and Tissue-Specific Toxicity among Inbred Mouse Strains: Kidney Effects

PubMed Central

Yoo, Hong Sik; Bradford, Blair U.; Kosyk, Oksana; Uehara, Takeki; Shymonyak, Svitlana; Collins, Leonard B.; Bodnar, Wanda M.; Ball, Louise M.; Gold, Avram; Rusyn, Ivan

2014-01-01

Trichloroethylene (TCE) is a well-known environmental and occupational toxicant that is classified as carcinogenic to humans based on the epidemiological evidence of an association with higher risk of renal cell carcinoma. A number of scientific issues critical for assessing human health risks from TCE remain unresolved, such as the amount of kidney-toxic glutathione conjugation metabolites formed, inter-species and -individual differences, and the mode of action for kidney carcinogenicity. We hypothesized that TCE metabolite levels in the kidney are associated with kidney-specific toxicity. Oral dosing with TCE was conducted in sub-acute (600 mg/kg/d; 5 days; 7 inbred mouse strains) and sub-chronic (100 or 400 mg/kg/d; 1, 2, or 4 weeks; 2 inbred mouse strains) designs. We evaluated the quantitative relationship between strain-, dose-, and time-dependent formation of TCE metabolites from cytochrome P450-mediated oxidation [trichloroacetic acid (TCA), dichloroacetic acid (DCA), and trichloroethanol] and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione], and various kidney toxicity phenotypes. In sub-acute study, we observed inter-strain differences in TCE metabolite levels in the kidney. In addition, we found that in several strains kidney-specific effects of TCE included induction of peroxisome proliferator-marker genes Cyp4a10 and Acox1, increased cell proliferation, and expression of KIM-1, a marker of tubular damage and regeneration. In sub-chronic study, peroxisome proliferator-marker gene induction and kidney toxicity diminished while cell proliferative response was elevated in a dose-dependent manner in NZW/LacJ, but not C57BL/6J mice. Overall, we show that TCE metabolite levels in the kidney are associated with kidney-specific toxicity and that these effects are strain-dependent. PMID:25424545

Oral toxicity of Miglyol 812(®) in the Göttingen(®) minipig.

PubMed

Le Bars, G; Dion, S; Gauthier, B; Mhedhbi, S; Pohlmeyer-Esch, G; Comby, P; Vivan, N; Ruty, B

2015-12-01

Miglyol 812(®), a mixture of medium-chain triglycerides, has been identified as an oral vehicle that could improve the solubility and possibly the bioavailability of orally administered drugs during the non-clinical safety assessment. The toxicity of Miglyol was assessed in Göttingen(®) minipigs upon daily oral administration (gavage) for six weeks, at dosing-volumes of 0.5 and 2 mL/kg/day, compared to controls receiving 0.5% CarboxyMethylCellulose/0.1% Tween(®) 80 in water at 2 mL/kg/day. The control vehicle did not induce any findings. Miglyol at 0.5 and 2 mL/kg/day induced transient tremors, abnormal color of feces and increase in triglycerides. Miglyol at 2 ml/kg/day also induced reduced motor activity, decreased food intake, respiratory signs (2/6 animals) and increased total and LDL-cholesterol. At necropsy, the lung of 3/6 animals treated at 2 mL/kg/day presented abnormal color and/or irregular surface correlated with a chronic bronchiolo-alveolar inflammation. This finding is probably due to aspiration pneumonia in relation to the administration method and the high viscosity of Miglyol. Overall, the oral administration of pure Miglyol 812(®) for six weeks up to 2 mL/kg was less tolerated than that of the control vehicle. Miglyol as vehicle for sub-chronic oral toxicity studies in minipigs should be used with a limited dosing-volume. Copyright © 2015 Elsevier Inc. All rights reserved.

SUBCHRONIC TOXICITY OF 1,3,5-TRINITROBENZENE IN FISCHER 344 RATS

EPA Science Inventory

The subchronic toxicity of 1,3,5-trinitrobenzene (TNB) in male and female Fischer 344 rats was evaluated by feeding a powdered certified laboratory diet containing 0, 66.7, 400 and 800 mg TNB/kg diet for 90 days. The calculated average TNB intake was 4.29, 24.70, and 49.28 mg/kg...

Subchronic toxicity of Nile tilapia with different exposure routes to Microcystis aeruginosa: Histopathology, liver functions, and oxidative stress biomarkers.

PubMed

Abdel-Latif, H M R; Khashaba, A M Abou

2017-08-01

Toxic cyanobacterial blooms ( Microcystis aeruginosa contains microcystins [MCs]) have been reported to induce clinicopathological alterations as well as different oxidative stress in aquatic biota. Three-week subchronic exposure experiment was carried out on Nile tilapia, to determine their effects on fish behavior, tissues, liver functions, antioxidant enzymes, and lipid peroxidation. Fish were exposed to four main treatments; orally fed diet plus toxic cells of M. aeruginosa (containing 3500 µg/g MC-LR), immersion in 500 µg MC-LR/L, intraperitoneal injection of M. aeruginosa MC-LR with a dose of 0.1 ml of extracted toxin at a dose of 200 μg/kg bwt, and the fourth one served as a control group, then the fish were sacrificed at the end of 3 rd week of exposure. The results revealed no recorded mortality with obvious behavioral changes and an enlarged liver with the congested gall bladder. Histopathology demonstrated fragmentation, hyalinization, and necrosis of the subcutaneous musculature marked fatty degeneration, and vacuolation of hepatopancreatic cells with adhesion of the secondary gill lamellae associated with severe leukocytic infiltration. Furthermore, liver functions enzymes (aspartate aminotransferase and alanine aminotransferase, and the activities of glutathione peroxidase, glutathione reductase, lipid peroxidase, and catalase enzymes) were significantly increased in all treatments starting from the 2 nd week as compared to the control levels. In this context, the study addresses the possible toxicological impacts of toxic M. aeruginosa contain MC-LR to Nile tilapia, and the results investigated that MC-LR is toxic to Nile tilapia in different routes of exposure as well as different doses.

Comparative Human Health and Environmental Toxicology Review of Seven Candidate Obscurant Smokes for Replacement of M83 Grenade

DTIC Science & Technology

2017-03-01

day; acute oral and dermal LD50 > 2000 mg/kg; inhalation LD50 > 20 mg/L Mixed evidence for carcinogenicity and mutagenicity (B2, 2...subchronic oral LOAEL 5–200 mg/kg/day; acute oral 25 < LD50 < 2000 mg/kg; dermal 50 < LD50 < 2000 mg/kg; inhalation 0.5 < LD50 < 20 mg/L Positive...corroborative evidence for carcinogenicity and mutagenicity; subchronic LOAEL < 5 mg/kg/day; acute oral LD50 ≤ 25 mg/kg; dermal LD50 ≤ 50 mg/kg

Sub-chronic (13-week) oral toxicity study, preceded by an in utero exposure phase and genotoxicity studies with fish source phosphatidylserine in rats.

PubMed

Lifshitz, Y; Levi, L; Eyal, I; Cohen, T; Tessler, S

2015-12-01

The safety of fish phosphatidylserine (PS) conjugated to DHA (InCog™) was examined in a series of toxicology studies as first step to support future use in infants and general population using in vitro genotoxicity tests and in a sub-chronic toxicity study with an in-utero exposure phase. PS is a major lipid in the cell membrane, active in various membrane-mediated processes. PS-DHA, present in human milk, has been suggested to be important for early brain development. Rats were exposed to diets containing 1.5%, 3% or 4.5% InCog or two control diets. Parental (F0) animals were fed throughout mating, gestation and lactation. Subsequently, a subchronic, 13-week study was conducted on the F1 animals followed by 4 weeks of recovery. The genotoxicity tests showed no mutagenicity potential. No significant toxicological findings were found in the F0 rats or the F1 pups. In the 13-weeks study, an increase in the presence of renal minimal-mild multifocal corticomedullary mineralization was noted in nine females of the high-dose group. This change was not associated with any inflammatory or degenerative changes in the kidneys. The no-observed-adverse-effect level (NOAEL) in the present study was placed at 3% in the diet (mid-dose group), equivalent to an overall intake of at least 2.1 g InCog/kg bw/day in the F1 generation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Safety and toxicological evaluation of Meratrim®: an herbal formulation for weight management.

PubMed

Saiyed, Zainulabedin M; Sengupta, Krishanu; Krishnaraju, Alluri V; Trimurtulu, Golakoti; Lau, Francis C; Lugo, James P

2015-04-01

Meratrim is a unique dietary ingredient consisting of extracts from Sphaeranthus indicus flower heads and Garcinia mangostana fruit rind. Clinical studies have demonstrated that Meratrim is effective and well-tolerated in weight management. Herein we assessed the broad spectrum safety of Meratrim in a battery of in vitro and animal toxicological studies including a sub-chronic repeated-dose 13-week oral toxicity study to determine the no-observable-adverse-effect-level (NOAEL). The LD50 levels of Meratrim in Sprague-Dawley (SD) rats, as determined by the acute oral and dermal toxicity studies, were >5000 and >2000 mg/kg body weight, respectively. The primary skin and eye irritation tests classified Meratrim as non-irritating to the skin and mildly irritating to the eye. Genotoxicity studies showed that Meratrim is non-mutagenic. In the repeated-dose 13-week oral toxicity study, SD rats were orally gavaged with Meratrim at 0, 250, 500 or 1000 mg/kg/day. No morbidity, mortality, or significant adverse events were observed either during the course of the study or on the 13th week. The NOAEL of Meratrim was concluded to be 1000 mg/kg of body weight/day in male and female SD rats. These results, combined with the tolerability of Meratrim in the human clinical trials, demonstrate the broad spectrum safety of Meratrim. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Methods to assess reproductive effects of environmental chemicals: studies of cadmium and boron administered orally.

PubMed Central

Dixon, R L; Lee, I P; Sherins, R J

1976-01-01

Results of a U.S.S.R.--U.S. cooperative laboratory effort to improve and validate experimental techniques used to assess subtle reproductive effects in male laboratory animals are reported. The present studies attempted to evaluate the reproductive toxicity of cadmium as cadmium chloride and boron as borax (Na2B4O7) and to investigate the mechanism of toxicity in the rat following acute and subchronic oral exposure. In vitro cell separation techniques, in vivo serial mating tests, and plasma assays for hormones were utilized. Effects on the seminal vesicle and prostate were evaluated with chemical and enzyme assays. Clinical chemistry was monitored routinely. Acute oral doses, expressed as boron were 45, 150, and 450 mg/kg while doses for cadmium equivalent were 6.25, 12.5, and 25 mg/kg. Rats were also allowed free access to drinking water containing either boron (0.3, 1.0, and 6.0 mg/l.) or cadmium (0.001, and 0.l mg/l.) for 90 days. Randomly selected animals were studied following 30, 60, and 90 days of treatment. These initial studies, utilizing a variety of methods to assess the reproductive toxicity of environmental substances in male animals, suggest that cadmium and boron at the concentrations and dose regimens tested are without significant reproductive toxicity. PMID:1269508

Effects of sub-chronic oral cyanide on endothelial function in rabbit aortic rings.

PubMed

Ozolu, R I; Okolie, N P; Ebeigbe, A B; Karikari, N

2007-02-01

We have investigated how the endothelium affects vascular responses following sub-chronic low dose cyanide administration. Cyanide exists in low levels in cassava foods, which are widely consumed in tropical Africa. Adult rabbits were administered 0.38 mg/kg per day KCN po for 25 days, and responses of the isolated aortic rings to noradrenaline (NA), calcium chloride (Ca2+) and acetylcholine (ACh) were measured in vitro in the presence and absence of the endothelium. In order to establish that the dose was not toxic, animal weight, some haematological indices, plasma alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured. Results show that endothelium denudation significantly (P <0.05) attenuates NA-induced contraction in rings from cyanide-treated rabbits. There was a similar reduction in response in Ca2+-depleted NA-precontracted endothelium-denuded aortic rings from cyanide-treated rabbits. Endothelium-denuded rings from cyanide-treated rabbits showed significantly (P <0.05) enhanced relaxation to ACh. In rings from control animals, the responses to NA and Ca2+ were not significantly altered, whether in the presence or absence of the endothelium. There were no significant changes in the studied toxicological indices. We conclude that endothelial compromise is necessary for low-dose sub-chronic cyanide-induced to alter vascular reactivity to NA and ACh.

Subchronic toxicity of Nile tilapia with different exposure routes to Microcystis aeruginosa: Histopathology, liver functions, and oxidative stress biomarkers

PubMed Central

Abdel-Latif, H. M. R.; Khashaba, A. M. Abou

2017-01-01

Background: Toxic cyanobacterial blooms (Microcystis aeruginosa contains microcystins [MCs]) have been reported to induce clinicopathological alterations as well as different oxidative stress in aquatic biota. Aim: Three-week subchronic exposure experiment was carried out on Nile tilapia, to determine their effects on fish behavior, tissues, liver functions, antioxidant enzymes, and lipid peroxidation. Materials and Methods: Fish were exposed to four main treatments; orally fed diet plus toxic cells of M. aeruginosa (containing 3500 µg/g MC-LR), immersion in 500 µg MC-LR/L, intraperitoneal injection of M. aeruginosa MC-LR with a dose of 0.1 ml of extracted toxin at a dose of 200 μg/kg bwt, and the fourth one served as a control group, then the fish were sacrificed at the end of 3rd week of exposure. Results: The results revealed no recorded mortality with obvious behavioral changes and an enlarged liver with the congested gall bladder. Histopathology demonstrated fragmentation, hyalinization, and necrosis of the subcutaneous musculature marked fatty degeneration, and vacuolation of hepatopancreatic cells with adhesion of the secondary gill lamellae associated with severe leukocytic infiltration. Furthermore, liver functions enzymes (aspartate aminotransferase and alanine aminotransferase, and the activities of glutathione peroxidase, glutathione reductase, lipid peroxidase, and catalase enzymes) were significantly increased in all treatments starting from the 2nd week as compared to the control levels. Conclusion: In this context, the study addresses the possible toxicological impacts of toxic M. aeruginosa contain MC-LR to Nile tilapia, and the results investigated that MC-LR is toxic to Nile tilapia in different routes of exposure as well as different doses. PMID:28919690

Sub-chronic safety evaluation of aqueous extract of Alangium salvifolium (L.f.) Wangerin leaves in rats.

PubMed

Kapoor, Bhupinder; Kaur, Gagandeep; Gupta, Mukta; Gupta, Reena

2017-01-01

Conventionally, the juice and extract of Alangium salvifolium leaves have been used for the treatment of diabetes, wound healing, dog bite, and as a poultice in rheumatism. To carry out the sub-chronic toxicity and thereafter safety evaluation of A. salvifolium leaves. The aqueous extract of A. salvifolium leaves was administered orally at the doses of 200, 400, and 800 mg/kg/day for 90 days. All the animals were observed daily for general behavior, changes in body weight, food, and water consumption. At the end of the treatment period, biochemical and hematological parameters were analyzed; and the animals were sacrificed for histopathological examination of heart, lungs, liver, and kidney. The general behavior and water intake were normal in all the rats. The increase in body weight was observed in female rats of all the groups while body weight was decreased in high dose group animals of both sexes. Hematological parameters were not disturbed by the continuous use of extract. A significant decrease in glucose level was observed in intermediate- and high-dose group animals while urea and creatinine level were significantly high in animals of high-dose group. Although histopathological examination of most of the organs exhibited no structural changes, some tubal damage in kidneys was observed in high-dose group animals. The high dose of extract has shown mild signs of toxicity on kidney function test, but no toxic response was observed on hematological and liver biochemical parameters. The extract also exhibited hypoglycemic potential.

Exposure to leachate from municipal battery recycling site: implication as key inhibitor of steroidogenic enzymes and risk factor of prostate damage in rats.

PubMed

Akintunde, Jacob K; Oboh, G

2013-01-01

Few or no studies have measured the effect of short- and long-term exposure to industrial leachate. Mature male Wistar strain albino rats (175-220 g) underwent sub-chronic exposure to leachate from the Elewi Odo municipal battery recycling site (EOMABRL) via oral administration for a period of 60 days at different doses (20%, 40%, 60%, 80%, and 100%) per kilogram of body weight to evaluate the toxic effects of the leachate on male reproductive function using steroidogenic enzymes and biomarkers of prostate damage. Control groups were treated equally but were given distilled water instead of the leachate. After the treatment periods, results showed that the treatment induced systemic toxicity at the doses tested by causing a significant (p<0.05) loss in absolute body weight and decline in growth rate. There was a marked significant decrease (p<0.05) in testicular activities of Δ(5)-3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase. Conversely, the activity of prostatic acid phosphatase, a key marker enzyme for prostrate damage was significantly (p<0.05) elevated in the treated rats. Similarly, the administration of EOMABRL significantly (p<0.05) exacerbated the activity of total acid phosphatase with concomitant increase in the activity of prostatic alkaline phosphatase. These findings conclude that exposure to leachate from a battery recycling site induces sub-chronic testicular toxicity by inhibiting key steroidogenic enzymes and activating key markers linked with prostate damage/cancer in rats.

Acute and subchronic toxicity of inhaled toluene in male Long Evans rats: oxidative stress markers in brain

EPA Pesticide Factsheets

Research interested in oxidative stress markers following exposure to VOCsThis dataset is associated with the following publication:Kodavanti , P., J. Royland , D.A. Moore-Smith, J. Beas, J. Richards , T. Beasley , P. Evansky , and P.J. Bushnell. Acute and Subchronic Toxicity of Inhaled Toluene in Male Long-Evans Rats: Oxidative Stress Markers in Brain. NEUROTOXICOLOGY. Elsevier B.V., Amsterdam, NETHERLANDS, 51: 10-19, (2015).

Subchronic Oral Bromocriptine Methanesulfonate Enhances Open Field Novelty-Induced Behavior and Spatial Memory in Male Swiss Albino Mice.

PubMed

Onaolapo, Olakunle James; Onaolapo, Adejoke Yetunde

2013-01-01

This study set out to assess the neurobehavioral effects of subchronic, oral bromocriptine methanesulfonate using the open field and the Y-maze in healthy male mice. Sixty adult Swiss albino mice were assigned into three groups. Controls received normal saline, while test groups received bromocriptine methanesulfonate at 2.5 and 5 mg/kg/day, respectively, for a period of 21 days. Neurobehavioral tests were carried out on days 1 and 21 after administration. Open field assessment on day 1 after administration revealed significant increase in grooming at 2.5 and 5 mg/kg, while horizontal and vertical locomotion showed no significant changes. Day 1 also showed no significant changes in Y-maze alternation. On day 21, horizontal locomotion, rearing, and grooming were increased significantly at 2.5 and 5 mg/kg doses after administration; also, spatial memory was significantly enhanced at 2.5 mg/kg. In conclusion, the study demonstrates the ability of oral bromocriptine to affect neurobehavior in normal mice. It also suggests that there is a cumulative effect of oral bromocriptine on the behaviors studied with more changes being seen after subchronic administration rather than after a single oral dose.

Acute and Subchronic Toxicological Evaluations of Allium rotundum L.: A Dietary Plant from Iran.

PubMed

Hosseinzadeh, Leila; Farhangian, Sajad; Hajialyani, Marziyeh; Bahari, Arash; Farzaei, Mohammad Hosein

2018-04-25

Allium rotundum L. is a dietary plant with diverse nutritional and herbal applications. According to its widespread application in Iranians' diets, understanding the possible adverse effects and toxic activities could be of major importance. The aim of this study was to establish the acute and subchronic toxicity profile of the hydroalcoholic extract of Allium rotundum on male and female Wistar rats. The acute study indicated no adverse effect or toxic activity after administration of the extract, suggesting that the LD 50 value is up to 5,000 mg/kg body weight for the extract. The subchronic study at three doses (250, 500, and 750 mg/kg body weight/day) supported the results of acute study and revealed that no abnormal change or toxicity was induced by the extract in both male and female Wistar rats. All the biochemical and hematological parameters of the treated rats were in historical range after long-term administration of the extract. The histopathological examination also revealed no lesion or alteration in the tissue of vital organs (kidney, liver, heart, lung, and spleen). The NOAEL (no observed adverse effect level) value was high enough (greater than 750 mg/kg body weight/ day) to conclude the nontoxic nature of this extract. The safety of this extract was affirmed by the acute and subchronic toxic studies and suggested that this plant could be a proper and effective dietary plant due to its high nutritive value and inherent therapeutic properties.

Toxicological evaluation of the ethanolic extract of Artemisia dracunculus L. for use as a dietary supplement and in functional foods.

PubMed

Ribnicky, David M; Poulev, Alexander; O'Neal, Joseph; Wnorowski, Gary; Malek, Dolores E; Jäger, Ralf; Raskin, Ilya

2004-04-01

TARRALIN is an ethanolic extract of Artemisia dracunculus (Russian tarragon), a common medicinal and culinary herb with centuries of use. Artemisia dracunculus is a close relative of the French or cooking tarragon and contains components common to many herbs that are routinely consumed without reported adverse effects. Since safety information of Artemisia dracunculus and its extract is limited to historical use, TARRALIN was examined in a series of toxicological studies. Complete Ames analysis did not reveal any mutagenic activity either with or without metabolic activation. TARRALIN was tested in an acute limit test at 5000 mg/kg with no signs of toxicity noted. In a 14 day repeated dose oral toxicity study, rats appeared to well tolerate 1000 mg/kg/day. Subsequently, TARRALIN was tested in an oral subchronic 90-day toxicity study (rat) at doses of 10, 100 and 1000 mg/kg/day. No noteworthy signs of toxicity were noted in feeding or body weight, functional observational battery or motor activity. Gross necropsy and clinical chemistry did not reveal any effects on organ mass or blood chemistry and microscopic examinations found no lesions associated with treatment. Therefore, TARRALIN appears to be safe and non-toxic in these studies and a no-observed adverse effect level in rats is established at 1000 mg/kg/day.

Sub-chronic oral toxicity of Cuminum cyminum L.'s essential oil in female Wistar rats.

PubMed

Taghizadeh, Mohsen; Ostad, Seyed Naser; Asemi, Zatollah; Mahboubi, Mohaddese; Hejazi, Sara; Sharafati-Chaleshtori, Reza; Rashidi, Aliakbar; Akbari, Hosein; Sharifi, Nasrin

2017-08-01

The current study was performed to evaluate the toxicity of Cuminum cyminum L. (C. cyminum)'s essential oil after 23 days and 45 days of repeated oral administration in female Wistar rats. A total of 80 healthy female Wistar rats were randomly selected and divided into 4 groups. The rats were gavaged with C. cyminum's essential oil at dose levels of 0, 250, 500 and 1000 mg/kg/day. Clinical signs, body weight, hematology, serum biochemistry and organ histopathology were assessed once after 23 days and again after 45 days passed from the start of the intervention. Oral administration of C. cyminum's essential oil had no observed adverse effects on clinical signs, mortality, body weight, hematology, biochemistry and organ histology (liver, kidneys, spleen and lungs) in a sample of healthy female Wistar rats after 23 days and 45 days from the start of the study. However, an increase in serum levels of alanine transaminase (ALT) was found only at dose level of 1000 mg/kg/d C. cyminum's essential oil, after the 23-days interval. We conservatively defined the non-observed adverse effect level (NOAEL) for C. cyminum's essential oil as 500 mg/kg/d in female Wistar rats. The present study results should be treated with cautious in terms of the other organs' toxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

DOMINANT LETHAL EFFECTS OF SUBCHRONIC ACRYLAMIDE ADMINISTRATION IN THE MALE LONG-EVANS RAT

EPA Science Inventory

Acrylamide, a widely used vinyl monomer, is well known as a neurotoxin but inactive as a mutagen in bacterial test systems. The experiments reported demonstrate that after subchronic oral dosing in the male rat, acrylamide induced significant elevations in both pre and post impla...

Testicular effects of 3-nitro-1,2,4-triazol-5-one (NTO) in mice when exposed orally.

PubMed

Mullins, Anna B; Despain, Kenneth E; Wallace, Shannon M; Honnold, Cary L; May Lent, Emily

2016-02-01

3-Nitro-1,2,4-triazol-5-one (NTO) is currently being investigated in the development of insensitive munitions. Rats orally exposed to NTO have demonstrated testicular toxicity in both subacute and subchronic studies; however, toxicity has not been verified in mice. Also, previous studies have not demonstrated the nature of NTO-induced testicular toxicity due to the prolonged dosing regimen utilized and effects of maturation depletion. In this study, a time-course design was used and the earliest pathological changes in testes of adult BALB/c mice orally dosed with NTO in corn oil suspensions at 0, 500 or 1000 mg/kg-day NTO for 1, 3, 7 or 14 d were evaluated. The earliest NTO-induced testicular changes occurred in the 1000 mg/kg-day group at day 7 and the 500 mg/kg-day group at day 14 as evident by the presence of bi- and multinucleated giant cells (MNGCs) of almost all spermatids in an isolated stage II-III tubule/step 2-3 and a stage IX tubule/step 9 in the 1000 and 500 mg/kg-day groups, respectively. Testicular toxicity was characterized by degeneration and the presence of bi- and MNGCs of spermatids (stages II-III and IX), which progressed to additional germ cell degeneration as dosing duration increased. Occasional step 16 spermatid retention was also noted in stage XII and I tubules in the day 14, 1000 mg/kg-day group. These data indicate that NTO is a testicular toxicant in mice and that spermatids are the most sensitive cell. The presence of retained spermatids warrants further investigation regarding NTO's role as a direct Sertoli cell toxicant.

Comparative Analysis of the Relationship between Trichloroethylene Metabolism and Tissue-Specific Toxicity among Inbred Mouse Strains: Liver Effects

PubMed Central

Yoo, Hong Sik; Bradford, Blair U.; Kosyk, Oksana; Shymonyak, Svitlana; Uehara, Takeki; Collins, Leonard B.; Bodnar, Wanda M.; Ball, Louise M.; Gold, Avram; Rusyn, Ivan

2014-01-01

Trichloroethylene (TCE) is a widely used organic solvent. Although TCE is classified as carcinogenic to humans, substantial gaps remain in our understanding of inter-individual variability in TCE metabolism and toxicity, especially in the liver. We tested a hypothesis that amounts of oxidative metabolites of TCE in mouse liver are associated with liver-specific toxicity. Oral dosing with TCE was conducted in sub-acute (600 mg/kg/d; 5 days; 7 inbred mouse strains) and sub-chronic (100 or 400 mg/kg/d; 1, 2, or 4 weeks; 2 inbred mouse strains) designs. We evaluated the quantitative relationship between strain-, dose-, and time-dependent formation of TCE metabolites from cytochrome P450-mediated oxidation [trichloroacetic acid (TCA), dichloroacetic acid (DCA), and trichloroethanol] and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione] in serum and liver, and various liver toxicity phenotypes. In sub-acute study, inter-strain variability in TCE metabolite amounts was observed in serum and liver. No induction of Cyp2e1 protein levels in liver was detected. Serum and liver levels of TCA and DCA were correlated with increased transcription of peroxisome proliferator-marker genes Cyp4a10 and Acox1, but not with degree of induction in hepatocellular proliferation. In sub-chronic study, serum and liver levels of oxidative metabolites gradually decreased over time despite continuous dosing. Liver protein levels of Cyp2e1, Adh and Aldh2 were unaffected by treatment with TCE. While the magnitude of induction of peroxisome proliferator-marker genes also declined, hepatocellular proliferation increased. This study offers a unique opportunity to provide a scientific data-driven rationale for some of the major assumptions in human health assessment of TCE. PMID:25424544

Acute and Subchronic Toxic Effects of the Fruits of Physalis peruviana L.

PubMed

Perk, Basak Ozlem; Ilgin, Sinem; Atli, Ozlem; Duymus, Hale Gamze; Sirmagul, Basar

2013-01-01

The fruit of Physalis peruviana L. (PPL) has been traditionally used as antispasmodic, diuretic, antiseptic, sedative, and analgesic all over the world. We aimed to perform qualitative content analysis of the fruits of PPL and to clarify the in vitro genotoxicity and in vivo acute and subchronic toxicity of the fruit. Lyophilized fruit juice does not induce genetic damage. In the acute toxicity studies, LD50 value of the fruit was found to be more than 5000 mg kg(-1) for both sexes. According to the subchronic toxicity studies, hepatic, renal, and hematological toxic effects were not induced in both sexes. Plasma troponin I (only in the group treated with 5000 mg kg(-1) of lyophilized fruit juice) and troponin T levels were significantly increased in male groups treated with lyophilized fruit juice compared to the control group. Furthermore, potassium level was significantly increased in the male group treated with 5000 mg kg(-1) of lyophilized fruit juice. These findings were considered to indicate the myocardial damage particularly in the male group treated with 5000 mg kg(-1) of lyophilized fruit juice. In conclusion, lyophilized fruit juice of PPL is shown to induce cardiac toxicity only at high doses and in male gender.

Acute and Subchronic Toxic Effects of the Fruits of Physalis peruviana L.

PubMed Central

Perk, Basak Ozlem; Ilgin, Sinem; Atli, Ozlem; Duymus, Hale Gamze; Sirmagul, Basar

2013-01-01

The fruit of Physalis peruviana L. (PPL) has been traditionally used as antispasmodic, diuretic, antiseptic, sedative, and analgesic all over the world. We aimed to perform qualitative content analysis of the fruits of PPL and to clarify the in vitro genotoxicity and in vivo acute and subchronic toxicity of the fruit. Lyophilized fruit juice does not induce genetic damage. In the acute toxicity studies, LD50 value of the fruit was found to be more than 5000 mg kg−1 for both sexes. According to the subchronic toxicity studies, hepatic, renal, and hematological toxic effects were not induced in both sexes. Plasma troponin I (only in the group treated with 5000 mg kg−1 of lyophilized fruit juice) and troponin T levels were significantly increased in male groups treated with lyophilized fruit juice compared to the control group. Furthermore, potassium level was significantly increased in the male group treated with 5000 mg kg−1 of lyophilized fruit juice. These findings were considered to indicate the myocardial damage particularly in the male group treated with 5000 mg kg−1 of lyophilized fruit juice. In conclusion, lyophilized fruit juice of PPL is shown to induce cardiac toxicity only at high doses and in male gender. PMID:24369482

Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models

PubMed Central

2014-01-01

Background Although ZnO nanoparticles (NPs) are used in many commercial products and the potential for human exposure is increasing, few in vivo studies have addressed their possible toxic effects after inhalation. We sought to determine whether ZnO NPs induce pulmonary toxicity in mice following sub-acute or sub-chronic inhalation exposure to realistic exposure doses. Methods Mice (C57Bl/6) were exposed to well-characterized ZnO NPs (3.5 mg/m3, 4 hr/day) for 2 (sub-acute) or 13 (sub-chronic) weeks and necropsied immediately (0 wk) or 3 weeks (3 wks) post exposure. Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid as well as measurements of pulmonary mechanics. Generation of reactive oxygen species was assessed in the lungs. Lungs were evaluated for histopathologic changes and Zn content. Zn concentration in blood, liver, kidney, spleen, heart, brain and BAL fluid was measured. Results An elevated concentration of Zn2+ was detected in BAL fluid immediately after exposures, but returned to baseline levels 3 wks post exposure. Dissolution studies showed that ZnO NPs readily dissolved in artificial lysosomal fluid (pH 4.5), but formed aggregates and precipitates in artificial interstitial fluid (pH 7.4). Sub-acute exposure to ZnO NPs caused an increase of macrophages in BAL fluid and a moderate increase in IL-12(p40) and MIP-1α, but no other inflammatory or toxic responses were observed. Following both sub-acute and sub-chronic exposures, pulmonary mechanics were no different than sham-exposed animals. Conclusions Our ZnO NP inhalation studies showed minimal pulmonary inflammation, cytotoxicity or lung histopathologic changes. An elevated concentration of Zn in the lung and BAL fluid indicates dissolution of ZnO NPs in the respiratory system after inhalation. Exposure concentration, exposure mode and time post exposure played an important role in the toxicity of ZnO NPs. Exposure for 13 wks with a cumulative dose of 10.9 mg/kg yielded increased lung cellularity, but other markers of toxicity did not differ from sham-exposed animals, leading to the conclusion that ZnO NPs have low sub-chronic toxicity by the inhalation route. PMID:24684892

Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models.

PubMed

Adamcakova-Dodd, Andrea; Stebounova, Larissa V; Kim, Jong Sung; Vorrink, Sabine U; Ault, Andrew P; O'Shaughnessy, Patrick T; Grassian, Vicki H; Thorne, Peter S

2014-04-01

Although ZnO nanoparticles (NPs) are used in many commercial products and the potential for human exposure is increasing, few in vivo studies have addressed their possible toxic effects after inhalation. We sought to determine whether ZnO NPs induce pulmonary toxicity in mice following sub-acute or sub-chronic inhalation exposure to realistic exposure doses. Mice (C57Bl/6) were exposed to well-characterized ZnO NPs (3.5 mg/m3, 4 hr/day) for 2 (sub-acute) or 13 (sub-chronic) weeks and necropsied immediately (0 wk) or 3 weeks (3 wks) post exposure. Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid as well as measurements of pulmonary mechanics. Generation of reactive oxygen species was assessed in the lungs. Lungs were evaluated for histopathologic changes and Zn content. Zn concentration in blood, liver, kidney, spleen, heart, brain and BAL fluid was measured. An elevated concentration of Zn2+ was detected in BAL fluid immediately after exposures, but returned to baseline levels 3 wks post exposure. Dissolution studies showed that ZnO NPs readily dissolved in artificial lysosomal fluid (pH 4.5), but formed aggregates and precipitates in artificial interstitial fluid (pH 7.4). Sub-acute exposure to ZnO NPs caused an increase of macrophages in BAL fluid and a moderate increase in IL-12(p40) and MIP-1α, but no other inflammatory or toxic responses were observed. Following both sub-acute and sub-chronic exposures, pulmonary mechanics were no different than sham-exposed animals. Our ZnO NP inhalation studies showed minimal pulmonary inflammation, cytotoxicity or lung histopathologic changes. An elevated concentration of Zn in the lung and BAL fluid indicates dissolution of ZnO NPs in the respiratory system after inhalation. Exposure concentration, exposure mode and time post exposure played an important role in the toxicity of ZnO NPs. Exposure for 13 wks with a cumulative dose of 10.9 mg/kg yielded increased lung cellularity, but other markers of toxicity did not differ from sham-exposed animals, leading to the conclusion that ZnO NPs have low sub-chronic toxicity by the inhalation route.

CARDIOPATHIC EFFECT OF 1,2,3-TRICHLOROPROPANE AFTER SUBACUTE AND SUBCHRONIC EXPOSURE IN RATS

EPA Science Inventory

1,2,3-Trichloropropane (1,2,3-TCP) is an industrial water contaminant with potential for human exposure by the oral route. The systemic toxicology of 1,2,3-TCP was evaluated after subacute or subchronic exposure in male and female Sprague Dawley rate. Animals were treated with 0....

Toxicologic evaluation of DHA-rich algal oil: Genotoxicity, acute and subchronic toxicity in rats.

PubMed

Schmitt, D; Tran, N; Peach, J; Bauter, M; Marone, P

2012-10-01

DHA-rich algal oil ONC-T18, tested in a battery of in vitro and in vivo genotoxicity tests, did not show mutagenic or genotoxic potential. The acute oral LD50 in rats has been estimated to be greater than 5000 mg/kg of body weight. In a 90-day subchronic dietary study, administration of DHA-rich algal oil at concentrations of 0, 10,000, 25,000, and 50,000 ppm in the diet for 13 weeks did not produce any significant toxicologic manifestations. The algal oil test article was well tolerated as evidenced by the absence of major treatment-related changes in the general condition and appearance of the rats, neurobehavioral endpoints, growth, feed and water intake, ophthalmoscopic examinations, routine hematology and clinical chemistry parameters, urinalysis, or necropsy findings. The no observed adverse effect level (NOAEL) was the highest level fed of 50,000 ppm which is equivalent to 3,305 and 3,679 mg/kg bw/day, for male and female rats, respectively. The studies were conducted as part of an investigation to examine the safety of DHA-rich algal oil. The results confirm that it possesses a toxicity profile similar to other currently marketed algal oils and support the safety of DHA-rich algal oil for its proposed use in food. Copyright © 2012 Elsevier Ltd. All rights reserved.

In Vivo and In Vitro Toxicity Evaluation of Hydroethanolic Extract of Kalanchoe brasiliensis (Crassulaceae) Leaves.

PubMed

Fonseca, Aldilane Gonçalves; Ribeiro Dantas, Luzia Leiros Sena Fernandes; Fernandes, Júlia Morais; Zucolotto, Silvana Maria; Lima, Adley Antoninni Neves; Soares, Luiz Alberto Lira; Rocha, Hugo Alexandre Oliveira; Lemos, Telma Maria Araújo Moura

2018-01-01

The species Kalanchoe brasiliensis , known as "Saião , " has anti-inflammatory, antimicrobial, and antihistamine activities. It also has the quercetin and kaempferol flavonoids, which exert their therapeutic activities. With extensive popular use besides the defined therapeutical properties, the study of possible side effects is indispensable. The objective of this study is to evaluate the toxicity in vitro and in vivo from the hydroethanolic extract of the leaves of K. brasiliensis . The action of the extract (concentrations from 0.1 to 1000 uL/100 uL) in normal and tumor cells was evaluated using the MTT method. Acute toxicity and subchronic toxicity were evaluated in mice with doses of 250 to 1000 mg/kg orally, following recognized protocols. The in vitro results indicated cytotoxic activity for 3T3 cell line (normal) and 786-0 (kidney carcinoma), showing the activity to be concentration-dependent, reaching 92.23% cell inhibition. In vivo , the extract showed no significant toxicity; only liver changes related to acute toxicity and some signs of liver damage, combining biochemical and histological data. In general, the extract showed low or no toxicity, introducing itself as safe for use with promising therapeutic potential.

[Subchronic toxicity testing of mold-ripened cheese].

PubMed

Schoch, U; Lüthy, J; Schlatter, C

1984-08-01

The biological effects of known mycotoxins of Penicillium roqueforti or P. camemberti and other still unknown, but potentially toxic metabolites in mould ripened cheese (commercial samples of Blue- and Camembert cheese) were investigated. High amounts of mycelium (equivalents of 100 kg cheese/man and day) were fed to mice in a subchronic feeding trial. The following parameters were determined: development of body weight, organ weights, hematology, blood plasma enzymes. No signs of adverse effects produced by cheese mycotoxins could be detected after 28 days. No still unknown toxic metabolites could be demonstrated. From these results no health hazard from the consumption of mould ripened cheese, even in high amounts, appears to exist.

Sub-chronic safety evaluation of aqueous extract of Alangium salvifolium (L.f.) Wangerin leaves in rats

PubMed Central

Kapoor, Bhupinder; Kaur, Gagandeep; Gupta, Mukta; Gupta, Reena

2017-01-01

Conventionally, the juice and extract of Alangium salvifolium leaves have been used for the treatment of diabetes, wound healing, dog bite, and as a poultice in rheumatism. To carry out the sub-chronic toxicity and thereafter safety evaluation of A. salvifolium leaves. The aqueous extract of A. salvifolium leaves was administered orally at the doses of 200, 400, and 800 mg/kg/day for 90 days. All the animals were observed daily for general behavior, changes in body weight, food, and water consumption. At the end of the treatment period, biochemical and hematological parameters were analyzed; and the animals were sacrificed for histopathological examination of heart, lungs, liver, and kidney. The general behavior and water intake were normal in all the rats. The increase in body weight was observed in female rats of all the groups while body weight was decreased in high dose group animals of both sexes. Hematological parameters were not disturbed by the continuous use of extract. A significant decrease in glucose level was observed in intermediate- and high-dose group animals while urea and creatinine level were significantly high in animals of high-dose group. Although histopathological examination of most of the organs exhibited no structural changes, some tubal damage in kidneys was observed in high-dose group animals. The high dose of extract has shown mild signs of toxicity on kidney function test, but no toxic response was observed on hematological and liver biochemical parameters. The extract also exhibited hypoglycemic potential. PMID:28795025

Nephritic cell damage and antioxidant status in rats exposed to leachate from battery recycling industry

PubMed Central

Oboh, Ganiyu

2016-01-01

Limited studies have assessed the toxic effect of sub-acute and sub-chronic exposure of leachate (mixture of metals) in mammalian kidney. The sub-acute and sub-chronic exposure of mature male Wistar-strain albino rats (200–220 g) were given by oral administration with leachate from Elewi Odo municipal battery recycling industry (EOMABRIL) for period of 7 and 60 days respectively, at different concentrations (20%, 40%, 60%, 80% and 100%). This was to evaluate its toxic effects on male renal functions using biomarkers of oxidative stress and nephro-cellular damage. Control groups were treated equally, but given distilled water instead of the leachate. All the groups were fed with the same standard food and had free access to drinking water. Following the exposure, results showed that the treatment induced systemic toxicity at the doses tested by causing a significant (p<0.05) alteration in enzymatic antioxidants-catalase (CAT) and superoxide dismutase (SOD) in the kidneys which resulted into elevated levels of malonaldehyde (MDA). Reduced glutathione (GSH) levels were found to be significantly (p<0.05) depleted relative to the control group. Considerable renal cortical congestion and numerous tubules with protein casts were observed in the lumen of EOMABRIL-treated rats. These findings conclude that possible mechanism by which EOMABRIL at the investigated concentrations elicits nephrotoxicity could be linked to the individual, additive, synergistic or antagonistic interactions of this mixture of metals with the renal bio-molecules, alteration of kidney detoxifying enzymes and necrosis of nephritic tubular epithelial cells. PMID:28652841

Nephritic cell damage and antioxidant status in rats exposed to leachate from battery recycling industry.

PubMed

Akintunde, Jacob K; Oboh, Ganiyu

2016-03-01

Limited studies have assessed the toxic effect of sub-acute and sub-chronic exposure of leachate (mixture of metals) in mammalian kidney. The sub-acute and sub-chronic exposure of mature male Wistar-strain albino rats (200-220 g) were given by oral administration with leachate from Elewi Odo municipal battery recycling industry (EOMABRIL) for period of 7 and 60 days respectively, at different concentrations (20%, 40%, 60%, 80% and 100%). This was to evaluate its toxic effects on male renal functions using biomarkers of oxidative stress and nephro-cellular damage. Control groups were treated equally, but given distilled water instead of the leachate. All the groups were fed with the same standard food and had free access to drinking water. Following the exposure, results showed that the treatment induced systemic toxicity at the doses tested by causing a significant ( p <0.05) alteration in enzymatic antioxidants-catalase (CAT) and superoxide dismutase (SOD) in the kidneys which resulted into elevated levels of malonaldehyde (MDA). Reduced glutathione (GSH) levels were found to be significantly ( p <0.05) depleted relative to the control group. Considerable renal cortical congestion and numerous tubules with protein casts were observed in the lumen of EOMABRIL-treated rats. These findings conclude that possible mechanism by which EOMABRIL at the investigated concentrations elicits nephrotoxicity could be linked to the individual, additive, synergistic or antagonistic interactions of this mixture of metals with the renal bio-molecules, alteration of kidney detoxifying enzymes and necrosis of nephritic tubular epithelial cells.

Safety evaluation of Chlorella sorokiniana strain CK-22 based on an in vitro cytotoxicity assay and a 13-week subchronic toxicity trial in rats.

PubMed

Himuro, Sayaka; Ueno, Sugi; Noguchi, Naoto; Uchikawa, Takuya; Kanno, Toshihiro; Yasutake, Akira

2017-08-01

The genus Chlorella contains unicellular green algae that have been used as food supplements. The purpose of this work was to evaluate the safety of the Chlorella sorokiniana strain CK-22 using powdered preparation (CK-22P) both by in vitro and in vivo assays. These included an experiment for cytotoxicity using Chinese hamster lung fibroblasts (V79 cells) and a 13-week repeated-dose oral toxicity trial using Wistar rats. The cytotoxicity was evaluated by MTT assay of a hot water extract (Hw-Ex) and 80% ethanol extract (Et-Ex) of CK-22P, and no effect on cell viability was observed. The 50% viability inhibitory effect (IC50) value for Hw-Ex and Et-Ex were estimated as greater than 73 and 17 μg/ml, respectively. In the subchronic toxicity test, pelleted rodent diet containing 0%, 2.5%, 5% or 10% CK-22P was given to Wistar rats (ten animals/sex/groups) for 13 weeks. During the experimental period, no CK-22P treatment-induced differences in general condition, body weight gain, food and water consumption, ophthalmology, urinalysis, hematology, clinical chemistry, gross pathology, organ weights, histopathology, or animal death were observed. The no-observed-adverse-effect levels (NOAEL) were estimated to be 5.94 g/kg body-weight/day for males and 6.41 g/kg body-weight/day for females. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Imbalanced immune responses involving inflammatory molecules and immune-related pathways in the lung of acute and subchronic arsenic-exposed mice.

PubMed

Li, Jinlong; Zhao, Lu; Zhang, Yang; Li, Wei; Duan, Xiaoxu; Chen, Jinli; Guo, Yuanyuan; Yang, Shan; Sun, Guifan; Li, Bing

2017-11-01

Inorganic arsenic has been claimed to increase the risk of pulmonary diseases through ingestion, as opposed to inhalation, which makes it a unique and intriguing environmental toxicant. However, the immunotoxic effects of lung, one of the targets of arsenic exposure, have not been extensively investigated in vivo. In the present study, we first confirmed that 2.5, 5 and 10mg/kg NaAsO 2 orally for 24h dose-dependently triggered the infiltration of neutrophils, lymphocytes and macrophages in BALF. Not only the transcription activity, but also the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α were consistently raised in the lung and BALF of acute arsenic-exposed mice. Acute oral administration of NaAsO 2 also raised pulmonary MPO activity and mRNA levels of chemokine Mip-2 and Mcp-1. Meanwhile, obvious histopathological damages with inflammatory cells infiltration and erythrocyte aggregation around the capillaries were verified in the lung of mice drank arsenic-rich water freely for 3 months. Furthermore, we affirmed notable disturbance of CD4 + T-cell differentiation in the lung of acute arsenic-exposed mice, as demonstrated by up-regulated mRNA levels of regulator Gata3 and cytokine Il-4 of Th2, enhanced Foxp3 and Il-10 of Treg, down-regulated T-bet and Ifn-γ of Th1, as well as lessened Ror-γt and Il-23 of Th17. However, impressive elevation of cytokine Ifn-γ and Il-23, as well as moderate enhancement of Il-4 and Il-10 were found in the lung by subchronic arsenic administration. Finally, our present study demonstrated that both a single and sustained arsenic exposure prominently increased the expression of immune-related p38, JNK, ERK1/2 and NF-κB proteins in the lung tissue. While disrupting the pulmonary redox homeostasis by increasing MDA levels, exhausting GSH and impaired enzyme activities of CAT and GSH-Px, antioxidant regulator NRF2 and its downstream targets HO-1 and GSTO1/2 were also up-regulated by both acute and subchronic arsenic treatment. Conclusively, our present study demonstrated both acute and subchronic oral administration of arsenic triggers multiple pulmonary immune responses involving inflammatory molecules and T-cell differentiation, which might be closely associated with the imbalanced redox status and activation of immune-related MAPKs, NF-κB and anti-inflammatory NRF2 pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats.

PubMed

Zhang, Xiaofang; Zhang, Xiaodong; Yuan, Bojun; Ren, Lijun; Zhang, Tianbao; Lu, Guocai

2016-11-30

Histone deacetylase inhibitors (HDACIs), such as vorinostat and panobinostat, have been shown to have active effects on many hematologic malignancies, including multiple myeloma and cutaneous T-cell lymphoma. Hydroxamate-based (Hb) HDACIs have very good toxicity profiles and are currently being tested in phases I and II clinical trials with promising results in selected neoplasms, such as bladder carcinoma. One of the Hb-HDACIs, HZ1006, has been demonstrated to be a promising drug for clinical use. The aim of our study was to determine the possible target of toxicity and to identify a non-toxic dose of HZ1006 for clinical use. In our studies, the repeated dosage toxicity of HZ1006 in Beagle dogs and Sprague Dawley (SD) rats was identified. Dogs and rats received HZ1006 orally (0-80 and 0-120 mg/kg/day, respectively) on a continuous daily dosing agenda for 28 days following a 14-day dosage-free period. HZ1006's NOAEL (No Observed Adverse Effect Level) by daily oral administration for dogs and rats was 5 mg/kg and 60 mg/kg, respectively, and the minimum toxic dose was 20 and 120 mg/kg, respectively. All the side effects indicated that the digestive tract, the male reproductive tract, the respiratory tract and the hematological systems might be HZ1006 toxic targets in humans. HZ1006 could be a good candidate or a safe succedaneum to other existing HDACIs for the treatment of some solid tumor and hematologic malignancies.

EFFECTS OF SUBCHRONIC EXPOSURE TO CONCENTRATED AMBIENT PARTICULATES IN SPONTANEOUSLY HYPERTENSIVE RATS

EPA Science Inventory

EFFECTS OF SUBCHRONIC EXPOSURE TO CONCENTRATED AMBIENT PARTICULATES IN SPONTANEOUSLY HYPERTENSIVE RATS. WP Watkinson1, LB Wichers2, JP Nolan1, DW Winsett1, UP Kodavanti1, MCJ Schladweiler1, and DL Costa1 1US EPA, ORD/NHEERL/ETD/PTB, RTP, NC; 2UNC SPH and Curriculum in Toxic...

SUBCHRONIC TOXICITY OF INHALED TOLUENE IN RATS: IMMUNOLOGY, CARDIAC GENE EXPRESSION AND MARKERS OF OXIDATIVE STRESS.

EPA Science Inventory

The health effects of long-term exposure to volatile organic compounds (VOCs) are poorly understood, due primarily to insufficient human exposure data and inconsistent animal models. To develop a rodent model of long-term exposure to VOCs, a sub-chronic inhalation study with mult...

Toxicological evaluation of Cladophora glomerata Kützing and Microspora floccosa Thuret in albino rats.

PubMed

Fahprathanchai, Prannapus; Saenphet, Kanokporn; Peerapornpisal, Yuwadee; Aritajat, Salika

2006-01-01

This study aimed to evaluate the toxicity of Cladophora glomerata and Microspora floccosa ethanolic extracts in rats. Acute toxicity was tested with a single oral administration of the extract at a dose of 25 g/kg bd wt. Mortality, behavior, amount of food intake, body weight, and any abnormalities of the visceral organs, were observed. The results showed that the extract caused neither mortality, nor abnormalities. Subchronic toxicity was tested by administering the extract at doses of 0.5 g/kg and 1.0 g/kg for 60 days. Differences in body weight, hematology and blood biochemistry (alanine aminotransferase, ALT; aspartate aminotransferase, AST; blood urea nitrogen, BUN and creatinine, Cre) were not detected among the control and treatment groups. Although the packed cell volume of the male rats treated with 1.0 g/kg extract was significantly lower than the controls (p< or =0.05), the level was in the standard range for rat hematocrit.

HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT ...

EPA Pesticide Factsheets

Health and Environmental Effects Documents (HEEDS) are prepared for the Office of Solid Waste and Emergency Response (OSWER). This document series is intended to support listings under the Resource Conservation and Recovery Act (RCRA) as well as to provide health-related limits and goals for emergency and remedial actions under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). Both published literature and information obtained from Agency Program Office files are evaluated as they pertain to potential human health, aquatic life and environmental effects of hazardous waste constituents. Several quantitative estimates are presented provided sufficient data are available. For systemic toxicants, these include Reference Doses (RfDs) for chronic and subchronic exposures for both the inhalation and oral exposures. In the case of suspected carcinogens, RfDs may not be estimated. Instead, a carcinogenic potency factor, or q1*, is provided. These potency estimates are derived for both oral and inhalation exposures where possible. In addition, unit risk estimates for air and drinking water are presented based on inhalation and oral data, respectively. Reportable quantities (RQs) based on both chronic toxicity and carcinogenicity are derived. The RQ is used to determine the quantity of a hazardous substance for which notification is required in the event of a release as specified under CERCLA.

Toxicological evaluation of ethanolic extract from Stevia rebaudiana Bertoni leaves: Genotoxicity and subchronic oral toxicity.

PubMed

Zhang, Qiannan; Yang, Hui; Li, Yongning; Liu, Haibo; Jia, Xudong

2017-06-01

Stevia rebaudiana Bertoni leaves have a long history of use as an abundant source of sweetener. The aqueous extract of stevia leaves and the predominant constitutes steviol glycosides have been intensively investigated. However, rare studies provided toxicological evaluation of bioactive components in the polar extract regarding their safety on human health. This study aimed to evaluate the toxicity of ethanolic extract of Stevia rebaudiana Bertoni leaves through a battery of in vitro and in vivo tests. Negative results were unanimously obtained from bacterial reverse mutation assay, mouse bone marrow micronucleus assay and mouse sperm malformation assay. Oral administration at dietary levels of 1.04%, 2.08% and 3.12% for 90 days did not induce significant behavioral, hematological, clinical, or histopathological changes in rats. Significant reduction of cholesterol, total protein and albumin was observed in female animals only at high dose level. The results demonstrated that Stevia rebaudiana Bertoni leaves ethanolic extract, which is rich in isochlorogenic acids, does not possess adverse effects through oral administration in this study. Our data provided supportive evidence for the safety of Stevia rebaudiana Bertoni leaves that may potentially be used in functional foods as well as nutritional supplements beyond sweetner. Copyright © 2017 Elsevier Inc. All rights reserved.

Repeated sub-chronic oral toxicity study of xylooligosaccharides (XOS) in dogs.

PubMed

Gao, Yonglin; Wang, Yunzhi; Li, Yanshen; Han, Rui; Li, Chunmei; Xiao, Lin; Cho, Susan; Ma, Yukui; Fang, Chao; Lee, Albert W

2017-06-01

In this study, Beagle dogs were administered xylooligosaccharide (XOS, CAS # 87099-0) at doses of 0, 1250, 2500, and 5000 mg/kg/day by oral gavage for 26 weeks. A 4-week recovery period was added to observe delayed or reversible toxicity. Measurements included body weight, food consumption, clinical observations, temperature, electrocardiogram (ECG), urinalysis, blood chemistry, hematology, organ weight, gross necropsy, and histopathological examination. Except for transient diarrhea or vomiting, no treatment-related adverse effects were noted. In the mid-dose groups, transitional diarrhea was observed in the initial 1-2 weeks. In the high-dose groups, diarrhea and/or vomiting were observed episodically over the duration of treatment. However, they disappeared after XOS was withdrawn in the recovery period. Although there was a tendency toward less weight gain in the high-dose group animal group, this is typical in animals and humans fed non-digestible carbohydrates. This chronic toxicity study demonstrated that the no observed adverse effect level (NOAEL) of XOS is 2500 mg/kg body weight (BW)/day. Based on body surface area (conversion factor of 0.54 for dogs to human), this corresponds to daily doses of 1350 mg/kg BW or 81-108 g XOS in human adults weighing 60-80 kg. Copyright © 2017. Published by Elsevier Inc.

The use of dogs as second species in regulatory testing of pesticides. Part II: Subacute, subchronic and chronic studies in the dog.

PubMed

Spielmann, H; Gerbracht, U

2001-03-01

Data on 172 pesticides (fungicides, herbicides, insecticides and other pesticides) submitted for regulatory purposes during the past 40 years to the German Federal Institute for the Health Protection of Consumers and Veterinary Medicine (BgVV) were analysed to determine whether chronic studies in dogs (52/104 weeks) provide essential additional specific toxicological compared with subchronic (13 weeks) or subacute (4 weeks) studies in the same species. Comparison of the lowest observed effect levels (LOELs) in dogs revealed no significant differences between subchronic and chronic studies but a significant difference between subacute studies and subchronic or chronic studies. Moreover, there was a significant correlation between the LOELs determined in subchronic studies and those determined in chronic studies in dogs (r = 0.78-0.84). The distribution of target organ toxicity determined in chronic studies in dogs was not significantly different from the distribution determined in subchronic studies, except for effects on the spleen in studies on herbicides which were only observed in chronic studies and in combined subchronic/chronic studies, but never in subchronic studies. Organ-specific effects that were observed in chronic studies but not in subchronic studies were found in 30 of 55 studies on fungicides, in 25 of 44 on herbicides, in 17 of 38 on insecticides and in 10 of 16 on other pesticides. Compared with 26-week studies, additional organ-specific toxic effects were found in three of five, in three of four, in one of three and in one of one 52/104-week studies on fungicides, of herbicides, of insecticides and other pesticides, respectively. The organ-specific effects that were seen only in the chronic dog studies were evaluated according to their severity, e.g. significant damage to organs versus changes in enzyme activities that do not affect organ function or histology. Such effects were not considered to be specific for dogs in chronic studies if similar effects were also found in chronic studies in rodents (rat or mouse). In 15 of 141 studies in dogs serious side effects were observed in chronic studies that were not observed in subchronic studies. Furthermore, for 9 of 172 pesticides significant new effects were seen in 52/104-week studies when compared with 4- or 13-week studies and in 7 of 141 52/104-week studies when compared with 13-week studies. Analysis of the severity of organ-specific toxic effects of pesticides revealed that chronic long-term studies (52/104 weeks) in dogs do not provide specific additional information to 26-week studies in the same species.

Comparison of neurotoxic effects and potential risks from oral administration or ingestion of tricresyl phosphate and jet engine oil containing tricresyl phosphate.

PubMed

Mackerer, C R; Barth, M L; Krueger, A J; Chawla, B; Roy, T A

1999-07-09

Neurotoxicity of tricresyl phosphates (TCPs) and jet engine oil (JEO) containing TCPs were evaluated in studies conducted in both rat and hen. Results for currently produced samples ("conventional" and "low-toxicity") were compared with published findings on older samples to identify compositional changes and relate those changes to neurotoxic potential. Finally, a human risk assessment for exposure by oral ingestion of currently produced TCPs in JEO at 3% (JEO + 3%) was conducted. TCPs and certain other triaryl phosphates administered as single doses inhibited brain neuropathy target esterase (B-NTE; neurotoxic esterase) in the rat and the hen (hen 3.25 times as sensitive), and both species were deemed acceptable for initial screening purposes. Neither rat nor hen was sensitive enough to detect statistically significant inhibition of B-NTE after single doses of IEO + 3% "conventional" TCP. Subacute administration of 2 g/kg/d of JEO + 3% "conventional" TCP to the hen produced B-NTE inhibition (32%), which did not result in organophosphorus-induced delayed neurotoxicity (OPIDN). Subchronic administration of JEO + 3% TCP but not JEO + 1% TCP at 2 g/kg/d produced OPIDN. Thus, the threshold for OPIDN was between 20 and 60 mg "conventional" TCP/kg/d in JEO for 10 wk. The current "conventional" TCPs used in JEO and new "low-toxicity" TCPs now used in some JEO are synthesized from phenolic mixtures having reduced levels of ortho-cresol and ortho-xylenols resulting in TCPs of very high content of meta- and para-substituted phenyl moieties; this change in composition results in lower toxicity. The "conventional" TCPs still retain enough inhibitory activity to produce OPIDN, largely because of the presence of ortho-xylyl moieties; the "low-toxicity" TCPs are largely devoid of ortho substituents and have extremely low potential to cause OPIDN. The TCPs produced in the 1940s and 1950s were more than 400 times as toxic as the "low-toxicity" TCPs produced today. Analysis of the doses required to produce OPIDN in a subchronic hen study suggests that the minimum toxic dose of "conventional" TCP for producing OPIDN in a 70-kg person would be 280 mg/d, and for JEO containing 3% TCP, 9.4 g/d. Food products could be inadvertently contaminated with neat "conventional" TCP but it is unlikely that food such as cooking oil would be contaminated with enough JEO + 3% TCP to cause toxicity. Further, at the dosage required for neurotoxicity, it would be virtually impossible for a person to receive enough JEO + 3% TCP in the normal workplace (or in an aircraft) to cause such toxicity. There is no record of a JEO formulated with the modern "conventional" TCP causing human neurotoxicity.

Haloacetonitriles: metabolism and toxicity.

PubMed

Lipscomb, John C; El-Demerdash, Ebtehal; Ahmed, Ahmed E

2009-01-01

The haloacetonitriles (HANs) exist in drinking water exclusively as byproducts of disinfection. HANs are found in drinking water more often, and in higher concentrations, when surface water is treated by chloramination. Human exposure occurs through consumption of finished drinking water; oral and dermal contact also occurs, and results from showering, swimming and other activities. HANs are reactive and are toxic to gastrointestinal tissues following oral administration. Such toxicity is characterized by GSH depletion, increased lipid peroxidation, and covalent binding of HAN-associated radioactivity to gut tissues. The presence of GSH in cells is an important protective mechanism against HAN toxicity; depletion of cellular GSH results in increased toxicity. Some studies have demonstrated an apparently synergistic effect between ROS and HAN administration, that may help explain effects observed in GI tissues. ROS are produced in gut tissues, and in vitro evidence indicates that ROS may contribute to the degradation and formation of reactive intermediates from HANs. The rationale for ROS involvement may involve HAN-induced depletion of GSH and the role of GSH in scavenging ROS. In addition to effects on GI tissues, studies show that HAN-derived radiolabel is found covalently bound to proteins and DNA in several organs and tissues. The addition of antioxidants to biologic systems protects against HAN-induced DNA damage. The protection offered by antioxidants supports the role of oxidative stress and the potential for a threshold in han-induced toxicity. However, additional data are needed to substantiate evidence for such a threshold. HANs are readily absorbed from the GI tract and are extensively metabolized. Elimination occurs primarily in urine, as unconjugated one-carbon metabolites. Evidence supports the involvement of mixed function oxidases, the cytochrome P450 enzyme family and GST, in HAN metabolism. Metabolism represents either a detoxification or bioactivation process, depending on the particular HAN and the enzyme involved. HANs can inhibit CYP2E1-mediated metabolism, an effect which may be dependent on a covalent interaction with the enzyme. In addition, HAN compounds inhibit GST-mediated conjugation, but this effect is reversible upon dialysis, indicating that the interaction does not represent covalent binding. No subchronic studies of HAN toxicity are available in the literature. However, studies show that HANs produce developmental toxicity in experimental animals. The nature of developmental toxicity is affected by the type of administration vehicle, which renders interpretation of results more difficult. Skin tumors have been found following dermal application of HANs, but oral studies for carcinogenicity are negative. Pulmonary adenomas were increased following oral administration of HANs, but the A/J strain of mice employed has a characteristically high background rate of such tumors. HANs interact with DNA to produce unscheduled DNA repair, SCE and reverse mutations in Salmonella. HANs did not induce micronuclei or cause alterations in sperm head morphology in mice, but did induce micronuclei in newts. Thus, there is concern for the potential carcinogenicity of HANs. It would be valuable to delineate any relationship between the apparent threshold for micronuclei formation in newts and the potential mechanism of toxicity involving HAN-induced oxidative stress. Dose-response studies in rodents may provide useful information on toxicity mechanisms and dose selection for longer term toxicity studies. Additional studies are warranted before drawing firm conclusions on the hazards of HAN exposure. Moreover, additional studies on HAN-DNA and HAN-protein interaction mechanisms, are needed. Such studies can better characterize the role of metabolism in toxicity of individual HANs, and delineate the role of oxidative stress, both of which enhance the capacity to predict risk. Most needed, now, are new subchronic (and chronic) toxicity studies; the results of such well-planned, controlled, conducted, interpreted and published investigations would be valuable in establishing margins of safety for HANs in human health risk assessment.

Safety assessment of lepidopteran insect-protected transgenic rice with cry2A* gene.

PubMed

Zou, Shiying; Huang, Kunlun; Xu, Wentao; Luo, Yunbo; He, Xiaoyun

2016-04-01

Numerous genetically modified (GM) crops expressing proteins for insect resistance have been commercialized following extensive testing demonstrating that the foods obtained from them are as safe as that obtained from their corresponding non-GM varieties. In this paper, we report the outcome of safety studies conducted on a newly developed insect-resistant GM rice expressing the cry2A* gene by a subchronic oral toxicity study on rats. GM rice and non-GM rice were incorporated into the diet at levels of 30, 50, and 70% (w/w), No treatment-related adverse or toxic effects were observed based on an examination of the daily clinical signs, body weight, food consumption, hematology, serum biochemistry, and organ weight or based on gross and histopathological examination. These results demonstrate that the GM rice with cry2A* gene is as safe for food as conventional non-GM rice.

A SURROGATE SUBCHRONIC TOXICITY TEST METHOD FOR WATERS WITH HIGH TOTAL DISSOLVED SOLIDS

EPA Science Inventory

Total dissolved solids (TDS) are often identified as a toxicant in whole-effluent toxicity (WET) testing. The primary test organism used in WET testing, Ceriodaphnia dubia, is very sensitive to TDS ions, which can be problematic when differentiating the toxicity of TDS from those...

76 FR 27256 - Saflufenacil; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-11

... reflection of a mild and transient general systemic toxicity and not a substance- specific neurotoxic effect. In the subchronic neurotoxicity study, systemic toxicity (anemia), but no evidence of neurotoxicity... systemic toxicity in males. A LOAEL was not established for females. Chronic dietary (All populations...

Toxicity Profile of a Nutraceutical Formulation Derived from Green Mussel Perna viridis

PubMed Central

Joseph, Deepu; Chakkalakal, Selsa J.

2014-01-01

The short-term (acute) and long-term (subchronic) toxicity profile, mean lethal dose 50 (LD50), and no-observed-adverse-effect level (NOAEL) of a nutraceutical formulation developed from green mussel Perna viridis, which showed in vitro and in vivo anti-inflammatory properties, were evaluated in the present study. The formulation was administered to the male and female Wistar rats at graded doses (0.5, 1.0, and 2.5 g/kg body weight) for two weeks of acute toxicity study and 0.5, 1.0, and 2.0 g/kg body weight for 90 days in subchronic toxicity study. The LD50, variations in clinical signs, changes in body weight, body weight, food/water consumption, organ weight (liver, kidney, spleen, and brain), hematology, serum chemistry, and histopathological changes were evaluated. The LD50 of the formulation was 5,000 mg/kg BW. No test article related mortalities as well as change in body weight, and food and water consumption were observed. No toxicity related significant changes were noted in renal/hepatic function, hematological indices, and serum biochemical parameters between the control and treated groups. Histopathological alterations were not observed in the vital organs of rats. The subchronic NOAEL for the formulation in rats is greater than 2000 mg/kg. This study demonstrated that the green mussel formulation is safe to consume without any adverse effects in the body. PMID:24995298

Safety assessment of widely used fermented virgin coconut oil (Cocos nucifera) in Malaysia: Chronic toxicity studies and SAR analysis of the active components.

PubMed

Ibrahim, Ahmad H; Khan, Md Shamsuddin Sultan; Al-Rawi, Sawsan S; Ahamed, Mohamed B Khadeer; Majid, Aman Shah Bin Abdul; Al-Suede, Fouad Saleih R; Ji, Dan; Majid, Amin Malik Shah Abdul

2016-11-01

Fermented Virgin Coconut Oil (FVCO) is widely used in the Southeast Asia as food and traditional medicine. The objective of the present study is the evaluation of chronic safety of the commercialized FVCO of Malaysia and other Southeast Asian countries. A single dose of 5000 mg/kg of FVCO was administered orally in rats (each group, n = 5) for the acute toxicity study and 175, 550 and 2000 mg/kg for sub-chronic and chronic studies (each group, n = 10), respectively. The behavior, mortality, and body weight of the rats were assessed to determine the toxic effects of FVCO. The haematology, biochemistry and histopathology of the treated rats were evaluated. The treated rats were safe with the dose of 5000 mg/kg in acute, sub-chronic and chronic indication. Abnormal clinical signs and morphology (gross necroscopy), changes of organ weight, anomalous haematology and biochemistry indexes were not found in comparison with the control (p > 0.05). In general, food and water intake were higher in the treated rats related to control. It was concluded that the presence of the antioxidant active compounds of FVCO might be the reason of safety. The structure activity relationship (SAR) provides a comprehensive mechanism to determine the safety that is the presence of the electron donating phenolic groups, carbonyl groups, and carboxylic acid in the ortho and meta position of the aromatic rings. The SAR showed the antioxidant properties of myristic acid and lauric acid determined by GC-MS analysis. This result suggests the safety of FVCO for chronic use, nutritional activity that FVCO formulation complies the requirements of regulatory agencies. Copyright © 2016 Elsevier Inc. All rights reserved.

Quantitative dose-response assessment of inhalation exposures to toxic air pollutants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jarabek, A.M.; Foureman, G.L.; Gift, J.S.

1997-12-31

Implementation of the 1990 Clean Air Act Amendments, including evaluation of residual risks. requires accurate human health risk estimates of both acute and chronic inhalation exposures to toxic air pollutants. The U.S. Environmental Protection Agency`s National Center for Environmental Assessment, Research Triangle Park, NC, has a research program that addresses several key issues for development of improved quantitative approaches for dose-response assessment. This paper describes three projects underway in the program. Project A describes a Bayesian approach that was developed to base dose-response estimates on combined data sets and that expresses these estimates as probability density functions. A categorical regressionmore » model has been developed that allows for the combination of all available acute data, with toxicity expressed as severity categories (e.g., mild, moderate, severe), and with both duration and concentration as governing factors. Project C encompasses two refinements to uncertainty factors (UFs) often applied to extrapolate dose-response estimates from laboratory animal data to human equivalent concentrations. Traditional UFs have been based on analyses of oral administration and may not be appropriate for extrapolation of inhalation exposures. Refinement of the UF applied to account for the use of subchronic rather than chronic data was based on an analysis of data from inhalation exposures (Project C-1). Mathematical modeling using the BMD approach was used to calculate the dose-response estimates for comparison between the subchronic and chronic data so that the estimates were not subject to dose-spacing or sample size variability. The second UF that was refined for extrapolation of inhalation data was the adjustment for the use of a LOAEL rather than a NOAEL (Project C-2).« less

Evaluation of the subchronic toxicity of kefir by oral administration in Wistar rats.

PubMed

Diniz Rosa, Damiana; Gouveia Peluzio, Maria do Carmo; Pérez Bueno, Tania; Vega Cañizares, Ernesto; Sánchez Miranda, Lilian; Mancebo Dorbignyi, Betty; Chong Dubí, Dainé; Espinosa Castaño, Ivette; Marcin Grzes Kowiak, Lukasz; Fortes Ferreira, Célia Lucia de Luces

2014-06-01

Kefir is obtained by fermentation of milk with complex microbial populations present in kefir grains. Several health-promoting benefits have been attributed to kefir consumption. The objective of this work was to conduct a subchronic toxicity study, offering the rats normal or high-doses of kefir and evaluating growth, hematology and blood chemistry, as well as assessing bacterial translocation and the integrity of the intestinal mucosa of animals. Wistar rats were randomly divided into three groups (n = 6/group): control group received 0.7 mL of water, kefir group received 0.7 mL/day of kefir, (normodose), and Hkefir group received 3.5 mL/day of kefir (fivefold higher dose). Feeding was carried out by gavage. The animals were housed in individual cages and maintained under standard conditions for 4 weeks. The normodose and high-dose of kefir supplementation did not harm the animals since growth, hematology and blood chemistry in rats, as well as the potential pathogenicity in tissues were within normal limits, demonstrating that consumption of normodose and highdose of kefir are safe. In addition, administration of the normodose of kefir reduced cholesterol levels and improved the intestinal mucosa of the rats. These results demonstrate that the consumption of kefir is safe. Importantly, while damages are not seen for the high-dose, the normodose consumption is recommended due to the pronounced beneficial effects, as safety is concerned. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Influence of Genista tinctoria L. or methylparaben on subchronic toxicity of bisphenol A in rats.

PubMed

Popa, Daniela-Saveta; Bolfa, Pompei; Kiss, Bela; Vlase, Laurian; Păltinean, Ramona; Pop, Anca; Cătoi, Cornel; Crişan, Gianina; Loghin, Felicia

2014-02-01

To evaluate the influence of an extract of Genista tinctoria L. herba (GT) or methylparaben (MP) on histopathological changes and 2 biomarkers of oxidative stress in rats subchronicly exposed to bisphenol A (BPA). Adult female Wistar rats were orally exposed for 90 d to BPA (50 mg/kg), BPA+GT (35 mg isoflavones/kg) or BPA+MP (250 mg/kg). Plasma and tissue samples were taken from liver, kidney, thyroid, uterus, ovary, and mammary gland after 30, 60, and 90 d of exposure respectively. Lipid peroxidation and in vivo hydroxyl radical production were evaluated by histological analysis along with malondialdehyde and 2,3-dihydroxybenzoic acid detection. The severity of histopathological changes in liver and kidneys was lower after GT treatment than after BPA or BPA+MP treatment. A minimal thyroid receptor antagonist effect was only observed after BPA+MP treatment. The abnormal folliculogenesis increased in a time-dependent manner, and the number of corpus luteum decreased. No significant histological alterations were found in the uterus. The mammary gland displayed specific estrogen stimulation changes at all periods. Both MP and GT revealed antioxidant properties reducing lipid peroxidation and BPA-induced hydroxyl radical generation. GT L. extract ameliorates the toxic effects of BPA and is proved to have antioxidant potential and antitoxic effect. MP has antioxidant properties, but has either no effect or exacerbates the BPA-induced histopathological changes. Copyright © 2014 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

In Vivo and In Vitro Toxicity Evaluation of Hydroethanolic Extract of Kalanchoe brasiliensis (Crassulaceae) Leaves

PubMed Central

Lima, Adley Antoninni Neves; Soares, Luiz Alberto Lira

2018-01-01

The species Kalanchoe brasiliensis, known as “Saião,” has anti-inflammatory, antimicrobial, and antihistamine activities. It also has the quercetin and kaempferol flavonoids, which exert their therapeutic activities. With extensive popular use besides the defined therapeutical properties, the study of possible side effects is indispensable. The objective of this study is to evaluate the toxicity in vitro and in vivo from the hydroethanolic extract of the leaves of K. brasiliensis. The action of the extract (concentrations from 0.1 to 1000 uL/100 uL) in normal and tumor cells was evaluated using the MTT method. Acute toxicity and subchronic toxicity were evaluated in mice with doses of 250 to 1000 mg/kg orally, following recognized protocols. The in vitro results indicated cytotoxic activity for 3T3 cell line (normal) and 786-0 (kidney carcinoma), showing the activity to be concentration-dependent, reaching 92.23% cell inhibition. In vivo, the extract showed no significant toxicity; only liver changes related to acute toxicity and some signs of liver damage, combining biochemical and histological data. In general, the extract showed low or no toxicity, introducing itself as safe for use with promising therapeutic potential. PMID:29593788

Acute and repeated dose (28 days) oral safety studies of an alkoxyglycerol extract from shark liver oil in rats.

PubMed

Anadón, Arturo; Martínez, Maria A; Ares, Irma; Ramos, Eva; Señoráns, Francisco J; Reglero, Guillermo; Torres, Carlos

2010-02-10

Shark liver oil has been used for over 50 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkoxyglycerols. Despite its popularity, there is little published toxicology data on alkoxyglycerols. The toxicity of a supercritical fluid extract of shark liver oil (AKG-1 extract) has been evaluated in acute and repeated dose (28 days) oral toxicity studies in rats at doses of 200 and 100 times the maximum recommended dose by supplement manufacturers in humans, respectively. The AKG-1 extract administered in a single oral gavage dose of 2000 mg kg(-1) of body weight resulted in no adverse events or mortality. The AKG-1 extract administered as a daily dose of 1000 mg kg(-1) of body weight for 28 days by gavage resulted in no adverse effects or mortality. For both studies, no abnormal clinical signs, behavioral changes, body weight changes, or change in food and water consumption occurred. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. It is concluded that the AKG-1 extract is well tolerated in rats at an acute dose of 2000 mg kg(-1) and at a subchronic (28 days) dose of 1000 mg kg(-1).

Mammalian Toxicology Testing: Problem Definition Study, Technical Plan.

DTIC Science & Technology

1981-03-01

Acute Oral Exposure Area, Rzdent 2. Subchrcnic Oral Exposure Area, .odent 3. Chronic Oral Exposure Area, Rodent 4. Subchronic Oral Eposure Area, "og...Alarms Fire Extinguisher First Aid Fiscal Year Record Fixtures (See Jigs, Fixtures & Molds Control System) Food Preparation/Blending Forms Control...Insurance Invoicing (See Bookkeeping) Janitorial Service Jigs, Fixtures & Molds Control System Key Control System Keypunch Control System Label

Subchronic Toxicity Studies on 1,3,5-Trinitrobenzene, 1,3- Dinitrobenzene, and Tetryl in Rats. Subchronic Toxicity Evaluation of 1,3,5- Trinitrobenzene in Fischer 344 Rats

DTIC Science & Technology

1994-05-01

cton ofMO,,natt. ’"An saqe jr~n ’edw tc.ngin o...rm to Wailoqto. HeCdos11#, ¶ n1e i Oueftoc D or.,e fwaft at~on OOWctl~t~ and AeoOat. 12 11 J~flfflOI 0S...controls in both sexes.3 14. SUBJECT TERMS 115 . NUMBER OF PAGES 16. PRICE CODE 17. SECURITv CLASSIFICATION 13. SECURITY CLASSIFICATION 19. SECURITY...NJ). Total red and white blood cell counts, platelet count, differential leukocyte count, hemoglobin, and packed cell volume were measured and

Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ito, Yuki, E-mail: yukey@med.nagoya-cu.ac.jp; Tomizawa, Motohiro; Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502

Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10 mg/kg FNT for 9more » weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. - Highlights: • Subchronic exposure to fenitrothion induces spermatotoxicity in rats. • The fatty acid amide hydrolase is a potential target for the spermatotoxicity. • Overstimulation of the endocannabinoid signal possibly leads to the spermatotoxicity.« less

20180312 - Reproducibility and variance of liver effects in subchronic and chronic repeat dose toxicity studies (SOT)

EPA Science Inventory

In vivo studies provide reference data to evaluate alternative methods for predicting toxicity. However, the reproducibility and variance of effects observed across multiple in vivo studies is not well understood. The US EPA’s Toxicity Reference Database (ToxRefDB) stores d...

Chemical properties and biotoxicity of several chromium picolinate derivatives.

PubMed

Liu, Bin; Liu, Yanfei; Chai, Jie; Hu, Xiangquan; Wu, Duoming; Yang, Binsheng

2016-11-01

As a man-made additive, chromium picolinate Cr(pic) 3 has become a popular dietary supplement worldwide. In this paper Cr(pic) 3 and its new derivatives Cr(6-CH 3 -pic) 3 (1), [Cr(6-NH 2 -pic) 2 (H 2 O) 2 ]NO 3 (2) and Cr(3-NH 2 -pic) 3 (3) were synthesized, and complexes 1 and 2 were characterized by X-ray crystal structure (where pic=2-carboxypyridine). The relationship between the chemical properties and biotoxicity of these complexes was fully discussed: (1) The dynamics stability of chromium picolinate complexes mainly depends on the CrN bonds length. (2) There is a positive correlation between the dynamics stability, electrochemical potentials and generation of reactive oxygen species through Fenton-like reaction. (3) However, no biological toxicity was observed through MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and sub-chronic oral toxicity study for these chromium picolinate compounds. Together, our findings establish a framework for understanding the structure-property-toxicity relationships of the chromium picolinate complexes. Copyright © 2016 Elsevier Inc. All rights reserved.

Toxicological study on MUNOPHIL, water extract of Panax ginseng and Hericium erinaceum in rats.

PubMed

Park, Il-Dong; Yoo, Hwa-Seung; Lee, Yeon-Weol; Son, Chang-Gue; Kwon, Min; Sung, Ha-Jung; Cho, Chong-Kwan

2008-12-01

As data on the safety profile of Panax ginseng and Hericium erinaceum is lacking, the safety of these two compounds was examined in a series of toxicological studies. MUNOPHIL, the water extract mixture of Panax ginseng and Hericium erinaceum was tested in an oral subchronic 28-day toxicity study in rats at doses of 1250, 2500 and 5000 mg/kg/day. In repeated dose toxicity studies, no mortality was observed when varying doses of the extracts were administered once daily for a period of 28 days. There were no significant differences in body weight, absolute and relative organ weights between controls and treated rats of both sexes. Hematological analysis showed no differences in most parameters examined. In the biochemistry parameter analysis, no significant change occurred. Pathologically, neither gross abnormalities nor histopathological changes were observed. Therefore, MUNOPHIL appears to be safe and non-toxic in these studies and a no-observed adverse effect level in rats was established at 5000 mg/kg/day. The data could provide satisfactory preclinical evidence of safety to launch clinical trials on standardized formulation of plant extracts.

Proteomic analysis of rat cerebral cortex following subchronic acrolein toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rashedinia, Marzieh; Lari, Parisa; Abnous, Khalil, E-mail: Abnouskh@mums.ac.r

2013-10-01

Acrolein, a member of reactive α,β-unsaturated aldehydes, is a major environmental pollutant. Acrolein is also produced endogenously as a toxic by-product of lipid peroxidation. Because of high reactivity, acrolein may mediate oxidative damages to cells and tissues. It has been shown to be involved in a wide variety of pathological states including pulmonary, atherosclerosis and neurodegenerative diseases. In this study we employed proteomics approach to investigate the effects of subchronic oral exposures to 3 mg/kg of acrolein on protein expression profile in the brain of rats. Moreover effects of acrolein on malondialdehyde (MDA) levels and reduced glutathione (GSH) content weremore » investigated. Our results revealed that treatment with acrolein changed levels of several proteins in diverse physiological process including energy metabolism, cell communication and transport, response to stimulus and metabolic process. Interestingly, several differentially over-expressed proteins, including β-synuclein, enolase and calcineurin, are known to be associated with human neurodegenerative diseases. Changes in the levels of some proteins were confirmed by Western blot. Moreover, acrolein increases the level of MDA, as a lipid peroxidation biomarker and decreased GSH concentrations, as a non-enzyme antioxidant in the brain of acrolein treated rats. These findings suggested that acrolein induces the oxidative stress and lipid peroxidation in the brain, and so that may contribute to the pathophysiology of neurological disorders. - Highlights: • Acrolein intoxication increased lipid peroxidation and deplete GSH in rat brain. • Effect of acrolein on protein levels of cerebral cortex was analyzed by 2DE-PAGE. • Levels of a number of proteins with different biological functions were increased.« less

Draft Test Guideline: Tadpole/Sediment Subchronic Toxicity Test

EPA Pesticide Factsheets

The following draft test guideline is part of a series of test guidelines that have been developed by EPA for use in the testing of pesticides and toxic substances, and the development of test data for submission to the Agency for review.

Effect of subchronic zinc toxicity on rat salivary glands and serum composition.

PubMed

Mizari, Nazer; Hirbod-Mobarakeh, Armin; Shahinpour, Shervin; Ghalichi-Tabriz, Mostafa; Beigy, Maani; Yamini, Ali; Dehpour, Ahmad Reza

2012-11-01

Zinc plays an important role in a wide variety of metabolic processes in animal systems. The role of zinc in preservative treatment, fungicidal action and medicine, and addition of supplementary zinc have increased the probability of zinc toxicity, specially the chronic type. It is known that the composition and quantity of saliva influence the oral health. Regarding people's exposure to zinc in routine life and the importance of saliva, our purpose was to investigate the effects of oral zinc intoxication on secretory function in rat salivary glands and also on serum composition. In this study, there were five groups of female rats. Four groups received zinc acetate dehydrate through their drinking water. After 3 months of experiment, the chemical characteristics and flow rate of saliva and weight of salivary glands were determined. The effects of zinc on hematological and chemical factors of plasma were assessed too. Flow rate of submandibular glands was significantly lower in experimental groups and there were significant changes in Na(+), Ca(2+) and K(+) concentration both in saliva and in plasma. The serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, glucose levels in the plasma and urine creatinine levels were also altered in experimental groups in comparison with the control group. Our results show that zinc toxicity will affect the quantity and quality of saliva probably through changes in the various neurologic pathways to the salivary glands or effects on acinar cells of the salivary glands. Furthermore, our results showed that zinc toxicity will affect the liver and renal function.

Comparison of in vivo toxicity, antioxidant and immunomodulatory activities of coconut, nipah and pineapple juice vinegars.

PubMed

Mohamad, Nurul Elyani; Keong Yeap, Swee; Beh, Boon Keen; Romli, Muhammad Firdaus; Yusof, Hamidah Mohd; Kristeen-Teo, Ye Wen; Sharifuddin, Shaiful Adzni; Long, Kamariah; Alitheen, Noorjahan Banu

2018-01-01

Vinegar is widely used as a food additive, in food preparation and as a food supplement. This study compared the phenolic acid profiles and in vivo toxicities, and antioxidant and immunomodulatory effects of coconut, nipah and pineapple juice vinegars, which were respectively prepared via a two-step fermentation using Saccharomyces cerevisiae 7013 INRA and Acetobacter aceti vat Europeans. Pineapple juice vinegar, which had the highest total phenolic acid content, also exhibited the greatest in vitro antioxidant capacity compared to coconut juice and nipah juice vinegars. Following acute and sub-chronic in vivo toxicity evaluation, no toxicity and mortality were evident and there were no significant differences in the serum biochemical profiles between mice administered the vinegars versus the control group. In the sub-chronic toxicity evaluation, the highest liver antioxidant levels were found in mice fed with pineapple juice vinegar, followed by coconut juice and nipah juice vinegars. However, compared to the pineapple juice and nipah juice vinegars, the mice fed with coconut juice vinegar, exhibited a higher population of CD4 + and CD8 + T-lymphocytes in the spleen, which was associated with greater levels of serum interleukin-2 and interferon-γ cytokines. Overall, the data suggested that not all vinegar samples cause acute and sub-chronic toxicity in vivo. Moreover, the in vivo immunity and organ antioxidant levels were enhanced, to varying extents, by the phenolic acids present in the vinegars. The results obtained in this study provide appropriate guidelines for further in vivo bioactivity studies and pre-clinical assessments of vinegar consumption. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

In vivo toxicity and antitumor activity of essential oils extract from agarwood (Aquilaria crassna).

PubMed

Dahham, Saad Sabbar; Hassan, Loiy E Ahmed; Ahamed, Mohamed B Khadeer; Majid, Aman Shah Abdul; Majid, Amin Malik Shah Abdul; Zulkepli, Nik Noriman

2016-07-22

Aquilaria crassna has been used in traditional Asian medicine to treat vomiting, rheumatism, asthma, and cough. Furthermore, earlier studies from our laboratory have revealed that the essential oil extract from agarwood inhibited colorectal carcinoma cells. Despite of the wide range of ethno-pharmacological uses of agarwood, its toxicity has not been previously evaluated through systematic toxicological studies. Therefore, the potential safety of essential oil extract and its in vivo anti-tumor activity had been investigated. In the acute toxicity study, Swiss female mice were given a single dose of the essential oil extract at 2000 mg/kg/day orally and screened for two weeks after administration. Meanwhile, in the sub-chronic study, two different doses of the extract were administered for 28 days. Mortality, clinical signs, body weight changes, hematological and biochemical parameters, gross findings, organ weights, and histological parameters were monitored during the study. Other than that, in vivo anti-tumor study was assessed by using subcutaneous tumors model established in nude mice. The acute toxicity study showed that the LD50 of the extract was greater than 2000 mg/kg. In the repeated dose for 28-day oral toxicity study, the administration of 100 mg/kg and 500 mg/kg of essential oil per body weight revealed insignificant difference in food and water intakes, bodyweight change, hematological and biochemical parameters, relative organ weights, gross findings or histopathology compared to the control group. Nevertheless, the essential oil extract, when supplemented to nude mice, caused significant growth inhibition of the subcutaneous tumor of HCT 116 colorectal carcinoma cells. Collectively, the data obtained indicated that essential oil extract from agarwood might be a safe material, and this essential oil is suggested as a potential anti-colon cancer candidate.

Subchronic toxicity study of corn silk with rats.

PubMed

Wang, Cuina; Zhang, Tiehua; Liu, Jun; Lu, Shuang; Zhang, Cheng; Wang, Erlei; Wang, Zuozhao; Zhang, Yan; Liu, Jingbo

2011-09-01

Corn silk is a traditional herbal medicine in China, which has been used in many parts of the world for the treatment of edema as well as for cystitis, gout, kidney stones, nephritis, prostatitis and similar ailments. However, there is little scientific evidence about its safety. As a part of its safety assessment, a subchronic toxicity was performed in this paper. The subchronic toxicity was investigated in male and female Wistar rats by dietary administration at concentrations of 0.5%, 2.0% and 8.0% (w/w) for 90 days. Overall health, body weight, food consumption, hematology, blood chemistry, organ weights, gross and microscopic appearance of tissues were compared between test and control groups. A number of significant differences were seen between groups, but none of them was considered to be adverse. Based on the present study, the no-observed-adverse-effect level (NOAEL) of corn silk is at least 8.0% which corresponds to a mean daily corn silk intake of approximately 9.354 and 10.308 g/day/kg body weight for males and females, respectively. The results obtained in the present study suggest that consumption of corn silk has no adverse effects and support the safety of corn silk for humans. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Evaluation of multiwalled carbon nanotubes toxicity in two fish species.

PubMed

Cimbaluk, Giovani Valentin; Ramsdorf, Wanessa Algarte; Perussolo, Maiara Carolina; Santos, Hayanna Karla Felipe; Da Silva De Assis, Helena Cristina; Schnitzler, Mariane Cristina; Schnitzler, Danielle Caroline; Carneiro, Pedro Gontijo; Cestari, Marta Margarete

2018-04-15

Carbon Nanotubes are among the most promising materials for the technology industry. Their unique physical and chemical proprieties may reduce the production costs and improve the efficiency of a large range of products. However, the same characteristics that have made nanomaterials interesting for industry may be responsible for inducing toxic effects on the aquatic organisms. Since the carbon nanotubes toxicity is still a controversial issue, we performed tests of acute and subchronic exposure to a commercial sample of multiwalled carbon nanotubes in two fish species, an exotic model (Danio rerio) and a native one (Astyanax altiparanae). Using the alkaline version of the comet assay on erythrocytes and the piscine micronucleous, also performed on erythrocytes, it was verified that the tested carbon nanotubes sample did not generate apparent genotoxicity by means of single/double DNA strand break or clastogenic/aneugenic effects over any of the species, independently of the exposure period. Although, our findings indicate the possibility of the occurrence of CNTs-DNA crosslinks. Apparently, the sample tested induces oxidative stress after subchronic exposure as shown by activity of superoxide dismutase and catalase. The data obtained by the activity levels of acetylcholinesterase suggests acute neurotoxicity in Astyanax altiparanae and subchronic neurotoxicity in Danio rerio. Copyright © 2017 Elsevier Inc. All rights reserved.

Safety evaluation of phytosterol esters. Part 8. Lack of genotoxicity and subchronic toxicity with phytosterol oxides.

PubMed

Lea, L J; Hepburn, P A; Wolfreys, A M; Baldrick, P

2004-05-01

Vegetable oil spreads containing phytosterol-esters are marketed as a cholesterol-lowering functional food in more than 20 countries worldwide. An extensive package of safety data has shown phytosterol-esters to be safe for human use. However, even though phytosterols are very stable molecules, oxidation may occur at low levels under extreme heating conditions, resulting in phytosterol oxides. As there is some suggestion of adverse biological effects in the literature for the related cholesterol oxidation products, safety data have been generated for phytosterol oxides. A phytosterol oxide concentrate (POC) was generated by prolonged heating of phytosterol-esters in the presence of oxygen. The genotoxicity and subchronic toxicity of this mixture was assessed in a series of in vitro genotoxicity assays (bacterial mutation, chromosome aberration and micronucleus) and a subchronic feeding study in the rat. Results showed that a phytosterol oxide concentrate containing approximately 30% phytosterol oxides did not possess genotoxic potential and no obvious evidence of toxicity when administered in the diet of the rat for 90 consecutive days. In the latter study, a NOEL was established at an estimated dietary level of phytosterol oxides of 128 mg/kg/day for males and 144 mg/kg/day for females. In conclusion, these materials have been shown to raise no obvious concerns for human safety.

Sub-chronic safety evaluation of the ethanol extract of Aralia elata leaves in Beagle dogs.

PubMed

Li, Fengjin; He, Xiaoli; Niu, Wenying; Feng, Yuenan; Bian, Jingqi; Kuang, Haixue; Xiao, Hongbin

2016-08-01

Aralia elata Seem. (A. elata) is a traditional Chinese medicine to treat some diseases. This investigation aims to evaluate the pharmaceutical safety of the ethanol extract of A. elata leaves, namely ethanol leaves extract (ELE), in Beagle dogs. In sub-chronic oral toxicity study, dogs were treated with the ELE at doses of 50, 100 and 200 mg/kg for 12 weeks and followed by 4 weeks recovery period. During experimental period, clinical signs, mortality, body temperature, food consumption and body weight were recorded. Analysis of electrocardiogram, urinalysis, ophthalmoscopy, hematology, serum biochemistry, organ weights and histopathology were performed. The results showed that both food consumption and body weight significantly decreased in high-dose group. Treatment-related side effects and mortality were observed in high-dose female dogs. Some parameters showed significant alterations in electrocardiogram, urinalysis, serum biochemistry and relative organ weights. These alterations were not related to dose or consistent across gender, which were ascribed to incidental and biological variability. The findings in this study indicated that the no-observed adverse effect level (NOAEL) of the ELE was 100 mg/kg in dogs and provided a vital reference for selecting a safe application dosage for human consumption. Copyright © 2016 Elsevier Inc. All rights reserved.

The properties of red seaweed (Kappaphycus alvarezii) and its effect on mammary carcinogenesis.

PubMed

Chang, Vi-Sion; Okechukwu, Patrick N; Teo, Swee-Sen

2017-03-01

The edible red seaweed (Kappaphycus alvarezii) is one of the algae species which was found to be rich in nutrients and nutraceutical. Hence, K. alvarezii may have the ability to suppress cancer through its antiproliferative properties. The aim of this study was to investigate the potential compounds of K. alvarezii, cytotoxicity properties of K. alvarezii extract on breast cancer cell line (MCF-7), investigated toxicity effect of high dosage K. alvarezii extract in rats and determined the effect of K. alvarezii on 7, 12-dimethylbenz[a]anthracene (DMBA) mammary carcinogenesis in rats. The method of LCMS/MS and MTT assay were used. For animal study, sub-chronic toxicity method was used, the rats were supplemented with 2000mg/kg body weight daily of K. alvarezii crude extracts by oral gavage. For the anticancer effect of K. alvarezii crude extracts, this study consisted of three groups of the experimental, untreated and normal group of rats. The experimental and untreated groups of rats were induced with mammary tumour with DMBA. The experimental group of rats was given with K. alvarezii crude extracts orally. The results were being used to compare with the untreated group of rats and normal group of rats. All the rats were fed with standard diet and water ad libitum. Mortality, behavior changes and tumour sizes were observed specifically. The differences between the three groups of rats were evaluated by using the ANOVA test. By using LCMS/MS method, six unknown compounds were analysed. K. alvarezii crude extract reduced the cell viability of MCF-7 from 84.91% to 0.81% and the IC 50 value is 4.1±0.69mg/mL. For sub-chronic and heavy metal toxicity studies, no significant difference was found in haematological and biochemical values of the control group and experimental group. The growth rate of tumours in the untreated group of rats was found significantly higher than the experimental group of rats. Besides that, the white blood cells level in untreated group was found significantly higher than the experimental group and the normal group. In conclusion, K. alvarezii extract might able to slow down the growth rate of the tumour cells, therefore, identification of an active compound of inhibition growth rate of the tumour cells can be positively carried out in the future. Copyright © 2016. Published by Elsevier Masson SAS.

The effect of tramadol hydrochloride on early life stages of fish.

PubMed

Sehonova, Pavla; Plhalova, Lucie; Blahova, Jana; Berankova, Petra; Doubkova, Veronika; Prokes, Miroslav; Tichy, Frantisek; Vecerek, Vladimir; Svobodova, Zdenka

2016-06-01

The aim of this study was to perform the fish embryo acute toxicity test (FET) on zebrafish (Danio rerio) and the early-life stage toxicity test on common carp (Cyprinus carpio) with tramadol hydrochloride. The FET was performed using the method inspired by the OECD guideline 236. Newly fertilized zebrafish eggs were exposed to tramadol hydrochloride at concentrations of 10; 50; 100 and 200μg/l for a period of 144h. An embryo-larval toxicity test on C. carpio was performed according to OECD guideline 210 also with tramadol hydrochloride at concentrations 10; 50; 100 and 200μg/l for a period of 32 days. Hatching was significantly influenced in both acute and subchronic toxicity assays. Subchronic exposure also influenced early ontogeny, both morphometric and condition characteristics and caused changes in antioxidant enzyme activity. The LOEC value was found to be 10μg/l tramadol hydrochloride. Copyright © 2016 Elsevier B.V. All rights reserved.

Mutagenicity Evaluation of Ammonium Picrate in the Ames Salmonella/Microsome Plate Test. Segment Report,

DTIC Science & Technology

1979-02-01

used by the I study director, and any % ppendices . All test and control results presented in this report are suppreted by raw data .which are permanently...dosage selection results are presented in Table 1. The acute and subchronic test results have been collected from raw data sheets and tabulated in...breakage in bone marrow cells of mice following oral exposure (per os). Both acute and subchronic dosing schedules were employed in this assay. Results

Subchronic exposure of benzo(a)pyrene interferes with the expression of Bcl-2, Ki-67, C-myc and p53, Bax, Caspase-3 in sub-regions of cerebral cortex and hippocampus.

PubMed

He, Jianlong; Ji, Xiaoying; Li, Yongfei; Xue, Xiaochang; Feng, Guodong; Zhang, Huqin; Wang, Huichun; Gao, Meilii

2016-01-01

Benzo[a]pyrene [B(a)P], a representative substance of the polycyclic aromatic hydrocarbons, is an ubiquitous environmental contaminant. However, the mechanism of B(a)P neurotoxicity is still not clear. The aim of this study was to investigate the molecular mechanism by assay the expression of Bcl-2, C-myc, Ki-67 oncogene and p53, Bax, Caspase-3 proapoptotic gene in sub-regions of cerebral cortex and hippocampus in brain. Mice were administrated with subchronic intraperitoneal injection and oral gavage of B(a)P (2.5, 5, 10mg/kg body weight) for 13 weeks. We observed that B(a)P induced the significant increase in relative brain weights and the slight proliferation phenomenon in hippocampus in the experiment. Significant increase of C-myc, Ki-67 and p53, Bax, Caspase-3 and dramatic decrease of Bcl-2 protein levels were observed through immunohistochemical analysis. The relative higher interference of Bcl-2, C-myc, Ki-67 and p53, Bax, Caspase-3 proteins was observed in hippocampus sub-regions of dentate gyrus, cornu ammonis 3 and cornu ammonis 1. The relative lower interference of the examined genes was found in cerebral cortex sub-regions of frontal cortex, temporal cortex and parietal cortex. The results showed a region-difference manner with accompanying dose-dependent manner in brain hippocampus and cerebral cortex induced by B(a)P. These findings indicate that B(a)P-induced subchronic neural toxicity may occur through the enhancement in Bcl-2, C-myc, Ki-67 oncogenes and p53, Bax, Caspase-3 proapoptotic genes expression. Copyright © 2015 Elsevier GmbH. All rights reserved.

Biochemical alterations induced by oral subchronic exposure to fipronil, fluoride and their combination in buffalo calves.

PubMed

Gill, Kamalpreet Kaur; Dumka, Vinod Kumar

2013-11-01

The effects of various pesticides and minerals on biochemical parameters have been explored in different species, but hardly any data exist regarding the combined toxicological effect of pesticides and minerals on these parameters in animals. The present study investigated the effects of fipronil and fluoride co-exposure on biochemical parameters in buffalo calves. Twenty-four healthy male buffalo calves divided into four groups were treated for 98 consecutive days. Group I, receiving no treatment served as the control. Animals of groups II and III were orally administered with fipronil @ 0.5mg/kg/day and sodium fluoride (NaF) @ 6.67 mg/kg/day, respectively, for 98 days. An additional group IV was co-administered fipronil and NaF at the same dosages as groups II and III. Administration of fipronil alone produced mild toxic signs, significant elevation in plasma proteins, blood glucose, blood urea nitrogen (BUN) and significant decline in the plasma cholesterol levels. NaF exposure produced toxic signs specifically of muscle weakness and brown and black discoloration of teeth. Significant elevation was seen in whole blood cholinesterase, BUN and creatinine levels. However, it produced significant decline in blood glucose, cholesterol and plasma protein levels. Combined exposure to fipronil and sodium fluoride produced toxic signs with greater intensity while biochemical alterations produced were similar to those that were produced by their individual exposures. Copyright © 2013 Elsevier B.V. All rights reserved.

A preliminary safety evaluation of polyhexamethylene guanidine hydrochloride.

PubMed

Asiedu-Gyekye, Isaac Julius; Mahmood, Seidu Abdulai; Awortwe, Charles; Nyarko, Alexander Kwadwo

2014-01-01

Polyhexamethylene guanidine hydrochloride (PHMGH) is used worldwide as an antimicrobial agent with broad spectra of activity and also for treating pool water. This non-GLP preliminary study aims at investigating in a subchronic toxicity study possible effects at supra-optimal doses of this biocide. Both acute and subchronic toxicity studies were conducted. LD(50) for PHMGH was estimated to be 600 mg/kg (ie LC(50) 2 ml of 7.5% solution) when administered as a single dose by gavage via a stomach tube in accordance with the expected route of administration. The acute studies showed that the median lethal dose (LD(50)) of 600 mg/kg was accompanied by signs of neurotoxicity. Haematological and biochemical parameters of subchronic toxicity studies were non-significant. Subchronic doses of 0.006 mg/kg, 0.012 mg/kg and 0.036 mg/kg were administered. 20% of the animals at a dose of 0.006 mg/kg and 0.036 mg/kg showed mild degrees of hydropic changes in proximal tubules while 10% of animals at all the doses had their liver tissues showing local areas of mild pericentral hepatocytes degeneration. PHMGH did not produce any major organ defect with regard to the kidney, heart, and liver. The LD(50) was much higher than the recommended dosage by a factor of about 50,000. The recommended residual concentration is far less than the median lethal dose using rats as test subjects. These results could serve as a basis for investigating the full toxicological profile if it is to be used for the treatment of raw water to make it potable. © The Author(s) 2014.

Ecotoxicological evaluation of industrial port of Venice (Italy) sediment samples after a decontamination treatment.

PubMed

Libralato, Giovanni; Losso, Chiara; Arizzi Novelli, Alessandra; Citron, Marta; Della Sala, Stefano; Zanotto, Emanuele; Cepak, Franka; Volpi Ghirardini, Annamaria

2008-12-01

This work assesses the ecotoxicological effects of polluted sediment after a decontamination treatment process using a new sediment washing technique. Sediment samples were collected from four sites in Marghera Port industrial channels (Venice, Italy). Ecotoxicological evaluations were performed with Vibrio fischeri and Crassostrea gigas bioassays. Whole sediment and elutriate were deemed as the most suitable environmental matrices for this study. Toxicity scores developed in the Lagoon of Venice for V. fischeri on whole sediment and for C. gigas on elutriate were considered for the final ranking of samples. Ecotoxicological results showed that the treated sediment samples presented both acute and sub-chronic toxicities, which were mainly attributed to the presence of some remaining chemicals such as metals and polyaromatic hydrocarbons. The acute toxicity ranged from low to medium, while the sub-chronic one from absent to very high, suggesting that treated sediments could not be reused in direct contact with seawater.

Identification of novel uncertainty factors and thresholds of toxicological concern for health hazard and risk assessment: Application to cleaning product ingredients.

PubMed

Wang, Zhen; Scott, W Casan; Williams, E Spencer; Ciarlo, Michael; DeLeo, Paul C; Brooks, Bryan W

2018-04-01

Uncertainty factors (UFs) are commonly used during hazard and risk assessments to address uncertainties, including extrapolations among mammals and experimental durations. In risk assessment, default values are routinely used for interspecies extrapolation and interindividual variability. Whether default UFs are sufficient for various chemical uses or specific chemical classes remains understudied, particularly for ingredients in cleaning products. Therefore, we examined publicly available acute median lethal dose (LD50), and reproductive and developmental no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values for the rat model (oral). We employed probabilistic chemical toxicity distributions to identify likelihoods of encountering acute, subacute, subchronic and chronic toxicity thresholds for specific chemical categories and ingredients in cleaning products. We subsequently identified thresholds of toxicological concern (TTC) and then various UFs for: 1) acute (LD50s)-to-chronic (reproductive/developmental NOAELs) ratios (ACRs), 2) exposure duration extrapolations (e.g., subchronic-to-chronic; reproductive/developmental), and 3) LOAEL-to-NOAEL ratios considering subacute/acute developmental responses. These ratios (95% CIs) were calculated from pairwise threshold levels using Monte Carlo simulations to identify UFs for all ingredients in cleaning products. Based on data availability, chemical category-specific UFs were also identified for aliphatic acids and salts, aliphatic alcohols, inorganic acids and salts, and alkyl sulfates. In a number of cases, derived UFs were smaller than default values (e.g., 10) employed by regulatory agencies; however, larger UFs were occasionally identified. Such UFs could be used by assessors instead of relying on default values. These approaches for identifying mammalian TTCs and diverse UFs represent robust alternatives to application of default values for ingredients in cleaning products and other chemical classes. Findings can also support chemical substitutions during alternatives assessment, and data dossier development (e.g., read across), identification of TTCs, and screening-level hazard and risk assessment when toxicity data is unavailable for specific chemicals. Copyright © 2018 Elsevier Ltd. All rights reserved.

Safety assessment of astaxanthin derived from engineered Escherichia coli K-12 using a 13-week repeated dose oral toxicity study and a prenatal developmental toxicity study in rats.

PubMed

Lin, Yin-Ju; Lin, Jian-Yu; Wang, Di-Sheng; Chen, Chien-Hao; Chiou, Ming-Hsi

2017-07-01

Astaxanthin is a natural carotenoid with strong antioxidant activity that has been used for decades as a nutrient/color additive and it has recently been marketed as a health supplement. Astaxanthin can be synthesized in a wide range of microalgae, yeast, and bacteria. As genes directing astaxanthin biosynthesis in various organisms have been cloned, this study assessed the safety of astaxanthin crystal produced by Escherichia coli K-12 harboring plasmids carrying astaxanthin biosynthetic genes. The astaxanthin crystal contains a total carotenoid content of 950 mg/g and an astaxanthin content of 795 mg/g. Subchronic oral toxicity and prenatal developmental toxicity of the astaxanthin in rats were conducted in accordance with the Guidelines of Health Food Safety Assessment promulgated by Food and Drug Administration of Taiwan which is based on OECD guidelines 408 and 414. Both male and female Sprague-Dawley (SD) rats (12 for each gender) receiving the astaxanthin crystal at 1.2, 240.0, or 750.0 mg/kg/day in olive oil via oral gavage for 90 days showed no changes in body weight gains, hematology and serum chemistry values and hepatic enzyme stability, organ integrity and organ weight. Except the higher food consumption observed in rats receiving 750.0 mg/g astaxanthin crystal, administration of the astaxanthin crystal to 25-27 pregnant female rats in each group throughout the period of organogenesis (G6-G15) produced no adverse effects on fetal organogenesis. Based on the results, we propose that the no-observable-adverse-effect level (NOAEL) of the astaxanthin crystal extracted from genetically modified E. coli K-12 is 750.0 mg/kg bw/day. Copyright © 2017 Elsevier Inc. All rights reserved.

AN "INJURY-TIME INTEGRAL" MODEL FOR RELATING ACUTE TO CHRONIC INJURY TO PHOSGENE

EPA Science Inventory

ABSTRACT
The present study compares acute and subchronic episodic exposures to phosgene to test the applicability of the "concentration x time" (C x T) product as a measure of exposure dose, and to relate acute toxicity and adaptive responses to chronic toxicity. Rats (m...

Safety assessment of non-animal chondroitin sulfate sodium: Subchronic study in rats, genotoxicity tests and human bioavailability.

PubMed

Miraglia, Niccolò; Bianchi, Davide; Trentin, Antonella; Volpi, Nicola; Soni, Madhu G

2016-07-01

Chondroitin sulfate, an amino sugar polymer made of glucuronic acid and N-acetyl-galactosamine, is used in dietary supplements to promote joint health. Commonly used chondroitin sulfate is of animal origin and can pose potential safety problems including bovine spongiform encephalopathy (BSE). The objective of the present study was to investigate potential adverse effects, if any, of microbial derived chondroitin sulfate sodium (CSS) in subchronic toxicity, genotoxicity and bioavailability studies. In the toxicity study, Sprague Dawley rats (10/sex/group) were gavaged with CSS at dose levels of 0, 250, 500 and 1000 mg/kg body weight (bw)/day for 90-days. No mortality or significant changes in clinical signs, body weights, body weight gain or feed consumption were noted. Similarly, no toxicologically relevant treatment-related changes in hematological, clinical chemistry, urinalysis and organ weights were noted. Macroscopic and microscopic examinations did not reveal treatment-related abnormalities. In vitro mutagenic and clastogenic potentials as evaluated by Ames assay, chromosomal aberration test and micronucleus assay did not reveal genotoxicity of CSS. In pharmacokinetic study in human, CSS showed higher absorption as compared to chondroitin sulfate of animal origin. The results of subchronic toxicity study supports the no-observed-adverse-effect level (NOAEL) for CSS as 1000 mg/kg bw/day, the highest dose tested. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of hypoglycemic and anti-hyperglycemic potential of Tridax procumbens (Linn.).

PubMed

Pareek, Hemant; Sharma, Sameer; Khajja, Balvant S; Jain, Kusum; Jain, G C

2009-11-29

Diabetes is a metabolic disorder affecting carbohydrate, fat and protein metabolism. Tridax procumbens Linn. (Family-Asteraceae; common name-Dhaman grass) is common herb found in India. Traditionally, the tribal inhabitants of Udaipur district in Rajasthan (India) uses the leaf powder (along with other herb) orally to treat diabetes. There is a need to evaluate extracts of this plant in order to provide scientific proof for it's application in traditional medicine system. Extraction of whole plant of T. procumbens using 50%methanol. The extract was tested for acute and sub-chronic anti-hyperglycemic activity in alloxan induced diabetic rats and for acute toxicity test among normal rats. Observations on body weight as well as on the oral glucose tolerance levels were also recorded. Oral administration of acute and sub chronic doses (250 and 500 mg/kg b.wt.) of T. procumbens extract showed a significant (p < 0.05) reduction in fasting blood glucose levels in diabetic rats, however the decline in blood sugar levels in normal rats was not observed. In acute study the maximum percent blood glucose reduction (68.26% at 250 mg/kg and 71.03% at 500 mg/kg body weight) in diabetic rats was observed at 6 h. The anti-hyperglycemic effects were not dependent of dose and the OGTT and Body weight supported the antihyperglycemic action of the drug. The results of anti-diabetic effect of T. procumbens were compared with the reference standard drug Glibenclamide (10 mg/kg b.wt.). These test results support traditional medicinal use of, T. procumbens for the treatment of diabetes mellitus with corrections in body weight and oral glucose tolerance and no visible signs or symptoms of toxicity in normal rats indicating a high margin of safety. These results warrant follow-up through bioassay-directed isolation of the active principles.

Toxic Hazards Research Unit 1989

DTIC Science & Technology

1990-10-01

frequently be developed to drive the experimental design and to assist in risk avsessments. The Toxic Hazards Division, Harry G. Armstrong Aerospace...postexposure, respectively. The experimental design (Section 3.3, Subchronic Inhalation Toxicity Studies on 3.1 Oil at Concentrations of 250, 50, and...sodium salt and the pH was adjusted to 7.4. 101 EXPERIMENTAL DESIGN Initiation Assessment A total of seven groups consisting of eight animals per

Acute and sub-chronic toxicity study of diaveridine in Wistar rats.

PubMed

Wang, Xu; Su, Shijia; Ihsan, Awais; Huang, Qin; Chen, Dongmei; Cheng, Guyue; Liu, Zhenli; Wang, Yulian; Yuan, Zonghui

2015-10-01

Diaveridine, a developed dihydrofolate reductase inhibitor, has been widely used as anticoccidial drug and antibacterial synergist. However, few studies have been performed to investigate its toxicity. To provide detailed toxicity with a wide spectrum of doses for diaveridine, acute and sub-chronic toxicity studies were conducted. Calculated LD50 was 2330 mg/kg b.w. in females and 3100 mg/kg b.w. in males, and chromodacryorrhea was noted in some females before their death. In the sub-chronic study, diaveridine was fed to Wistar rats during 90 days at dietary levels of 0, 23, 230, 1150 and 2000 mg/kg, which were about 0, 2.0-2.3, 21.0-23.5, 115.2-126.9 and 212.4-217.9 mg/kg b.w., respectively. Significant decrease in body weights in both genders at 1150 and 2000 mg/kg groups and significant increases in relative weights of brain in both genders, liver in females, kidneys and testis in males, alkaline phosphatase and potassium in both genders at 2000 mg/kg diet were noted. Significant decrease in absolute weights of several organs, hemoglobin and red blood cell count in both genders, albumin and total protein in females were observed at 2000 mg/kg diet. Fibroblasts in the kidneys, cell swelling of the glomerular zone in the adrenals and inflammation in the liver were found at 2000 mg/kg group. The no-observed-adverse-effect level of diaveridine was 230 mg/kg diet (21.0-23.5 mg/kg b.w./day). Copyright © 2015 Elsevier Inc. All rights reserved.

Acute and subchronic toxicity analysis of surface modified paclitaxel attached hydroxyapatite and titanium dioxide nanoparticles.

PubMed

Venkatasubbu, Gopinath Devanand; Ramasamy, S; Gaddam, Pramod Reddy; Kumar, J

2015-01-01

Nanoparticles are widely used for targeted drug delivery applications. Surface modification with appropriate polymer and ligands is carried out to target the drug to the affected area. Toxicity analysis is carried out to evaluate the safety of the surface modified nanoparticles. In this study, paclitaxel attached, folic acid functionalized, polyethylene glycol modified hydroxyapatite and titanium dioxide nanoparticles were used for targeted drug delivery system. The toxicological behavior of the system was studied in vivo in rats and mice. Acute and subchronic studies were carried out. Biochemical, hematological, and histopathological analysis was also done. There were no significant alterations in the biochemical parameters at a low dosage. There was a small change in alkaline phosphatase (ALP) level at a high dosage. The results indicate a safe toxicological profile.

40 CFR 79.62 - Subchronic toxicity study with specific health effect assessments.

Code of Federal Regulations, 2014 CFR

2014-07-01

... exposure and control groups are anaesthetized and heart punctures are performed on all members. After... control group when combining a 90-day toxicity study with a fertility assessment. (C) The tester shall provide a group of 10 animals (five animals per sex per experimental/control groups) in addition to the...

40 CFR 79.62 - Subchronic toxicity study with specific health effect assessments.

Code of Federal Regulations, 2013 CFR

2013-07-01

... exposure and control groups are anaesthetized and heart punctures are performed on all members. After... control group when combining a 90-day toxicity study with a fertility assessment. (C) The tester shall provide a group of 10 animals (five animals per sex per experimental/control groups) in addition to the...

40 CFR 79.62 - Subchronic toxicity study with specific health effect assessments.

Code of Federal Regulations, 2011 CFR

2011-07-01

... exposure and control groups are anaesthetized and heart punctures are performed on all members. After... control group when combining a 90-day toxicity study with a fertility assessment. (C) The tester shall provide a group of 10 animals (five animals per sex per experimental/control groups) in addition to the...

40 CFR 79.62 - Subchronic toxicity study with specific health effect assessments.

Code of Federal Regulations, 2012 CFR

2012-07-01

... exposure and control groups are anaesthetized and heart punctures are performed on all members. After... control group when combining a 90-day toxicity study with a fertility assessment. (C) The tester shall provide a group of 10 animals (five animals per sex per experimental/control groups) in addition to the...

40 CFR 79.62 - Subchronic toxicity study with specific health effect assessments.

Code of Federal Regulations, 2010 CFR

2010-07-01

... exposure and control groups are anaesthetized and heart punctures are performed on all members. After... control group when combining a 90-day toxicity study with a fertility assessment. (C) The tester shall provide a group of 10 animals (five animals per sex per experimental/control groups) in addition to the...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2010 CFR

2010-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2013 CFR

2013-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2014 CFR

2014-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2012 CFR

2012-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2011 CFR

2011-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

Further development of the theory and mathematical description of combined toxicity: An approach to classifying types of action of three-factorial combinations (a case study of manganese-chromium-nickel subchronic intoxication).

PubMed

Katsnelson, Boris A; Panov, Vladimir G; Minigaliyeva, Ilzira A; Varaksin, Anatoly N; Privalova, Larisa I; Slyshkina, Tatyana V; Grebenkina, Svetlana V

2015-08-06

For characterizing the three-factorial toxicity, we proposed a new health risk-oriented approach, the gist of which is a classification of effects depending on whether a binary combined toxicity's type remains virtually the same or appears to be either more or less adverse when modeled against the background of a third toxic. To explore possibilities of this approach, we used results of an experiment in which rats had been injected ip 3 times a week (up to 20 injections) with a water solution of either one of the toxics (Mn, Ni or Cr-VI salts) in a dose equivalent to 0.05 LD50, or any two of them, or all the three in the same doses, the controls receiving injections of the same volume of distilled water (4mL per rat). Judging by more than 30 indices for the organism's status, all exposures caused subchronic intoxication of mild to moderate strength. For each two-factorial exposure, we found by mathematical modeling based on the isobolograms that the binary combined subchronic toxicity either was of additive type or departed from it (predominantly toward subadditivity) depending on the effect assessed, dose, and effect level. For the three-factorial combination, different classes of effects were observed rather consistently: class A - those regarding which the third toxic's addition made the binary toxicity type more unfavorable for the organism, class B - those regarding which the result was opposite, and class C - those regarding which the type of binary combined toxicity on the background of a third toxic virtually remained the same as in its absence. We found a complicated reciprocal influence of combined metals on their retention in kidneys, liver, spleen and brain which might presumably be one of the possible mechanisms of combined toxicity, but the lack of an explicit correspondence between the above influence and the influence on toxicity effects suggests that this mechanism is not always the most important one. The relevance of the proposed classification to health risk analysis and management is briefly discussed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs.

PubMed

Johnson, William D; Muzzio, Miguel; Detrisac, Carol J; Kapetanovic, Izet M; Kopelovich, Levy; McCormick, David L

2011-11-18

CP-31398 (N'-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride) is a styrylquinazoline that stabilizes the DNA binding conformation of p53, thereby maintaining the activity of p53 as a transcription factor and tumor suppressor. In consideration of the potential use of p53 stabilizers for cancer prevention and therapy, 28-day studies (with recovery) were performed to characterize the toxicity of CP-31398 in rats and dogs. In the rat study, groups of 15 CD rats/sex received daily gavage exposure to CP-31398 at 0, 40, 80, or 160mg/kg/day (0, 240, 480, or 960mg/m(2)/day). In the dog study, groups of five beagle dogs received daily gavage exposure to CP-31398 at 0, 10, 20, or 40mg/kg/day (0, 200, 400, or 800mg/m(2)/day). The high dose of CP-31398 induced mortality in both species: seven male rats and four female rats died as a result of hepatic infarcts, and two female dogs died as a result of hepatic necrosis without evidence of thrombosis. No deaths were seen in the mid- or low-dose groups in either species. In dogs, sporadic emesis was seen in the high dose and mid dose groups, and reductions in body weight gain were observed in all drug-exposed groups. CP-31398 induced mild anemia in both species; clinical pathology data also demonstrated hepatic toxicity, renal toxicity, inflammatory reactions, and coagulopathies in rats in the high dose and mid dose groups. Treatment-related microscopic changes in high dose and mid dose rats were identified in the liver, kidney, heart, bone marrow, lung, adrenals, spleen, thymus, skeletal muscle, and ovary; microscopic changes in the liver, heart, lung, and adrenals persisted through the recovery period. In dogs, microscopic changes were identified in the central nervous system, lung, and liver; changes in all tissues remained at the end of the recovery period. The liver is the primary site of limiting toxicity for CP-31398 in rats, and is also a key site of toxicity in dogs. The maximum tolerated dose (MTD) for subchronic oral administration of CP-31398 is 80mg/kg/day (480mg/m(2)/day) in rats and 20mg/kg/day (400mg/m(2)/day) in dogs. Although only modest and apparently reversible toxicities (microscopic changes in rats; reductions in body weight gain and alterations in red cell parameters in dogs) were seen in the low dose groups, no observed adverse effect levels (NOAELs) for CP-31398 could not be established for either species. The toxicity of CP-31398 suggests that this agent may not be suitable for use in cancer prevention. However, should in vivo antitumor efficacy be achievable at doses that do not induce limiting toxicity, CP-31398 may have utility as a cancer therapeutic. Modification of the primary sites of CP-31398 metabolism (N-demethylation of the alkyl side chain; hydroxylation and O-demethylation of the styryl benzene group) may result in the development of CP-31398 analogs with comparable pharmacologic activity and reduced toxicity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs

PubMed Central

Johnson, William D.; Muzzio, Miguel; Detrisac, Carol J.; Kapetanovic, Izet M.; Kopelovich, Levy; McCormick, David L.

2011-01-01

CP-31398 (N′-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride) is a styrylquinazoline that stabilizes the DNA binding conformation of p53, thereby maintaining the activity of p53 as a transcription factor and tumor suppressor. In consideration of the potential use of p53 stabilizers for cancer prevention and therapy, 28-day studies (with recovery) were performed to characterize the toxicity of CP-31398 in rats and dogs. In the rat study, groups of 15 CD rats/sex received daily gavage exposure to CP-31398 at 0, 40, 80, or 160 mg/kg/day (0, 240, 480, or 960 mg/m2/day). In the dog study, groups of five beagle dogs received daily gavage exposure to CP-31398 at 0, 10, 20, or 40 mg/kg/day (0, 200, 400, or 800 mg/m2/day). The high dose of CP-31398 induced mortality in both species: seven male rats and four female rats died as a result of hepatic infarcts, and two female dogs died as a result of hepatic necrosis without evidence of thrombosis. No deaths were seen in the mid- or low dose groups in either species. In dogs, sporadic emesis was seen in the high dose and mid dose groups, and reductions in body weight gain were observed in all drug-exposed groups. CP-31398 induced mild anemia in both species; clinical pathology data also demonstrated hepatic toxicity, renal toxicity, inflammatory reactions, and coagulopathies in rats in the high dose and mid dose groups. Treatment-related microscopic changes in high dose and mid dose rats were identified in the liver, kidney, heart, bone marrow, lung, adrenals, spleen, thymus, skeletal muscle, and ovary; microscopic changes in the liver, heart, lung, and adrenals persisted through the recovery period. In dogs, microscopic changes were identified in the central nervous system, lung, and liver; changes in all tissues remained at the end of the recovery period. The liver is the primary site of limiting toxicity for CP-31398 in rats, and is also a key site of toxicity in dogs. The Maximum Tolerated Dose (MTD) for subchronic oral administration of CP-31398 is 80 mg/kg/day (480 mg/m2/day) in rats and 20 mg/kg/day (400 mg/m2/day) in dogs. Although only modest and apparently reversible toxicities (microscopic changes in rats; reductions in body weight gain and alterations in red cell parameters in dogs) were seen in the low dose groups, No Observed Adverse Effect Levels (NOAELs) for CP-31398 could not be established for either species. The toxicity of CP-31398 suggests that this agent may not be suitable for use in cancer prevention. However, should in vivo antitumor efficacy be achievable at doses that do not induce limiting toxicity, CP-31398 may have utility as a cancer therapeutic. Modification of the primary sites of CP-31398 metabolism (N-demethylation of the alkyl side chain; hydroxylation and O-demethylation of the styryl benzene group) may result in the development of CP-31398 analogs with comparable pharmacologic activity and reduced toxicity. PMID:21864638

In vivo toxicity of the culturable marine cyanobacterium Geitlerinema pseudacutissimum CNP 1019 extract on male Swiss albino mice (Mus musculus).

PubMed

Maruthanayagam, Veerabadhran; Nagarajan, Manivel; Sundararaman, Muthuraman

2014-01-01

In this study, we investigated the in vivo toxicity of Geitlerinema pseudacutissimum CNP 1019 organic extract in a murine host. A single intraperitoneal injection of 1 g extract kg⁻¹ body weight (BW) did not exhibit mortality, whereas 3 g extract kg⁻¹ BW (approximate lethal dose) resulted in mortality within 5 days. To perform subchronic exposure toxicity analyses (i.e., daily exposure for a total of 14 days), a maximum concentration of ≤1 g extract kg⁻¹ BW was used. Subchronic toxicity studies in the treated mice, showed fluctuations of feed intake, loss of body weight, increase in specific activity of serum lactate dehydrogenase, alanine aminotransferase and decrease in whole serum protein concentration. LDH isoenzyme expression was found, and levels of the various isoforms were decreased as a result of the treatment. Histopathology studies in liver, kidney, and spleen isolated from the treated mice showed the presence of necrotic debris, hemorrhage, and micronuclei revealing the toxicity of the extract. The dose-dependent alterations in biochemical parameters in conjunction with the histological lesions noted in the animals treated with the prepared extract illustrate the likely potential toxicity to mammals from any encounters with the studied cyanobacterium.

40 CFR 799.1575 - Diethylenetriamine (DETA).

Code of Federal Regulations, 2013 CFR

2013-07-01

.../Importers Alliance (DPIA): “Ninety-Day (subchronic) dietary toxicity study with diethylenetriamine in albino.... The effective date for paragraph (d)(2) of this section is May 21, 1991. (2) The guidelines and other...

40 CFR 799.1575 - Diethylenetriamine (DETA).

Code of Federal Regulations, 2014 CFR

2014-07-01

.../Importers Alliance (DPIA): “Ninety-Day (subchronic) dietary toxicity study with diethylenetriamine in albino.... The effective date for paragraph (d)(2) of this section is May 21, 1991. (2) The guidelines and other...

40 CFR 799.1575 - Diethylenetriamine (DETA).

Code of Federal Regulations, 2012 CFR

2012-07-01

.../Importers Alliance (DPIA): “Ninety-Day (subchronic) dietary toxicity study with diethylenetriamine in albino.... The effective date for paragraph (d)(2) of this section is May 21, 1991. (2) The guidelines and other...

40 CFR 799.1575 - Diethylenetriamine (DETA).

Code of Federal Regulations, 2011 CFR

2011-07-01

.../Importers Alliance (DPIA): “Ninety-Day (subchronic) dietary toxicity study with diethylenetriamine in albino.... The effective date for paragraph (d)(2) of this section is May 21, 1991. (2) The guidelines and other...

Acute and subchronic toxicity analysis of surface modified paclitaxel attached hydroxyapatite and titanium dioxide nanoparticles

PubMed Central

Venkatasubbu, Gopinath Devanand; Ramasamy, S; Gaddam, Pramod Reddy; Kumar, J

2015-01-01

Nanoparticles are widely used for targeted drug delivery applications. Surface modification with appropriate polymer and ligands is carried out to target the drug to the affected area. Toxicity analysis is carried out to evaluate the safety of the surface modified nanoparticles. In this study, paclitaxel attached, folic acid functionalized, polyethylene glycol modified hydroxyapatite and titanium dioxide nanoparticles were used for targeted drug delivery system. The toxicological behavior of the system was studied in vivo in rats and mice. Acute and subchronic studies were carried out. Biochemical, hematological, and histopathological analysis was also done. There were no significant alterations in the biochemical parameters at a low dosage. There was a small change in alkaline phosphatase (ALP) level at a high dosage. The results indicate a safe toxicological profile. PMID:26491315

Acute and subchronic toxicity of 20  kHz and 60  kHz magnetic fields in rats

PubMed Central

Oshima, Atsushi; Shibuya, Kazumoto; Mitani, Takashi; Negishi, Tadashi

2015-01-01

Abstract Despite increasing use of intermediate frequency (IF) magnetic fields (MFs) in occupational and domestic settings, scientific evidence necessary for health risk assessments of IF MF is insufficient. Male and female Crl:CD(SD) rats (12 per sex per group) were exposed to 20 kHz, 0.20 mT(root mean square, rms) or 60 kHz, 0.10 mT(rms) sinusoidal MFs for 22 h day−1 for 14 days (acute) or 13 weeks (subchronic). Experiments were duplicated for each frequency to ensure outcome reproducibility, and examinations were blinded for quality assurance. All rats survived without significant clinical signs until the end of experiments. Some changes in body weight between the MF‐exposed and control groups were observed over the course of exposure, although the directions of the changes were inconsistent and not statistically significant after subchronic exposure. There were significant differences between MF‐exposed and control groups in some organ weights and parameters in hematology and clinical chemistry, but these were minor in magnitude and not repeated in duplicate experiments. Histopathological findings reflecting toxicity were sporadic. Frequencies of other findings were similar to historic data in this rat strain, and findings had no specific relationship to changes in organ weight or parameters of hematology and clinical chemistry in each animal. The changes observed throughout this study were considered biologically isolated and were attributable to chance associations rather than to MF exposure. The results, in particular the histopathological evidence, indicate an absence of toxicity in IF MF‐exposed rats and do not support the hypothesis that IF MF exposure produces significant toxicity. Copyright © 2015. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd. PMID:25982482

40 CFR 716.21 - Chemical specific reporting requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... bioconcentration, environmental fate studies on biodegradation, and health effects studies on pharmacokinetics... fate studies on hydrolysis and biodegradation and health effects studies on pharmacokinetics... on biodegradation and health effects studies on pharmacokinetics, subchronic toxicity, neurotoxicity...

40 CFR 716.21 - Chemical specific reporting requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... bioconcentration, environmental fate studies on biodegradation, and health effects studies on pharmacokinetics... fate studies on hydrolysis and biodegradation and health effects studies on pharmacokinetics... on biodegradation and health effects studies on pharmacokinetics, subchronic toxicity, neurotoxicity...

40 CFR 716.21 - Chemical specific reporting requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... bioconcentration, environmental fate studies on biodegradation, and health effects studies on pharmacokinetics... fate studies on hydrolysis and biodegradation and health effects studies on pharmacokinetics... on biodegradation and health effects studies on pharmacokinetics, subchronic toxicity, neurotoxicity...

40 CFR 716.21 - Chemical specific reporting requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... bioconcentration, environmental fate studies on biodegradation, and health effects studies on pharmacokinetics... fate studies on hydrolysis and biodegradation and health effects studies on pharmacokinetics... on biodegradation and health effects studies on pharmacokinetics, subchronic toxicity, neurotoxicity...

40 CFR 716.21 - Chemical specific reporting requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... bioconcentration, environmental fate studies on biodegradation, and health effects studies on pharmacokinetics... fate studies on hydrolysis and biodegradation and health effects studies on pharmacokinetics... on biodegradation and health effects studies on pharmacokinetics, subchronic toxicity, neurotoxicity...

Hydroethanolic extract of the inner stem bark of Cedrela odorata has low toxicity and reduces hyperglycemia induced by an overload of sucrose and glucose.

PubMed

Giordani, Morenna Alana; Collicchio, Thiago Carvalho Mamede; Ascêncio, Sergio Donizeti; Martins, Domingos Tabajara de Oliveira; Balogun, Sikiru Olaitan; Bieski, Isanete Geraldini Costa; da Silva, Leilane Aparecida; Colodel, Edson Moleta; de Souza, Roberto Lopes; de Souza, Damiana Luiza Pereira; de França, Suélem Aparecida; Andrade, Claudia Marlise Balbinotti; Kawashita, Nair Honda

2015-03-13

Cedrela odorata L. (Meliaceae) is a native plant of the Amazon region and its inner stem bark is used in the treatment of diabetes in the form of maceration in Brazilian popular medicine. Until now, there is no scientific study on this activity. The present study was aimed at evaluating the anti-hyperglycemic activity, anti-diabetic, toxicity, antioxidant and potential mechanism of action of hydroethanolic extract of the inner stem bark of Cedrela odorata. The inner stem bark extract of Cedrela odorata was prepared by maceration in 70% ethanol for 7 days to obtain hydroethanolic extract of Cedrela odorata (HeECo). The preliminary phytochemical analysis was performed according to procedures described in the literature. Selected secondary metabolites detected were quantified by high performance liquid chromatography (HPLC). Acute toxicity of HeECo was investigated in male and female mice with oral administration of graded doses of HeECo from 10 to 5000 mg/kg. Subchronic oral toxicity study was done by oral administration of HeECo (500 mg/kg) and vehicle for 30 days to both sexes of Wistar rats. Clinical observations and toxicological related parameters were determined. Blood was collected for biochemical and hematological analyses, while histological examinations were performed on selected organs. Anti-hiperglycemic and antidiabetic effects were evaluated in streptozotocin-induced diabetic rats. In acute evaluation, the animals received pretreatment with 250 and 500 mg/kg of HeECo, before carbohydrate overload. For subchronic effect, the antidiabetic activity of HeECo was evaluated using the same doses for 21 days. At the end of the treatments, the levels of triacylglycerols, malondialdehyde, total antioxidant status, superoxide dismutase and glutathione peroxidase activities were evaluated in the plasma. The extract showed low acute toxicity. HeECo exhibited inhibitory activity against α-glucosidase and caused a lowering in the peak levels of blood glucose in animals that received glucose overload by 36.7% and 24.1% in the area under the glucose curve (AUC). When the overload was sucrose, HeECo reduced the blood glucose level by 44.4% without affecting AUC. Treatment with HeECo of the blood glucose of the diabetic animals for 21 days did not lead to improvement in weight gain and regularization of the blood glucose level, but reduced the triacylglycerol and malondialdehyde levels by 36.6% and 48.1%, respectively. The activity of the antioxidant enzymes, superoxide dismutase and glutathione peroxidase were significantly increased when compared to diabetic control rats. HPLC analysis showed the presence of polyphenols, such as gallic acid, (-)- gallocatechin and (+)- catechin, the latter is present in higher quantity. Collectively, these data showed that HeECo could blunt the postprandial glycemic surge in rats; possibly through inhibition of alpha-glucosidase and positive modulation of antioxidant enzymes. Our findings confirmed the anti-hiperglycemic activity of HeECo in STZ- diabetic rats. Cedrela odorata is effective in diminishing glucose levels in vitro and in vivo and in ameliorating oxidative damage that occurs in diabetes and/or due to hyperglycemia in rats. According to our results, the efficacy of Cedrela odorata preparation could be due to the presence of active principles with different mode of actions at the molecular level, including α-glycosidases and glucose transporter inhibitors and antioxidant property. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Subchronic toxicity study in vivo and allergenicity study in vitro for genetically modified rice that expresses pharmaceutical protein (human serum albumin).

PubMed

Sheng, Yao; Qi, Xiaozhe; Liu, Yifei; Guo, Mingzhang; Chen, Siyuan; He, Xiaoyun; Huang, Kunlun; Xu, Wentao

2014-10-01

Genetically modified (GM) crops that express pharmaceutical proteins have become an important focus of recent genetic engineering research. Food safety assessment is necessary for the commercial development of these crops. Subchronic toxicity study in vivo and allergenicity study in vitro were designed to evaluate the food safety of the rice variety expressing human serum albumin (HSA). Animals were fed rodent diets containing 12.5%, 25.0% and 50.0% GM or non-GM rice for 90 days. The composition analysis of the GM rice demonstrated several significant differences. However, most of the differences remained within the ranges reported in the literature. In the animal study, a range of indexes including clinical observation, feed efficiency, hematology, serum chemistry, organ weights and histopathology were examined. Random changes unrelated to the GM rice exposure, within the range of historical control values and not associated with any signs of illness were observed. The results of heat stability and in vitro digestion of HSA indicated no evidence of potential allergenicity of the protein. Overall, the results of these studies suggest that the GM rice appears to be safe as a dietary ingredient when it is used at up to 50% in the diet on a subchronic basis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mitochondrionopathy phenotype in doxorubicin-treated Wistar rats depends on treatment protocol and is cardiac-specific.

PubMed

Pereira, Gonçalo C; Pereira, Susana P; Pereira, Claudia V; Lumini, José A; Magalhães, José; Ascensão, António; Santos, Maria S; Moreno, António J; Oliveira, Paulo J

2012-01-01

Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations.

Mitochondrionopathy Phenotype in Doxorubicin-Treated Wistar Rats Depends on Treatment Protocol and Is Cardiac-Specific

PubMed Central

Pereira, Gonçalo C.; Pereira, Susana P.; Pereira, Claudia V.; Lumini, José A.; Magalhães, José; Ascensão, António; Santos, Maria S.; Moreno, António J.; Oliveira, Paulo J.

2012-01-01

Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations. PMID:22745682

Toxicological evaluation of two novel bitter modifying flavour compounds: 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)imidazolidine-2,4-dione and 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione.

PubMed

Karanewsky, Donald S; Arthur, Amy J; Liu, Hanghui; Chi, Bert; Ida, Lily; Markison, Stacy

2016-01-01

A toxicological evaluation of two novel bitter modifying flavour compounds, 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1 H -pyrazol-4-yl)-1-(3-hydroxybenzyl)imidazolidine-2,4-dione (S6821, CAS 1119831-25-2) and 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1 H -pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (S7958, CAS 1217341-48-4), were completed for the purpose of assessing their safety for use in food and beverage applications. S6821 undergoes oxidative metabolism in vitro , and in rat pharmacokinetic studies both S6821 and S7958 are rapidly converted to the corresponding O-sulfate and O-glucuronide conjugates. S6821 was not found to be mutagenic or clastogenic in vitro , and did not induce micronuclei in bone marrow polychromatic erythrocytes in vivo . S7958, a close structural analog of S6821, was also found to be non-mutagenic in vitro . In short term and subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for both S7958 and S6821 was 100 mg/kg bw/day (highest dose tested) when administered as a food ad-mix for either 28 or 90 consecutive days, respectively. Furthermore, S6821 demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOAEL of 1000 mg/kg bw/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.

A subchronic 90-day oral rat toxicity study and in vitro genotoxicity studies with a conjugated linoleic acid product.

PubMed

O'Hagan, S; Menzel, A

2003-12-01

Conjugated linoleic acid (CLA) is the term given to a group of positional and geometric isomers of the essential fatty acid linoleic acid. CLA is found naturally in foods such as dairy and meat products. CLA is reported to have a number of beneficial effects including anticarcinogenic activity. However, safety data are limited. Clarinol G80 is a commercial preparation containing equal amounts of the 9cis,11trans and 10trans,12cis CLA isomers in the form of glycerides. In order to support the safety-in-use of Clarinol G80 as an ingredient in food, the preparation was tested in two in vitro mutagenicity assays, an Ames test and an in vitro cytogenetics assay, and a 90-day repeat-dose oral toxicity rat study. Clarinol G80 was non-mutagenic in both in vitro assays. In the 90-day study, Clarinol G80 produced hepatocellular hypertrophy in female rats at the highest dose level (15% w/w). This effect was an adaptive effect in response to feeding high levels of Clarinol G80 in the diet and was reversible upon withdrawal of test material. An increase in plasma insulin levels was also observed female rats fed 15% w/w Clarinol G80 but there was no effect on plasma glucose levels. A No Observed Adverse Effect Level of 2433 mg/kg bw/day for male and 2728 mg/kg bw/day female rats was identified in the study.

Acute and sub-chronic toxicity of four cytostatic drugs in zebrafish.

PubMed

Kovács, Róbert; Bakos, Katalin; Urbányi, Béla; Kövesi, Judit; Gazsi, Gyöngyi; Csepeli, Andrea; Appl, Ádám János; Bencsik, Dóra; Csenki, Zsolt; Horváth, Ákos

2016-08-01

The acute and sub-chronic effects of four cytostatic drugs-5-fluorouracil (5-FU), cisplatin (CisPt), etoposide (ET) and imatinib mesylate (IM)-on zebrafish (Danio rerio) were investigated. Acute tests were carried out in a static system in accordance with the OECD guideline 203 for adult fish and the draft guideline for fish embryos (FET test) in order to find the LC50 values of the four cytostatic drugs. Early-life stage toxicity test on zebrafish was conducted according the OECD guideline 210 using the cytostatic drugs 5-FU and IM in a semistatic system with the objective of investigating the sub-chronic effects of the cytostatic drugs on fish. In adult fish, the cytostatic drugs 5-FU and ET did not pass the limit test, thus, are considered non-toxic. In case of cisplatin, LC50 was calculated at 64.5 mg L(-1), whereas in case of IM, LC50 was at 70.8 mg L(-1). In the FET test, LC50 of 5-FU at 72-h post fertilization (hpf) was 2441.6 mg L(-1). In case of CisPt, LC50 was 349.9 mg L(-1) at 48 hpf and it progressively decreased to 81.3 mg L(-1) at 120 hpf. In addition, CisPt caused a significant delay in the hatch of larvae. In case of ET, LC50 values were not calculable as they were higher than 300 mg L(-1) at which concentration the substance crystallized in the solution. LC50 values of IM were 48 hpf; 158.3 mg L(-1) , 72 hpf; 141.6 mg L(-1), 96 hpf; 118.0 mg L(-1), and 120 hpf; 65.9 mg L(-1). In the Early-life Stage Test with 5-FU, embryonic deformities were not detected during the tests. Regarding mortalities, the 10 mg L(-1) concentration can be considered as LOEC, as statistically significant difference in mortalities was detected in this group alone. Concerning dry body weight and standard length, 1 mg L(-1) is the LOEC. In case of IM, the highest tested concentration (10 mg L(-1)) can be considered LOEC for mortalities, however, the treatment did not have an effect on the other investigated parameters (dry and wet weight, standard length). All four cytostatic drugs were characterized by low toxicity in zebrafish in acute and sub-chronic tests.

The Toxicity of Perfluoro-N-Decanoic Acid and 2,3,7,8- Tetrachlorodibenzo-P-Dioxin in L5178Y Mouse Lymphoma Cells

DTIC Science & Technology

1983-03-01

ABSTRACT (Continue on reverse side If necessary and identify by block number) Perfluoro -n-decanoic acid ( PFDA ) causes toxic sequelae in vivo very similar to...acid analogs. All polyfluorinated acids tested (either perfluorinated or w-hydro-analogs) with chain length 9 or greater caused impairment of clone...of 5 to 7. The acute and subchronic toxicity of ammonium perfluoro -n-octanoate ( PFOA ) has been described in detail in both rats and rhesus monkeys

Antioxidant status in oral subchronic toxicity of fipronil and fluoride co-exposure in buffalo calves.

PubMed

Gill, Kamalpreet Kaur; Dumka, Vinod Kumar

2016-02-01

The effects of fipronil and fluoride co-exposure were investigated on antioxidant status of buffalo calves. A total of 24 healthy male buffalo calves divided into 4 groups were treated for 98 consecutive days. Group I, receiving no treatment, served as the control. Animals of groups II and III were orally administered with fipronil at the dosage of 0.5 mg/kg/day and sodium fluoride (NaF) at the dosage of 6.67 mg/kg/day, respectively, for 98 days. Group IV was coadministered with fipronil and NaF at the same dosages as groups II and III. Administration of fipronil alone produced significant elevation in lipid peroxidation (LPO) and decrease in the levels of nonenzymatic antioxidant glutathione (GSH). However, it did not produce any significant effect on the activities of enzymatic antioxidants including glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). NaF exposure led to enhanced oxidative stress as shown by significant increase in the LPO and SOD activities while GPx and CAT activities and GSH levels were significantly decreased. Co-exposure to fipronil and NaF showed additive effects on LPO, GPx activity, and GSH levels. © The Author(s) 2013.

RIFM fragrance ingredient safety assessment, α-Ionone, CAS Registry Number 127-41-3.

PubMed

Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

2016-11-01

The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 10 mg/kg/day. A dietary 90-day subchronic toxicity study conducted in rats resulted in a MOE of 182 while assuming 100% absorption from skin contact and inhalation. A MOE of >100 is deemed acceptable. Copyright © 2015 Elsevier Ltd. All rights reserved.

RIFM fragrance ingredient safety assessment, isoeugenol, CAS Registry Number 97-54-1.

PubMed

Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

2016-11-01

The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 37.5 mg/kg/day. A gavage 13-week subchronic toxicity study conducted in mice resulted in a MOE of 5769 while considering 38.4% absorption from skin contact and 100% from inhalation. A MOE of >100 is deemed acceptable. Copyright © 2015 Elsevier Ltd. All rights reserved.

Screening-Level Risk Assessment for Styrene-Acrylonitrile (SAN) Trimer Detected in Soil and Groundwater

PubMed Central

Kirman, C. R.; Gargas, M. L.; Collins, J. J.; Rowlands, J. C.

2012-01-01

A screening-level risk assessment was conducted for styrene-acrylonitrile (SAN) Trimer detected at the Reich Farm Superfund site in Toms River, NJ. Consistent with a screening-level approach, on-site and off-site exposure scenarios were evaluated using assumptions that are expected to overestimate actual exposures and hazards at the site. Environmental sampling data collected for soil and groundwater were used to estimate exposure point concentrations. Several exposure scenarios were evaluated to assess potential on-site and off-site exposures, using parameter values for exposures to soil (oral, inhalation of particulates, and dermal contact) and groundwater (oral, dermal contact) to reflect central tendency exposure (CTE) and reasonable maximum exposure (RME) conditions. Three reference dose (RfD) values were derived for SAN Trimer for short-term, subchronic, and chronic exposures, based upon its effects on the liver in exposed rats. Benchmark (BMD) methods were used to assess the relationship between exposure and response, and to characterize appropriate points of departure (POD) for each RfD. An uncertainty factor of 300 was applied to each POD to yield RfD values of 0.1, 0.04, and 0.03 mg/kg-d for short-term, subchronic, and chronic exposures, respectively. Because a chronic cancer bioassay for SAN Trimer in rats (NTP 2011a) does not provide evidence of carcinogenicity, a cancer risk assessment is not appropriate for this chemical. Potential health hazards to human health were assessed using a hazard index (HI) approach, which considers the ratio of exposure dose (i.e., average daily dose, mg/kg-d) to toxicity dose (RfD, mg/kg-d) for each scenario. All CTE and RME HI values are well below 1 (where the average daily dose is equivalent to the RfD), indicating that there is no concern for potential noncancer effects in exposed populations even under the conservative assumptions of this screening-level assessment. PMID:23030654

Safety assessment of freeze-dried powdered Tenebrio molitor larvae (yellow mealworm) as novel food source: Evaluation of 90-day toxicity in Sprague-Dawley rats.

PubMed

Han, So-Ri; Lee, Byoung-Seok; Jung, Kyung-Jin; Yu, Hee-Jin; Yun, Eun-Young; Hwang, Jae Sam; Moon, Kyoung-Sik

2016-06-01

Worldwide demand for novel food source has grown and edible insects are a promising food sources for humans. Tenebrio molitor, as known as yellow mealworm, has advantages of being rich in protein, and easy to raise as a novel food source. The objective of this study was to evaluate subchronic toxicity, including potential hypersensitivity, of freeze-dried powdered T. molitor larvae (fdTML) in male and female Sprague-Dawley rats. The fdTML was administered orally once daily at dose levels of 0, 300, 1000 and 3000 mg/kg/day for 90 days. A toxicological assessment was performed, which included mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings, histopathologic examination and allergic reaction. There were no fdTML- related findings in clinical signs, urinalysis, hematology and serum chemistry, gross examination, histopathologic examination or allergic reaction. In conclusion, the No Observed Adverse Effect Level (NOAEL) for fdTML was determined to be in excess of 3000 mg/kg/day in both sexes of rats under the experimental conditions of this study. Copyright © 2016 Elsevier Inc. All rights reserved.

Subchronic toxicity evaluation of γ-aminobutyric acid (GABA) in rats.

PubMed

Takeshima, Kazuhito; Yamatsu, Atsushi; Yamashita, Yusuke; Watabe, Kazuya; Horie, Noriko; Masuda, Kazuyuki; Kim, Mujo

2014-06-01

γ-Aminobutyric acid (GABA) is an amino acid compound contained in vegetables such as tomatoes and also widely distributed in mammals. GABA acts as an inhibitory neurotransmitter and promotes parasympathetic activity to provide several beneficial effects, for instance, relaxation, anti-stress, and insomnia. GABA, produced via a fermentation process, has been available as a functional food ingredient. As part of a program to assess its safety, GABA was administered by oral gavage at doses of 500, 1250, and 2500mg/kg body weight to groups of 10 male and 10 female Sprague-Dawley rats for 13weeks. Treatment was not associated with the test substance-related mortality and appeared to be well tolerated. There were no toxicologically and statistically significant changes in urinalysis, hematology, clinical chemistry parameters, and in necropsy findings. A few statistically significant changes in food consumption and body weights were noted in the male groups while any significant changes were not noted in female groups. There was no effect of treatment on organ weights or on the results of the histopathological examinations. The results of toxicity evaluation support the safety use of GABA and the potential use as a functional food ingredient. Copyright © 2014 Elsevier Ltd. All rights reserved.

Safety assessment of the calcium-binding protein, apoaequorin, expressed by Escherichia coli.

PubMed

Moran, Daniel L; Tetteh, Afua O; Goodman, Richard E; Underwood, Mark Y

2014-07-01

Calcium-binding proteins are ubiquitous modulators of cellular activity and function. Cells possess numerous calcium-binding proteins that regulate calcium concentration in the cytosol by buffering excess free calcium ion. Disturbances in intracellular calcium homeostasis are at the heart of many age-related conditions making these proteins targets for therapeutic intervention. A calcium-binding protein, apoaequorin, has shown potential utility in a broad spectrum of applications for human health and well-being. Large-scale recombinant production of the protein has been successful; enabling further research and development and commercialization efforts. Previous work reported a 90-day subchronic toxicity test that demonstrated this protein has no toxicity by oral exposure in Sprague-Dawley rodents. The current study assesses the allergenic potential of the purified protein using bioinformatic analysis and simulated gastric digestion. The results from the bioinformatics searches with the apoaequorin sequence show the protein is not a known allergen and not likely to cross-react with known allergens. Apoaequorin is easily digested by pepsin, a characteristic commonly exhibited by many non-allergenic dietary proteins. From these data, there is no added concern of safety due to unusual stability of the protein by ingestion. Copyright © 2014 Elsevier Inc. All rights reserved.

Safety assessment of myristic acid as a food ingredient.

PubMed

Burdock, George A; Carabin, Ioana G

2007-04-01

Myristic acid is used in the food industry as a flavor ingredient. It is found widely distributed in fats throughout the plant and animal kingdom, including common human foodstuffs, such as nutmeg. Myristic acid (a 14-carbon, straight-chain saturated fatty acid) has been shown to have a low order of acute oral toxicity in rodents. It may be irritating in pure form to skin and eyes under exaggerated exposure conditions, but is not known or predicted to induce sensitization responses. Myristic acid did not induce a mutagenic response in either bacterial or mammalian systems in vitro. Relevant subchronic toxicity data are available on closely related fatty acid analogs. In particular, a NOEL of >6000mg/kg was reported for lauric acid (a 12-carbon, straight-chain saturated fatty acid) following dietary exposure to male rats for 18 weeks and a NOEL of >5000mg/kg was reported for palmitic acid (a 16-carbon, straight-chain saturated fatty acid) following dietary exposure to rats for 150 days. The data and information that are available indicate that at the current level of intake, food flavoring use of myristic acid does not pose a health risk to humans.

Toxicological evaluation of an Allium-based commercial product in a 90-day feeding study in Sprague-Dawley rats.

PubMed

Mellado-García, P; Puerto, M; Pichardo, S; Llana-Ruiz-Cabello, M; Moyano, R; Blanco, A; Jos, A; Cameán, A M

2016-04-01

Proallium AP(®) is a commercial Allium extract intended to be used in active food packaging as the antibacterial and antioxidant effects of some organosulfur compounds are well known. However, there is little information on its toxicity and the Scientific Committee on Food (UE) requires the safety assessment of substances used in food contact materials. Thus, the aim of this study was to conduct for the first time a subchronic oral toxicity study of Proallium AP(®) with groups of 10 males and 10 females Sprague-Dawley rats fed a diet containing 0, 25, 100, 400 mg/kg/d for 90 days. No treatment-related clinical signs or mortality were noted. Besides, no treatment-related effects with regard to any of the toxicological biomarkers considered were observed, including biochemical, haematological and histopathology parameters. In conclusion, the non-observed-adverse-effect-level (NOAEL) for Proallium AP(®) in rats was determined to be a dietary dose of 400 mg/kg/d under the present experimental conditions, a value 500-fold higher than the exposure derived from its potential use in active packaging. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of hypoglycemic and anti-hyperglycemic potential of Tridax procumbens (Linn.)

PubMed Central

2009-01-01

Background Diabetes is a metabolic disorder affecting carbohydrate, fat and protein metabolism. Tridax procumbens Linn. (Family-Asteraceae; common name-Dhaman grass) is common herb found in India. Traditionally, the tribal inhabitants of Udaipur district in Rajasthan (India) uses the leaf powder (along with other herb) orally to treat diabetes. There is a need to evaluate extracts of this plant in order to provide scientific proof for it's application in traditional medicine system. Methods Extraction of whole plant of T. procumbens using 50%methanol. The extract was tested for acute and sub-chronic anti-hyperglycemic activity in alloxan induced diabetic rats and for acute toxicity test among normal rats. Observations on body weight as well as on the oral glucose tolerance levels were also recorded. Results Oral administration of acute and sub chronic doses (250 and 500 mg/kg b.wt.) of T. procumbens extract showed a significant (p < 0.05) reduction in fasting blood glucose levels in diabetic rats, however the decline in blood sugar levels in normal rats was not observed. In acute study the maximum percent blood glucose reduction (68.26% at 250 mg/kg and 71.03% at 500 mg/kg body weight) in diabetic rats was observed at 6 h. The anti-hyperglycemic effects were not dependent of dose and the OGTT and Body weight supported the antihyperglycemic action of the drug. The results of anti-diabetic effect of T. procumbens were compared with the reference standard drug Glibenclamide (10 mg/kg b.wt.). Conclusion These test results support traditional medicinal use of, T. procumbens for the treatment of diabetes mellitus with corrections in body weight and oral glucose tolerance and no visible signs or symptoms of toxicity in normal rats indicating a high margin of safety. These results warrant follow-up through bioassay-directed isolation of the active principles. PMID:19943967

Subchronic exposure to kalach 360 SL-induced endocrine disruption and ovary damage in female rats.

PubMed

Hamdaoui, Latifa; Naifar, Manel; Rahmouni, Fatma; Harrabi, Bahira; Ayadi, Fatma; Sahnoun, Zouheir; Rebai, Tarek

2018-02-01

Kalach 360 SL (KL), glyphosate (G) surfactant-based herbicides, is a systemic herbicide effective against weeds. It was applied in agriculture in Tunisia and throughout the world, which can represent a risk to non-target organisms. The aim of this study was to investigate the morphological and biochemical aspects of ovary injury after exposure to KL. Female Wistar rats were divided into three groups: group 1 was used as a control; group 2 orally received 0.07 ml of KL, (126 mg of G/kg) and group 3 orally received 0.175 ml of KL (315 mg of G/kg) each day for 60 days. The subchronic exposure of KL induces impaired folliculogenesis, ovary development, decreased oestrogen secretion, promoted oxidative stress and impairments of ovary histological aspects. Histological finding shows necrosis cell, vacuolisation of follicles, dissociated oocytes and granulosa cell, associated with several atretic follicles. We conclude that KL induces endocrine disruption and ovary damage in female rats.

Dynamic changes in metabolic profiles of rats subchronically exposed to mequindox.

PubMed

Jiang, Limiao; Zhao, Xiuju; Huang, Chongyang; Lei, Hehua; Tang, Huiru; Wang, Yulan

2014-11-01

Mequindox is widely used as an antibacterial veterinary drug and a feeding additive for farm animals in China. Although its toxicity has been widely studied, little is known regarding the metabolic effects of subchronic exposure to mequindox, which is vital for the health of meat producing livestock. Here, we characterized the dose- and time-dependent metabolic alterations in female Wistar rats subchronically exposed to mequindox through dietary supplementation at the level of 40, 110 and 280 mg kg(-1) for 13 weeks, employing a NMR based metabonomics approach with supplementary information from serum clinical chemistry. We found that urinary metabolic profiles were significantly affected in all dosed groups during the supplementation period; plasma and hepatic metabolic profiles were significantly affected only in rats dosed with moderate and high levels of mequindox. We also observed a return to control levels, for the profiles of urine and liver, at all dose levels after a two weeks washout period. However, this was not the case for the metabolic profiles of plasma from rats dosed at high levels. At the molecular level, we showed that subchronic exposure to mequindox resulted in tricarboxylic acid cycle (TCA cycle) stimulation, suppression of glycolysis, and promotion of gluconeogenesis and lipid oxidation in rats. In addition, subchronic exposure to mequindox induced oxidative stress in rats. Furthermore, a disturbance of gut microbiota, manifested by alterations in the urinary excretion of hippurate, phenylacetylglycine, 3-(3-hydroxyphenyl)propionate, p-cresol glucuronide, methylamine, dimethylamine, and formate, was associated with mequindox exposure. The present study provided important holistic metabolic information on the effects of subchronic dosage of mequindox on rats, which is useful for evaluating the safety of mequindox usage in meat producing animals.

In vivo toxicity assessment of deoxynivalenol-contaminated wheat after ozone degradation.

PubMed

Wang, Li; Wang, Ying; Shao, Huili; Luo, Xiaohu; Wang, Ren; Li, Yongfu; Li, Yanan; Luo, Yingpeng; Zhang, Dongjie; Chen, Zhengxing

2017-01-01

The effect of ozone on deoxynivalenol (DON) detoxification was investigated. Ozone treatment could significantly reduce the levels of DON in wheat; 53% of DON in wheat was decomposed with 90 mg l -1 of ozone at a flow rate of 15 l min -1 for 4 h. The safety of DON-contaminated wheats (DCWs) untreated/treated by ozone was also evaluated. Institute of Cancer Research (ICR) mice were divided into a standard diet group and five experimental diet groups for a 51-day orally administration experiment. In the experiment, no remarkable changes in the general appearance of the mice were observed, and all the mice survived until the scheduled necropsy. The results of sub-chronic toxicity indicated that mice fed on DCWs alone had significantly decreased in body weight gain, thymus and spleen weights, ratios of liver, thymus and spleen to body weight, blood indices (red blood cell, haemoglobin, white blood cell), and pro-inflammatory cytokines (interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α)), while showing a significant increase in alanine aminotransferase, aspartate aminotransferase, blood creatinine and blood urea nitrogen levels. Histopathological examination indicate that DON elicited some degree of toxicity on the liver, kidney and thymus tissue. Mice fed on DCWs treated by ozone mitigated the adverse effects compared with mice fed on DCWs. All the results suggested that the deleterious effects of DON could be highly reduced by ozone, and ozone itself shows minor toxic effects on animals in this process.

Combined subchronic fluoride-lead intoxication and its attenuation with the help of a complex of bioprotectors.

PubMed

Katsnelson, B A; Privalova, L I; Kireyeva, Y P; Yeremenko, O S; Sutunkova, M P; Valamina, I E; Varaksin, A N; Panov, V G; Kazmer, J I

2012-01-01

Combined toxicity of lead and fluoride has been studied insufficiently, and there is no known information about attempts to inhibit it with any bioprotectors. Lead acetate and sodium fluoride, administered separately or in combination, were injected i.p. to rats at isoeffective sublethal doses 3 times a week for 6 weeks. Some of the rats were exposed to the same combination against the background of oral administration of a bioprotector complex (BPC) comprising pectin, glutamate, and multivitamin/multimineral preparations. Following exposure, functional and biochemical indices and histopathological examinations of the femur of exposed and control rats were evaluated for signs of toxicity. We have shown that with regard to a number of effects on the organism level the combined toxicity of lead and fluoride may be evaluated as additive or even superadditive, but lead reduces fluoride accumulation in the bone, and pathological changes in the bone tissue proved to be less marked for combined exposure compared with separate exposures. The BPC has been demonstrated to attenuate a range of the combined harmful effects of lead and fluoride, including those on the bone tissue. In spite of the fact that fluoride and lead may reciprocally attenuate their harmful effects on the bone tissue in case of combined exposure, they prove to be more toxic for soft tissues just in combination than when administered separately. The development of combined intoxication may be substantially inhibited by means of the tested set of innocuous biologically active agents.

Subchronic exposure to arsenic through drinking water alters expression of cancer-related genes in rat liver.

PubMed

Cui, Xing; Li, Song; Shraim, Amjad; Kobayashi, Yayoi; Hayakawa, Toru; Kanno, Sanae; Yamamoto, Megumi; Hirano, Seishiro

2004-01-01

Although arsenic exposure causes liver disease and/or hepatoma, little is known about molecular mechanisms of arsenic-induced liver toxicity or carcinogenesis. We investigated the effects of arsenic on expression of cancer-related genes in a rat liver following subchronic exposure to sodium arsenate (1, 10, 100 ppm in drinking water), by using real-time quantitative RT-PCR and immunohistochemical analyses. Arsenic accumulated in the rat liver dose-dependently and caused hepatic histopathological changes, such as disruption of hepatic cords, sinusoidal dilation, and fatty infiltration. A 1-month exposure to arsenic significantly increased hepatic mRNA levels of cyclin D1 (10 ppm), ILK (1 ppm), and p27(Kip1) (10 ppm), whereas it reduced mRNA levels of PTEN (1 ppm) and beta-catenin (100 ppm). In contrast, a 4-month arsenic exposure showed increased mRNA expression of cyclin D1 (100 ppm), ILK (1 ppm), and p27(Kip1) (1 and 10 ppm), and decreased expression of both PTEN and beta-catenin at all 3 doses. An immunohistochemical study revealed that each protein expression accords closely with each gene expression of mRNA level. In conclusion, subchronic exposure to inorganic arsenate caused pathological changes and altered expression of cyclin D1, p27(Kip1), ILK, PTEN, and beta-catenin in the liver. This implies that arsenic liver toxicity involves disturbances of some cancer-related molecules.

Failure of antimony trioxide to induce micronuclei or chromosomal aberrations in rat bone-marrow after sub-chronic oral dosing.

PubMed

Kirkland, David; Whitwell, James; Deyo, James; Serex, Tessa

2007-03-05

Antimony trioxide (Sb2O3, CAS 1309-64-4) is widely used as a flame retardant synergist in a number of household products, as a fining agent in glass manufacture, and as a catalyst in the manufacture of various types of polyester plastics. It does not induce point mutations in bacteria or mammalian cells, but is able to induce chromosomal aberrations (CA) in cultured cells in vitro. Although no CA or micronuclei (MN) have been induced after acute oral dosing of mice, repeated oral dosing for 14 or 21 days resulted in increased CA in one report, but did not result in increased MN in another. In order to further investigate its in vivo genotoxicity, Sb2O3 was dosed orally to groups of rats for 21 days at 250, 500 and 1000 mg/kg day. There were no clinical signs of toxicity in the Sb2O3-exposed animals except for some reductions in body-weight gain in the top dose group. Toxicokinetic measurements in a separate study confirmed bone-marrow exposure, and at higher levels than would have been achieved by single oral dosing. Large numbers of cells were scored for CA (600 metaphases/sex group) and MN (12,000 PCE/sex group) but frequencies of CA or MN in Sb2O3-treated rats were very similar to controls, and not biologically or statistically different, at all doses. These results provide further indication that Sb2O3 is not genotoxic to the bone marrow of rodents after 21 days of oral administration at high doses close to the maximum tolerated dose.

Acute, subchronic, and developmental toxicological properties of lubricating oil base stocks.

PubMed

Dalbey, Walden E; McKee, Richard H; Goyak, Katy Olsavsky; Biles, Robert W; Murray, Jay; White, Russell

2014-01-01

Lubricating oil base stocks (LOBs) are substances used in the manufacture of finished lubricants and greases. They are produced from residue remaining after atmospheric distillation of crude oil that is subsequently fractionated by vacuum distillation and additional refining steps. Initial LOB streams that have been produced by vacuum distillation but not further refined may contain polycyclic aromatic compounds (PACs) and may present carcinogenic hazards. In modern refineries, LOBs are further refined by multistep processes including solvent extraction and/or hydrogen treatment to reduce the levels of PACs and other undesirable constituents. Thus, mildly (insufficiently) refined LOBs are potentially more hazardous than more severely (sufficiently) refined LOBs. This article discusses the evaluation of LOBs using statistical models based on content of PACs; these models indicate that insufficiently refined LOBs (potentially carcinogenic LOBs) can also produce systemic and developmental effects with repeated dermal exposure. Experimental data were also obtained in ten 13-week dermal studies in rats, eight 4-week dermal studies in rabbits, and seven dermal developmental toxicity studies with sufficiently refined LOBs (noncarcinogenic and commonly marketed) in which no observed adverse effect levels for systemic toxicity and developmental toxicity were 1000 to 2000 mg/kg/d with dermal exposures, typically the highest dose tested. Results in both oral and inhalation developmental toxicity studies were similar. This absence of toxicologically relevant findings was consistent with lower PAC content of sufficiently refined LOBs. Based on data on reproductive organs with repeated dosing and parameters in developmental toxicity studies, sufficiently refined LOBs are likely to have little, if any, effect on reproductive parameters.

NEW METHODS FOR THE ASSESSMENT OF IMMUNOTOXICITY OF CHEMICAL SUBSTANCES

EPA Science Inventory

The immune system is a target of toxic insult following subchronic or chronic exposure to environmental chemicals, therapeutic drugs or abused drugs. nteraction of xenobiotics with the immune system may result in undesirable effects of three principal types; (a) those manifested ...

Acute and Subchronic Toxicity of Inhaled Toluene in Male ...

EPA Pesticide Factsheets

The effects of exposure to volatile organic compounds (VOCs), which are of concern to the EPA, are poorly understood, in part because of insufficient characterization of how human exposure duration impacts VOC effects. Two inhalation studies with multiple endpoints, one acute and one subchronic, were conducted to seek effects of the VOC, toluene, in rats and to compare the effects between acute and subchronic exposures. Adult male Long-Evans rats were exposed to toluene vapor (n = 6 per group) at a concentration of 0 or l 019 ± 14 ppm for 6 h in the acute study and at 0 ± 0, 10 ± 1.4, 97 ± 7, or 995 ± 43 ppm for 6 h/d, 5 d/week for 13 weeksin the subchronic study. For the acute study, brains were dissected on ice within 30 min of the end of exposure, while for the subchronic study, brains were dissected 18 h after the last exposure. Frontal cortex, hippocampus, cerebellum, and striatum were assayed for a variety of oxidative stress (OS) parameters including total aconitase (TA), protein carbonyls, glutathione peroxidase (GPX), glutathione reductase (GRD), glutathione transferase (GST), y-­glutamylcysteine synthetase (GCS), superoxide dismutase (SOD), total antioxidants (TAS), NADPH quinone oxidoreductase- 1 (NQO1 ), and NADH ubiquinone reductase (UBIQ-RD) activities using commercially available kits. Following acute exposure, UBIQ-RD, GCS and GRD were increased significantly only in the cerebellum, while TAS was increased in frontal cortex. On the other

Biological responses of Neotropical freshwater fish Lophiosilurus alexandri exposed to ammonia and nitrite.

PubMed

Dos Santos Silva, Márcio José; da Costa, Franklin Fernando Batista; Leme, Fabiola Paes; Takata, Rodrigo; Costa, Deliane Cristina; Mattioli, Cristiano Campos; Luz, Ronald Kennedy; Miranda-Filho, Kleber Campos

2018-03-01

This study aimed to elucidate the responses of the Neotropical fish Lophiosilurus alexandri exposed to ammonia and nitrite, following a period of recovering. Acute toxicity tests lasted 96h, subchronic toxicity tests lasted eight days and the detoxification trial lasted four days. Groups of 12 juveniles were maintained in 90-L tanks and treated with increasing concentrations of ammonia and nitrite, except during the recovery test. All treatments were performed with two replicates. The median lethal concentrations (LC 50 ) of 24, 48, 72 and 96h were estimated at 30.12; 24.35; 19.24 and 18.68mg·L -1 TA-N; 5.37; 4.57; 3.75 and 3.66mg·L -1 NH 3 -N and 20.37; 7.78; 7.09 and 5.86mg·L -1 NO 2 - -N, respectively. The NO 2 - caused significant decrease in hematocrit and increase in the urea levels during short-term exposure, with recovery of homeostasis after the subchronic and detox period. Acute exposure to ammonia increased the enzyme profile of transaminases, glucose and urea. Urea concentration remained high in the subchronic and detox tests. Histopathologies were observed in animals exposed to ammonia in both toxicity tests. It was highlighted detachment of epithelium, hyperemia and necrosis in the gills. Exposure to NO 2 - caused epithelium detachment and aneurysm. Vacuolization and swelling of hepatocytes were the most common injury for both nitrogenous compounds. We concluded that the L. alexandri has moderate tolerance to ammonia and nitrite. The recovery period revealed remedial response to ammonia and nitrite exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

Protective efficacy of 2-PAMCl, atropine and curcumin against dichlorvos induced toxicity in rats

PubMed Central

Yadav, Preeti; Jadhav, Sunil E.; Kumar, Vinesh; Kaul, Kirtee K.; Pant, Satish C.; Flora, Swaran J.S.

2012-01-01

The effect of 2- pyridine aldoxime methyl chloride (2-PAMCl) and atropine with or without curcumin was investigated in dichlorvos (2,2-dichlorovinyl dimethyl phosphate; DDVP) induced toxicity in rats. Rats were exposed to DDVP (2 mg/kg sub-cutaneously) once daily for the period of 21 days. Post DDVP exposure, rats were further treated with 2-PAMCl (50 mg/kg intramuscular, once daily) + atropine (10 mg/kg, i.m. once daily) with or without curcumin (200 mg/kg; oral; once daily) for further 21 days. We observed a significant increase in lipid peroxidation (LPO), reactive oxygen species (ROS), oxidized glutathione (GSSG), while there was a significant decrease in antioxidant enzymes, brain acetylcholinesterase (AChE) and 5-hydroxy tryptamine (5-HT) activity on DDVP exposure of rats. These alterations were restored significantly by co-administration of 2-PAMCl + atropine in DDVP exposed rats. Curcumin when co-supplemented with 2-PAMCl + atropine also significantly protected serum aspartate aminotransferase (AST) and restored brain AChE activity and 5-HT level in animals sub-chronically exposed to DDVP. Histopathological observations along with biochemical changes in rat blood and tissues revealed significant protection offered by 2-PAMCl + atropine against DDVP. The results indicate that DDVP-induced toxicity can be significantly protected by co-administration of 2-PAMCl + atropine individually, however, curcumin co-supplementation with 2-PAMCl + atropine provides more pronounced protection, concerning particularly neurological disorders. PMID:22783142

Toxicologic assessment of a commercial decolorized whole leaf aloe vera juice, lily of the desert filtered whole leaf juice with aloesorb.

PubMed

Sehgal, Inder; Winters, Wallace D; Scott, Michael; David, Andrew; Gillis, Glenn; Stoufflet, Thaya; Nair, Anand; Kousoulas, Konstantine

2013-01-01

Aloe vera, a common ingredient in cosmetics, is increasingly being consumed as a beverage supplement. Although consumer interest in aloe likely stems from its association with several health benefits, a concern has also been raised by a National Toxicology Program Report that a nondecolorized whole leaf aloe vera extract taken internally by rats was associated with intestinal mucosal hyperplasia and ultimately malignancy. We tested a decolorized whole leaf (DCWL) aloe vera, treated with activated charcoal to remove the latex portion of the plant, for genotoxicity in bacteria, acute/subacute toxicity in B6C3F1 mice, and subchronic toxicity in F344 rats. We found this DCWL aloe vera juice to be nongenotoxic in histidine reversion and DNA repair assays. Following acute administration, mice exhibited no adverse signs at 3- or 14-day evaluation periods. When fed to male and female F344 rats over 13 weeks, DCWL aloe led to no toxicity as assessed by behavior, stools, weight gain, feed consumption, organ weights, and hematologic or clinical chemistry profiles. These rats had intestinal mucosal morphologies-examined grossly and microscopically-that were similar to controls. Our studies show that oral administration of this DCWL aloe juice has a different toxicology profile than that of the untreated aloe juice at exposures up to 13 weeks.

Two-week aerosol inhalation study on polyethylene glycol (PEG) 3350 in F-344 rats.

PubMed

Klonne, D R; Dodd, D E; Losco, P E; Troup, C M; Tyler, T R

1989-03-01

PEGs in the 3000 to 4000 MW range are used in many pharmaceutical and cosmetic applications; they produce little ocular or dermal irritation and have extremely low acute and subchronic toxicity by oral and dermal routes of administration. However, little information exists on the potential of aerosols of these materials to produce adverse health effects. F-344 rats were exposed to aerosols of PEG 3350 (20% w:w in water) at 0, 109, 567, or 1008 (highest attainable) mg/m3 for 6 hr/d, 5 d/wk for 2 wk. No exposure-related toxicity was found with regard to clinical signs, ophthalmology, serum chemistry, urinalysis, or gross pathology. Exposure-related effects included: a 50% increase in the neutrophil count (males only) at 1008 mg/m3; decreased body weight gain (16%) for both the 567 and 1008 mg/m3 groups (males only); absolute lung weights of both sexes were increased 10 and 18% for the 567 and 1008 mg/m3 groups, respectively. A slight increase in the number of macrophages in the alveoli was the only change observed histologically in all PEG 3350-exposed groups. Therefore, inhalation of aerosols of PEG 3350 at concentrations up to 1008 mg/m3 produced relatively little toxicity in rats, the lung was the target organ, and the no-observable-effect-level was between 109 to 567 mg/m3.

Toxicologic Assessment of a Commercial Decolorized Whole Leaf Aloe Vera Juice, Lily of the Desert Filtered Whole Leaf Juice with Aloesorb

PubMed Central

Winters, Wallace D.; Scott, Michael; David, Andrew; Gillis, Glenn; Stoufflet, Thaya; Nair, Anand; Kousoulas, Konstantine

2013-01-01

Aloe vera, a common ingredient in cosmetics, is increasingly being consumed as a beverage supplement. Although consumer interest in aloe likely stems from its association with several health benefits, a concern has also been raised by a National Toxicology Program Report that a nondecolorized whole leaf aloe vera extract taken internally by rats was associated with intestinal mucosal hyperplasia and ultimately malignancy. We tested a decolorized whole leaf (DCWL) aloe vera, treated with activated charcoal to remove the latex portion of the plant, for genotoxicity in bacteria, acute/subacute toxicity in B6C3F1 mice, and subchronic toxicity in F344 rats. We found this DCWL aloe vera juice to be nongenotoxic in histidine reversion and DNA repair assays. Following acute administration, mice exhibited no adverse signs at 3- or 14-day evaluation periods. When fed to male and female F344 rats over 13 weeks, DCWL aloe led to no toxicity as assessed by behavior, stools, weight gain, feed consumption, organ weights, and hematologic or clinical chemistry profiles. These rats had intestinal mucosal morphologies—examined grossly and microscopically—that were similar to controls. Our studies show that oral administration of this DCWL aloe juice has a different toxicology profile than that of the untreated aloe juice at exposures up to 13 weeks. PMID:23554812

An ecotoxicological approach for hazard identification of energy ash.

PubMed

Stiernström, S; Hemström, K; Wik, O; Carlsson, G; Bengtsson, B-E; Breitholtz, M

2011-02-01

Within the EU, ash should be classified by its inherent hazardous effects under criterion H-14 (ecotoxic) in the Directive on waste (2008/98/EC). Today, however, there are no harmonized quantitative criterions for such a classification, but it is stated that biological test systems can be used. In this study seven ash materials were leached and characterized, both biologically and chemically. The objectives were to evaluate if (a) clear concentration-response relationships could be achieved for the selected toxicity tests (bacteria, algae, crustacean and fish), (b) some test(s) are generally more sensitive and (c) the toxic responses were consistent with the chemical analyzes. Interestingly, our results indicate that high concentrations of non-hazardous components (Ca, K) influenced the toxicity of almost all ash eluates, whereas hazardous components (e.g. Zn, Pb) only influenced the toxicity of the eluates ranked as most hazardous. If considering both hazardous and non-hazardous substances, the observed toxic responses were relatively consistent with the chemical analyzes. Our results further showed that the (sub)chronic tests were much more sensitive than the acute tests. However, the use of extrapolation factors to compensate for using the less sensitive acute tests will likely lead to either over- or underestimations of toxicity. Our recommendation is therefore that classification of waste according to H-14 should be based on (sub)chronic test data. Finally, given that treatment of the eluates prior to toxicity testing has a major significance on the concentration and speciation of released substances, further studies are needed in order to propose a relevant testing scheme. Copyright © 2010 Elsevier Ltd. All rights reserved.

Toxicity of naproxen sodium and its mixture with tramadol hydrochloride on fish early life stages.

PubMed

Sehonova, Pavla; Plhalova, Lucie; Blahova, Jana; Doubkova, Veronika; Prokes, Miroslav; Tichy, Frantisek; Fiorino, Emma; Faggio, Caterina; Svobodova, Zdenka

2017-12-01

Pharmaceuticals occur in water bodies as a consequence of their incomplete removal during waste water treatment processes. The occurence of pharmaceuticals in surface waters as well as their possible impact on aquatic vertebrates have received considerable attention in recent years. However, there is still a lack of informations on the chronic effects of widely used drugs as well as their possible mixture toxicity on non-target aquatic vertebrates as well as their possible mixture toxicity. The aim of this study was to assess the effects of naproxen sodium on early life stages of fish and evaluate its mixture toxicity with tramadol hydrochloride, which was assessed in our earlier study as a single substance. Two embryo-larval toxicity tests with common carp (Cyprinus carpio) were performed according to the OECD guideline 210 (Fish, Early-life Stage Toxicity Test) in order to assess the subchronic toxicity of naproxen sodium and tramadol hydrochlorid-naproxen sodium mixture at the concentrations of 10; 50; 100 and 200 μg/L. These experiments were conducted for 32 days. The subchronic exposure to naproxen sodium and naproxen sodium and tramadol hydrochloride mixture had a strong effect on the early life stages of common carp. Hatching, developmental rate, morphology, histopathology and, in the case of the naproxen sodium and tramadol hydrochloride mixture, mortality were influenced. The bioindicators of oxidative stress were also influenced. The LOEC was determined at 10 μg/L for both naproxen sodium and naproxen sodium and tramadol hydrochloride mixture. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of sub-chronic toxic effects of petroleum ether, a laboratory solvent in Sprague-Dawley rats

PubMed Central

Parasuraman, Subramani; Sujithra, Jeyabalan; Syamittra, Balakrishnan; Yeng, Wong Yeng; Ping, Wu Yet; Muralidharan, Selvadurai; Raj, Palanimuthu Vasanth; Dhanaraj, Sokkalingam Arumugam

2014-01-01

Background: In general, organic solvents are inhibiting many physiological enzymes and alter the behavioural functions, but the available scientific knowledge on laboratory solvent induced organ specific toxins are very limited. Hence, the present study was planned to determine the sub-chronic toxic effects of petroleum ether (boiling point 40–60°C), a laboratory solvent in Sprague-Dawley (SD) rats. Materials and Methods: The SD rats were divided into three different groups viz., control, low exposure petroleum ether (250 mg/kg; i.p.) and high exposure petroleum ether (500 mg/kg; i.p.) administered group. The animals were exposed with petroleum ether once daily for 2 weeks. Prior to the experiment and end of the experiment animals behaviour, locomotor and memory levels were monitored. Before initiating the study animals were trained for 2 weeks for its learning process and its memory levels were evaluated. Body weight (BW) analysis, locomotor activity, anxiogenic effect (elevated plus maze) and learning and memory (Morris water navigation task) were monitored at regular intervals. On 14th day of the experiment, few ml of blood sample was collected from all the experimental animals for estimation of biochemical parameters. At the end of the experiment, all the animals were sacrificed, and brain, liver, heart, and kidney were collected for biochemical and histopathological analysis. Results: In rats, petroleum ether significantly altered the behavioural functions; reduced the locomotor activity, grip strength, learning and memory process; inhibited the regular body weight growth and caused anxiogenic effects. Dose-dependent organ specific toxicity with petroleum ether treated group was observed in brain, heart, lung, liver, and kidney. Extrapyramidal effects that include piloerection and cannibalism were also observed with petroleum ether administered group. These results suggested that the petroleum ether showed a significant decrease in central nervous system (CNS) activity, and it has dose-dependent toxicity on all vital organs. Conclusion: The dose-dependent CNS and organ specific toxicity was observed with sub-chronic administration of petroleum ether in SD rats. PMID:25316988

Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent History of War Zone Stress Exposure

DTIC Science & Technology

2013-07-01

brain injury, rats treated subchronically (two weeks) with orally gavaged atorvastatin or simvastatin showed evidence of diminished loss of cells in...203. Lu D, Goussev A, Chen J, et al. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in

Hypoglycemic and hypolipidemic effects of Coriandrum sativum L. in Meriones shawi rats.

PubMed

Aissaoui, Abderrahmane; Zizi, Soumia; Israili, Zafar H; Lyoussi, Badiâa

2011-09-01

The use of an aqueous extract of coriander (Coriandrum sativum L.; Apiaceae, Umbelliferae) seeds (CS-extract) in Moroccan traditional treatment of diabetes remains to be experimentally validated. The study aim was to investigate potential hypoglycemic (and hypolipidemic) activity of CS-extract after a single oral dose and after daily dosing for 30 days (sub-chronic study) in normal and obese-hyperglycemic-hyperlipidemic (OHH) Meriones shawi rats. After a single oral dose of CS-extract (20mg/kg; predetermined as optimum), plasma glucose, insulin, total cholesterol (TC), and triglycerides (TG) were measured in normal and OHH rats (hypercaloric diet and forced limited physical activity); glibenclamide (GLB; 2.5mg/kg) was used as reference. In the sub-chronic study, the effect of CS-extract and GLB (at the above doses) on body weight (BW), plasma glucose, insulin, TC, LDL-cholesterol, HDL-cholesterol, TG, urea and creatinine was determined in normal and OHH rats; insulin resistance (IR as HOMA-IR), atherosclerotic and cardioprotective indices were calculated. A single dose of CS-extract or GLB suppressed hyperglycemia in OHH rats, and normo-glycemia was achieved at 6-h post-dose; there was no effect on lipids, TG or insulin, but IR decreased significantly. The hypoglycemic effect was lower in normal rats. In the sub-chronic study in OHH rats, the test substances (CS-extract>GLB) reduced plasma glucose (normoglycemia on Day 21), insulin and IR, TC, LDL-cholesterol, and TG. Atherosclerotic index decreased while cardioprotective indices increased only by CS-extract, with no effect on BW, urea or creatinine. Sub-chronic administration of CS-extract in OHH Meriones shawi rats normalized glycemia and decreased the elevated levels of insulin, IR, TC, LDL-cholesterol and TG. Since, the CS-extract decreased several components of the metabolic syndrome and decreased atherosclerotic and increased cardioprotective indices, CS-extract may have cardiovascular protective effect. The present study validates the traditional use of coriander in diabetes. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Reproduction and subchronic feeding study of carnauba wax in rats.

PubMed

Parent, R A; Re, T A; Babish, J G; Cox, G E; Voss, K A; Becci, P J

1983-02-01

The reproductive performance of Wistar rats fed carnauba wax at levels of 0.1, 0.3 or 1% in the diet and the effects of subchronic administration of carnauba wax at these dose levels on the resultant progeny were studied. Reproductive indices, body-weight gain, food consumption, haematological and clinical chemical data, ophthalmic, gross and histopathological examinations were used to study the possible toxic or pathological effects. Serum free fatty acid levels were found to be decreased in male and female rats fed carnauba wax at dietary levels of 0.3 and 1.0%. No other effects of feeding carnauba wax at levels up to 1.0% of the diet were observed.

The comparative toxicity of operational Air Force hydraulic fluids.

PubMed

Mattie, D R; Hoeflich, T J; Jones, C E; Horton, M L; Whitmire, R E; Godin, C S; Flemming, C D; Andersen, M E

1993-01-01

The subchronic (26 day) oral toxicities of two AF hydraulic fluids (MIL-H-5606 [H5], MIL-H-83282 [H8]), a commercial phosphate ester (PE), and two candidate hydraulic fluids (low temperature version of MIL-H-83282 [LT] and chlorotrifluorethylene oligomers [polyCTFE]) were compared in male F-344 rats. Oral dosing was used in order to quickly compare these fluids to PolyCTFE, the only fluid at the time to have been tested in a 90-day inhalation study. Rats were initially dosed with 1.0 g/kg/day of each fluid. H8 increased alkaline phosphatase (ALKP) while LT produced an anemia and leukocytosis. Exposure to H5 fluid resulted in lymphocytopenia and persistent diuresis. Due to their greater toxicity, resulting in lethality in the first dosing study, only 0.5 g/kg/day of PE and PolyCTFE were administered in the second study. Exposure to PE (0.5 g/kg) resulted in an anemia and decreases in BW (day 10 until day 25), spleen/BW ratio, blood urea nitrogen (BUN), and creatinine (CREAT). PolyCREAT (0.5 g/kg) decreased BW (day 11 to the end of the study) and testicular weight. PolyCTFE (0.5 g/kg) increased relative spleen weights, various clinical chemistry parameters, and triggered a reversible diuresis. PolyCTFE (0.5 g/kg), PE (0.5 g/kg), and H5 produced an increase in absolute and relative liver weights compared to control livers. Peroxisomal beta oxidation, an indicator of peroxisomal proliferation, was significantly increased above control levels in the livers of all rats except the PE (0.5 g/kg) group, where the increase was not significant. Hydrocarbon nephropathy, indicated by increased levels of hyaline droplets in kidney tubules, was severe in H5, mild in H8, LT, and PolyCTFE (0.5 g/kg), and minimal in PE (0.5 g/kg). The MIL-H-83282 fluids (H8 and LT) were the least toxic hydraulic fluids. PolyCTFE and PE were the most toxic, with H5 intermediate.

Effect of burdock extract on physical performance and physiological fatigue in mice

PubMed Central

CHEN, Wen-Chyuan; HSU, Yi-Ju; LEE, Mon-Chien; LI, Hua Shuai; HO, Chun-Sheng; HUANG, Chi-Chang; CHEN, Fu-An

2017-01-01

Burdock (BD) is a common vegetable with many pharmacological properties. However, few studies have examined the effect of BD on exercise performance and physical fatigue. We aimed to evaluate the potential beneficial effects of BD on fatigue and ergogenic functions following physical challenge in mice. Methods: Male ICR mice were divided into four groups to receive either vehicle, or BD at 348.5, 697 or 1,742.5 mg/kg/day, by daily oral gavage for 4 weeks. Exercise performance and fatigue were evaluated from forelimb grip strength, exhaustive swimming time, and post-exercise levels of physical fatigue-related biomarkers serum lactate, ammonia, glucose, and creatine kinase (CK). Results: BD supplementation elevated endurance and grip strength in a dose-dependent manner. It also significantly decreased lactate, ammonia, and CK levels after physical challenge. In addition, BD supplementation had few subchronic toxic effects. Conclusions: Supplementation with BD has a wide spectrum of bioactive effects, including health promotion, performance improvement, and fatigue reduction. PMID:28890521

Sub-Chronic Oral Exposure to Iridium (III) Chloride Hydrate in Female Wistar Rats: Distribution and Excretion of the Metal

PubMed Central

Iavicoli, Ivo; Fontana, Luca; Bergamaschi, Antonio; Conti, Marcelo Enrique; Pino, Anna; Mattei, Daniela; Bocca, Beatrice; Alimonti, Alessandro

2012-01-01

Iridium tissue distribution and excretion in female Wistar rats following oral exposure to iridium (III) chloride hydrate in drinking water (from 1 to 1000 ng/ml) in a sub-chronic oral study were determined. Samples of urine, feces, blood and organs (kidneys, liver, lung, spleen and brain) were collected at the end of exposure. The most prominent fractions of iridium were retained in kidney and spleen; smaller amounts were found in lungs, liver and brain. Iridium brain levels were lower than those observed in other tissues but this finding can support the hypothesis of iridium capability to cross the blood brain barrier. The iridium kidney levels rose significantly with the administered dose. At the highest dose, important amounts of the metal were found in serum, urine and feces. Iridium was predominantly excreted via feces with a significant linear correlation with the ingested dose, which is likely due to low intestinal absorption of the metal. However, at the higher doses iridium was also eliminated through urine. These findings may be useful to help in the understanding of the adverse health effects, particularly on the immune system, of iridium dispersed in the environment as well as in identifying appropriate biological indices of iridium exposure. PMID:22942873

Bioaccumulation and Subchronic Toxicity of 14 nm Gold Nanoparticles in Rats.

PubMed

Rambanapasi, Clinton; Zeevaart, Jan Rijn; Buntting, Hylton; Bester, Cornelius; Kotze, Deon; Hayeshi, Rose; Grobler, Anne

2016-06-10

Colloidal suspensions of 14 nm gold nanoparticles (AuNPs) were repeatedly administered intravenously at three dose levels (0.9, 9 and 90 µg) to male Sprague Dawley rats weekly for 7 weeks, followed by a 14-day washout period. After sacrificing, the amount of gold was quantified in the liver, lungs, spleen, skeleton and carcass using neutron activation analysis (NAA). During the study, pre- and post (24 h) administration blood samples were collected from both the test and control groups, the latter which received an equal injection volume of normal saline. General health indicators were monitored together with markers of kidney and liver damage for acute and subchronic toxicity assessment. Histopathological assessments were done on the heart, kidneys, liver, lungs and spleen to assess any morphological changes as a result of the exposure to AuNPs. The mass measurements of all the groups showed a steady increase with no signs of overt toxicity. The liver had the highest amount of gold (µg) per gram of tissue after 56 days followed by the spleen, lungs, skeleton and carcass. Markers of kidney and liver damage showed similar trends between the pre and post samples within each group and across groups. The histopathological examination also showed no hepatotoxicity and nephrotoxicity. There was accumulation of Au in tissues after repeated dosing, albeit with no observable overt toxicity, kidney or liver damage.

SUBCHRONIC PULMONARY PATHOLOGY, IRON-OVERLOAD AND TRANSCRIPTIONAL ACTIVITY AFTER LIBBY AMPHIBOLE EXPOSURE IN RAT MODELS OF CARDIOVASCULAR DISEASE

EPA Science Inventory

Background: Surface-available iron (Fe) is proposed to contribute to asbestos-induced toxicity through the production of reactive oxygen species.Objective: Our goal was to evaluate the hypothesis that rat models of cardiovascular disease with coexistent Fe overload would be incre...

Acute and Subchronic Toxicity of Inhaled Toluene in Male Long-Evans Rats: Oxidative Stress Markers in Brain

EPA Science Inventory

The effects of exposure to volatile organic compounds (VOCs), which are of concern to the EPA, are poorly understood, in part because of insufficient characterization of how human exposure duration impacts VOC effects. Two inhalation studies with multiple endpoints, one acute an...

Mixtures of benzo(a)pyrene, dichlorodiphenyltrichloroethane and tributyltin are more toxic to neotropical fish Rhamdia quelen than isolated exposures.

PubMed

Oliveira, Heloísa H P; Liebel, Samuel; Rossi, Stéfani C; Azevedo, Ana C B; Barrera, Ellie A L; Garcia, Juan Ramon Esquivel; Grötzner, Sônia Regina; Neto, Francisco Filipak; Randi, Marco A F; Ribeiro, Ciro A O

2015-12-01

The effects of benzo(a)pyrene (BaP), dichlorodiphenyltrichloroethane (DDT) and tributyltin (TBT) association were investigated through a multi-biomarker approach. Ten Rhamdia quelen fish per group were exposed through intraperitoneal injections either to BaP (0.3; 3 or 30 mg kg(-1)), DDT or TBT (0.03; 0.3 or 3 mg kg(-1)) or BaP/DDT, BaP/TBT, DDT/TBT or BaP/DDT/TBT on their lowest doses. The experiments were divided in acute (one dose, 5-day) and sub-chronic (3 doses, 15-day). Control groups received an equal volume of PBS or canola oil (1 ml kg(-1)). The three tested contaminants altered AChE activity in brain and muscle in similar ways; the mixtures antagonized the increase evoked by the contaminants alone. BaP and TBT increased GSH content and mixtures reduced it. GPx activity was increased by DDT and TBT in the 15-day experiment and reduced by the mixtures. BaP increased GST activity in sub-chronic experiment while TBT reduced it in the acute experiment. BaP/TBT increased GST activity compared to all groups; the other mixtures reduced it compared to BaP or DDT in the 5-day experiment. BaP, DDT and TBT increased δ-ALAd activity mainly in acute exposure; the mixtures also increased δ-ALAd compared to DDT or TBT in 5 and 15-day. BaP, TBT and BaP/DDT decreased LPO in the acute experiment. In the sub-chronic experiment DDT/TBT increased LPO when compared to TBT. None of the contaminants alone altered PCO, but all mixtures increased it compared to one or another contaminant. Contaminants isolated had a more acute effect in ALT plasma level; their lowest dose, which had no effect alone, in combination has led to an increase of this enzyme, especially after 15 days. DDT increased AST in the acute and sub-chronic experiments, while TBT did the same in the latter. DDT/TBT decreased AST opposing the effect of the contaminants alone in the 5-day experiment. Hepatic lesions index could be explained by a more acute effect of the contaminants alone or combined and by activation of cell defenses after the sub-chronic exposure. TBT increased melanomacrophages counting in the 5-day experiment and the mixtures increased it in the 5 and 15-day experiments. Overall, the majority of the biomarkers pointed to a more toxic effect when these contaminants were combined, leading to unexpected toxicities compared to individual exposure scenarios. These findings are relevant considering environmental exposure conditions, since organisms are often exposed to different combinations of contaminants. Copyright © 2015 Elsevier Inc. All rights reserved.

A Health Assessment of Technical Grade Dinitrotoluene ...

EPA Pesticide Factsheets

Technical grade dinitrotoluene (tgDNT) is a mixture of dinitrotoluene isomers. It is composed of 76% 2,4 DNT and 19% 2,6 DNT with the remaining 5% a combination of the other four dinitrotoluene isomers (2,3 , 2,5 , 3,4 , and 3,5 DNT). The toxicological effects of tgDNT were reviewed and the critical effects were identified by evaluating available human occupational and animal studies mainly via inhalation and oral exposure routes. In occupational studies of workers from DNT manufacturing plants, tgDNT exposure (predominately via the inhalation route) associates with clinical symptoms, adverse reproductive effects, and adverse effects on the cardiovascular system. However, these occupational studies are limited due to co-exposure to other known and/or unknown chemicals and lack of useful exposure information. Oral studies in F344 rats showed that tgDNT has a broad toxicity profile in both males and females including significantly increased reticulocytes and Heinz bodies, increased relative liver weight and kidney weight, spleen hemosiderin and extramedullary hematopoiesis, increased incidence of chronic interstitial nephritis, and hepatotoxicity characterized by increased incidences of hepatocyte necrosis, hyperbasophilic hepatocytes, and hepatocyte megalocytosis . The incidence of testicular degeneration in male rats is also significantly increased by tgDNT. In order to identify the most sensitive non-cancer effect(s), all toxicological endpoints from subchron

Anti-malarial activity and toxicity assessment of Himatanthus articulatus, a plant used to treat malaria in the Brazilian Amazon.

PubMed

Vale, Valdicley V; Vilhena, Thyago C; Trindade, Rafaela C Santos; Ferreira, Márlia Regina C; Percário, Sandro; Soares, Luciana F; Pereira, Washington Luiz A; Brandão, Geraldo C; Oliveira, Alaíde B; Dolabela, Maria F; De Vasconcelos, Flávio

2015-03-27

Plasmodium falciparum has become resistant to some of the available drugs. Several plant species are used for the treatment of malaria, such as Himatanthus articulatus in parts of Brazil. The present paper reports the phyto-chemistry, the anti-plasmodial and anti-malarial activity, as well as the toxicity of H. articulatus. Ethanol and dichloromethane extracts were obtained from the powder of stem barks of H. articulatus and later fractionated and analysed. The anti-plasmodial activity was assessed against a chloroquine resistant strain P. falciparum (W2) in vitro, whilst in vivo anti-malarial activity against Plasmodium berghei (ANKA strain) was tested in mice, evaluating the role of oxidative stress (total antioxidant capacity--TEAC; lipid peroxidation--TBARS, and nitrites and nitrates--NN). In addition, cytotoxicity was evaluated using the HepG2 A16 cell-line. The acute oral and sub-chronic toxicity of the ethanol extract were evaluated in both male and female mice. Plumieride was isolated from the ethyl acetate fraction of ethanol extract, Only the dichloromethane extract was active against clone W2. Nevertheless, both extracts reduced parasitaemia in P. berghei-infected mice. Besides, a significant reduction in pulmonary and cerebral levels of NN (nitrites and nitrates) was found, as well as in pulmonary TBARS, indicating a reduced oxidative damage to these organs. The ethanol extract showed low cytotoxicity to HepG2 A16 cells in the concentrations used. No significant changes were observed in the in vivo toxicity studies. The ethanol extract of H. articulatus proved to be promising as anti-malarial medicine and showed low toxicity.

Subchronic safety evaluation of CMS-1 (a botanical antihypertensive product derived from Semen Cnidium monnieri) in Sprague-Dawley rats and beagle dogs.

PubMed

Gong, Xue-Lian; Gao, Ting-Ting; Zhao, Li-Jun; Zhu, Hai; Xia, Zhen-Na; Lu, Wen; Lu, Guo-Cai

2014-08-01

CMS-1, mainly composed of imperatorin as its active compound, is a partially purified fraction of a Chinese herbal medicine, Semen Cnidium monnieri. CMS-1 has the potential to be further developed as a new treatment for hypertension. Thus, we studied its toxicity in both Sprague-Dawley rats and beagle dogs. Rats (0-900mg/kg/day) and dogs (0-450mg/kg/day) received CMS-1 orally for 30 consecutive days, followed by a 15-day recovery period. The major target organs of CMS-1 toxicity are the GI (inappetence), liver (hepatocellular necrosis, enzyme elevation), thymus (atrophy), cardiovascular (hypotension), changes in ECG T and P waveforms, elevation of nitrous oxide levels and hematological (RBC parameters disturbances) systems. Most treatment-induced adverse effects were reversible or showed a progressive recovery upon discontinuation of the treatment. The No Observed Adverse Effect Level (NOAEL) was 100mg/kg/day for rats and 50mg/kg/day for dogs. This non-clinical study suggests that clinical monitoring of CMS-1 in patients should focus on the gastrointestinal system, blood tests for liver functions, electrolytes, and blood homeostasis, cardiovascular functions, and immune functions. Copyright © 2014 Elsevier Inc. All rights reserved.

Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

PubMed

Dent, M P

2007-08-01

The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert for possible effects on fertility (or early embryonic development), the biological significance of which can be ascertained in a littering (e.g. 2-generation) study. From the chemicals reviewed it would appear that where there are no alerts from a repeat-dose toxicity study, a pre-natal developmental toxicity study and sex steroid receptor binding assays, there exists a low priority for animal studies to address the fertility endpoint. The ability for these types of tests to provide alerts for effects on fertility is clearly dependent on the mode of action of the toxicant in question. Further work should therefore be performed to determine the 'failure rate' of this type of approach when applied to a larger group of chemicals with diverse modes of action.

Effects of subchronic malathion exposure on the pharmacokinetic disposition of pefloxacin.

PubMed

Suresh Babu, N; Malik, J K; Rao, G S; Aggarwal, Manoj; Ranganathan, V

2006-09-01

Malathion is one of the most extensively used organophosphorus pesticides applied in agriculture, mosquito eradication and in the control of animal ectoparasites and human body lice. The widespread use of malathion has raised concern over its potential to cause untoward health effects in humans, animals and birds. Malathion inhibits cytochrome P450 monooxygenases and has the potential to alter pharmacokinetic profiles of therapeutic agents that are metabolized in the liver. The present study was undertaken to evaluate the impact of subchronic exposure of malathion on the pharmacokinetic disposition of pefloxacin. Chickens were given either normal diet or malathion through food at a concentration of 1000ppm for 28 days. Subsequently, pefloxacin was administered either intravenously or orally (control) to birds fed normal diet and orally to malathion-exposed chickens at a dosage of 10mgkg(-1) body weight. Blood samples were drawn from the brachial vein at predetermined time intervals after drug administration. Plasma was separated and analyzed for pefloxacin by reverse-phase high performance liquid chromatography. The plasma concentration-time data were analyzed by non-compartmental techniques. Following intravenous administration of pefloxacin, elimination half-life (t(1/2β)), area under the plasma concentration-time curve (AUC) and mean residence time (MRT) were 8.2±0.7h, 66±9μghml(-1) and 10.5±1.1h, respectively, and when the drug was administered orally, the respective values of pharmacokinetic parameters were 8.2±0.4h, 31±3.1μghml(-1) and 11.7±0.6h. Malathion exposure significantly increased maximum plasma drug concentration, t(1/2β), AUC and MRT of pefloxacin to 54, 22, 117 and 37% of control, respectively. These findings provide evidence that subchronic malathion exposure markedly influences the elimination kinetics of pefloxacin which may be due to malathion-mediated inhibition of metabolism of pefloxacin.

How Subchronic and Chronic Health Effects can be Neglected for GMOs, Pesticides or Chemicals

PubMed Central

Séralini, Gilles-Eric; de Vendômois, Joël Spiroux; Cellier, Dominique; Sultan, Charles; Buiatti, Marcello; Gallagher, Lou; Antoniou, Michael; Dronamraju, Krishna R.

2009-01-01

Chronic health effects are increasing in the world such as cancers, hormonal, reproductive, nervous, or immune diseases, even in young people. During regulatory toxicological subchronic tests to prevent these on mammalian health, prior commercialization of chemicals, including pesticides and drugs, or GMOs, some statistically significant findings may be revealed. This discussion is about the need to investigate the relevant criteria to consider those as biologically significant. The sex differences and the non linear dose or time related effects should be considered in contrast to the claims of a Monsanto-supported expert panel about a GMO, the MON 863 Bt maize, but also for pesticides or drugs, in particular to reveal hormone-dependent diseases and first signs of toxicities. PMID:19584953

How subchronic and chronic health effects can be neglected for GMOs, pesticides or chemicals.

PubMed

Séralini, Gilles-Eric; de Vendômois, Joël Spiroux; Cellier, Dominique; Sultan, Charles; Buiatti, Marcello; Gallagher, Lou; Antoniou, Michael; Dronamraju, Krishna R

2009-06-17

Chronic health effects are increasing in the world such as cancers, hormonal, reproductive, nervous, or immune diseases, even in young people. During regulatory toxicological subchronic tests to prevent these on mammalian health, prior commercialization of chemicals, including pesticides and drugs, or GMOs, some statistically significant findings may be revealed. This discussion is about the need to investigate the relevant criteria to consider those as biologically significant. The sex differences and the non linear dose or time related effects should be considered in contrast to the claims of a Monsanto-supported expert panel about a GMO, the MON 863 Bt maize, but also for pesticides or drugs, in particular to reveal hormone-dependent diseases and first signs of toxicities.

Propylene glycol monomethyl ether (PGME): inhalation toxicity and carcinogenicity in Fischer 344 rats and B6C3F1 mice.

PubMed

Spencer, Pamela J; Crissman, James W; Stott, William T; Corley, Richard A; Cieszlak, Frank S; Schumann, Alan M; Hardisty, Jerry F

2002-01-01

A series of inhalation studies with propylene glycol monomethyl ether (PGME) vapor were undertaken to characterize its subchronic toxicity in mice and chronic toxicity/oncogenicity in rats and mice. Groups of male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 300, 1,000, or 3,000 ppm vapor from 1 week to 2 years. Primary treatment-related effects included: initial sedation of animals exposed to 3,000 ppm and its subsequent resolution correlating with induction of hepatic mixed function oxidase activity and S-phase DNA synthesis; elevated mortality in high-exposure male rats and mice (chronic study); elevated deposition of alpha2u-globulin (alpha2U-G) and associated nephropathy and S-phase DNA synthesis in male rat kidneys; accelerated atrophy of the adrenal gland X-zone in female mice (subchronic study only); and increased occurrence and/or severity of eosinophilic foci of altered hepatocytes in male rats. No toxicologically relevant statistically significant increases in neoplasia occurred in either species. A numerical increase in the incidence of kidney adenomas occurred in intermediate-exposure male rats; however, the association with alpha2U-G nephropathy, a male rat specific effect, indicated a lack of relevance for human risk assessment.

Comparative toxicity of low dose tributyltin chloride on serum, liver, lung and kidney following subchronic exposure.

PubMed

Mitra, Sumonto; Gera, Ruchi; Singh, Vikas; Khandelwal, Shashi

2014-02-01

Tributyltin (TBT) pollution is rampant worldwide and is a growing threat due to its bio-accumulative property. Isolated studies of TBT toxicity on different organs are available but consolidated information is greatly lacking. We planned this study to delineate the effect of subchronic (1 month) exposure to low dose TBT-chloride (TBTC) (1 and 5 mg/kg) in male Wistar rats. Total tin concentration was found to be significantly increased in liver, kidney and blood, and marginally in lungs. Organo-somatic indices were seen to be altered with little effect on serum biochemical markers (liver and kidney function, and general parameters). Reactive oxygen species but not lipid peroxidation content was observed to be significantly elevated both in the tissues and serum. TBTC was found to act as a hyperlipidemic agent and it also affected heme biosynthetic pathway. Hematological analysis showed that TBTC exposure resulted in minor alterations in RBC parameters. Histological studies demonstrated marked tissue damage in all the 3 organs. Calcium inhibitors (BAPTA-AM, EGTA) and antioxidants (NAC, C-PC) significantly restored TBTC induced loss in cell viability, under ex-vivo conditions. Antioxidants were evidently more efficient in comparison to the calcium inhibitors, implying major role of oxidative stress pathways in TBTC toxicity. Copyright © 2013 Elsevier Ltd. All rights reserved.

TCDD-MEDIATED OXIDATIVE STRESS IN MALE RAT PUPS FOLLOWING PERINATAL EXPOSURE

EPA Science Inventory

TCDD is a highly persistent trace environmental contaminant and is one of the most potent toxicants known to man. Our laboratory has previously reported an increase in the production of reactive oxygen species (ROS) in the brain of female B6C3F1 mice following subchronic exposur...

76 FR 76309 - Isoxaflutole; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-07

...). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk..., dermal, and inhalation routes of exposure and it is not a dermal sensitizer. In long-term studies via the... offspring exhibited ocular and liver toxicities as seen in long- term studies. In the acute and subchronic...

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Subchronic Toxicity Study of Lewisite in Rats

DTIC Science & Technology

1989-07-31

buffered formalin (NBF). To standardize the degree of distension of pulmonary alveoli with fixative, the lungs were fixed by inserting a blunted needle into...the thickness of the mucosa, submucosa and muscular layers of the stomach and involved the serosa. Epithelial hyperplasia and hyperkeratosis of the

40 CFR 79.63 - Fertility assessment/teratology.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., conception, and fertility. Since this is a one-generation test that ends with examination of full-term... females in both test and control groups are mated after nine weeks of exposure. Exposures for pregnant... subchronic toxicity study, pursuant to the provisions in § 79.62. (d) Limit test. If a test at one dose level...

40 CFR 79.63 - Fertility assessment/teratology.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., conception, and fertility. Since this is a one-generation test that ends with examination of full-term... females in both test and control groups are mated after nine weeks of exposure. Exposures for pregnant... subchronic toxicity study, pursuant to the provisions in § 79.62. (d) Limit test. If a test at one dose level...

40 CFR 79.63 - Fertility assessment/teratology.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., conception, and fertility. Since this is a one-generation test that ends with examination of full-term... females in both test and control groups are mated after nine weeks of exposure. Exposures for pregnant... subchronic toxicity study, pursuant to the provisions in § 79.62. (d) Limit test. If a test at one dose level...

40 CFR 79.63 - Fertility assessment/teratology.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., conception, and fertility. Since this is a one-generation test that ends with examination of full-term... females in both test and control groups are mated after nine weeks of exposure. Exposures for pregnant... subchronic toxicity study, pursuant to the provisions in § 79.62. (d) Limit test. If a test at one dose level...

40 CFR 79.63 - Fertility assessment/teratology.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., conception, and fertility. Since this is a one-generation test that ends with examination of full-term... females in both test and control groups are mated after nine weeks of exposure. Exposures for pregnant... subchronic toxicity study, pursuant to the provisions in § 79.62. (d) Limit test. If a test at one dose level...

Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol.

PubMed

Toyoda, Takeshi; Cho, Young-Man; Akagi, Jun-Ichi; Mizuta, Yasuko; Matsushita, Kohei; Nishikawa, Akiyoshi; Imaida, Katsumi; Ogawa, Kumiko

2017-01-01

3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been shown to be a nongenotoxic renal carcinogen. Although the toxicity of 3-MCPD has been widely investigated for decades, there is a further concern that 3-MCPD might exert more potent toxicity in high-risk population with underlying diseases such as hyperlipidemia associated with obesity. In the present study, we performed a 13-week subchronic toxicity study for 3-MCPD using an obesity rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 9, 28.5, 90, 285, or 900 ppm 3-MCPD in drinking water for 13 weeks. 3-MCPD treatment decreased body weight gain, increased relative kidney weights, induced anemia, and induced epithelial cell necrosis in epididymal ducts in all 3 strains. The degrees of epididymal damage were higher in F344 and lean rats than in fatty rats, while renal toxicity was most potent in F344 rats and comparable in lean and fatty rats. In contrast, the hematology data indicated that anemia was worse in fatty rats than in F344 and lean rats, and a significant decrease in hematopoietic cells in the bone marrow was observed only in fatty rats. The no-observed-adverse-effect level was estimated to be 28.5 ppm in all 3 strains for 3-MCPD. These results suggested that obese Zucker rats may be more susceptible to 3-MCPD-dependent toxicity in the hematopoietic tissues than their lean counterparts.

Final report on the safety assessment of ethoxyethanol and ethoxyethanol acetate.

PubMed

Johnson, Wilbur

2002-01-01

Ethoxyethanol is an ether alcohol described as a solvent and viscosity-decreasing agent for use in cosmetics. Ethoxyethanol Acetate is the ester of Ethoxyethanol and acetic acid described as a solvent for use in cosmetics. Although these ingredients have been used in the past, neither ingredient is in current use. Ethoxyethanol is produced by reacting ethylene oxide with ethyl alcohol. Ethoxyethanol Acetate is produced via an esterification of Ethoxyethanol and acetic acid, acetic acid anhydride, or acetic chloride. Ethoxyethanol is metabolized to ethoxyacetaldehyde, which is further metabolized to ethoxyacetic acid, which is also a metabolite of Ethoxyethanol Acetate. Low to moderate acute inhalation toxicity is seen in animals studies. Acute oral toxicity studies in several species reported kidney damage, including extreme tubular degeneration. Kidney damage was also seen in acute dermal toxicity studies in rats and rabbits. Minor liver and kidney damage was also seen in short-term studies of rats injected subcutaneously with Ethoxyethanol, but was absent in dogs dosed intravenously. Mixed toxicity results were also seen in subchronic tests in mice and rats. Ethoxyethanol and Ethoxyethanol Acetate were mild to moderate eye irritants in rabbits; mild skin irritants in rabbits, and nonsensitizing in guinea pigs. Most genotoxicity tests were negative, but chromosome aberrations and sister-chromatid exchanges were among the positive results seen. Numerous reproductive and developmental toxicity studies, across several species, involving various routes of administration, indicate that Ethoxyethanol and Ethoxyethanol Acetate are reproductive toxicants and teratogens. Mild anemia was reported in individuals exposed occupationally to Ethoxyethanol, which resolved when the chemical was not used. Reproductive effects have been noted in males exposed occupationally to Ethoxyethanol. Although there are insufficient data to determine the potential carcinogenic effects of Ethoxyethanol or Ethoxyethanol Acetate, there is evidence that these chemicals are absorbed across human skin and that they are reproductive and developmental toxicants via dermal exposure. Therefore, these ingredients are unsafe for use in cosmetic formulations.

Toxicological assessment of polyhexamethylene biguanide for water treatment

PubMed Central

Mahmood, Abdulai Seidu; Awortwe, Charles; Nyarko, Alexander K.

2015-01-01

Polyhexamethylene biguanide (PHMB) is an antiseptic with antiviral and antibacterial properties used in a variety of products including wound care dressings, contact lens cleaning solutions, perioperative cleansing products, and swimming pool cleaners. There are regulatory concerns with regard to its safety in humans for water treatment. We decided to assess the safety of this chemical in Sprague-Dawley rats. PHMB was administered in a single dose by gavage via a stomach tube as per the manufacturer's instruction within a dose range of 2 mg/kg to 40 mg/kg. Subchronic toxicity studies were also conducted at doses of 2 mg/kg, 8 mg/kg and 32 mg/kg body weight and hematological, biochemical and histopathological findings of the major organs were assessed. Administration of a dose of 25.6 mg/kg, i.e. 1.6 mL of 0.4% PHMB solution (equivalent to 6.4x103 mg/L of 0.1% solution) resulted in 50% mortality. Histopathological analysis in the acute toxicity studies showed that no histopathological lesions were observed in the heart and kidney samples but 30% of the animals had mild hydropic changes in zone 1 of their liver samples, while at a dosage of 32 mg/kg in the subchronic toxicity studies, 50% of the animals showed either mild hepatocyte cytolysis with or without lymphocyte infiltration and feathery degeneration. Lymphocyte infiltration was, for the first time, observed in one heart sample, whereas one kidney sample showed mild tubular damage. The acute studies showed that the median lethal dose (LD50) is 25.6 mg/kg (LC50 of 1.6 mL of 0.4% PHMB. Subchronic toxicological studies also revealed few deleterious effects on the internal organs examined, as seen from the results of the biochemical parameters evaluated. These results have implications for the use of PHMB to make water potable. PMID:27486381

Food additive carrageenan: Part II: A critical review of carrageenan in vivo safety studies.

PubMed

Weiner, Myra L

2014-03-01

Carrageenan (CGN) is a seaweed-derived high molecular weight (Mw) hydrocolloid, primarily used as a stabilizer and thickener in food. The safety of CGN regarding its use in food is reviewed. Based on experimental studies in animals, ingested CGN is excreted quantitatively in the feces. Studies have shown that CGN is not significantly degraded by low gastric pH or microflora in the gastrointestinal (GI) tract. Due to its Mw, structure and its stability when bound to protein, CGN is not significantly absorbed or metabolized. CGN also does not significantly affect the absorption of nutrients. Subchronic and chronic feeding studies in rodents indicate that CGN at doses up to 5% in the diet does not induce any toxicological effects other than soft stools or diarrhea, which are a common effect for non-digestible high molecular weight compounds. Review of several studies from numerous species indicates that food grade CGN does not produce intestinal ulceration at doses up to 5% in the diet. Effects of CGN on the immune system following parenteral administration are well known, but not relevant to food additive uses. The majority of the studies evaluating the immunotoxicity potential were conducted with CGN administered in drinking water or by oral gavage where CGN exists in a random, open structured molecular conformation, particularly the lambda form; hence, it has more exposure to the intestinal mucosa than when bound to protein in food. Based on the many animal subchronic and chronic toxicity studies, CGN has not been found to affect the immune system, as judged by lack of effects on organ histopathology, clinical chemistry, hematology, normal health, and the lack of target organ toxicities. In these studies, animals consumed CGN at orders of magnitude above levels of CGN in the human diet: ≥1000 mg/kg/d in animals compared to 18-40 mg/kg/d estimated in the human diet. Dietary CGN has been shown to lack carcinogenic, tumor promoter, genotoxic, developmental, and reproductive effects in animal studies. CGN in infant formula has been shown to be safe in infant baboons and in an epidemiology study on human infants at current use levels.

Anti-inflammatory and antiallergic activity in vivo of lipophilic Isatis tinctoria extracts and tryptanthrin.

PubMed

Recio, María-Carmen; Cerdá-Nicolás, Miguel; Potterat, Olivier; Hamburger, Matthias; Ríos, José-Luis

2006-05-01

The effects of a supercritical CO2 (SFE) extract, a dichloromethane (DCM) extract from Isatis tinctoria leaf and the alkaloidal constituent tryptanthrin were studied in acute and subchronic experimental models of inflammation. The SFE and DCM extracts showed anti-inflammatory activity in the carrageenan-induced acute mouse paw oedema (ED50 values of 78 mg/kg and 165 mg/kg P. O., respectively) and in the acute tetradecanoylphorbol acetate (TPA)-induced mouse ear oedema in oral (62% and 32% oedema reduction at 100 and 125 mg/kg, respectively) and topical application (37% and 33% reduction of oedema at 0.5 mg/ear). In contrast, tryptanthrin showed no significant anti-inflammatory effect. The DCM extract inhibited oedema formation and neutrophil infiltration in subchronic inflammation in mice induced by repeated application of TPA. The extract showed activity after oral and topical administration by reducing the various parameters of the inflammatory response. The DCM extract (1 mg/ear) inhibited the delayed-type hypersensitivity (DTH) reaction induced by application of dinitrofluorobenzene (DNFB) after topical application. The response during the induction phase (24 h) was decreased by 48%, and the inflammatory phase (48 to 96 h) was reduced by 53 to 56%. The extract had no effect in this model when administered orally. The DCM extract (200 mg/kg P. O.) inhibited the acetic acid-induced writhing by 49%.

Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies.

PubMed

Priprem, Aroonsri; Johns, Jeffrey R; Limsitthichaikoon, Sucharat; Limphirat, Wanwisa; Mahakunakorn, Pramote; Johns, Nutjaree Prateepawanit

2017-06-01

Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

Toxicodynamic and toxicokinetic descriptors of combined chromium (VI) and nickel toxicity.

PubMed

Minigaliyeva, Ilzira A; Katsnelson, Boris A; Privalova, Larisa I; Gurvich, Vladimir B; Panov, Vladimir G; Varaksin, Anatoly N; Makeyev, Oleg H; Sutunkova, Marina P; Loginova, Nadezhda V; Kireyeva, Ekaterina P; Grigoryeva, Ekaterina V; Slyshkina, Tatyana V; Ganebnykh, Eugenia V; Grebenkina, Svetlana V

2014-01-01

After repeated intraperitoneal injections of nickel and chromium (VI) salts to rats, we found, and confirmed by mathematical modeling, that their combined subchronic toxicity can either be of additive type or depart from it (predominantly toward subadditivity) depending on the effect assessed. Against the background of moderate systemic toxicity, the combination under study proved to possess a marked additive genotoxicity assessed by means of the random amplification of polymorphic DNA test. We also demonstrated that chromium and nickel reciprocally influenced the retention of these metals in some organs (especially in the spleen) but not their urinary excretion in this study. © The Author(s) 2014.

Assessing the Toxicity and Bioavailability of 2,4-Dinitroanisole in Acute and Sub-Chronic Exposures Using the Earthworm, Eisenia fetida

DTIC Science & Technology

2010-06-01

different methods, 2nd method chosen for final study: ► Coelomocytes collected in 2 ml Guaiacol Glyceryl Ether ( GGE ) solution, centrifuged, decanted...worm to GGE t= 2mins collect coelomocyte solution 1 row per worm/treatment, obtain measurements through spectrophotometer NRRT analysis 1) 2) BUILDING

SUBCHRONIC SENSITIVITY OF ONE-, FOUR-, AND SEVEN-DAY-OLD FATHEAD MINNOW (PIMEPHALES PROMELAS) LARVAE TO FIVE TOXICANTS

EPA Science Inventory

The fathead minnow (pimephales promelas) larval survival and growth test was used to evaluate the relative sensitivity of 1-,4-, and 7-d-old larvae to five contaminants, KC1, NaC1, 1-octanol, carbaryl, and benzaldehyde. The no observable effect concentration (NOEC) for survival o...

TRANSCRIPTOMIC ANALYSIS OF F344 RAT NASAL EPITHELIUM SUGGESTS THAT THE LACK OF CARCINOGENIC RESPONSE TO GLUTARALDEHYDE IS DUE TO ITS GREATER TOXICITY COMPARED TO FORMALDEHYDE

EPA Science Inventory

Formaldehyde is cytotoxic and carcinogenic to the rat nasal respiratory epithelium inducing tumors after 12 months. Glutaraldehyde is also cytotoxic but is not carcinogenic to nasal epithelium even after 24 months. Both aldehydes induce similar acute and subchronic histopathology...

Investigation of the Effects of Subchronic Low Dose Oral Exposure to Bisphenol A (BPA) and Ethinyl Estradiol (EE) on Estrogen Receptor Expression in the Juvenile and Adult Female Rat Hypothalamus

PubMed Central

Rebuli, Meghan E.; Cao, Jinyan; Sluzas, Emily; Delclos, K. Barry; Camacho, Luísa; Lewis, Sherry M.; Vanlandingham, Michelle M.; Patisaul, Heather B.

2014-01-01

Concerns have been raised regarding the long-term impacts of early life exposure to the ubiquitous environmental contaminant bisphenol A (BPA) on brain organization. Because BPA has been reported to affect estrogen signaling, and steroid hormones play a critical role in brain sexual differentiation, there is also concern that BPA exposure could alter neural sex differences. Here, we examine the impact of subchronic exposure from gestation to adulthood to oral doses of BPA below the current no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day on estrogen receptor (ESR) expression in sexually dimorphic brain regions of prepubertal and adult female rats. The dams were gavaged daily with vehicle (0.3% carboxymethylcellulose), 2.5, 25, 260, or 2700 μg BPA/kg bw/day, or 0.5 or 5.0 μg ethinyl estradiol (EE)/kg bw/day from gestational day 6 until labor began. Offspring were then gavaged directly from the day after birth until the day before scheduled sacrifice on postnatal days 21 or 90. Using in situ hybridization, one or more BPA doses produced significant decreases in Esr1 expression in the juvenile female rat anteroventral periventricular nucleus (AVPV) of the hypothalamus and significant decreases in Esr2 expression in the adult female rat AVPV and medial preoptic area (MPOA), relative to vehicle controls. BPA did not simply reproduce EE effects, indicating that BPA is not acting solely as an estrogen mimic. The possible consequences of long-term changes in hypothalamic ESR expression resulting from subchronic low dose BPA exposure on neuroendocrine effects are discussed and being addressed in ongoing, related work. PMID:24752507

Toxicity studies on agent GA (Phase 2): 90 day subchronic study of GA (Tabun) in cd rats. Appendices. Final report, July 1985-August 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1992-03-01

The purpose of the report is to provide essential toxicologic information on Tabun administration over a 90 day period. This toxicologic information may be used to adjust the maximum-tolerated dose for subsequent dominant-lethal and two-generation reproduction studies. The objectives were to determine the toxic effects of nerve agent exposure (e.g., target organs); and to determine the effects of nerve agent GA on sperm morphology and motility and vaginal cytology.

Combined Subchronic Toxicity of Aluminum (III), Titanium (IV) and Silicon (IV) Oxide Nanoparticles and Its Alleviation with a Complex of Bioprotectors.

PubMed

Minigalieva, Ilzira A; Katsnelson, Boris A; Privalova, Larisa I; Sutunkova, Marina P; Gurvich, Vladimir B; Shur, Vladimir Y; Shishkina, Ekaterina V; Valamina, Irene E; Makeyev, Oleg H; Panov, Vladimir G; Varaksin, Anatoly N; Bushueva, Tatiana V; Sakhautdinova, Renata R; Klinova, Svetlana V; Solovyeva, Svetlana N; Meshtcheryakova, Ekaterina Y

2018-03-13

Stable suspensions of metal/metalloid oxide nanoparticles (MeO-NPs) obtained by laser ablation of 99.99% pure elemental aluminum, titanium or silicon under a layer of deionized water were used separately, or in three binary combinations, or in a ternary combination to induce subchronic intoxications in rats. To this end, the MeO-NPs were repeatedly injected intraperitoneally (i.p.) 18 times during 6 weeks before measuring a large number of functional, biochemical, morphological and cytological indices for the organism's status. In many respects, the Al₂O₃-NP was found to be the most toxic species alone and the most dangerous component of the combinations studied. Mathematical modeling with the help of the Response Surface Methodology showed that, as well as in the case of any other binary toxic combinations previously investigated by us, the organism's response to a simultaneous exposure to any two of the MeO-NP species under study was characterized by a complex interaction between all possible types of combined toxicity (additivity, subadditivity or superadditivity of unidirectional action and different variants of opposite effects) depending on which outcome this type was estimated for and on effect and dose levels. With any third MeO-NP species acting in the background, the type of combined toxicity displayed by the other two remained virtually the same or changed significantly, becoming either more or less unfavorable. Various harmful effects produced by the (Al₂O₃-NP + TiO₂-NP + SiO₂-NP)-combination, including its genotoxicity, were substantially attenuated by giving the rats per os during the entire exposure period a complex of innocuous bioactive substances expected to increase the organism's antitoxic resistance.

Combined Subchronic Toxicity of Aluminum (III), Titanium (IV) and Silicon (IV) Oxide Nanoparticles and Its Alleviation with a Complex of Bioprotectors

PubMed Central

Minigalieva, Ilzira A.; Katsnelson, Boris A.; Privalova, Larisa I.; Sutunkova, Marina P.; Gurvich, Vladimir B.; Shur, Vladimir Y.; Shishkina, Ekaterina V.; Valamina, Irene E.; Makeyev, Oleg H.; Panov, Vladimir G.; Varaksin, Anatoly N.; Bushueva, Tatiana V.; Sakhautdinova, Renata R.; Klinova, Svetlana V.; Solovyeva, Svetlana N.; Meshtcheryakova, Ekaterina Y.

2018-01-01

Stable suspensions of metal/metalloid oxide nanoparticles (MeO-NPs) obtained by laser ablation of 99.99% pure elemental aluminum, titanium or silicon under a layer of deionized water were used separately, or in three binary combinations, or in a ternary combination to induce subchronic intoxications in rats. To this end, the MeO-NPs were repeatedly injected intraperitoneally (i.p.) 18 times during 6 weeks before measuring a large number of functional, biochemical, morphological and cytological indices for the organism’s status. In many respects, the Al2O3-NP was found to be the most toxic species alone and the most dangerous component of the combinations studied. Mathematical modeling with the help of the Response Surface Methodology showed that, as well as in the case of any other binary toxic combinations previously investigated by us, the organism’s response to a simultaneous exposure to any two of the MeO-NP species under study was characterized by a complex interaction between all possible types of combined toxicity (additivity, subadditivity or superadditivity of unidirectional action and different variants of opposite effects) depending on which outcome this type was estimated for and on effect and dose levels. With any third MeO-NP species acting in the background, the type of combined toxicity displayed by the other two remained virtually the same or changed significantly, becoming either more or less unfavorable. Various harmful effects produced by the (Al2O3-NP + TiO2-NP + SiO2-NP)-combination, including its genotoxicity, were substantially attenuated by giving the rats per os during the entire exposure period a complex of innocuous bioactive substances expected to increase the organism’s antitoxic resistance. PMID:29534019

Rh2E2, a novel metabolic suppressor, specifically inhibits energy-based metabolism of tumor cells

PubMed Central

Bai, Li-Ping; Jiang, Zhi-Hong; Guo, Yue; Kong, Ah-Ng Tony; Wang, Rui; Kam, Richard Kin Ting; Law, Betty Yuen Kwan; Hsiao, Wendy Wen Luen; Chan, Ka Man; Wang, Jingrong; Chan, Rick Wai Kit; Guo, Jianru; Zhang, Wei; Yen, Feng Gen; Zhou, Hua; Leung, Elaine Lai Han; Yu, Zhiling; Liu, Liang

2016-01-01

Energy metabolism in cancer cells is often increased to meet their higher proliferative rate and biosynthesis demands. Suppressing cancer cell metabolism using agents like metformin has become an attractive strategy for treating cancer patients. We showed that a novel ginsenoside derivative, Rh2E2, is as effective as aspirin in preventing the development of AOM/DSS-induced colorectal cancer and suppresses tumor growth and metastasis in a LLC-1 xenograft. A sub-chronic and acute toxicity LD50 test of Rh2E2 showed no harmful reactions at the maximum oral dosage of 5000 mg/kg body weight in mice. Proteomic profiling revealed that Rh2E2 specifically inhibited ATP production in cancer cells via down-regulation of metabolic enzymes involving glycolysis, fatty acid β-oxidation and the tricarboxylic acid cycle, leading to specific cytotoxicity and S-phase cell cycle arrest in cancer cells. Those findings suggest that Rh2E2 possesses a novel and safe anti-metabolic agent for cancer patients by specific reduction of energy-based metabolism in cancer cells. PMID:26799418

Zeaxanthin: Review of Toxicological Data and Acceptable Daily Intake

PubMed Central

Edwards, James A.

2016-01-01

Zeaxanthin is a nutritional carotenoid with a considerable amount of safety data based on regulatory studies, which form the basis of its safety evaluation. Subchronic OECD guideline studies with mice and rats receiving beadlet formulations of high purity synthetic zeaxanthin in the diet at dosages up to 1000 mg/kg body weight (bw)/day, and in dogs at over 400 mg/kg bw/day, produced no adverse effects or histopathological changes. In developmental toxicity studies, there was no evidence of fetal toxicity or teratogenicity in rats or rabbits at dosages up to 1000 or 400 mg/kg bw/day, respectively. Formulated zeaxanthin was not mutagenic or clastogenic in a series of in vitro and in vivo tests for genotoxicity. A 52-week chronic oral study in Cynomolgus monkeys at doses of 0.2 and 20 mg/kg bw/day, mainly designed to assess accumulation and effects in primate eyes, showed no adverse effects. In a rat two-generation study, the NOAEL was 150 mg/kg bw/day. In 2012, this dosage was used by EFSA (NDA Panel), in association with a 200-fold safety factor, to propose an Acceptable Daily Intake equivalent to 53 mg/day for a 70 kg adult. The requested use level of 2 mg/day was ratified by the EU Commission. PMID:26885380

Biological Networks for Predicting Chemical Hepatocarcinogenicity Using Gene Expression Data from Treated Mice and Relevance across Human and Rat Species

PubMed Central

Thomas, Reuben; Thomas, Russell S.; Auerbach, Scott S.; Portier, Christopher J.

2013-01-01

Background Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. Objectives To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Methods Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Results Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Conclusions Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. PMID:23737943

Biological networks for predicting chemical hepatocarcinogenicity using gene expression data from treated mice and relevance across human and rat species.

PubMed

Thomas, Reuben; Thomas, Russell S; Auerbach, Scott S; Portier, Christopher J

2013-01-01

Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species.

Assessing the fate and effects of nano aluminum oxide in the terrestrial earthworm, Eisenia fetida.

PubMed

Coleman, Jessica G; Johnson, David R; Stanley, Jacob K; Bednar, Anthony J; Weiss, Charles A; Boyd, Robert E; Steevens, Jeffery A

2010-07-01

Nano-sized aluminum is currently being used by the military and commercial industries in many applications including coatings, thermites, and propellants. Due to the potential for wide dispersal in soil systems, we chose to investigate the fate and effects of nano-sized aluminum oxide (Al2O3), the oxidized form of nano aluminum, in a terrestrial organism. The toxicity and bioaccumulation potential of micron-sized (50-200 microm, nominal) and nano-sized (11 nm, nominal) Al2O3 was comparatively assessed through acute and subchronic bioassays using the terrestrial earthworm, Eisenia fetida. Subchronic (28-d) studies were performed exposing E. fetida to nano- and micron-sized Al2O3-spiked soils to assess the effects of long-term exposure. No mortality occurred in subchronic exposures, although reproduction decreased at >or=3,000 mg/kg nano-sized Al2O3 treatments, with higher aluminum body burdens observed at 100 and 300 mg/kg; no reproductive effects were observed in the micron-sized Al2O3 treatments. In addition to toxicity and bioaccumulation bioassays, an acute (48-h) behavioral bioassay was conducted utilizing a soil avoidance wheel in which E. fetida were given a choice of habitat between control, nano-, or micron-sized Al2O3 amended soils. In the soil avoidance bioassays, E. fetida exhibited avoidance behavior toward the highest concentrations of micron- and nano-sized Al2O3 (>5,000 mg/kg) relative to control soils. Results of the present study indicate that nano-sized Al2O3 may impact reproduction and behavior of E. fetida, although at high levels unlikely to be found in the environment. Copyright (c) 2010 SETAC.

TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC AND ITS METHYLATED METABOLITES IN C57BL/6 MICE FOLLOWING SUBCHRONIC EXPOSURE TO ARSENATE (ASV) IN DRINKING WATER

EPA Science Inventory

The relationship of exposure and tissue concentration of parent chemical and metabolites over prolonged exposure is a critical issue for chronic toxicities mediated by metabolite(s) rather than parent chemical alone. This is an issue for AsV because its trivalent metabolites hav...

Tissue Distribution And Urinary Excretion Of Inorganic Arsenic And Its Methylated Metabolites In C57BL6 Mice Following Subchronic Exposure To Arsenate In Drinking Water

EPA Science Inventory

The relationship of exposure and tissue concentration of parent chemical and metabolites over prolonged exposure is a critical issue for chronic toxicities mediated by metabolite(s) rather than parent chemical alone. This is an issue for As^V because its trivalent meta...

Megakaryocyte expansion and macrophage infiltration in bone marrow of rats subchronically treated with MNX, N-nitroso environmental degradation product of munitions compound RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine).

PubMed

Ramasahayam, Sindhura; Jaligama, Sridhar; Atwa, Sahar M; Salley, Joshua T; Thongdy, Marissa; Blaylock, Benny L; Meyer, Sharon A

2017-08-01

Hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), causes seizures in rats with acute oral exposure like parent RDX. Our previous studies have additionally reported hematotoxicity with acute MNX exposure manifested as myelosuppression, anemia and splenic hemosiderosis. This study explored whether MNX administered subchronically continued to target bone marrow to elicit peripheral blood cytopenia. Female Sprague-Dawley rats were gavaged daily for 4 or 6 weeks with 47 mg kg -1  day -1 MNX (¼ LD 50 ) or vehicle (5% dimethyl sulfoxide in corn oil) and hematological and clinical chemistry parameters, spleen weights, spleen and bone marrow histopathology and immunohistochemistry with ED1 anti-CD68 macrophage marker were evaluated 24 h after the last dose. Unexpectedly, no decrease in blood erythroid parameters was seen with subchronic MNX and convulsions and tremors ceased after 2 weeks of treatment. Toxicological effects observed were MNX-induced increases in blood granulocyte and platelet counts and in bone marrow megakaryocyte and ED1 + -macrophage density. MNX was without effect on bone marrow cellularity and picrosirius red stained/collagen fiber deposition. Spleen weight increased modestly with extramedullary hematopoiesis evident, but hemosiderin and relative red and white pulp areas were unaffected. Collectively, this study demonstrated that erythroid effects characteristic of acute MNX exposure were not evident with subchronic exposure. However, megakaryocyte proliferation in bone marrow coincident with thrombocytosis after subchronic MNX exposure suggested continued hematotoxicity, but with a qualitatively different outcome. Granulocytosis and increased bone marrow macrophages implicated an inflammatory component in MNX hematotoxicity. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

An analysis of lethal and sublethal interactions among type I and type II pyrethroid pesticide mixtures using standard Hyalella azteca water column toxicity tests.

PubMed

Hoffmann, Krista Callinan; Deanovic, Linda; Werner, Inge; Stillway, Marie; Fong, Stephanie; Teh, Swee

2016-10-01

A novel 2-tiered analytical approach was used to characterize and quantify interactions between type I and type II pyrethroids in Hyalella azteca using standardized water column toxicity tests. Bifenthrin, permethrin, cyfluthrin, and lambda-cyhalothrin were tested in all possible binary combinations across 6 experiments. All mixtures were analyzed for 4-d lethality, and 2 of the 6 mixtures (permethrin-bifenthrin and permethrin-cyfluthrin) were tested for subchronic 10-d lethality and sublethal effects on swimming motility and growth. Mixtures were initially analyzed for interactions using regression analyses, and subsequently compared with the additive models of concentration addition and independent action to further characterize mixture responses. Negative interactions (antagonistic) were significant in 2 of the 6 mixtures tested, including cyfluthrin-bifenthrin and cyfluthrin-permethrin, but only on the acute 4-d lethality endpoint. In both cases mixture responses fell between the additive models of concentration addition and independent action. All other mixtures were additive across 4-d lethality, and bifenthrin-permethrin and cyfluthrin-permethrin were also additive in terms of subchronic 10-d lethality and sublethal responses. Environ Toxicol Chem 2016;35:2542-2549. © 2016 SETAC. © 2016 SETAC.

A subchronic dietary toxicity study of rice hull fiber in rats.

PubMed

Gao, Yonglin; Shen, Jingyu; Yin, Jungang; Li, Chunmei; Fu, Chengyu; Cho, Susan

2013-01-01

We conducted a 90-day feeding study to investigate subchronic toxicity of rice hull fiber. Sprague Dawley rats were randomly divided into four groups; each received a diet containing 0%, 2.5%, 3.75% and 5.0% (w/w) rice hull fiber for 90days. Clinical observations were carried out daily, with weekly measurements of body weight and food consumption. We performed ophthalmic and histological examinations at termination. Blood and urine samples were collected to measure hematology and clinical chemistry parameters. No mortality, ophthalmic abnormalities, or adverse treatment-related effects were seen during clinical observations, hematological tests, or analyses of urine. Macroscopic or microscopic examinations of organs revealed no treatment related abnormalities. The only treatment related significant changes were reduced concentrations of fasting blood glucose (up to 17.6%) and cholesterol (up to 22.0%), typical benefits of dietary fiber, in males treated with 3.75 and 5% rice hull fiber. The no-observed-adverse-effect-level (NOAEL) for rice hull fiber was 5.0% for both genders (females, 3.80g/kg body weight/day; males, 4.11g/kg body weight/day). Copyright © 2012 Elsevier Ltd. All rights reserved.

A subchronic toxicity study in rats and genotoxicity tests with an aqueous ethylcellulose dispersion.

PubMed

DeMerlis, C C; Schoneker, D R; Borzelleca, J F

2005-09-01

Surelease Aqueous Ethylcellulose Dispersion is an excipient used as a modified release coating for beads, granules, non-pariels, drug crystals and tablets and for taste masking applications for drug products and dietary supplement products. A study was conducted to assess the toxicity of spray-dried Surelease when administered orally, via dietary admixture, to Sprague-Dawley CD rats (20/sex/group) at dose levels of 0, 2000, 3500, and 5000 mg/kg/day for a period of at least 3 months. After 3 months of treatment, all rats scheduled for terminal sacrifice were killed and selected organs were weighed. Complete macroscopic examinations and histopathological evaluation of selected tissues were conducted on all animals. Neuropathological evaluations were performed on 5 animals/sex/group. No mortality occurred during the study. Clinical observations, ophthalmology, body weight and food consumption, hematology, coagulation, clinical chemistry, urinalysis, functional observational assessments, motor activity, organ weights and ratios and macroscopic and microscopic observations did not reveal any significant, consistent, dose-dependent test article-related adverse effects. The NOAEL (no-observed-adverse-effect-level) is 5000 mg/kg/day, the highest dose tested. A series of genotoxicity tests were conducted with Surelease. Surelease showed no evidence of mutagenic activity in the bacterial reverse mutation test with and without metabolic activation and in the in vitro cell mutation assay under the experimental conditions employed. Surelease did not show any evidence of causing chromosome damage or bone marrow cell toxicity when administered by gavage in the mouse micronucleus in vivo test procedure. These findings support the safety of Surelease for use as an excipient.

Improved sexual behavior in male rats treated with a Chinese herbal extract: hormonal and neuronal implications.

PubMed

Zanoli, Paola; Benelli, Augusta; Zavatti, Manuela; Rivasi, Marianna; Baraldi, Claudia; Baraldi, Mario

2008-11-01

To investigate the influence of an extract obtained from five Chinese medicinal plants on sexual behavior of adult male rats. The extract was administered at doses of 30, 60 and 120 mg/kg by oral gavage, acutely (one time, 45 min before mating test) or subchronically (daily for 10 days) in sexually potent and sexually sluggish/impotent rats. Sexual behavior, serum levels of luteinizing hormone (LH) and testosterone (T) were evaluated in treated rats and compared with controls receiving vehicle. The effect of the extract on central dopaminergic neurotransmission was assessed in the nucleus accumbens using a microdialysis technique. In sexually potent rats, both acute and subchronic treatment with the extract dosed at 30 and 60 mg/kg reduced mount latency and intromission latency. In sluggish/impotent rats, the acutely administered extract at the dose of 60 mg/kg shortened ejaculation latency, whereas subchronically administered at the doses of 30 and 60 mg/kg, reduced mount, intromission and ejaculation latencies, increasing also the percentage of mounting and ejaculating rats. The extract dosed at 60 mg/kg significantly increased LH and T following acute and subchronic administration and increased 3,4-dihydroxyphenylacetic acid levels in the nucleus accumbens, 30 min after the acute administration. The improvement in both appetitive and consummatory components of sexual behavior observed in male rats treated with the extract could be ascribed to increased serum T level in parallel with the activation of the central dopaminergic system. (c) 2008, Asian Journal of Andrology, SIMM and SJTU. All rights reserved.

Predicting pulmonary fibrosis in humans after exposure to multi-walled carbon nanotubes (MWCNTs).

PubMed

Sharma, Monita; Nikota, Jake; Halappanavar, Sabina; Castranova, Vincent; Rothen-Rutishauser, Barbara; Clippinger, Amy J

2016-07-01

The increased production and use of multi-walled carbon nanotubes (MWCNTs) in a diverse array of consumer, medical, and industrial applications have raised concerns about potential human exposure to these materials in the workplace and ambient environments. Inhalation is a primary route of exposure to MWCNTs, and the existing data indicate that they are potentially hazardous to human health. While a 90-day rodent inhalation test (e.g., OECD Test No. 413: subchronic inhalation toxicity: 90-day study or EPA Health Effects Test Guidelines OPPTS 870.3465 90-day inhalation toxicity) is recommended by the U.S. Environmental Protection Agency Office of Pollution Prevention and Toxics for MWCNTs (and other CNTs) if they are to be commercially produced (Godwin et al. in ACS Nano 9:3409-3417, 2015), this test is time and cost-intensive and subject to scientific and ethical concerns. As a result, there has been much interest in transitioning away from studies on animals and moving toward human-based in vitro and in silico models. However, given the multiple mechanisms of toxicity associated with subchronic exposure to inhaled MWCNTs, a battery of non-animal tests will likely be needed to evaluate the key endpoints assessed by the 90-day rodent study. Pulmonary fibrosis is an important adverse outcome related to inhalation exposure to MWCNTs and one that the non-animal approach should be able to assess. This review summarizes the state-of-the-science regarding in vivo and in vitro toxicological methods for predicting MWCNT-induced pulmonary fibrosis.

Oral warfarin affects peripheral blood leukocyte IL-6 and TNFα production in rats.

PubMed

Popov, Aleksandra; Belij, Sandra; Subota, Vesna; Zolotarevski, Lidija; Mirkov, Ivana; Kataranovski, Dragan; Kataranovski, Milena

2013-01-01

Warfarin is a Vitamin K (VK) antagonist that affects Vitamin K-dependent (VKD) processes, including blood coagulation, as well as processes unrelated to hemostasis such as bone growth, calcification, and growth of some cell types. In addition, warfarin exerts influence on some non-VKD-related activities, including anti-tumor and immunomodulating activity. With respect to the latter, both immune stimulating and suppressive effects have been noted in different experimental systems. To explore the in vivo immunomodulatory potential of warfarin on one type of activity (i.e., cytokine production) in two different immune cell populations (i.e., mononuclear or polymorphonuclear cells), effects of subchronic oral warfarin intake in rats on pro-inflammatory cytokine (i.e., TNFα, IL-6) production by peripheral blood mononuclear and polymorphonuclear cells (granulocytes) was examined. Differential effects of warfarin intake on TNFα and IL-6 were noted, depending on the type of peripheral blood leukocytes and on the cytokine examined. Specifically, a lack of effect on TNFα and a priming of IL-6 production by mononuclear cells along with a decrease in TNFα and a lack of effect on IL-6 in polymorphonuclear cells were seen in warfarin-exposed hosts. The cell- and cytokine-dependent effects from subchronic oral warfarin intake on peripheral blood leukocytes demonstrated in this study could, possibly, differentially affect reactions mediated by these cells. Ultimately, the observed effects in rats might have implications for those humans who are on long-term/prolonged warfarin therapy.

Subchronic 13-week inhalation exposure of rats to multiwalled carbon nanotubes: toxic effects are determined by density of agglomerate structures, not fibrillar structures.

PubMed

Pauluhn, Jürgen

2010-01-01

Wistar rats were nose-only exposed to multiwalled carbon nanotubes (MWCNT, Baytubes) in a subchronic 13-week inhalation study. The focus of study was on respiratory tract and systemic toxicity, including analysis of MWCNT biokinetics in the lungs and lung-associated lymph nodes (LALNs). The time course and concentration dependence of pulmonary effects were examined by bronchoalveolar lavage (BAL) and histopathology up to 6 months postexposure. Particular emphasis was directed to the comparative characterization of MWCNT structures prior to and after micronization and dry powder dispersion into inhalation chambers. These determinations were complemented by additional analyses in digested BAL cells. Animals were exposed on 6 h/day, 5 days per week for 13 consecutive weeks to 0, 0.1, 0.4, 1.5, and 6 mg/m(3). The subchronic exposure to respirable solid aerosols of MWCNT was tolerated without effects suggestive of systemic toxicity. Kinetic analyses demonstrated a markedly delayed clearance of MWCNT from lungs at overload conditions. Translocation into LALNs occurred at 1.5 and 6 mg/m(3) and required at least 13 weeks of study to become detectable. At these exposure levels, the lung and LALN weights were significantly increased. Sustained elevations in BAL polymorphonuclear neutrophils and soluble collagen occurred at these concentrations with borderline effects at 0.4 mg/m(3). Histopathology revealed principal exposure-related lesions at 0.4 mg/m(3) and above in the upper respiratory tract (goblet cell hyper- and/or metaplasia, eosinophilic globules, and focal turbinate remodeling) and the lower respiratory tract (inflammatory changes in the bronchioloalveolar region and increased interstitial collagen staining). Granulomatous changes and a time-dependent increase of a bronchioloalveolar hyperplasia occurred at 6 mg/m(3). All end points examined were unremarkable at 0.1 mg/m(3) (no-observed-adverse-effect-level). In summary, this study demonstrates that the induced pathological changes are consistent with overload-related phenomena. Hence, the etiopathological sequence of inflammatory events caused by this type of MWCNT appears to be related to the high displacement volume of the low-density MWCNT assemblage structure rather than to any yet ill-defined intrinsic toxic property. Thus, the hypothesis of study is verified, namely, common denominators between carbon black and MWCNT do exist.

Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC.

PubMed

Karschner, Erin L; Schwope, David M; Schwilke, Eugene W; Goodwin, Robert S; Kelly, Deanna L; Gorelick, David A; Huestis, Marilyn A

2012-10-01

Determining time since last cannabis/Δ9-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing. Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography-mass spectrometry. Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11-hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1-5h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5h after the last THC dose, respectively. Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily. Published by Elsevier Ireland Ltd.

Developmental sub-chronic exposure to chlorpyrifos reduces anxiety-related behavior in zebrafish larvae

PubMed Central

Richendrfer, Holly; Pelkowski, Sean D.; Colwill, Ruth M.; Créton, Robbert

2013-01-01

Neurobehavioral disorders such as anxiety, autism, and attention deficit hyperactivity disorders are typically influenced by genetic and environmental factors. Although several genetic risk factors have been identified in recent years, little is known about the environmental factors that either cause neurobehavioral disorders or contribute to their progression in genetically predisposed individuals. One environmental factor that has raised concerns is chlorpyrifos, an organophosphate pesticide that is widely used in agriculture and is found ubiquitously in the environment. In the present study, we examined the effects of sub-chronic chlorpyrifos exposure on anxiety-related behavior during development using zebrafish larvae. We found that sub-chronic exposure to 0.01 or 0.1 μM chlorpyrifos during development induces specific behavioral defects in 7-day-old zebrafish larvae. The larvae displayed decreases in swim speed and thigmotaxis, yet no changes in avoidance behavior were seen. Exposure to 0.001 μM chlorpyrifos did not affect swimming, thigmotaxis, or avoidance behavior and exposure to 1 μM chlorpyrifos induced behavioral defects, but also induced defects in larval morphology. Since thigmotaxis, a preference for the edge, is an anxiety-related behavior in zebrafish larvae, we propose that sub-chronic chlorpyrifos exposure interferes with the development of anxiety-related behaviors. The results of this study provide a good starting point for examination of the molecular, cellular, developmental, and neural mechanisms that are affected by environmentally relevant concentrations of organophosphate pesticides. A more detailed understanding of these mechanisms is important for the development of predictive models and refined health policies to prevent toxicant-induced neurobehavioral disorders. PMID:22579535

Evaluation of the toxic properties of naturally weathered Exxon Valdez crude oil to surrogate wildlife species

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stubblefield, W.A.; Hancock, G.A.; Ford, W.H.

1995-12-31

The toxic properties of naturally weathered Exxon Valdez crude oil (WEVC) to avian and mammalian wildlife species were evaluated using the surrogate species, mallard duck, Anas platyrhynchos, and European ferret, Mustela putorius. This study was conducted to evaluate the potential for toxic (rather than physical) injury to wildlife species that may have been exposed to WEVC, either through external contact or through dietary uptake. Previous studies have assessed the toxicity of unweathered crude oils, including Alaska North Slope Crude, but little information exists regarding the toxicity of a naturally weathered crude oil, typical of that encountered following a spill. Amore » battery of laboratory toxicity tests was conducted, in compliance with standard and published test procedures, to evaluate acute and subchronic toxicity of WEVC. These included tests of food avoidance, reproductive effects, and direct eggshell application toxicity. Naturally weathered EVC, recovered postspill from Prince William Sound, was used as the test material. 36 refs., 7 figs., 4 tabs.« less

ACUTE AND SUBCHRONIC TOXICITY OF 2,4-DICHLOROPHENOL IN DC-1 MICE

EPA Science Inventory

Male and female CD-1 mice were exposed to 2,4-dichlorophenol (DCP) in drinking water containing 10% emulphor for 90 days at concentrations of 0.2, 0.6, and 2.0 mg/ml. The mean daily consumption values ranged from 46.3 to 542 mg/kg/day for females and 34.9 and 419 mg/kg/day in mal...

Does oral exposure to cadmium and lead mediate susceptibility to colitis? The dark-and-bright sides of heavy metals in gut ecology

NASA Astrophysics Data System (ADS)

Breton, Jérôme; Daniel, Catherine; Vignal, Cécile; Body-Malapel, Mathilde; Garat, Anne; Plé, Coline; Foligné, Benoît

2016-01-01

Although the heavy metals cadmium (Cd) and lead (Pb) are known environmental health concerns, their long-term impacts on gut ecology and susceptibility to gastrointestinal autoimmune diseases have not been extensively investigated. We sought to determine whether subchronic oral exposure to Cd or Pb is a risk factor for the development and progression of inflammatory bowel disease (IBD). Mice were exposed to various doses of CdCl2 or PbCl2 in drinking water for 1, 4 or 6 weeks prior to infection with Salmonella, the induction of colitis with dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS). In human cell-based models, exposure to Cd and Pb is associated with reduced transepithelial electric resistance and changes in bacteria-induced cytokine responses. Although 1- and 6-week exposures did not have clear effects on the response to Salmonella infectious challenges, 1-week short-term treatments with CdCl2 tended to enhance intestinal inflammation in mice. Unexpectedly, subchronic exposure to Cd and (to a lesser extent) Pb significantly mitigated some of the symptoms of DSS-induced colitis and reduced the severity of TNBS colitis in a dose-dependent manner. The possible adaptive and immunosuppressive mechanisms by which heavy metals might reduce intestinal inflammation are explored and discussed.

Classification and Dose-Response Characterization of ...

EPA Pesticide Factsheets

Thirty years and over a billion of today’s dollars worth of pesticide registration toxicity studies, historically stored as hardcopy and scanned documents, have been digitized into highly standardized and structured toxicity data, within the U.S. Environmental Protection Agency’s (EPA) Toxicity Reference Database (ToxRefDB). The source toxicity data in ToxRefDB covers multiple study types, including subchronic, developmental, reproductive, chronic, and cancer studies, resulting in a diverse set of endpoints and toxicities. Novel approaches to chemical classification are performed as a model application of ToxRefDB and as an essential need for highly detailed chemical classifications within the EPA’s ToxCast™ research program. In order to develop predictive models and biological signatures utilizing high-throughput screening (HTS) and in vitro genomic data, endpoints and toxicities must first be identified and globally characterized for ToxCast Phase I chemicals. Secondarily, dose-response characterization within and across toxicity endpoints provide insight into key precursor toxicity events and overall endpoint relevance. Toxicity-based chemical classification and dose-response characterization utilizing ToxRefDB prioritized toxicity endpoints and differentiated toxicity outcomes across a large chemical set.

Acute and subchronic inhalation exposures of hamsters to nickel-enriched fly ash

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wehner, A.P.; Moss, O.R.; Milliman, E.M.

1979-08-01

One 6-h inhalation exposure of hamsters to Ni-enriched fly ash (NEFA) aerosol (respirable aerosol concentration approx. 200 ..mu..g/liter) deposited about 80 ..mu..g in the deep lung, of which 75 ..mu..g was still present 30 days postexposure. The animals tolerated the exposure well during the 30-day postexposure observation period. Two-month exposures of hamsters to NEFA or fly ash (FA) aerosols (approx. 185 ..mu..g/liter) resuled in a deep lung burden of about 5.7 mg, dark discoloration of lungs, heavily dust-laden macrophages, and significantly higher lung weights than in controls, but only minimal inflammatory reaction and no deaths. There was no difference betweenmore » NEFA and FA effects. The NEFA contained 9% Ni; FA contained 0.03% Ni. The results of this study indicate low acute and subchronic toxicity and slow lung clearance of NEFA and FA.« less

Effect of subchronic administration of nutmeg (Myristica fragrans Houtt) ethanolic extract to hematological parameters in rat

NASA Astrophysics Data System (ADS)

Bachri, M. S.; Yuliani, S.; Sari, A. K.

2017-11-01

Nutmeg is dried kernel of broadly ovoid seed of Myristica fragrans Houtt. It has been mentioned in ethnomedical literature as aphrodisiac, stomachic, carminative, tonic, and nervous stimulant. In order to establish the safety of nutmeg, the effect of the repeated administration of nutmeg is needed. The study was aimed to determine the toxic effect of subchronic administration of nutmeg ethanolic extract to hematological parameters in rat. A total of 28 male adult Wistar rats divided into 4 groups. Group I as control was given by 0.5% CMC-suspension, group II, III, and IV were given by 50, 100, and 200 mg/kg bw, respectively, of nutmeg ethanolic extract. The treatments were administered daily for 31 days. On day 31 bloods were taken from orbital sinus. The hematological parameter consisted of the numbers of erythrocyte and leukocyte as well as hemoglobin and total protein levels were measured. The data were statistically analyzed by one way Anova followed by LSD test. All of observed hematological parameters in rats showed that there were no significant difference between the nutmeg ethanolic extract treated groups and control group. The result indicated that the subchronic administration of 50, 100, and 200 mg/kg bw of nutmeg ethanolic extract did not cause the change of hematological parameters in rat.

A probabilistic risk assessment for deployed military personnel after the implementation of the "Leishmaniasis Control Program" at Tallil Air Base, Iraq.

PubMed

Schleier, Jerome J; Davis, Ryan S; Barber, Loren M; Macedo, Paula A; Peterson, Robert K D

2009-05-01

Leishmaniasis has been of concern to the U.S. military and has re-emerged in importance because of recent deployments to the Middle East. We conducted a retrospective probabilistic risk assessment for military personnel potentially exposed to insecticides during the "Leishmaniasis Control Plan" (LCP) undertaken in 2003 at Tallil Air Base, Iraq. We estimated acute and subchronic risks from resmethrin, malathion, piperonyl butoxide (PBO), and pyrethrins applied using a truck-mounted ultra-low-volume (ULV) sprayer and lambda-cyhalothrin, cyfluthrin, bifenthrin, chlorpyrifos, and cypermethrin used for residual sprays. We used the risk quotient (RQ) method for our risk assessment (estimated environmental exposure/toxic endpoint) and set the RQ level of concern (LOC) at 1.0. Acute RQs for truck-mounted ULV and residual sprays ranged from 0.00007 to 33.3 at the 95th percentile. Acute exposure to lambda-cyhalothrin, bifenthrin, and chlorpyrifos exceeded the RQ LOC. Subchronic RQs for truck-mounted ULV and residual sprays ranged from 0.00008 to 32.8 at the 95th percentile. Subchronic exposures to lambda-cyhalothrin and chlorpyrifos exceeded the LOC. However, estimated exposures to lambda-cyhalothrin, bifenthrin, and chlorpyrifos did not exceed their respective no observed adverse effect levels.

Acute, subacute and subchronic safety assessment of betalains rich Rivina humilis L. berry juice in rats.

PubMed

Khan, Mohammad Imtiyaj; Denny Joseph, K M; Muralidhara; Ramesh, H P; Giridhar, P; Ravishankar, G A

2011-12-01

Rivina humilis L. (Phytolaccaceae) accumulates vacuolar pigments betalains. These pigments are synthesized by plants of 11 families in the order caryophyllales. Red beet is the only industrial source of these hydrophilic and low acidic pigments. Betalains rich R. humilis berry juice (RBJ) could be used as alternative source of these pigments. However, there is no information on safety of these berries. In this research work, RBJ was fed to adult (single-dose: 1, 2 and 5 g RBJ/kg bw) and growing (repeated-dosing: 2.5 and 5 g RBJ/kg bw for 35 days; dietary feeding: 0.5%, 1% and 2% RBJ in diet, w/w for 90 days) male rats to assess acute, subacute and subchronic toxic responses. In all the three studies, RBJ was well tolerated plus the feed intake, body and organ weights of RBJ administered groups were comparable to that of untreated control rats. Data on hematology, histology of vital organs, biochemical measurements in serum and liver of RBJ treated rats were comparable to that of control in repeated-dosing and subchronic dietary study. These results suggest that intake of RBJ does not affect growth and normal biochemical homeostasis. Hence, RBJ is safe to consume without any adverse effects in the body. Copyright © 2011 Elsevier Ltd. All rights reserved.

Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Min-Ho; Kim, Mingoo; Lee, Byung-Hoon

2008-02-01

Valproic acid (VPA) is used clinically to treat epilepsy, however it induces hepatotoxicity such as microvesicular steatosis. Acute hepatotoxicity of VPA has been well documented by biochemical studies and microarray analysis, but little is known about the chronic effects of VPA in the liver. In the present investigation, we profiled gene expression patterns in the mouse liver after subchronic treatment with VPA. VPA was administered orally at a dose of 100 mg/kg/day or 500 mg/kg/day to ICR mice, and the livers were obtained after 1, 2, or 4 weeks. The activities of serum liver enzymes did not change, whereas triglyceridemore » concentration increased significantly. Microarray analysis revealed that 1325 genes of a set of 32,996 individual genes were VPA responsive when examined by two-way ANOVA (P < 0.05) and fold change (> 1.5). Consistent with our previous results obtained using an acute VPA exposure model (Lee et al., Toxicol Appl Pharmacol. 220:45-59, 2007), the most significantly over-represented biological terms for these genes included lipid, fatty acid, and steroid metabolism. Biological pathway analysis suggests that the genes responsible for increased biosynthesis of cholesterol and triglyceride, and for decreased fatty acid {beta}-oxidation contribute to the abnormalities in lipid metabolism induced by subchronic VPA treatment. A comparison of the VPA-responsive genes in the acute and subchronic models extracted 15 commonly altered genes, such as Cyp4a14 and Adpn, which may have predictive power to distinguish the mode of action of hepatotoxicants. Our data provide a better understanding of the molecular mechanisms of VPA-induced hepatotoxicity and useful information to predict steatogenic hepatotoxicity.« less

A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats.

PubMed

Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko

2014-04-01

3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

Subchronic feeding study of carnauba wax in beagle dogs.

PubMed

Parent, R A; Cox, G E; Babish, J G; Gallo, M A; Hess, F G; Becci, P J

1983-02-01

Carnauba wax fed at levels of 0.1, 0.3 and 1% in the diet to beagle dogs for 28 wk did not produce evidence of toxicity or pathological effects. Body weight gain, food consumption, clinical chemical, haematological, and urine analysis data, and organ weights of animals fed carnauba wax were comparable with those of control animals. Ophthalmic, gross and histopathological examinations revealed no significant treatment-related findings.

Safety assessment of [3S, 3'S]-astaxanthin--Subchronic toxicity study in rats.

PubMed

Buesen, R; Schulte, S; Strauss, V; Treumann, S; Becker, M; Gröters, S; Carvalho, S; van Ravenzwaay, B

2015-07-01

Astaxanthin, a naturally occurring xanthophyll, is commercially used as a coloring agent in salmon feed, but also marketed as a dietary supplement. The objective of this study was to investigate the subchronic toxicity of synthetic [3S, 3'S]-Astaxanthin in rats. A powder formulation containing approximately 20% [3S, 3'S]-Astaxanthin was administered via the diet to groups of 10 male and 10 female Wistar rats at concentrations of 5000, 15,000 and 50,000 ppm for a period of 13 weeks. A formulation of comparable composition but without [3S, 3'S]-Astaxanthin served as a placebo control. There were no effects observed on survival, clinical examinations, clinical pathology, estrous cycle as well as on sperm parameters. At terminal necropsy, a macroscopically visible brown-blue discoloration of the gastrointestinal contents was noted which was considered to be secondary to the violet-brown color of the test material. No other significant or dose-related abnormalities were found in the tissues collected at termination. Our observations support that ingestion of [3S, 3'S]-Astaxanthin of up to 700-920 mg/kg bw/day in rats in a gelatin/carbohydrate formulation is without adverse effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Toxic effects of sub-chronic exposure of male albino rats to emamectin benzoate and possible ameliorative role of Foeniculum vulgare essential oil.

PubMed

El-Sheikh, El-Sayed A; Galal, Azza A A

2015-05-01

Emamectin benzoate (EB) is an avermectin insecticide used extensively in pest control on vegetable and field crops. Few studies have been done for evaluating adverse effects of EB. In the current study, we evaluated the toxic effects of EB on male rats and the possible ameliorative role of fennel essential oil (FEO). Thirty two male rats were randomly divided into 4 equal groups. All groups were treated orally with distilled water (control group), 0.5mlFEOkg(-1) BW (FEO group), 2.5mgEBkg(-1) BW (EB group), and 0.5mlFEOkg(-1) BW+2.5mgEBkg(-1) BW (FEO+EB group) for 28 days. The obtained results showed that EB treatment resulted in a significant decrease in body weight, body weight gain, RBC count, Hb concentration, % PCV, MCV and MCHC. Moreover, EB significantly decreased total leukocyte, lymphocyte, monocyte and platelet count but significantly increased granulocyte count. EB markedly decreased total protein, albumin, globulin, IgG and IgM concentrations with a significant increase in TNF-α secretion. EB had a negative impact on the liver as it significantly increased ALT, ALP, and MDA, while decreasing SOD activity. Regarding to the histopathological examination, EB treatment induced coagulative necrosis and blood vessels congestion of the liver in treated rats. Furthermore, it resulted in depletion and necrosis of the white pulp of the spleen in treated rats. The co-administration of FEO with EB, however, improved the majority of parameters studied, suggesting that FEO is an important substance in decreasing toxic effects of EB. Copyright © 2015 Elsevier B.V. All rights reserved.

Transgenic maize event TC1507: Global status of food, feed, and environmental safety

PubMed Central

Baktavachalam, Gajendra B; Delaney, Bryan; Fisher, Tracey L; Ladics, Gregory S; Layton, Raymond J; Locke, Mary EH; Schmidt, Jean; Anderson, Jennifer A; Weber, Natalie N; Herman, Rod A; Evans, Steven L

2015-01-01

Maize (Zea mays) is a widely cultivated cereal that has been safely consumed by humans and animals for centuries. Transgenic or genetically engineered insect-resistant and herbicide-tolerant maize, are commercially grown on a broad scale. Event TC1507 (OECD unique identifier: DAS-Ø15Ø7–1) or the Herculex®# I trait, an insect-resistant and herbicide-tolerant maize expressing Cry1F and PAT proteins, has been registered for commercial cultivation in the US since 2001. A science-based safety assessment was conducted on TC1507 prior to commercialization. The safety assessment addressed allergenicity; acute oral toxicity; subchronic toxicity; substantial equivalence with conventional comparators, as well as environmental impact. Results from biochemical, physicochemical, and in silico investigations supported the conclusion that Cry1F and PAT proteins are unlikely to be either allergenic or toxic to humans. Also, findings from toxicological and animal feeding studies supported that maize with TC1507 is as safe and nutritious as conventional maize. Maize with TC1507 is not expected to behave differently than conventional maize in terms of its potential for invasiveness, gene flow to wild and weedy relatives, or impact on non-target organisms. These safety conclusions regarding TC1507 were acknowledged by over 20 regulatory agencies including United States Environment Protection Agency (US EPA), US Department of Agriculture (USDA), Canadian Food Inspection Agency (CFIA), and European Food Safety Authority (EFSA) before authorizing cultivation and/or food and feed uses. A comprehensive review of the safety studies on TC1507, as well as some benefits, are presented here to serve as a reference for regulatory agencies and decision makers in other countries where authorization of TC1507 is or will be pursued. PMID:26018138

Subchronic rat inhalation study with Skydrol 500B-4 fire resistant hydraulic fluid.

PubMed

Healy, C E; Nair, R S; Ribelin, W E; Bechtel, C L

1992-03-01

Skydrol 500B-4 fire resistant hydraulic fluid, a proprietary phosphate ester mixture composed principally of dibutyl phenyl phosphate (DBPP) and tributyl phosphate (TBP) and used as a commercial airline hydraulic fluid, was evaluated in an inhalation toxicity study of Sprague-Dawley rats. Target exposure levels used in the study were 0, 5, 100, and 300 mg/m3, and exposures were maintained for 6 hr/day, 5 days/week. Mass median aerodynamic diameters determined for particles in the mid- and high-exposure inhalation chambers were 2.85 microns and 3.31 microns, with geometric standard deviations of 1.99 microns and 1.92 microns, respectively. The percentage of particles less than 10 microns in diameter were 96.4% in the mid-exposure chamber and 95.5% in the high-exposure chamber. After 6 weeks of Skydrol exposure, 10 rats/sex/group were euthanized and then assessed for indications of possible chemical toxicity. Another 15 rats/sex/group were studied for a total of 13 weeks of exposure. The only clinical sign of chemical toxicity was the observation of a reddish nasal discharge with accompanying oral salivation in mid- and high-exposure animals of both sexes, indicative of an irritant response. Statistically significant reduced body weights; increased absolute and relative liver weights; and decreased erythrocyte counts, hemoglobin levels, and hematocrit values were observed in high-exposure female rats euthanized after 13 weeks of Skydrol exposure. High-exposure male rats also had increased absolute and relative liver weights and decreased hematocrit values after 13 weeks. Plasma cholinesterase levels were decreased in high-exposure female rats both 6 and 13 weeks after the study was initiated.(ABSTRACT TRUNCATED AT 250 WORDS)

Final report on the safety assessment of triacetin.

PubMed

Fiume, Monice Zondlo

2003-01-01

Triacetin, also known as Glyceryl Triacetate, is reported to function as a cosmetic biocide, plasticizer, and solvent in cosmetic formulations, at concentrations ranging from 0.8% to 4.0%. It is a commonly used carrier for flavors and fragrances. Triacetin was affirmed as a generally recognized as safe (GRAS) human food ingredient by the Food and Drug Administration (FDA). Triacetin was not toxic to animals in acute oral or dermal exposures, nor was it toxic in short-term inhalation or parenteral studies, and subchronic feeding and inhalation studies. Triacetin was, at most, slightly irritating to guinea pig skin. However, in one study, it caused erythema, slight edema, alopecia, and desquamation, and did cause some irritation in rabbit eyes. Triacetin was not sensitizing in guinea pigs. Triacetin was not an irritant or a sensitizer in a clinical maximization study, and only very mild reactions were seen in a Duhring-chamber test using a 50% dilution. In humans, Triacetin reportedly has caused ocular irritation but no injury. Triacetin was not mutagenic. Although there were no available reproductive and developmental toxicity data, Triacetin was quickly metabolized to glycerol and acetic acid and these chemicals were not developmental toxins. Reports of 1,2-glyceryl diesters, which may be present in Triacetin, affecting cell growth and proliferation raised the possibility of hyperplasia and/or tumor promotion. The Cosmetic Ingredient Review (CIR) Expert Panel concluded, however, that the effects of 1,2-glyceryl diesters on cell growth and proliferation require longer ester chains on the glycerin backbone than are present when acetic acid is esterified with glycerin, as in Triacetin. On the basis of the available information, the CIR Expert Panel concluded that Triacetin is safe as used in cosmetic formulations.

Toxicity and carcinogenicity studies of boric acid in male and female B6C3F1 mice.

PubMed Central

Dieter, M P

1994-01-01

Toxicity and potential carcinogenicity studies of boric acid were investigated in mice to verify in a second rodent species that this was a noncarcinogenic chemical. Earlier chronic studies in rats indicated boric acid was not a carcinogen. The chemical is nominated for testing because over 200 tons are produced annually, there are multiple uses for the product, and there is potential for widespread human exposure, both orally and dermally. Both sexes of B6C3F1 mice were offered diets mixed with boric acid for 14 days, 13 weeks, or 2 years. Dietary doses used in the acute, 14-day study were 0, 0.62, 1.25, 2.5, 5, and 10%; those in the subchronic, 13-week study were 0, 0.12, 0.25, 0.50, 1, and 2%; and doses in the 2-year, chronic study were 0, 0.25, and 0.50% in the diet. Mortality, clinical signs of toxicity, estimates of food consumption, body weight gain, and histopathologic examination of selected tissues constituted the variables measured. In the 14-day study mortality was proportional to dose and time of exposure in both sexes, occurring in dose groups as low as 2.5% and as early as 7 days of exposure. Body weights were depressed more than 10% below controls in the higher dose groups of both sexes. Mortality in the 13-week study was confined to the two highest dose groups in male mice and to the 2%-dose group in females. Body weight depression from 8 to 23% below those of controls occurred in the 0.50% and higher dose groups of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7889889

Combined effects of cadmium and tetrabromobisphenol a (TBBPA) on development, antioxidant enzymes activity and thyroid hormones in female rats.

PubMed

Yu, Yunjiang; Ma, Ruixue; Yu, Lin; Cai, Ze; Li, Hongyan; Zuo, You; Wang, Zhengdong; Li, Hui

2018-04-24

Tetrabromobisphenol A (TBBPA) is one of the world's most widely used brominated flame retardants (BFRs) and considered as persistent halogenated contaminant. E-wastes contain a range of toxic chemicals, including BFRs and heavy metals, exerting adverse impacts to human health and environment. Nevertheless, comprehensive evaluation on combined toxicity of these co-existing pollutants is limited. This study conducted a subchronic effects of cadmium and TBBPA on the development and antioxidative defense system as well as thyroid functions in female rats through single and combined exposure at environmentally relevant doses for a 20-day consecutive administration. Body indexes, histopathology, redox status, and thyroid hormones levels were assessed. Slower body weight gains and reduced ovary weight (20.8% and 32.4% for combined and single-Cd exposures, respectively) were observed with significant variation from controls in high dose treatments. Co-exposure resulted in a slight enhancement in TSH levels compared to control (by 7.6% for high dose) without significance. TBBPA-Cd interactions are involved in the changes of kidney weight as well as the induction of SOD activities and MDA levels. The disturbances in the redox status may be a result of an independent effect of Cd and/or TBBPA and also of their interaction. The results implied under these treatment, kidney was more sensitive with significant increased organ coefficient and alteration for antioxidative indices (increasing by 46% for SOD activity). This study represents the toxic effects of Cd and TBBPA co-exposure through oral administration in pubertal rats, which may provide useful information for health risk assessment for young exposed individuals. Copyright © 2018 Elsevier B.V. All rights reserved.

Transgenic maize event TC1507: Global status of food, feed, and environmental safety.

PubMed

Baktavachalam, Gajendra B; Delaney, Bryan; Fisher, Tracey L; Ladics, Gregory S; Layton, Raymond J; Locke, Mary Eh; Schmidt, Jean; Anderson, Jennifer A; Weber, Natalie N; Herman, Rod A; Evans, Steven L

2015-01-01

Maize (Zea mays) is a widely cultivated cereal that has been safely consumed by humans and animals for centuries. Transgenic or genetically engineered insect-resistant and herbicide-tolerant maize, are commercially grown on a broad scale. Event TC1507 (OECD unique identifier: DAS-Ø15Ø7-1) or the Herculex®(#) I trait, an insect-resistant and herbicide-tolerant maize expressing Cry1F and PAT proteins, has been registered for commercial cultivation in the US since 2001. A science-based safety assessment was conducted on TC1507 prior to commercialization. The safety assessment addressed allergenicity; acute oral toxicity; subchronic toxicity; substantial equivalence with conventional comparators, as well as environmental impact. Results from biochemical, physicochemical, and in silico investigations supported the conclusion that Cry1F and PAT proteins are unlikely to be either allergenic or toxic to humans. Also, findings from toxicological and animal feeding studies supported that maize with TC1507 is as safe and nutritious as conventional maize. Maize with TC1507 is not expected to behave differently than conventional maize in terms of its potential for invasiveness, gene flow to wild and weedy relatives, or impact on non-target organisms. These safety conclusions regarding TC1507 were acknowledged by over 20 regulatory agencies including United States Environment Protection Agency (US EPA), US Department of Agriculture (USDA), Canadian Food Inspection Agency (CFIA), and European Food Safety Authority (EFSA) before authorizing cultivation and/or food and feed uses. A comprehensive review of the safety studies on TC1507, as well as some benefits, are presented here to serve as a reference for regulatory agencies and decision makers in other countries where authorization of TC1507 is or will be pursued.

A subchronic toxicity study of elemental Nano-Se in Sprague-Dawley rats.

PubMed

Jia, X; Li, N; Chen, J

2005-03-11

The subchronic toxicity of Nano-Se was compared with selenite and high-selenium protein in rats. Groups of Sprague-Dawley rats (12 males and 12 females per group) were fed diets containing Nano-Se, selenite and high-selenium protein at concentrations of 0, 2, 3, 4 and 5 ppm Se, respectively, for 13 weeks. Clinical observations were made and body weight and food consumption were recorded weekly. At the end of the study, the rats were subjected to a full necropsy, blood samples were collected for hematology and clinical chemistry determination. Histopathological examination was performed on selected tissues. At the two higher doses (4 and 5 ppm Se), significant abnormal changes were found in body weight, hematology, clinical chemistry, relative organ weights and histopathology parameters. However, the toxicity was more pronounced in the selenite and high-selenium protein groups than the Nano-Se group. At the dose of 3 ppm Se, significant growth inhibition and degeneration of liver cells were found in the selenite and high-selenium protein groups. No changes attributable to administration of Nano-Se at the dose of 3 ppm Se were found. Taken together, the no-observed-adverse-effect level (NOAEL) of Nano-Se in male and female rats was considered to be 3 ppm Se, equivalent to 0.22 mg/kg bw/day for males and 0.33 mg/kg bw/day for females. On the other hand, the NOAELs of selenite and high-selenium protein in males and females were considered to be 2 ppm Se, equivalent to 0.14 mg/kg bw/day for males and 0.20 mg/kg bw/day for females. In addition, studies have shown that Nano-Se has a similar bioavailability in rat, and much less acute toxicity in mice compared with selenite. In conclusion, Nano-Se is less toxic than selenite and high-selenium protein in the 13-week rat study.

Effect of Curcumin Supplementation on Physiological Fatigue and Physical Performance in Mice

PubMed Central

Huang, Wen-Ching; Chiu, Wan-Chun; Chuang, Hsiao-Li; Tang, Deh-Wei; Lee, Zon-Min; Wei, Li; Chen, Fu-An; Huang, Chi-Chang

2015-01-01

Curcumin (CCM) is a well-known phytocompound and food component found in the spice turmeric and has multifunctional bioactivities. However, few studies have examined its effects on exercise performance and physical fatigue. We aimed to evaluate the potential beneficial effects of CCM supplementation on fatigue and ergogenic function following physical challenge in mice. Male ICR mice were divided into four groups to receive vehicle or CCM (180 μg/mL) by oral gavage at 0, 12.3, 24.6, or 61.5 mL/kg/day for four weeks. Exercise performance and anti-fatigue function were evaluated after physical challenge by forelimb grip strength, exhaustive swimming time, and levels of physical fatigue-associated biomarkers serum lactate, ammonia, blood urea nitrogen (BUN), and glucose and tissue damage markers such as aspartate transaminase (AST), alanine transaminase (ALT), and creatine kinase (CK). CCM supplementation dose-dependently increased grip strength and endurance performance and significantly decreased lactate, ammonia, BUN, AST, ALT, and CK levels after physical challenge. Muscular glycogen content, an important energy source for exercise, was significantly increased. CCM supplementation had few subchronic toxic effects. CCM supplementation may have a wide spectrum of bioactivities for promoting health, improving exercise performance and preventing fatigue. PMID:25647661

Ninety-day oral toxicity studies on two genetically modified maize MON810 varieties in Wistar Han RCC rats (EU 7th Framework Programme project GRACE).

PubMed

Zeljenková, Dagmar; Ambrušová, Katarína; Bartušová, Mária; Kebis, Anton; Kovrižnych, Jevgenij; Krivošíková, Zora; Kuricová, Miroslava; Líšková, Aurélia; Rollerová, Eva; Spustová, Viera; Szabová, Elena; Tulinská, Jana; Wimmerová, Soňa; Levkut, Mikuláš; Révajová, Viera; Ševčíková, Zuzana; Schmidt, Kerstin; Schmidtke, Jörg; La Paz, Jose Luis; Corujo, Maria; Pla, Maria; Kleter, Gijs A; Kok, Esther J; Sharbati, Jutta; Hanisch, Carlos; Einspanier, Ralf; Adel-Patient, Karine; Wal, Jean-Michel; Spök, Armin; Pöting, Annette; Kohl, Christian; Wilhelm, Ralf; Schiemann, Joachim; Steinberg, Pablo

2014-12-01

The GMO Risk Assessment and Communication of Evidence (GRACE; www.grace-fp7.eu ) project is funded by the European Commission within the 7th Framework Programme. A key objective of GRACE is to conduct 90-day animal feeding trials, animal studies with an extended time frame as well as analytical, in vitro and in silico studies on genetically modified (GM) maize in order to comparatively evaluate their use in GM plant risk assessment. In the present study, the results of two 90-day feeding trials with two different GM maize MON810 varieties, their near-isogenic non-GM varieties and four additional conventional maize varieties are presented. The feeding trials were performed by taking into account the guidance for such studies published by the EFSA Scientific Committee in 2011 and the OECD Test Guideline 408. The results obtained show that the MON810 maize at a level of up to 33 % in the diet did not induce adverse effects in male and female Wistar Han RCC rats after subchronic exposure, independently of the two different genetic backgrounds of the event.

Acute and long-term effects of trophic exposure to silver nanospheres in the central nervous system of a neotropical fish Hoplias intermedius.

PubMed

Klingelfus, T; Lirola, J R; Oya Silva, L F; Disner, G R; Vicentini, M; Nadaline, M J B; Robles, J C Z; Trein, L M; Voigt, C L; Silva de Assis, H C; Mela, M; Leme, D M; Cestari, M M

2017-12-01

Nanotechnologies are at the center of societal interest, due to their broad spectrum of application in different industrial products. The current concern about nanomaterials (NMs) is the potential risks they carry for human health and the environment. Considering that NMs can reach bodies of water, there is a need for studying the toxic effects of NMs on aquatic organisms. Among the NMs' toxic effects on fish, the interactions between NMs and the nervous system are yet to be understood. For this reason, our goal was to assess the neurotoxicity of polyvinylpyrrolidone coated silver nanospheres [AgNS (PVP coated)] and compare their effects in relation to silver ions (Ag + ) in carnivorous Hoplias intermedius fish after acute and subchronic trophic exposure through the analysis of morphological (retina), biochemical (brain) and genetic biomarkers (brain and blood). For morphological biomarkers, damage by AgNS (PVP coated) in retina was found, including morphological changes in rods, cones, hemorrhage and epithelium rupture, and also deposition of AgNS (PVP coated) in retina and sclera. In the brain biomarkers, AgNS (PVP coated) did not disturb acetylcholinesterase activity. However, lowered migration of the DNA tail in the Comet Assay of blood and brain cells was observed for all doses of AgNS (PVP coated), for both acute and subchronic bioassays, and in a dose-dependent manner in acute exposure. Ag + also reduced the level of DNA damage only under subchronic conditions in the brain cells. In general, the results demonstrated that AgNS (PVP coated) do not cause similar effects in relation to Ag + . Moreover, the lowered level of DNA damage detected by Comet Assay suggests that AgNS (PVP coated) directly interacts with DNA of brain and blood cells, inducing DNA-DNA or DNA-protein crosslinks. Therefore, the AgNS (PVP coated) accumulating, particularly in the retina, can lead to a competitive disadvantage for fish, compromising their survival. Copyright © 2017 Elsevier B.V. All rights reserved.

The endocrine disruptor nonylphenol induces sublethal toxicity in vascular plant development at environmental concentrations: A risk for riparian plants and irrigated crops?

PubMed

Esteban, S; Llamas, P M; García-Cortés, H; Catalá, M

2016-09-01

In recent years, there is a growing concern among the scientific community about the presence of the so-called emergent pollutants in waters of different countries, especially endocrine-disrupting compounds (EDCs) that have the ability to alter the hormonal system. One of the substances found almost ubiquitously and in higher concentrations is the alkylphenol nonylphenol. Albeit this compound is included in priority lists as a probable risk for human health and the environment, little is known about its effects on developing plants. The aim of this work is to assess the acute and sub-chronic toxicity of environmental concentrations of nonylphenol in riparian vascular plant development using spores of the fern Polystichum setiferum and a biomarker-based approach: mitochondrial activity (cell viability), chlorophyll (plant physiology) and DNA content (growth). Mitochondrial activity and DNA content show that nonylphenol induces acute and sub-chronic toxicity at 48 h and after 1 week, respectively. Significant effects are observed in both parameters in fern spores at ng L(-1) but chlorophyll autofluorescence shows little changes. The inhibition of germination by natural allelochemicals has been reported to be related with the active hydroxyl group of phenolic compounds and largely independent of the structural nucleus to which it is attached. Results presented in this study suggest that environmental concentrations of nonylphenol could interfere with higher plant germination development by mimicking natural allelochemicals and/or phytohormones acting as a "phytoendocrine disruptor" likely posing ecophysiological risks. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of short- and long-term exposures to copper on lethal and reproductive endpoints of the harpacticoid copepod Tigriopus fulvus.

PubMed

Biandolino, Francesca; Parlapiano, Isabella; Faraponova, Olga; Prato, Ermelinda

2018-01-01

The long-term exposure provides a realistic measurement of the effects of toxicants on aquatic organisms. The harpacticoid copepod Tigriopus fulvus has a wide geographical distribution and is considered as an ideal model organism for ecotoxicological studies for its good sensitivity to different toxicants. In this study, acute, sub-chronic and chronic toxicity tests based on lethal and reproductive responses of Tigriopus fulvus to copper were performed. The number of moults during larval development was chosen as an endpoint for sub-chronic test. Sex ratio, inhibitory effect on larval development, hatching time, fecundity, brood number, nauplii/brood, total newborn production, etc, were calculated in the chronic test (28d). Lethal effect of copper to nauplii showed the LC50-48h of 310 ± 72µgCu/L (mean ± sd). It was observed a significant inhibition of larval development at sublethal copper concentrations, after 4 and 7 d. After 4d, the EC50 value obtained for the endpoint in "moult naupliar reduction" was of 55.8 ± 2.5µgCu/L (mean ± sd). The EC50 for the inhibition of naupliar development into copepodite stage, was of 21.7 ± 4.4µgCu/L (mean ± sd), after 7 days. Among the different traits tested, copper did not affect sex ratio and growth, while fecundity and total nauplii production were the most sensitive endpoints. The reproductive endpoints offer the advantage of being detectable at very low pollutant concentrations. Copyright © 2017 Elsevier Inc. All rights reserved.

Toxicological Evaluation of Depleted Uranium in Rats: Six-Month Evaluation Point

DTIC Science & Technology

1998-02-01

mild renal dysfunction with increased urinary excretion of beta2-microglobulin and various amino acids. In rats exposed subchronically to low doses...reabsorption. Urinary enzymes are sen- sitive, non-invasive markers of toxicity primarily in the kidney tubules [46]. NAG is a lysosomal enzyme found...studies. Environmental Research 61:323-336 42. Neuman WF (1950) Urinary uranium as a meas- ure of exposure hazard. Industrial Medicine and Surgery 19

Chemical Carcinogenesis Testing and Related Issues - Subchronic Studies and Related Issues

DTIC Science & Technology

1985-05-01

example, necrosis of i degree to be associated with a significant amount of regeneraW-In may ccmplicate the interpre- tation of a neoplastic rosponse...and not a formal mandate for the described procedure. Evidence of moderate to marked necrosis , (3+ to 4+), degen- eration, irritation, inflammation, or...test animals at a given dose to judge that dose to yield positive toxicity. If the degree of necrosis , degeneration, irritation, inflammation, or atrophy

Subchronic Toxicity of Copper Oxide Nanoparticles and Its Attenuation with the Help of a Combination of Bioprotectors

PubMed Central

Privalova, Larisa I.; Katsnelson, Boris A.; Loginova, Nadezhda V.; Gurvich, Vladimir B.; Shur, Vladimir Y.; Valamina, Irene E.; Makeyev, Oleg H.; Sutunkova, Marina P.; Minigalieva, Ilzira A.; Kireyeva, Ekaterina P.; Rusakov, Vadim O.; Tyurnina, Anastasia E.; Kozin, Roman V.; Meshtcheryakova, Ekaterina Y.; Korotkov, Artem V.; Shuman, Eugene A.; Zvereva, Anastasia E.; Kostykova, Svetlana V.

2014-01-01

In the copper metallurgy workplace air is polluted with condensation aerosols, which a significant fraction of is presented by copper oxide particles <100 nm. In the scientific literature, there is a lack of their in vivo toxicity characterization and virtually no attempts of enhancing organism’s resistance to their impact. A stable suspension of copper oxide particles with mean (±SD) diameter 20 ± 10 nm was prepared by laser ablation of pure copper in water. It was being injected intraperitoneally to rats at a dose of 10 mg/kg (0.5 mg per mL of deionized water) three times a week up to 19 injections. In parallel, another group of rats was so injected with the same suspension against the background of oral administration of a “bio-protective complex” (BPC) comprising pectin, a multivitamin-multimineral preparation, some amino acids and fish oil rich in ω-3 PUFA. After the termination of injections, many functional and biochemical indices for the organism’s status, as well as pathological changes of liver, spleen, kidneys, and brain microscopic structure were evaluated for signs of toxicity. In the same organs we have measured accumulation of copper while their cells were used for performing the Random Amplification of Polymorphic DNA (RAPD) test for DNA fragmentation. The same features were assessed in control rats infected intraperitoneally with water with or without administration of the BPC. The copper oxide nanoparticles proved adversely bio-active in all respects considered in this study, their active in vivo solubilization in biological fluids playing presumably an important role in both toxicokinetics and toxicodynamics. The BPC proposed and tested by us attenuated systemic and target organs toxicity, as well as genotoxicity of this substance. Judging by experimental data obtained in this investigation, occupational exposures to nano-scale copper oxide particles can present a significant health risk while the further search for its management with the help of innocuous bioprotectors seems to be justified. PMID:25026171

Subchronic toxicity of copper oxide nanoparticles and its attenuation with the help of a combination of bioprotectors.

PubMed

Privalova, Larisa I; Katsnelson, Boris A; Loginova, Nadezhda V; Gurvich, Vladimir B; Shur, Vladimir Y; Valamina, Irene E; Makeyev, Oleg H; Sutunkova, Marina P; Minigalieva, Ilzira A; Kireyeva, Ekaterina P; Rusakov, Vadim O; Tyurnina, Anastasia E; Kozin, Roman V; Meshtcheryakova, Ekaterina Y; Korotkov, Artem V; Shuman, Eugene A; Zvereva, Anastasia E; Kostykova, Svetlana V

2014-07-14

In the copper metallurgy workplace air is polluted with condensation aerosols, which a significant fraction of is presented by copper oxide particles<100 nm. In the scientific literature, there is a lack of their in vivo toxicity characterization and virtually no attempts of enhancing organism's resistance to their impact. A stable suspension of copper oxide particles with mean (±SD) diameter 20±10 nm was prepared by laser ablation of pure copper in water. It was being injected intraperitoneally to rats at a dose of 10 mg/kg (0.5 mg per mL of deionized water) three times a week up to 19 injections. In parallel, another group of rats was so injected with the same suspension against the background of oral administration of a "bio-protective complex" (BPC) comprising pectin, a multivitamin-multimineral preparation, some amino acids and fish oil rich in ω-3 PUFA. After the termination of injections, many functional and biochemical indices for the organism's status, as well as pathological changes of liver, spleen, kidneys, and brain microscopic structure were evaluated for signs of toxicity. In the same organs we have measured accumulation of copper while their cells were used for performing the Random Amplification of Polymorphic DNA (RAPD) test for DNA fragmentation. The same features were assessed in control rats infected intraperitoneally with water with or without administration of the BPC. The copper oxide nanoparticles proved adversely bio-active in all respects considered in this study, their active in vivo solubilization in biological fluids playing presumably an important role in both toxicokinetics and toxicodynamics. The BPC proposed and tested by us attenuated systemic and target organs toxicity, as well as genotoxicity of this substance. Judging by experimental data obtained in this investigation, occupational exposures to nano-scale copper oxide particles can present a significant health risk while the further search for its management with the help of innocuous bioprotectors seems to be justified.

Diuretic activity and toxicity study of the aqueous extract of Cola nitida seed on markers of renal function and electrolytes in rats.

PubMed

Nnemdi Ashibuogwu, Mirian; Isaac Adeosun, Olukayode; Ojo Akomolafe, Rufus; Olaniyi Sanni, Douglas; Sesan Olukiran, Olaoluwa

2016-12-01

BackgroundCola nitida is a plant, conventionally used in Africa in the treatment of various ailments such as migraine, morning sickness and indigestion. The aim of the present study was to explore the diuretic activity of the aqueous extract of C. nitida seed (AECONS) and alteration caused by its subchronic administration on the structure and function of the kidney of male Wistar rats. MethodsThe study was divided into diuretic and subchronic studies. Twenty-five male Wistar rats weighing between 140 and 180 g were divided into five groups of five rats each. The first 24 h of this study investigated the possible diuretic activity of C. nitida seed. Group I (the control) received 25 mL/kg of normal saline. Group II (the standard) received 20 mg/kg/day of furosemide. Groups III, IV, V received 400, 600 and 800 mg/kg/day of AECONS, respectively, and orally. Urine volume, pH, specific gravity and electrolytes were estimated in the samples of urine collected after 6 h of the study. From the second day onward and up to a period of 4 weeks, the rats in each group were given normal saline, furosemide and AECONS once daily as was done on the first day. At the end of the 4-week treatment period, blood and urine samples were collected for the determination of creatinine, urea, Na+, K+ and Cl- concentrations. Results The results of the diuretic study showed that the AECONS at all doses used and furosemide produced a significant increase in urine output with respect to the control group. AECONS also induced a significant increase in the urine concentrations of Na+, K+, Cl- in the experimental and standard groups when compared with the control group, except for group III which showed no significant variation in K+ concentration. In the subchronic study, AECONS caused a significant increase in the urine levels of Na+, K+, Cl- in the experimental and standard groups when compared with the control rats. The plasma Na+ concentration of groups IV and V was significantly lower than that of the control group. Photomicrographs of the kidneys of the experimental and standard groups revealed no significant alterations in the histology of their kidney tissues. Conclusions It is concluded that AECONS induced diuresis which is associated with increased Na+, K+ and Cl- loss in rats without any significant alteration in the structure of their kidneys.

Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC*

PubMed Central

Karschner, Erin L.; Schwope, David M.; Schwilke, Eugene W.; Goodwin, Robert S.; Kelly, Deanna L.; Gorelick, David A.; Huestis, Marilyn A.

2012-01-01

Background Determining time since last cannabis/Δ9-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing. Methods Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography-mass spectrometry. Results Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5 h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11-hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1-5 h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5 h after the last THC dose, respectively. Conclusions Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily. PMID:22464363

Potential Occupational Risks Associated with Pulmonary Toxicity of Carbon Nanotubes.

PubMed

Manke, Amruta; Luanpitpong, Sudjit; Rojanasakul, Yon

Given their remarkable properties, carbon nanotubes (CNTs) have made their way through various industrial and medicinal applications and the overall production of CNTs is expected to grow rapidly in the next few years, thus requiring an additional recruitment of workers. However, their unique applications and desirable properties are fraught with concerns regarding occupational exposure. The concern about worker exposure to CNTs arises from the results of recent animal studies. Short-term and sub-chronic exposure studies in rodents have shown consistent adverse health effects such as pulmonary inflammation, granulomas, fibrosis, genotoxicity and mesothelioma after inhalation or instillation of several types of CNTs. Furthermore, physicochemical properties of CNTs such as dispersion, functionalization and particle size can significantly affect their pulmonary toxicity. Risk estimates from animal studies necessitate implementation of protective measures to limit worker exposure to CNTs. Information on workplace exposure is very limited, however, studies have reported that CNTs can be aerosolized and attain respirable airborne levels during synthesis and processing activities in the workplace. Quantitative risk assessments from sub-chronic animal studies recommend the health-based need to reduce exposures below the recommended exposure limit of 1 µg/m 3 . Practice of prevention measures including the use of engineering controls, personal protective equipment, health surveillance program, safe handling and use, as well as worker training can significantly minimize worker exposure and improve worker health and safety.

Genotoxicity and subchronic toxicity evaluation of dried Euglena gracilis ATCC PTA-123017.

PubMed

Simon, Ryan R; Vo, Trung D; Levine, Robert

2016-10-01

Euglena gracilis is a microalga capable of synthesizing various nutrients of interest in human and animal nutrition. When cultivated aerobically in the dark, Euglena synthesize paramylon, a storage polysaccharide comprised of high molecular weight beta-1,3-D-glucose polymers organized in cytoplasmic granules. Beta-glucans have been shown to have immune modulation effects, including anti-microbial, anti-tumor, and anti-oxidant properties, and metabolic effects, such as regulation of cholesterol and blood sugar levels. Preparations of E. gracilis and paramylon may therefore have potential utility as functional food ingredients for human and animal nutrition. A battery of toxicological studies was conducted on a dried preparation of E. gracilis and paramylon to support their safe food use. The dried alga was not genotoxic in a bacterial reverse mutation test and mammalian micronucleus test. In the subchronic toxicity study, rats were provided E. gracilis in the diet at levels of 0, 12,500, 25,000 or 50,000 ppm. Paramylon was provided at a concentration of 50,000 ppm. No effects that could be attributable to treatment were observed in clinical observations, body weight, food consumption, ophthalmology, hematology and clinical chemistry, urinalysis, and macroscopic and microscopic findings. A NOAEL of 50,000 ppm in the diet was determined for both ingredients. Copyright © 2016 Elsevier Inc. All rights reserved.

Protective effect of crocin against apoptosis induced by subchronic exposure of the rat vascular system to diazinon.

PubMed

Razavi, Bibi Marjan; Hosseinzadeh, Hossein; Abnous, Khalil; Khoei, Alireza; Imenshahidi, Mohsen

2016-07-01

Research has suggested that natural antioxidant, crocin, an active ingredient of saffron, may protect against diazinon (DZN)-induced toxicity. Although increased production of lipid peroxidation by DZN in rat aorta has been shown previously, the effects of DZN on oxidative stress-induced apoptosis in vascular system have not been evaluated. In this study, the effect of crocin on DZN-induced apoptosis in rat vascular system was investigated. The rats were divided into 7 groups: corn oil (control), DZN (15 mg/kg/day, gavage), crocin (12.5, 25, and 50 mg/kg/day, intraperitoneally (i.p.)) + DZN, vitamin E (200 IU/kg, i.p., 3 days a week) + DZN, and crocin (50 mg/kg/day, i.p.). The treatments were continued for 4 weeks. Levels of apoptotic (Bax, caspase 3, and caspase 9) and antiapoptotic proteins (Bcl2) were analyzed by Western blotting. Transcript levels of Bax and Bcl2 genes were determined using quantitative real-time polymerase chain reaction. Results showed DZN-induced apoptosis by activation of caspase 9 and caspase 3 and by increasing the Bax/Bcl2 ratio (both protein and messenger RNA levels). Crocin and vitamin E inhibited apoptosis induced by DZN. In summary, subchronic exposure to DZN induced caspase-mediated apoptosis, and crocin reduced the toxic effects of DZN by inhibiting apoptosis in aortic tissue. © The Author(s) 2014.

Edible Safety Assessment of Genetically Modified Rice T1C-1 for Sprague Dawley Rats through Horizontal Gene Transfer, Allergenicity and Intestinal Microbiota.

PubMed

Zhao, Kai; Ren, Fangfang; Han, Fangting; Liu, Qiwen; Wu, Guogan; Xu, Yan; Zhang, Jian; Wu, Xiao; Wang, Jinbin; Li, Peng; Shi, Wei; Zhu, Hong; Lv, Jianjun; Zhao, Xiao; Tang, Xueming

2016-01-01

In this study, assessment of the safety of transgenic rice T1C-1 expressing Cry1C was carried out by: (1) studying horizontal gene transfer (HGT) in Sprague Dawley rats fed transgenic rice for 90 d; (2) examining the effect of Cry1C protein in vitro on digestibility and allergenicity; and (3) studying the changes of intestinal microbiota in rats fed with transgenic rice T1C-1 in acute and subchronic toxicity tests. Sprague Dawley rats were fed a diet containing either 60% GM Bacillus thuringiensis (Bt) rice T1C-1 expressing Cry1C protein, the parental rice Minghui 63, or a basic diet for 90 d. The GM Bt rice T1C-1 showed no evidence of HGT between rats and transgenic rice. Sequence searching of the Cry1C protein showed no homology with known allergens or toxins. Cry1C protein was rapidly degraded in vitro with simulated gastric and intestinal fluids. The expressed Cry1C protein did not induce high levels of specific IgG and IgE antibodies in rats. The intestinal microbiota of rats fed T1C-1 was also analyzed in acute and subchronic toxicity tests by DGGE. Cluster analysis of DGGE profiles revealed significant individual differences in the rats' intestinal microbiota.

Foraging enrichment modulates open field response to monosodium glutamate in mice.

PubMed

Onaolapo, Olakunle J; Onaolapo, Adejoke Y; Akanmu, Moses A; Olayiwola, Gbola

2015-07-01

Environmental enrichment can enhance expression of species-specific behaviour. While foraging enrichment is encouraged in laboratory animals, its impact on novelty induced behaviour remain largely unknown. Here, we studied behavioural response of mice to acute and subchronic oral monosodium glutamate (MSG) in an open field with /without foraging enrichment. Adult male mice, assigned to five groups were administered vehicle (distilled water), or one of four selected doses of MSG (10, 20, 40 and 80 mg/kg) for 21 days. Open field novelty induced behaviours i.e. horizontal locomotion, rearing and grooming were assessed after the first and last doses of MSG. Results were analysed using MANOVA followed by Tukey HSD multiple comparison test and expressed as mean ± S.E.M. Following acute MSG administration without enrichment, locomotor activity reduced, grooming increased, while rearing activity reduced at lower doses and increased at higher doses. Subchronic administration without enrichment was associated with increased locomotor activity and reduction in grooming, rearing activity however still showed a biphasic response. Addition of enrichment with acute administration resulted in sustained reduction in locomotor and rearing activities with a biphasic grooming response. Subchronically, there was reduction in horizontal locomotion, biphasic rearing response and sustained increase in grooming activity. Behavioural response to varying doses of MSG as observed in the open field is affected by modifications such as foraging enrichment, which can reverse or dampen the central effects seen irrespective of duration of administration.

Antidiabetic, antidyslipidemic and toxicity profile of ENV-2: A potent pyrazole derivative against diabetes and related diseases.

PubMed

Hernández-Vázquez, Eduardo; Ocampo-Montalban, Hugo; Cerón-Romero, Litzia; Cruz, Miguel; Gómez-Zamudio, Jaime; Hiriart-Valencia, Guadalupe; Villalobos-Molina, Rafael; Flores-Flores, Angelica; Estrada-Soto, Samuel

2017-05-15

Diabetes is a major health problem and a predisposition factor for further degenerative complications and, therefore, novel therapies are urgently needed. Currently, cannabinoid receptor 1 (CB 1 receptor) antagonists have been considered as promissory entities for metabolic disorders treatment. Accordingly, the purpose of this work was the evaluation of the sub-acute antidiabetic, anti-hyperglycemic, antidyslipidemic and toxicological profile of ENV-2, a potent hypoglycemic and antioxidant CB 1 receptor antagonist. In this study, ENV-2 showed a pronounced anti-hyperglycemic effect even at a dose of 5mg/kg (P<0.05) in a glucose tolerance test on normoglycemic rats. Moreover, after administration of ENV-2 (16mg/kg) to diabetic rats, a prominent antidiabetic activity was observed (P<0.05), which was higher than glibenclamide. Sub-acute treatment (10 days) of ENV-2 resulted in a significant reduction of plasma glucose (P<0.05). Also, the levels of peripheral lipids were improved; blood triacylglycerols (TG) and cholesterol (CHOL) were diminished (P<0.05). In addition, it was found that ENV-2 reduced IL-1β and IL-18 mRNA expression in adipose tissue (P<0.05). Due to the satisfactory outcomes, we were interested in evaluating the toxicity of ENV-2 in both acute and sub-chronic approaches. Regarding the acute administration, the compound resulted to be non-toxic and was grouped in category 5 according to OECD. It was also found that sub-chronic administration did not increase the size of the studied organs, while no structural damage was observed in heart, lung, liver and kidney tissues. Finally, neither AST nor ALT damage hepatic markers were augmented. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparative sensitivity of aquatic invertebrate and vertebrate species to wastewater from an operational coal mine in central Queensland, Australia.

PubMed

Lanctôt, C; Wilson, S P; Fabbro, L; Leusch, F D L; Melvin, S D

2016-07-01

Coal excavation and refinement processes generate substantial volumes of contaminated effluent that may be detrimental to aquatic ecosystems. As such, understanding the impacts of coal mine water releases on aquatic animals and ecosystems is essential for effectively managing and protecting neighboring environments. Such information will ultimately be applied towards developing ongoing monitoring strategies that are protective of native wildlife. Despite intensive mining operations in Australia, few studies have documented toxicity associated with coal mine wastewater (CMW) on native species. To address existing knowledge gaps, we investigated acute toxicity (48-96h) using eight native invertebrate species and sub-chronic effects (2 week) using three vertebrate species following exposure to wastewater from two dams (CMW1 and CMW2) located at an open-cut coal mine licensed to discharge into the Fitzroy catchment (Queensland, Australia). Wastewater from these sites is characterized by elevated conductivity, pH, sulfates as well as relatively high total and dissolved metal(loid)s (including As, Al, B, Cu, Mn, Ni, Se and Zn). Acute exposures revealed cladocerans (Daphnia carinata) and planarians (Dugesia sp.) to be the most sensitive species, exhibiting significant mortality after 48 and 96h exposure to CMW2, respectively. Neither wastewater was found to elicit acute toxicity in vertebrates, but a range of sub-lethal morphological effects were observed following the sub-chronic exposures. The overall response pattern was characterized by decreased condition factor and hepatosomatic index in the fish Hypseleotris compressa and Pseudomugil signifier, and in Limnodynastes peronii tadpoles. Tadpoles were generally more sensitive compared to the two fish species. Differences in responses were observed amongst CMW1 and CMW2, which likely relates to differences in physico-chemical properties between sites. Our results have identified several candidate vertebrate and invertebrate species that show promise for ongoing monitoring of water quality and toxicity risk in Central Queensland, Australia. Copyright © 2016 Elsevier Inc. All rights reserved.

Health Risk Assessment of Embedded Depleted Uranium: Behavior, Physiology, Histology and Biokenetic Modeling.

DTIC Science & Technology

1996-11-01

increased urinary excretion of beta2-microglobulin and various amino acids. In rats exposed subchronically to low doses (cumulative dose: 0.66 or 1.32 mg/kg...leakage or failure of tubule reabsorption. Urinary enzymes are sensitive, non- invasive markers of toxicity primarily in the kidney tubules46. NAG is a...42 Neuman, W.F., Urinary uranium as a measure of exposure hazard, Industrial. Med. Surgery, 19 (1950) 185-191. 43 Neuman, W.F., Fleming, R.W., Dounce

Safety assessment of heated diacylglycerol oil: subchronic toxicity study in rats.

PubMed

Morita, Osamu; Tamaki, Yasushi; Kirkpatrick, Jeannie B; Chengelis, Christopher P

2008-08-01

Diacylglycerol oil is an edible oil with similar taste and usability characteristics as conventional edible oil rich in triacylglycerol oil. The objective of the present study was to evaluate potential adverse effects of heated diacylglycerol and triacylglycerol oil in rats following subchronic administration. The heated diacylglycerol and triacylglycerol oils were prepared separately following deep frying potato slices at 180 degrees C for 8h per day for three days. Sprague Dawley rats were fed diets containing different ratios (concentrations) of heated to unheated diacylglycerol oil. The ratio of heated to unheated diacylglycerol was as follows: 0%/5.5% (control-1; Group 1), 1.0%/4.5% (Group 2), 2.75%/2.75% (Group 3), and 5.5%/0% (Group 4). Two additional groups received the feed containing 5.5% of unheated or 5.5% of heated triacylglycerol oil. Compared to the unheated oils, feeding of heated diacylglycerol or triacylglycerol oil did not reveal any toxicologically significant changes in clinical observation, body weights, body weight gains, feed consumption, ophthalmic examinations, functional observational battery and motor activity, clinical pathology evaluations and organ weights. Similarly, terminal necropsy did not reveal treatment-related gross or histopathology findings. Based on the results of this subchronic study, the no-observed-effect levels (NOELs) of heated diacylglycerol or triacylglycerol oil were 5.5%, the highest levels tested. The mean dietary exposure levels at the highest dose for the heated diacylglycerol and triacylglycerol oil for male and female rats ranged from 3,178 to 4,120 mg/kg/day.

Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the syrian golden hamster. Part I. Results of a subchronic study and dose selection for a chronic study.

PubMed

Hesterberg, T W; Axten, C; McConnell, E E; Hart, G A; Miiller, W; Chevalier, J; Everitt, J; Thevenaz, P; Oberdörster, G

1999-09-01

A multidose, subchronic inhalation study was used to estimate the maximum tolerated dose (MTD) of 901 fiberglass (MMVF10.1) for a chronic inhalation study using hamsters. Subchronic study results indicated that 30 mg/m(3) [250-300 WHO fibers (>5 microm long)/cm(3) and 100-130 fibers/cm(3) >20 microm long] meets or exceeds the estimated MTD, and chronic study results confirmed this. For the subchronic study, hamsters were exposed 6 h/day, 5 days/wk, for 13 wk to MMVF10.1 at 3, 16, 30, 45, and 60 mg/m(3) (36, 206, 316, 552, or 714 WHO fibers/cm(3)), then monitored for 10 wk. Results demonstrating MTD were: inflammatory response (all fiber exposures); elevated lung cell proliferation with @ges;16 mg/m(3); lung lavage neutrophil elevations with @ges;16 mg/m(3) and lactate dehydrogenase (LDH) and protein elevations with > or = 30 mg/m(3); and persistent abnormal macrophage/fiber clumps in lungs exposed to 45 and 60 mg/m(3), which suggest overloading of clearance mechanisms. For the chronic study, hamsters were exposed for 78 wk to MMVF10a (901 fiber glass) or MMVF33 (special-application 475 fiberglass) at approximately 300 WHO fibers/cm(3) ( approximately 100 fibers/cm(3) @gt;20 @mu;m long), or to amosite asbestos at an equivalent concentration and 2 lower concentrations. All fiber-exposed animals had pulmonary inflammation, elevated lung lavage cells, and increased lung cell proliferation. Between 52 and 78 wk of exposure, lung burdens of all fibers increased at an accelerated rate, suggesting impairment of clearance mechanisms. MMVF33 and amosite induced fibrosis and pleural mesothelioma. These findings substantiate that exposures in the chronic study adequately tested the toxic potential of fiberglass.

Toxicity Studies on Antiradiation Agents.

DTIC Science & Technology

1979-03-01

Mice 193-403 WI 2823 Acute Oral and IP Toxicity in Guinea Pigs 193-404 WR 2823 14-Day IV Toxicity in Rats 193-405 WI 2823 Acute IV Toxicity in Dogs ...193-406 W 2823 14-Day Subacute IV Toxicity in Dogs 193-407 WI 2721 28-Day Oral Toxicity in Monkeys 193-408 WI 2529 Acute Oral Toxicity in Mice 193-409... Dogs 193-415 WI 149, 024 Acute IV Toxicity in Monkeys 193-416 WI 149, 024 2-Week IV Toxicity in Dogs 193-417 WI 149, 024 2-Week Toxicity in Monkeys 193

Evaluation of the toxicity and antimicrobial activity of hydroethanolic extract of Arrabidaea chica (Humb. & Bonpl.) B. Verl.

PubMed

Mafioleti, Luciano; da Silva Junior, Iberê Ferreira; Colodel, Edson Moleta; Flach, Adriana; Martins, Domingos Tabajara de Oliveira

2013-11-25

Arrabidaea chica (Bignoniaceae) is a vine native to the Amazon Rainforest, popularly known as "crajiru" and whose infusion and decoction of the leaves are used to treat diseases such as gastric ulcers, inflammations, infections, anemia, herpes, jaundice among others. It is also used as a natural dye. This work aimed to evaluate the in vitro and in vivo toxicity, antimicrobial activity including analysis of chemical constitution of the hydroethanolic extract of the leaves of Arrabidaea chica (HEAc). Acute and subchronic toxicity of HEAc was evaluated in mice and rats, respectively, and by Alamar blue (cytotoxicity assay) using CHO-K1 cells. Antimicrobial activity of HEAc was tested by broth microdilution method using a panel of bacteria and yeast of clinical interest. The preliminary phytochemical analysis of HEAc was performed by electrospray ionization mass spectrometry [ESI(+)-MS]. Secondary metabolites were quantified by colorimetric methods. When administered in vivo at doses up to 3000 mg/kg v.o., HEAc did not cause any signs and symptoms of acute toxicity in mice and no cytotoxicity in CHO-K1 cells. Administration for 30 days caused leukocytosis (200 mg/kg) and reversible reductions in non-dose dependent of body weight, total weight gain and feed intake in rats given 200mg/kg and 500 mg/kg of HEAc, but were not accompanied by behavioral and clinical changes (laboratory and histopathological) that may have demonstrated evidences of subchronic toxicity HEAc demonstrated a pronounced activity against Helicobacter pylori (MIC=12.5 μg/mL) and moderate activity against Enterococcus faecalis (MIC=100 μg/mL) in broth microdilution. Preliminary phytochemical analysis of HEAc by colorimetric methods revealed that mainly the presence of phenolic compounds (16.6%), especially flavones and flavonols (4.02%). [ESI(+)-MS] fingerprint analyses of HEAc revealed the presence of 3-deoxyanthocyanidins and kaempferol. Our data provide evidence that HEAc is safe and can be useful in infections related to Helicobacter pylori and Enterococcus faecalis. Phytochemical analysis revealed the predominant presence of flavones and flavonols, possibly involved in the antimicrobial action of HEAc. © 2013 Elsevier Ireland Ltd. All rights reserved.

Pulmonary toxicity of simulated lunar and Martian dusts in mice: II. Biomarkers of acute responses after intratracheal instillation

NASA Technical Reports Server (NTRS)

Lam, Chiu-Wing; James, John T.; Latch, Judith N.; Hamilton, Raymond F Jr; Holian, Andrij

2002-01-01

Volcanic ashes from Arizona and Hawaii, with chemical and mineral properties similar to those of lunar and Martian soils, respectively, are used by the National Aeronautics and Space Administration (NASA) to simulate lunar and Martian environments for instrument tests. NASA needs toxicity data on these volcanic soils to assess health risks from potential exposures of workers in facilities where these soil simulants are used. In this study we investigated the acute effects of lunar soil simulant (LSS) and Martian soil simulant (MSS), as a complement to a histopathological study assessing their subchronic effects (Lam et al., 2002). Fine dust of LSS, MSS, TiO(2), or quartz suspended in saline was intratracheally instilled into C57Bl/6J mice (4/group) in single doses of 0.1 mg/mouse or 1 mg/mouse. The mice were euthanized 4 or 24 h after the dust treatment, and bronchoalveolar lavage fluid (BALF) was obtained. Statistically significant lower cell viability and higher total protein concentration in the BALF were seen only in mice treated with the high dose of quartz for 4 h and with the high dose of MSS or quartz for 24 h, compared to mice treated only with saline. A significant increase in the percentage of neutrophils was not observed with any dust-treated group at 4 h after the instillation, but was observed after 24 h in all the dust-treated groups. This observation indicates that these dusts were not acutely toxic and the effects were gradual; it took some time for neutrophils to be recruited into and accumulate significantly in the lung. A statistically significant increase in apoptosis of lavaged macrophages from mice 4 h after treatment was found only in the high-dose silica group. The overall results of this study on the acute effects of these dusts in the lung indicate that LSS is slightly more toxic than TiO(2), and that MSS is comparable to quartz. These results were consistent with the subchronic histopathological findings in that the order of severity of lung toxicity was TiO(2) < LSS < MSS < quartz.

Sub-chronic 90-day toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Yanli

Neamine, an inhibitor of angiogenin (ANG), is a new investigative anticancer drug currently in preclinical stage. Here we report the 90-day sub-chronic toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. Neamine has a No Observed Adverse Effect Level (NOAEL) of 12 and 16 mg·kg{sup −1}·d{sup −1} for female and male rats, respectively. No mortality was found. The adverse effects included increased organ coefficients of spleen and kidney, increased BUN in both female and male rats at high dose, increased CR and decreased organ coefficients of heart and liver in male rats atmore » high dose. All of which, except the kidney coefficient and BUN in males, returned to normal levels after 28-day recovery. Histopathological examination revealed vacuolar degeneration of glomerulus, degeneration of renal tubules and cast in the kidneys, which were also recovered except in males of high-dosing group. These results indicate that kidney is the most susceptible organ for neamine toxicity. Tissue microarray analysis validated that ANG is up-regulated in hepatocellular carcinoma accompanied by increased nuclear translocation, suggesting that ANG is a possible target for drug development in liver cancer treatment. Neamine blocked nuclear translocation of ANG in HUVEC and HepG2 cells, and inhibited ANG-stimulated cell proliferation without affecting basal level cell proliferation. Neamine also inhibited progression of HepG2 xenografts in athymic mice accompanied by decreased angiogenesis and cancer cell proliferation. These results suggest that neamine is a specific ANG inhibitor with low toxicity and high anti-liver cancer efficacy. - Highlights: • The NOAEL of neamine is 12 mg·kg{sup −1}·d{sup −1} for females and 16 mg·kg{sup −}1·d{sup −1} for males. • The most susceptible organ for neamine toxicity is kidney. • Neamine inhibits the progression of xenograft HepG2 liver cancer in athymic mice.« less

Subchronic toxicity evaluation of sulfur mustard in rats.

PubMed

Sasser, L B; Miller, R A; Kalkwarf, D R; Cushing, J A; Dacre, J C

1996-01-01

Occupational exposure criteria have not been established for sulfur mustard (bis(2-chlorethyl) sulfide), a strong alkylating agent with known mutagenic properties. Seventy-two Sprague-Dawley rats of each sex, 6-7 weeks old, were divided into six groups (12 of each sex per group) and gavaged with 0, 0.003, 0.01, 0.03, 0.1 or 0.3 mg kg-1 sulfur mustard in sesame oil for 5 days a week for 13 weeks. No dose-related mortality was observed. A significant decrease (P > 0.05) in body weight was observed in both sexes of rats only in the 0.3 mg kg-1 group. Hematological evaluations and clinical chemistry measurements found non consistent treatment-related effects at the doses studied. The only treatment-related lesion associated with gavage exposure upon histopathological evaluation was epithelial hyperplasia of the forestomach of both sexes at 0.3 mg kg-1 and of males at 0.1 mg kg-1. The hyperplastic change was minimal and characterized by cellular disorganization of the basilar layer, apparent increase in mitotic activity of the basilar epithelial cells and thickening of the epithelial layer due to the apparent increase in cellularity. The estimated no-observed-effect level (NOEL) for sulfur mustard in this 90-day study was 0.1 mg kg-1 day-1 when administered orally.

Neuroprotective and cognitive-enhancing effects of the combined extract of Cyperus rotundus and Zingiber officinale.

PubMed

Sutalangka, Chatchada; Wattanathorn, Jintanaporn

2017-03-03

Currently, food supplements to improve age-related dementia are required. Therefore, we aimed to determine the effect of the combined extract of Cyperus rotundus and Zingiber officinale (CP1) on the improvement of age-related dementia in rats with AF64A-induced memory deficits. Male Wistar rats weighing 180-200 g were orally given CP1 at doses of 100, 200 and 300 mg.kg -1 BW for a period of 14 days after bilateral intracerebroventricular administration of AF64A. Spatial memory was assessed in all rats every 7 days throughout the 14 day-experimental period. At the end of the study, neuronal density, acetylcholinesterase (AChE) activity, oxidative stress status and the activation of MAPK cascades in the hippocampus were determined. Enhanced memory, increased neuronal density, decreased AChE activity and decreased oxidative stress status together with activated pERK1/2 were observed in the hippocampus of CP1-treated rats. These results suggested that CP1 might improve memory via enhanced cholinergic function and decreased neurodegeneration and oxidative stress. CP1 is a potential novel food supplement for dementia. However, further investigations on the subchronic toxicity of CP1 and drug interactions are required.

Toxicological approach to setting spacecraft maximum allowable concentrations for carbon monoxide

NASA Technical Reports Server (NTRS)

Wong, K. L.; Limero, T. F.; James, J. T.

1992-01-01

The Spacecraft Maximum Allowable Concentrations (SMACs) are exposure limits for airborne chemicals used by NASA in spacecraft. The aim of these SMACs is to protect the spacecrew against adverse health effects and performance decrements that would interfere with mission objectives. Because of the 1 and 24 hr SMACs are set for contingencies, minor reversible toxic effects that do not affect mission objectives are acceptable. The 7, 30, or 180 day SMACs are aimed at nominal operations, so they are established at levels that would not cause noncarcinogenic toxic effects and more than one case of tumor per 1000 exposed individuals over the background. The process used to set the SMACs for carbon monoxide (CO) is described to illustrate the approach used by NASA. After the toxicological literature on CO was reviewed, the data were summarized and separated into acute, subchronic, and chronic toxicity data. CO's toxicity depends on the formation of carboxyhemoglobin (COHb) in the blood, reducing the blood's oxygen carrying capacity. The initial task was to estimate the COHb levels that would not produce toxic effects in the brain and heart.

Critique on the use of the standardized avian acute oral toxicity test for first generation anticoagulant rodenticides

USGS Publications Warehouse

Vyas, Nimish B.; Rattner, Barnett A.

2012-01-01

Avian risk assessments for rodenticides are often driven by the results of standardized acute oral toxicity tests without regards to a toxicant's mode of action and time course of adverse effects. First generation anticoagulant rodenticides (FGARs) generally require multiple feedings over several days to achieve a threshold concentration in tissue and cause adverse effects. This exposure regimen is much different than that used in the standardized acute oral toxicity test methodology. Median lethal dose values derived from standardized acute oral toxicity tests underestimate the environmental hazard and risk of FGARs. Caution is warranted when FGAR toxicity, physiological effects, and pharmacokinetics derived from standardized acute oral toxicity testing are used for forensic confirmation of the cause of death in avian mortality incidents and when characterizing FGARs' risks to free-ranging birds.

Bioactive compounds, antioxidant potential, and hepatoprotective activity of sea cucumber (Holothuria atra) against thioacetamide intoxication in rats.

PubMed

Esmat, Amr Y; Said, Mahmoud M; Soliman, Amel A; El-Masry, Khaled S H; Badiea, Elham Abdel

2013-01-01

The identification of the active phenolic compounds in the mixed extract of sea cucumber (Holothuria atra) body wall by high-performance liquid chromatography and an assessment of its hepatoprotective activity against thioacetamide-induced liver fibrosis in rats. Female Swiss albino rats were divided into four groups: normal controls; oral administration of a sea cucumber mixed extract (14.4 mg/kg of body weight) on days 2, 4, and 6 weekly for 8 consecutive weeks; intoxication with thioacetamide (200 mg/kg of body weight, intraperitoneally) on days 2 and 6 weekly for 8 wk; and oral administration of a sea cucumber extract and then intoxication with thioacetamide 2 h later for 8 wk. High-performance liquid chromatographic analysis of the sea cucumber mixed extract revealed the presence of some phenolic components, such as chlorogenic acid, pyrogallol, rutin, coumaric acid, catechin, and ascorbic acid. In vitro studies have shown that the extract has a high scavenging activity for the nitric oxide radical, a moderate iron-chelating activity, and a weak inhibitory effect of lipid peroxidation. The subchronic oral administration of sea cucumber extract to the rats did not show any toxic side effects but increased hepatic superoxide dismutase and glutathione peroxidase activities. The coadministration of sea cucumber extract and thioacetamide (protection modality) normalized serum direct bilirubin, alanine and aspartate aminotransferases, hepatic malondialdehyde, and hydroxyproline concentrations and antioxidant enzyme activities. In addition, the histologic examination of liver sections from the protection group that were stained with hematoxylin and eosin showed substantial attenuation of the degenerative cellular changes and regressions in liver fibrosis and necrosis induced by the thioacetamide intoxication. Sea cucumber mixed extract contains physiologically active phenolic compounds with antioxidant activity, which afforded a potential hepatoprotective activity against thioacetamide-induced liver injury in a rat model. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparative study between two animal models of extrapyramidal movement disorders: prevention and reversion by pecan nut shell aqueous extract.

PubMed

Trevizol, Fabiola; Benvegnú, Dalila M; Barcelos, Raquel C S; Pase, Camila S; Segat, Hecson J; Dias, Verônica Tironi; Dolci, Geisa S; Boufleur, Nardeli; Reckziegel, Patrícia; Bürger, Marilise E

2011-08-01

Acute reserpine and subchronic haloperidol are animal models of extrapyramidal disorders often used to study parkinsonism, akinesia and tardive dyskinesia. In humans, these usually irreversible and disabling extrapyramidal disorders are developed by typical antipsychotic treatment, whose pathophysiology has been related to oxidative damages development. So far, there is no treatment to prevent these problems of the psychiatric clinic, and therefore further studies are needed. Here we used the animal models of extrapyramidal disorders cited above, which were performed in two distinct experiments: orofacial dyskinesia (OD)/catalepsy induced by acute reserpine and subchronic haloperidol after (experiment 1) and before (experiment 2) oral treatment with pecan shell aqueous extract (AE), a natural and promissory antioxidant. When administered previously (exp.1), the AE prevented OD and catalepsy induced by both reserpine and haloperidol. When reserpine and haloperidol were administered before the extract (exp.2), the animals developed OD and catalepsy all the same. However, the orofacial parameter (but not catalepsy) in both animal models was reversed after 7 and 14 days of AE treatment. These results indicate that, acute reserpine and subchronic haloperidol administrations induced similar motor disorders, although through different mechanisms, and therefore are important animal models to study the physiopathology of extrapyramidal disorders. Comparatively, the pecan shell AE was able to both prevent and reverse OD but only to prevent catalepsy. These results reinforce the role of oxidative stress and validate the two animal models used here. Our findings also favor the idea of prevention of extrapyramidal disorders, rather than their reversal. Copyright © 2011 Elsevier B.V. All rights reserved.

Determination of LC50 and sub-chronic neurotoxicity of diesel exhaust nanoparticles.

PubMed

Durga, M; Devasena, T; Rajasekar, A

2015-09-01

Air pollution is a major problem faced globally and is seen associated with central nervous system (CNS) disorders like neuropathology and neuro-inflammation. Here, we investigated the CNS disorders as a result of sub-chronic exposure (90 days) to diesel exhaust nanoparticles (DENPs) and explored the minimal levels of DENPs needed to exhibit the early mediators of neuro-inflammation and neuropathology. Male and female wistar rats (6 rats per group) were exposed to DENPs (1/5th, 1/10th and 1/15th LC50) by inhalation for 4h per day, 5 days per week over 90 days and neurotoxicity end-points were analyzed. DENP exposure caused elevation in levels of pro-inflammatory cytokines, amyloid beta 42 (Aβ 42), reactive oxygen species (ROS), hydrogen peroxide (H2O2), nitrate (NO3(-)), nitrite (NO2(-)) and apurinic/apyrimidinic sites (AP) at varying degrees at different sections of rat brain. Hence, exposure to DENPs resulted in dose-dependent toxicity and was closely correlated to increased inflammation, DNA damage and oxidative stress. Copyright © 2015 Elsevier B.V. All rights reserved.

Acute oral toxicity test of chemical compounds in silkworms.

PubMed

Usui, Kimihito; Nishida, Satoshi; Sugita, Takuya; Ueki, Takuro; Matsumoto, Yasuhiko; Okumura, Hidenobu; Sekimizu, Kazuhisa

2016-02-01

This study performed an acute oral toxicity test of 59 compounds in silkworms. These compounds are listed in OECD guidelines as standard substances for a cytotoxicity test, and median lethal dose (LD(50)) werecalculated for each compound. Acute oral LD(50) values in mammals are listed in OECD guidelines and acute oral LD(50) values in silkworms were determined in this study. R(2) for the correlation between LD(50) values in mammals and LD(50) values in silkworms was 0.66. In addition, the acute oral toxicity test in silkworms was performed by two different facilities, and test results from the facilities were highly reproducible. These findings suggest that an acute oral toxicity test in silkworms is a useful way to evaluate the toxicity of compounds in mammals.

Toxicological, medical and industrial hygiene aspects of glutaraldehyde with particular reference to its biocidal use in cold sterilization procedures.

PubMed

Ballantyne, B; Jordan, S L

2001-01-01

Aqueous solutions of > or =5% glutaraldehyde (GA) are of moderate acute peroral toxicity and those of < or =2% are of slight toxicity. By single sustained skin contact, aqueous GA solutions of > or =45% are of moderate acute percutaneous toxicity, those of 25% are of slight toxicity and those of or =5%. Primary skin irritation depends on the duration and contact site, occlusion and solvent. By sustained contact, the threshold for skin irritation is 1%, above which erythema and edema are dose related. With 45% and higher, skin corrosion may occur. There is a low incidence of skin sensitizing reactions, with an eliciting threshold of 0.5% aqueous GA. However, GA is neither phototoxic nor photosensitizing. Subchronic repeated exposure studies by the peroral route show only renal physiological compensatory effects, secondary to reduced water consumption. Repeated skin contact shows only minor skin irritant effects without systemic toxicity. By subchronic vapor exposure, effects are limited to the nasal mucosa at 1.0 ppm, with a no-effect concentration generally at 0.1 ppm. There is no evidence for systemic target organ or tissue toxicity by subchronic repeated exposure by any route. A chronic drinking water study showed an apparent increase, in females only, of large granular cell lymphocytic leukemia but this was not dosage related. This is most likely the result of a modifying effect on the factor(s) responsible for the expression of this commonly occurring rat neoplasm. A chronic (2-year) inhalation toxicity/oncogenicity study showed inflammatory changes in the anterior nasal cavity but no neoplasms or systemic toxicity. In vitro genotoxicity studies--bacterial mutagenicity, forward gene mutation (HGPRT and TK loci), sister chromatid exchange, chromosome aberration, UDS and DNA repair tests--have given variable results, ranging from no effect through to weak positive. In vivo genotoxicity studies--micronucleus, chromosome aberration, dominant lethal and Drosophila tests--generally have shown no activity but one mouse intraperitoneal study showed bone marrow cell chromosome aberrations. Developmental toxicity studies show GA not to be teratogenic, and a two-generation study showed no adverse reproductive effects. Percutaneous pharmacokinetic studies showed low skin penetration, with lowest values measured in vitro in rats and human skin. Overexposure of humans produces typical sensory irritant effects on the eye, skin and respiratory tract. Some reports have described an asthmatic-like reaction by overexposure to GA vapor. In most cases this resembles reactive airways dysfunction syndrome, and the role of immune mechanisms is uncertain. Local mucosal effects may occur if medical instruments or endoscopes are not adequately decontaminated. Protection of individuals from the potential adverse effects of GA exposure requires that there be adequate protection of the skin, eyes and respiratory tract. The airborne concentration of GA vapor should be kept below the recommended safe exposure level (e.g. the threshold limit value) by the use of engineering controls. Those who work with GA should, through a training program, be aware of the properties of GA, its potential adverse effects, how to handle the material safely and how to deal with accidental situations involving GA. If effects develop in exposed workers, the reasons should be determined immediately and corrective methods initiated. (c) 2001 John Wiley & Sons, Ltd.

In vivo assessment of the hepatotoxicity of a new Nostoc isolate from the Nile River: Nostoc sp. strain NRI.

PubMed

Abu-Serie, Marwa M; Nasser, Nermine; Abd El-Wahab, Abeer; Shehawy, Rehab; Pienaar, Harrison; Baddour, Nahed; Amer, Ranya

2018-03-01

Nostoc sp. is one of the most widely distributed cyanobacterial genera that produce potentially protein phosphatase (PP) inhibitor; microcystins (MCs). MCs have posed a worldwide concern due to predominant hepatotoxicity to human health. We have previously isolated a Nostoc strain (NR1) from the Nile River (the main water supply in Egypt) and this strain exerted production of rare and highly toxic MC; demethylated microcystin-LR. There is no data concerning risk factors of liver diseases for human and animal exposure to NR1-contaminated drinking water yet. It is thus important to evaluate acute (LD 50 dose), subacute (0.01% and 10% of LD 50 dose) and subchronic (0.01% and 10% of LD 50 dose) hepatotoxicity's NR1 extract using experimental mice. Mice groups, who orally received 0.01% LD 50 , represented a permissible concentration of the World Health Organization (WHO) for MC in drinking water. Several parameters were detected, including hepatotoxicity (i.e. PP activity, liver function, oxidative stress markers and DNA fragmentation), pro-inflammatory cytokine (TNF-α) and liver histopathology. Our results demonstrated LD 50 of NR1 extract was at 15,350 mg/kg body weight and caused hepatotoxicity that attributed to PP inhibition and a significant increase of hepatic damage biomarkers with lipid accumulation. Moreover, NR1 extract induced hepatic oxidative damage that may have led to DNA fragmentation and production of TNF-α. As demonstrated from the histopathological study, NR1 extract caused a severe collapse of cytoskeleton with subsequent focal degeneration of hepatocytes, necroinflammation and steatosis. The grade of hepatotoxicity in subacute (10% of LD 50 ) group was higher than that in the subchronic (10% of LD 50 and 0.01% of LD 50 , WHOch, respectively) groups. No significant hepatotoxicity was detectable for subacute (0.01% of LD 50 , WHOac) group. NR1 is therefore considered as one of the harmful and life-threatening cyanobacteria for Egyptian people being exposed to dose above WHO guideline. Thus, biological indicators and thresholds for water treatment are extremely needed. Copyright © 2018. Published by Elsevier Ltd.

Subchronic exposure to low-doses of the nerve agent VX: Physiological, behavioral, histopathological and neurochemical studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bloch-Shilderman, Eugenia; Rabinovitz, Ishai; Egoz, Inbal

The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 {mu}g/kg/day, 0.05 LD{sub 50}) for three months via implanted mini osmotic pumps. The rapidly attained continuousmore » and marked whole-blood cholinesterase inhibition ({approx} 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction ({approx} 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.« less

Safety evaluation and lipid-lowering effects of food-grade biopolymer complexes (ε-polylysine-pectin) in mice fed a high-fat diet.

PubMed

Song, Mingyue; Lopez-Pena, Cynthia Lyliam; McClements, David Julian; Decker, Eric Andrew; Xiao, Hang

2017-05-24

ε-Polylysine (ε-PL) is a potent cationic antimicrobial, but its application as a food additive is currently limited because it tends to precipitate with anionic species in food matrices. Previous research has shown that the formation of an electrostatic complex between cationic ε-PL and anionic pectin (P) improved the physical stability of ε-PL while maintaining its antimicrobial activity. However, the impact of complexation on the effects of ε-PL on health is currently unknown. A subchronic toxicity study was therefore carried out to determine the safety of ingested ε-PL-P complexes using high-fat diet-fed male and female mice. After a 13-week dietary treatment with P, ε-PL, or ε-PL-P complexes, no significant toxicological effects were observed on the survival, mean body weight, food consumption, and organ weights of the animals, suggesting that the complexes were safe for oral consumption. Interestingly, the ε-PL-P complexes were found to have several beneficial health effects: suppression of high-fat diet-induced elevation of serum aspartate aminotransferase and alanine aminotransferase activities, reduction in serum total triglyceride and cholesterol levels, and an increase in fecal excretion of triglycerides. These effects were much stronger in female mice than in male mice. Moreover, the lipid-lowering effects were observed only for the ε-PL-P complexes but not for ε-PL or P alone at the same doses. Overall, our results demonstrate the oral safety of ε-PL-P complexes and their gender-specific lipid-lowering effects in high-fat diet-fed mice, which provide an important basis for the utilization of ε-PL-P complexes in food systems as functional ingredients.

Aluminum Exposure at Human Dietary Levels for 60 Days Reaches a Threshold Sufficient to Promote Memory Impairment in Rats.

PubMed

Martinez, Caroline S; Alterman, Caroline D C; Peçanha, Franck M; Vassallo, Dalton V; Mello-Carpes, Pâmela B; Miguel, Marta; Wiggers, Giulia A

2017-01-01

Aluminum (Al) is a significant environmental contaminant. While a good deal of research has been conducted on the acute neurotoxic effects of Al, little is known about the effects of longer-term exposure at human dietary Al levels. Therefore, the purpose of this study was to investigate the effects of 60-day Al exposure at low doses for comparison with a model of exposure known to produce neurotoxicity in rats. Three-month-old male Wistar rats were divided into two major groups: (1) low aluminum levels, and (2) a high aluminum level. Group 1 rats were treated orally by drinking water for 60 days as follows: (a) control-received ultrapure drinking water; (b) aluminum at 1.5 mg/kg b.w., and (c) aluminum at 8.3 mg/kg b.w. Group 2 rats were treated through oral gavages for 42 days as follows: (a) control-received ultrapure water; (b) aluminum at 100 mg/kg b.w. We analyzed cognitive parameters, biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in hippocampus and prefrontal cortex. Al treatment even at low doses promoted recognition memory impairment seen in object recognition memory testing. Moreover, Al increased hippocampal reactive oxygen species and lipid peroxidation, reduced antioxidant capacity, and decreased AChE activity. Our data demonstrate that 60-day subchronic exposure to low doses of Al from feed and added to the water, which reflect human dietary Al intake, reaches a threshold sufficient to promote memory impairment and neurotoxicity. The elevation of oxidative stress and cholinergic dysfunction highlight pathways of toxic actions for this metal.

The Subchronic Inhalation Toxicity of DF2 (Diesel Fuel) Used in Vehicle Engine Exhaust Smoke Systems (VEESS).

DTIC Science & Technology

1986-03-01

4-I +4 .- -+ + _C tL+ + + +i + T + +- + - -) 4. c_ --- - * - 4A _ __ _ -- 0 0 ICx" C ) 4j cliou 0 N4cr(\\lc’ + + ++ ++ + + +1 -4++111+ = 0 m x...Charles L. Crouse SP6 David C . Burnett Garnet E. Affleck Dale H. Heitkamp Edmund G. Cummings, Ph.D. Carlyle Lilly Richard L. Farrand, Ph.D. Joseph J...Feeney, Ph.D. Robert W. Dorsey Michael Rausa SP6 Mohammed S. Ghumman Ernest H. Kandel Robert D. Armstrong Jeffrey D. Bergmann William C . Stark. John

Symposium Entitled: Particle Lung Interactions: ’Overload’ Related Phenomena. A Journal of Aerosol Medicine - Deposition, Clearance, and Effects in the Lung. Volume 3, Supplement 1

DTIC Science & Technology

1991-04-01

week and two years (subchronic GMRL studies versus chronic ITRI and Fh-ITA studies ); exposure concentrations were changed by a factor of 40 (Fh-ITA...a forum for the publication of studies involving inhalation of particles and gases in the respiratory tract, covering the use of aerosols as tools to... study basic physiologic phenomena, their use as selective delivery systems for medication, and the toxic effects of inhaled agents. JOURNAL OF AEROSOL

Impact of aflatoxin B1 on the pharmacokinetic disposition of enrofloxacin in broiler chickens.

PubMed

Kalpana, Starling; Srinivasa Rao, G; Malik, Jitendra K

2015-09-01

The potential impact of subchronic exposure of aflatoxin B1 was investigated on the pharmacokinetic disposition of enrofloxacin in broiler chickens. Broiler chickens given either normal or aflatoxin B1 (750μg/kg diet) supplemented diet for 6 weeks received a single oral dose of enrofloxacin (10mg/kg body wt). Blood samples were drawn from the brachial vein at predetermined time intervals after drug administration. Enrofloxacin plasma concentrations analyzed by RP-HPLC were significantly lower in aflatoxin B1-exposed broiler chickens at 0.167, 0.5 and 1.0h after drug administration. In aflatoxin B1-exposed broiler chickens, the absorption rate constant (ka) of enrofloxacin (0.20±0.05h(-1)) was significantly decreased as compared to the unexposed birds (0.98±0.31h(-1)). The values of [Formula: see text] , tmax and AUC0-∞ of enrofloxacin were nonsignificantly increased by 17%, 26% and 17% in aflatoxin-exposed broiler chickens, respectively. Subchronic aflatoxin B1 exposure markedly decreased the initial absorption of enrofloxacin without significantly influencing other pharmacokinetic parameters in broiler chickens. Copyright © 2015 Elsevier B.V. All rights reserved.

Subchronic (26- and 52-week) toxicity and irritation studies of a novel microbicidal gel formulation containing sodium lauryl sulfate in animal models.

PubMed

Piret, Jocelyne; Laforest, Geneviève; Bussières, Martin; Bergeron, Michel G

2008-03-01

The safety of an ethylene oxide/propylene oxide gel formulation containing sodium lauryl sulfate (2%, w/w), that could be a potent candidate as a topical microbicide, has been evaluated. More specifically, the subchronic (26- and 52-week) toxicity of the formulation when applied intravaginally as well as its irritating potential for the rectal, penile, eye, skin and buccal mucosa have been examined in animal models. The results showed that the vaginal administration of the gel formulation containing sodium lauryl sulfate once and twice daily (with doses 12 +/- 2 h apart) for 26 weeks to rats and for 52 weeks to rabbits induced slight to moderate histopathological alterations. When the formulation was applied intrarectally to male and female rabbits once and twice daily (with doses 12 +/- 2 h apart) for 14 days, no macroscopic or microscopic changes were reported. For both vaginal and rectal dosing, no effect was seen on the haematology, coagulation and serum chemistry parameters as well as on the body weight of animals and the relative organ weights. Other sporadic macroscopic and histopathological findings were incidental in origin and of no toxicological significance. The gel formulation containing sodium lauryl sulfate was considered as mildly irritating for the penile mucosa of rabbits, non-irritating for the eye of rabbits, mildly irritating for the skin in a rabbit model and non-irritating for the hamster cheek pouch. It is suggested that the gel formulation containing sodium lauryl sulfate is safe for most tissues that could be exposed to the product under normal use.

Development of an acute oral toxicity dataset to facilitate assessment of existing QSARs and development of new models (WC10)

EPA Science Inventory

Acute oral toxicity data are used to meet both regulatory and non-regulatory needs. Recently, there have been efforts to explore alternative approaches for predicting acute oral toxicity such as QSARs. Evaluating the performance and scope of existing models and investigating the ...

Amended final report of the safety assessment of dibutyl adipate as used in cosmetics.

PubMed

Andersen, Alan

2006-01-01

Dibutyl Adipate, the diester of butyl alcohol and adipic acid, functions as a plasticizer, skin-conditioning agent, and solvent in cosmetic formulations. It is reportedly used at a concentration of 5% in nail polish and 8% in suntan gels, creams, and liquids. Dibutyl Adipate is soluble in organic solvents, but practically insoluble in water. Dibutyl Adipate does not absorb radiation in the ultraviolet (UV) region of the spectrum. Dibutyl Adipate is not toxic in acute oral or dermal animal toxicity tests. In a subchronic dermal toxicity study, 1.0 ml/kg day-1 caused a significant reduction in body weight gain in rabbits, but 0.5 ml/kg/day1 was without effect. In a study with dogs, no adverse effects were observed when an emulsion containing 6.25% Dibutyl Adipate was applied to the entire body twice a week for 3 months. Dibutyl Adipate was tested for dermal irritation using rabbits and mice and a none to minimal irritation was observed. Dibutyl Adipate at a concentration of 25% was not a sensitizer in a guinea pig maximization study. Undiluted Dibutyl Adipate was minimally irritating to the eyes of rabbits and 0.1% was nonirritating. A significant increase in fetal gross abnormalities was observed in rats given intraperitoneal injections of Dibutyl Adipate at 1.75 ml/kg on 3 separate days during gestation, but no effect was seen in animals given 1.05 ml/kg. Dibutyl Adipate was not genotoxic in either bacterial or mammalian test systems. Clinical patch tests confirmed the absence of skin irritation found in animal tests. Clinical phototoxicity tests were negative. Dibutyl Adipate at 0.1% was not an ocular irritant in two male volunteers. In a clinical test of comedogenicity, Dibutyl Adipate produced no effect. The Cosmetic Ingredient Review (CIR) Expert Panel recognized that use of Dibutyl Adipate in suntan cosmetic products will result in repeated, frequent exposure in a leave-on product. The available data demonstrate no skin sensitization or cumulative skin irritation, no comedogenicity, and no genotoxicity. Combined with the data demonstrating little acute toxicity, no skin or ocular irritation, and no reproductive or developmental toxicity, these data form an adequate basis for reaching a conclusion that Dibutyl Adipate is safe as a cosmetic ingredient in the practices of use and concentrations as reflected in this safety assessment.

Some considerations concerning the theory of combined toxicity: a case study of subchronic experimental intoxication with cadmium and lead.

PubMed

Varaksin, Anatoly N; Katsnelson, Boris A; Panov, Vladimir G; Privalova, Larisa I; Kireyeva, Ekaterina P; Valamina, Irene E; Beresneva, Olga Yu

2014-02-01

Rats were exposed intraperitoneally (3 times a week up to 20 injections) to either Cadmium and Lead salts in doses equivalent to their 0.05 LD50 separately or combined in the same or halved doses. Toxic effects were assessed by more than 40 functional, biochemical and morphometric indices. We analysed the results obtained aiming at determination of the type of combined toxicity using either common sense considerations based on descriptive statistics or two mathematical models based (a) on ANOVA and (b) on Mathematical Theory of Experimental Design, which correspond, respectively, to the widely recognised paradigms of effect additivity and dose additivity. Nevertheless, these approaches have led us unanimously to the following conclusions: (1) The above paradigms are virtually interchangeable and should be regarded as different methods of modelling the combined toxicity rather than as reflecting fundamentally differing processes. (2) Within both models there exist not merely three traditionally used types of combined toxicity (additivity, subadditivity and superadditivity) but at least 10 variants of it depending on exactly which effect is considered and on its level, as well as on the dose levels and their ratio. Copyright © 2013 Elsevier Ltd. All rights reserved.

Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity.

PubMed

Lin, Xia; Zhang, Bo; Zhang, Keru; Zhang, Yu; Wang, Juan; Qi, Na; Yang, Shenshen; He, Haibing; Tang, Xing

2012-12-01

The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM). Pharmacokinetics, biodistribution, antitumor efficacy and drug safety assessment (including acute toxicity, subchronic toxicity, hemolysis testing, intravenous stimulation and injection anaphylaxis) of NLM were carried out in comparison with the commercial product disodium norcantharidate injection (NI). The pharmacokinetics of NLM in rats was similar to that of NI, and a non-linear correlation was observed between AUC and dose. A comparable antitumor efficacy of NLM and NI was observed in mice inoculated with A549, BEL7402 and BCAP-37 cell lines. It was worth noting that the NLM produced a lower drug concentration in heart compared with NI, and significantly reduced the cardiac and renal toxicity. The LD(50) of NLM was twice higher than that of NI. In NLM, over 80% of NCTD was loaded in the lipid phase or bound with phospholipids. Thus, NCTD was sequestered by direct contacting with body fluids and largely avoided distribution into tissues, consequently leading to significantly reduced cardiac and renal toxicity. These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.

Exposure to silver nanoparticles produces oxidative stress and affects macromolecular and metabolic biomarkers in the goodeid fish Chapalichthys pardalis.

PubMed

Valerio-García, Roberto Carlos; Carbajal-Hernández, Ana Laura; Martínez-Ruíz, Erika Berenice; Jarquín-Díaz, Víctor Hugo; Haro-Pérez, Catalina; Martínez-Jerónimo, Fernando

2017-04-01

Silver nanoparticles (AgNPs) are the most commercialized nanomaterial worldwide, mainly due to their microbicidal activity. Although, AgNPs have been shown to be toxic to aquatic species, their effect on endemic fish, like Goodeidae, has not been demonstrated. Endemic species are under strong pressures by anthropogenic contamination and destruction of their habitat; therefore, we studied adult Chapalichthys pardalis, an endemic fish of Mexico. We evaluated the toxic effect of AgNPs through oxidative stress, macromolecular and metabolic biomarkers. We determined the LC 50 (96h) and performed subchronic tests (21days) using sublethal AgNPs concentrations (equivalent to CL 1 and CL 10 ). At the end of the bioassay, we quantified 10 stress biomarkers in the liver, gills, and muscle, including the antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], and glutathione [GPx]), thiobarbituric acid reactive species (TBARS), protein oxidation (CO), macromolecules (proteins, lipids, and carbohydrates), and metabolites (glucose and lactate). In addition, we determined the integrated biomarkers response (IBR). LC 50 was of 10.32mgL -1 . Results of subchronic exposure (21days) revealed that AgNPs produce oxidative stress in C. pardalis adults, as evidenced by a diminution in antioxidant enzymes activity and an increase in TBARS and oxidized proteins. AgNPs also diminished levels of macromolecules and generated a high-energy consumption, reflected in the reduction of glucose levels, although lactate levels were not altered. The IBR analysis evidenced that the largest effect was produced in organisms exposed to LC 10 , being the liver and gills the organs with the greatest damage. Results demonstrated that exposure to AgNPs induces acute and chronic toxic effects on C. pardalis and forewarns about the impact that these nanomaterials can exert on these ecologically relevant aquatic organisms. Copyright © 2017 Elsevier B.V. All rights reserved.

Does a concomitant exposure to lead influence unfavorably the naphthalene subchronic toxicity and toxicokinetics?

PubMed

Katsnelson, Boris A; Minigaliyeva, Ilzira A; Degtyareva, Tamara D; Privalova, Larisa I; Beresneva, Tatyana A

2014-01-01

Rats were given 20 times during 40 d either naphthalene per gavage or the same and lead acetate intraperitoneally in single doses corresponding to 5% of the respective 50% lethal doses. The concomitant exposure to lead not only added some typical indicators of lead toxicity to the moderate naphthalene intoxication picture but also exaggerated some less specific indices for intoxication. However, a number of such indices testified to attenuation of naphthalene's adverse effects under the impact of lead. Lead also lowered urinary excretion of both total and conjugated naphthalene, while the free- to total naphthalene ratio in urine sharply increased. These results corroborate implicitly the initial hypothesis that lead, being an inhibitor of cytochrome P450, hinders phase I of the naphthalene biotransformation and, thus, the formation of derivates which can be more toxic but are capable of entering into reactions of conjugation with resulting detoxication and elimination of naphthalene from the body. © 2013 SETAC.

Effects of heat-induced food contaminant furan on reproductive system of male rats from weaning through postpuberty.

PubMed

Karacaoğlu, Elif; Selmanoğlu, Güldeniz

2010-05-01

Furan (C(4)H(4)O) is a volatile, colorless liquid and is used in some segments of the chemical manufacturing industry. It is found in variety of foods such as coffee, jarred and canned foods that undergo heat treatment. This study was designed to investigate the effect of furan exposure on reproductive system of male rats. Three to four weeks old rats were exposed to furan at 2, 4 and 8 mg/kg/day doses by orally for 90 days. Hematology, weights, histology and morphometry of reproductive organs, serum LH and testosterone levels, sperm count and morphology and apoptosis in testis were evaluated. Slight changes were observed in hematological parameters of furan-treated rats. The weights of seminal vesicle reduced significantly whereas the weights of prostate increased significantly in the highest furan dose group. LH and testosterone levels decreased in furan-treated rats. Histological examinations have revealed that furan caused impairments in testis, epididymis and prostate gland. Furan showed no effects on sperm counts and morphology. On the other hand apoptotic cells in testis increased significantly. According to morphometrical examination, the epithelial heights and lumen diameters of the reproductive organs have changed in treatment groups. These results indicate that subchronic furan treatment induces toxicity of the male reproductive system. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Potential fluoride toxicity from oral medicaments: A review.

PubMed

Ullah, Rizwan; Zafar, Muhammad Sohail; Shahani, Nazish

2017-08-01

The beneficial effects of fluoride on human oral health are well studied. There are numerous studies demonstrating that a small amount of fluoride delivered to the oral cavity decreases the prevalence of dental decay and results in stronger teeth and bones. However, ingestion of fluoride more than the recommended limit leads to toxicity and adverse effects. In order to update our understanding of fluoride and its potential toxicity, we have described the mechanisms of fluoride metabolism, toxic effects, and management of fluoride toxicity. The main aim of this review is to highlight the potential adverse effects of fluoride overdose and poorly understood toxicity. In addition, the related clinical significance of fluoride overdose and toxicity has been discussed.

Toxicological responses of Laeonereis acuta (Polychaeta, Nereididae) after acute, subchronic and chronic exposure to cadmium.

PubMed

Dolagaratz Carricavur, Arantxa; Chiodi Boudet, Leila; Romero, María Belén; Polizzi, Paula; Marcovecchio, Jorge Eduardo; Gerpe, Marcela

2018-03-01

The objective of this study was to analyze the toxicological responses of the estuarine polychaete Laeonereis acuta after acute (96h), subchronic (7 days) and chronic (14 days) exposure to cadmium (Cd). Concentrations of metallothioneins (MT), lipid peroxidation (LPO), total Cd and metal-rich granules (MRG) were evaluated. Seasonal variations of MT and LPO levels in the wild were also measured. Polychaetes were obtained in the Quequén estuary located southeast of Buenos Aires Province, Argentina. For the acute toxicity assay, individuals were exposed to 10; 30, 65; 310; 600; 1300; 2000; 4300; 8100; 16300µgCdL -1 , which included levels of environmental relevance and median lethal concentrations (LC 50 ) for related species of polychaete. Based on 96h LC 50 values, polychaetes were exposed to sublethal doses of Cd. The concentrations for both subchronic and chronic assays were: 10; 30; 65; 310; 600; 1300; 2000; 4300µgCdL -1 . The 96h LC 50 value was 8234.9µgL -1 , which was within the values reported for other species of polychaete, indicating a high tolerance to Cd. MT induction was not observed for any time exposure. In additoin, LPO levels showed no differences with respect to control levels, which indicated an absence of oxidative damage caused by Cd. However, the total Cd and MRG-Cd concentrations in L. acuta in all tested treatments showed significant differences with respect to control levels. L. acuta were able to accumulate Cd in their tissues in the form of granules which are the main mechanism of Cd detoxification. Copyright © 2017 Elsevier Inc. All rights reserved.

Community exposures to airborne agricultural pesticides in California: ranking of inhalation risks.

PubMed Central

Lee, Sharon; McLaughlin, Robert; Harnly, Martha; Gunier, Robert; Kreutzer, Richard

2002-01-01

We assessed inhalation risks to California communities from airborne agricultural pesticides by probability distribution analysis using ambient air data provided by the California Air Resources Board and the California Department of Pesticide Regulation. The pesticides evaluated include chloropicrin, chlorothalonil, chlorpyrifos, S,S,S-tributyl phosphorotrithioate, diazinon, 1,3-dichloropropene, dichlorvos (naled breakdown product), endosulfan, eptam, methidathion, methyl bromide, methyl isothiocyanate (MITC; metam sodium breakdown product), molinate, propargite, and simazine. Risks were estimated for the median and 75th and 95th percentiles of probability (50, 25, and 5% of the exposed populations). Exposure estimates greater than or equal to noncancer reference values occurred for 50% of the exposed populations (adults and children) for MITC subchronic and chronic exposures, methyl bromide subchronic exposures (year 2000 monitoring), and 1,3-dichloropropene subchronic exposures (1990 monitoring). Short-term chlorpyrifos exposure estimates exceeded the acute reference value for 50% of children (not adults) in the exposed population. Noncancer risks were uniformly higher for children due to a proportionately greater inhalation rate-to-body weight ratio compared to adults and other factors. Target health effects of potential concern for these exposures include neurologic effects (methyl bromide and chlorpyrifos) and respiratory effects (1,3-dichloropropene and MITC). The lowest noncancer risks occurred for simazine and chlorothalonil. Lifetime cancer risks of one-in-a-million or greater were estimated for 50% of the exposed population for 1,3-dichloropropene (1990 monitoring) and 25% of the exposed populations for methidathion and molinate. Pesticide vapor pressure was found to be a better predictor of inhalation risk compared to other methods of ranking pesticides as potential toxic air contaminants. PMID:12460795

Safety evaluation of genetically modified DAS-40278-9 maize in a subchronic rodent feeding study.

PubMed

Zou, Shiying; Lang, Tianqi; Liu, Xu; Huang, Kunlun; He, Xiaoyun

2018-07-01

Genetically modified (GM) maize, DAS-40278-9, expresses the aryloxyalkanoate dioxygenase-1 (AAD-1) protein, which confers tolerance to 2,4-dichlorophenoxyacetic acid (2,4-D) and aryloxyphenoxypropionate (AOPP) herbicides. The aad-1 gene, which expresses the AAD-1 protein, was derived from Gram-negative soil bacterium, Sphingobium herbicidovorans. A 90-day sub-chronic toxicity study was conducted on rats as a component of the safety evaluation of DAS-40278-9 maize. Rats were given formulated diets containing maize grain from DAS-40278-9 or a non-GM near isogenic control comparator at an incorporation rate of 12.5%, 25%, or 50% (w/w), respectively for 90 days. In addition, another group of rats was fed a basic rodent diet. Animals were evaluated by cage-side and hand-held detailed clinical observations, ophthalmic examinations, body weights/body weight gains, feed consumption, hematology, serum chemistry, selected organ weights, and gross and histopathological examinations. Under the condition of this study, DAS-40278-9 maize did not cause any treatment-related effects in rats compared with rats fed diets containing non-GM maize. Copyright © 2018 Elsevier Inc. All rights reserved.

Blueberry (Vaccinium ashei Reade) extract ameliorates ovarian damage induced by subchronic cadmium exposure in mice: Potential δ-ALA-D involvement.

PubMed

Izaguirry, Aryele Pinto; Soares, Melina Bucco; Vargas, Laura Musacchio; Spiazzi, Cristiano Chiapinotto; Dos Santos Brum, Daniela; Noremberg, Simone; Mendez, Andreas Sebastian Loureiro; Santos, Francielli Weber

2017-01-01

Females are born with a finite number of oocyte-containing follicles and ovary damage results in reduced fertility. Cadmium accumulates in the reproductive system, damaging it, and the cigarette smoke is a potential exposure route. Natural therapies are relevant to health benefits and disease prevention. This study verified the effect of cadmium exposure on the ovaries of mice and the blueberry extract as a potential therapy. Blueberry therapy was effective in restoring reactive species levels and δ-aminolevulinate dehydratase activity, and partially improved the viability of cadmium-disrupted follicles. This therapy was not able to restore the 17 β-hydroxysteroid dehydrogenase activity. Extract HPLC evaluation indicated the presence of quercetin, quercitrin, isoquercetin, and ascorbic acid. Ascorbic acid was the major substance and its concentration was 620.24 µg/mL. Thus, cadmium accumulates in the ovaries of mice after subchronic exposure, inducing cellular damage, and the blueberry extract possesses antioxidant properties that could protect, at least in part, the ovarian tissue from cadmium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 188-196, 2017. © 2015 Wiley Periodicals, Inc.

Final report of the cosmetic ingredient review expert panel on the safety assessment of Polyisobutene and Hydrogenated Polyisobutene as used in cosmetics.

PubMed

2008-01-01

Polyisobutene and Hydrogenated Polyisobutene are homopolymers of isobutene. These ingredients are produced in a wide range of molecular weights. Polybutene is a chemically related cosmetic ingredient previously determined to be safe as used in cosmetic products. Polyisobutene is used in cosmetic products as a binder, film former, and nonaqueous viscosity-increasing agent. Hydrogenated Polyisobutene functions as a skin-conditioning agent-emollient and nonaqueous viscosity-increasing agent with a wide range of uses in cosmetic formulations. The estimated octanol water partition coefficient for Hydrogenated Polyisobutene and Polybutene is log K(ow) of 13.27 and the estimated water solubility was 5.6 x 10(-3) ng/L for Hydrogenated Polyisobutene and Polybutene. Acute oral toxicity testing demonstrated no effects other than lethargy in one rat study. The oral LD(50) was > 5.0 g/kg in rats. No short-term or subchronic animal toxicity data were available. A 2-year chronic oral toxicity study of Polybutene revealed no gross or microscopic pathological changes, and no changes in body weights or food consumption, hematological results, urology, or tumor formation that could be correlated with Polybutene ingestion, except that in the 20,000 ppm group, three out of six males that died between weeks 17 and 24 exhibited hematuria. In a 2-year chronic oral toxicity study of Polybutene in Beagle dogs, no abnormalities in body weight, food consumption, survival, behavioral patterns, hematology, blood chemistry, urinalysis, liver function, gross and histopathologic examinations, or organ weights and ratios were reported. In a three-generation reproductive study in Charles River albino rats that ingested Polybutene, none of the animals in successive generations differed from controls with regard to weight gain, litter size, the number of stillborn, and the number of viable pups during lactation. The survival, body weights, and reactions of test animals were comparable to those of controls. Neither Polyisobutene nor Hydrogenated Polyisobutene were ocular irritants, nor were they dermal irritants or sensitizers. Polyisobutene was not comedogenic in a rabbit ear study. Polyisobutene did not induce transformation in the Syrian hamster embryo (SHE) cell transformation assay, but did enhance 3-methylcholanthrene-induced transformation of C3H/10T1/2 cells. In a carcinogenicity study in mice, Polyisobutene was not carcinogenic, nor did it promote the carcinogenicity of 7,12-dimethylbenz(alpha)anthracene. Clinical patch tests uncovered no evidence of dermal irritation and repeat-insult patch tests with a product containing 4% Hydrogenated Polyisobutene or 1.44% Hydrogenated Polyisobutene found no reactions greater than slight erythema. These products also were not phototoxic or photoallergenic. The product containing 4% Hydrogenated Polyisobutene was not an ocular irritant in a clinical test. The Cosmetic Ingredient Review (CIR) Expert Panel recognized that there are data gaps regarding use and concentration of these ingredients. However, the overall information available on the types of products in which these ingredients are used and at what concentrations indicate a pattern of use, which was considered by the Expert Panel in assessing safety. Although there is an absence of dermal absorption data for Polyisobutene and Hydrogenated Polyisobutene, the available octanol water partition coefficient data and the low solubility in water suggest very slow absorption, so additional data are not needed. Gastrointestinal absorption is also not a major concern due to the low solubility of these chemicals. Although one in vitro study did report that Polyisobutene did promote cellular transformation, a mouse study did not find evidence of tumor promotion. Because lifetime exposure studies using rats and dogs exposed to Polybutene failed to demonstrate any carcinogenic or tumor promotion effect, and a three-generation reproductive/developmental toxicity study produced no adverse effects, the CIR Expert Panel does not believe these large, mostly insoluble polymers present any risks in the practices of use and concentration as described in this safety assessment.

Physiological stress and pathology in European whitefish (Coregonus lavaretus) induced by subchronic exposure to environmentally relevant densities of Planktothrix rubescens.

PubMed

Ernst, Bernhard; Hoeger, Stefan J; O'brien, Evelyn; Dietrich, Daniel R

2007-04-20

Planktothrix rubescens belongs to the most ubiquitous cyanobacterial species in mesotrophic and oligotrophic lakes in the pre-alpine regions. In most of these lakes, coregonids are among the dominant species of the ichthyofauna with great importance for the professional fishery. A possible link between the occurrence of toxic Planktothrix blooms and the recurrent slumps in coregonid yields has been suggested. Indeed, acute toxic effects of microcystins and other cyanobacterial toxins have been shown for various fish species. However, chronic exposure scenarios appear to be more common and thus more environmentally realistic than acute intoxications. The aim of this study was therefore to investigate the physiological stress response and organ pathology in coregonids sub-chronically exposed to ambient water containing low, medium and high P. rubescens densities, known to be typical of pre-alpine lakes. Coregonid hatchlings were exposed in four tanks containing 0 (sham-control) and approximately 1500 (low), 15,000 (medium) and 55,000 (high) P. rubescens cells/ml for up to 28 days. Temperature, oxygen concentration, pH-value, P. rubescens cell density and microcystin concentration were recorded and the fish were observed for behavioural changes and examined for parasite infestations. Gill ventilation rates, general condition factors and mortalities were determined and liver, kidney, gut and gill were assessed histopathologically and immunhistologically. Depending on the cell density, exposed fish showed behavioural changes, including increased ventilation rates possibly representing a physiological stress response. Susceptibility to ectoparasitic infestation and increased mortality in exposed fish suggested P. rubescens associated effects on fish fitness. Histopathological alterations in liver, gastrointestinal tract and kidney, which were also immunopositive for microcystin suggested causality of tissue damage and the presence of microcystins. In contrast, observed gill pathology appeared to result primarily from mechanical abrasion and irritation due to ectoparasitic infestation. The current exposure experiment confirmed the hypothesis that subchronic and chronic exposure to low cyanobacterial cell densities and hence microcystins can exacerbate physiological stress and sustained pathological alterations in exposed coregonids. The study therefore supports the theory that P. rubescens blooms may be causal to the observed weight reduction and hence fitness of coregonids in pre-alpine lakes such as Lake Ammersee (Germany).

Final report on the safety assessment of benzaldehyde.

PubMed

Andersen, Alan

2006-01-01

Benzaldehyde is an aromatic aldehyde used in cosmetics as a denaturant, a flavoring agent, and as a fragrance. Currently used in only seven cosmetic products, its highest reported concentration of use was 0.5% in perfumes. Benzaldehyde is a generally regarded as safe (GRAS) food additive in the United States and is accepted as a flavoring substance in the European Union. Because Benzaldehyde rapidly metabolizes to Benzoic Acid in the skin, the available dermal irritation and sensitization data demonstrating no adverse reactions to Benzoic Acid were considered supportive of the safety of Benzaldehyde. Benzaldehyde is absorbed through skin and by the lungs, distributes to all well-perfused organs, but does not accumulate in any specific tissue type. After being metabolized to benzoic acid, conjugates are formed with glycine or glucuronic acid, and excreted in the urine. Little acute toxicity was seen. The oral LD(50) of Benzaldehyde in rats and mice ranged from 800 to 2850 mg/kg. The intraperitoneal LD(50) in white rats was 3265 mg/kg. In short-term oral studies, the no observed adverse effect level (NOAEL) was 400 mg/kg in rats and mice. In subchronic oral studies, the NOAEL was 400 mg/kg in rats and 600 mg/kg in mice. In a 16-week feeding study, rats given up to 10,000 ppm showed no signs of toxicity. Repeated inhalation of volatilized Benzaldehyde produced ocular and nasal irritation at 500 ppm and death in rabbits at 750 ppm. Undiluted Benzaldehyde was irritating to rabbit eyes, causing edema, erythema, and pain. Benzaldehyde was determined not to be a contact sensitizer, but did produce allergic reactions in a maximization test. Clinical reports of allergy to Benzaldehyde are rare. Benzoic Acid did not produce irritation or sensitization reactions in human clinical studies. Benzoic Acid also failed to produce reactions in phototoxicity and photosensitization tests. Neither Benzaldehyde, Benzoic Acid, nor Sodium Benzoate are reproductive or developmental toxicants at doses that are nontoxic to the mother. In a behavioral study, blood levels of 0.12 ng/ml Benzaldehyde produced a 44% reduction in motor activity in mice. Benzaldehyde did not produce mutations in bacterial assays, but did produce chromosomal abnormalities in Chinese hamster cells and increased mutations in a mouse lymphoma forward mutation assay. Benzaldehyde was evaluated by the National Toxicology Program, which found no evidence of carcinogenicity in rats, and some evidence of carcinogenicity in mice. Several studies have suggested that Benzaldehyde can have carcinostatic or antitumor properties. Overall, at the concentrations used in cosmetics, Benzaldehyde was not considered a carcinogenic risk to humans. Although there are limited irritation and sensitization data available for Benzaldehyde, the available dermal irritation and sensitization data and ultraviolet (UV) absorption and phototoxicity data demonstrating no adverse reactions to Benzoic Acid support the safety of Benzaldehyde as currently used in cosmetic products.

Congo red dye affects survival and reproduction in the cladoceran Ceriodaphnia dubia. Effects of direct and dietary exposure.

PubMed

Hernández-Zamora, Miriam; Martínez-Jerónimo, Fernando; Cristiani-Urbina, Eliseo; Cañizares-Villanueva, Rosa Olivia

2016-12-01

Nearly 7 00000 tons of dyes are produced annually throughout the world. Azo dyes are widely used in the textile and paper industries due to their low cost and ease of application. Their extensive use results in large volumes of wastewater being discharged into aquatic ecosystems. Large volume discharges constitute a health risk since many of these dyes, such as Congo Red, are elaborated with benzidine, a known carcinogenic compound. Information regarding dye toxicity in aquatic ecosystems is limited. Therefore, the aim of the present study was to evaluate the effect of Congo Red on survival and reproduction of Ceriodaphnia dubia. We determined the 48 h median lethal concentration (LC 50 ) and evaluated the effects of sublethal concentrations in subchronic exposures by using as food either fresh algae or algae previously exposed to the dye. LC 50 was 13.58 mg L -1 . In subchronic assays, survival was reduced to 80 and 55 %, and fertility to 40 and 70 %, as compared to the control, in C. dubia fed with intoxicated cells or with the mix of intoxicated + fresh algae, respectively, so the quantity and type of food had a significant effect. We determined that Congo Red is highly toxic to C. dubia since it inhibits survival and fertility in concentrations exceeding 3 mg L -1 . Our results show that this dye produces negative effects at very low concentrations. Furthermore, our findings warn of the risk associated with discharging dyes into aquatic environments. Lastly, the results emphasize the need to regulate the discharge of effluents containing azo dyes.

Noni juice is not hepatotoxic

PubMed Central

West, Brett J; Jensen, C Jarakae; Westendorf, Johannes

2006-01-01

Noni juice (Morinda citrifolia) has been approved for use as a safe food within the European Union, following a review of safety. Since approval, three cases of acute hepatitis in Austrian noni juice consumers have been published, where a causal link is suggested between the liver dysfunction and ingestion of anthraquinones from the plant. Measurements of liver function in a human clinical safety study of TAHITIAN NONI® Juice, as well as subacute and subchronic animal toxicity tests revealed no evidence of adverse liver effects at doses many times higher than those reported in the case studies. Additionally, M. citrifolia anthraquinones occur in the fruit in quantities too small to be of any toxicological significance. Further, these do not have chemical structures capable of being reduced to reactive anthrone radicals, which were implicated in previous cases of herbal hepototoxicity. The available data reveals no evidence of liver toxicity. PMID:16773722

Preparation of positional renal slices for study of cell-specific toxicity.

PubMed

Ruegg, C E; Gandolfi, A J; Nagle, R B; Krumdieck, C L; Brendel, K

1987-04-01

To reduce structural complexity, rabbit kidneys were sliced perpendicular to their cortical-papillary axis to isolate four distinct cell groupings. This positional orientation allows identification of each renal cell type based on its location within the slice. A mechanical slicer was used to make several precision-cut slices rapidly from an oriented cylindrical core of renal tissue, with minimal tissue trauma. Slices were then submerged under a gently circulating oxygenated media in a fritted glass support system that maintains viability (intracellular K+/DNA ratio) and structural integrity (histology) for at least 30 h. A high dose of mercuric chloride (10(-3) M) was used to demonstrate the structural and biochemical changes of intoxicated slices. This method provides a controlled subchronic in vitro system for the study of the individual cell types involved in cell-specific renal toxicities and may also be a useful tool for addressing other pharmacological and physiological research questions.

Safety assessment of the aqueous extract of the flowers of Nymphaea lotus Linn (Nymphaeaceae): Acute, neuro- and subchronic oral toxicity studies in albinos Wistar rats.

PubMed

Kameni Poumeni, Mireille; Bilanda, Danielle Claude; Dzeufiet Djomeni, Paul Désiré; Mengue Ngadena, Yolande Sandrine; Mballa, Marguerite Francine; Ngoungoure, Madeleine Chantal; Ouafo, Agnès Carolle; Dimo, Théophile; Kamtchouing, Pierre

2017-03-24

Background Nymphaea lotus Linn (N. lotus) is a medicinal plant widely used in Cameroon popular medicine, to treat neuropsychiatric conditions, male sexual disorders or as food supplement. However, scientific data on the pharmacotoxic profile of this plant are not available. The safety of N. lotus was assessed in acute, neuro- and subchronic toxicity studies by following the OECD guidelines. Effectively, no data have been published until now in regard to its safety on the nervous system. Methods Aqueous extract of N. lotus at doses of 200, 400 and 600 mg/kg body weight (BW) was evaluated for nitrites contents and orally administered to rats daily for 28 days (5 male, 5 female per group). The control group received distilled water (10 mL/kg) and a satellite group was used to observe reversal effects. Neurotoxicity of the plant was determined using open field test for motor coordination, ataxia and gait analysis. Clinical signs and state of livelihood were recorded during the 24 h, then for 28 days of treatments. At the end of 28-day period, animals were anesthetized and decapitated. The whole brain was homogenized for neurobiochemical analysis. Blood samples were collected with or without anticoagulant for hematological examinations and serum analysis. Specimens of liver, kidney, testis, ovaries, and brain were fixed in 10 % formalin and processed for histopathological examinations. Results Our findings indicate dose-dependent elevation of nitrites contents in the flowers aqueous extract of N. lotus. Acute toxicity study revealed no signs of toxicity neither at the dose 2,000 mg/kg nor at 5,000 mg/kg. Thus the LD50 value of aqueous extract of N. lotus flowers is superior to 5,000 mg/kg. The repeated administration of N. lotus during 28 days, induced no signs of neurobehavioral changes in male, but female rats exhibited dose-dependent response in the open field test, suggesting sex and dose-relative psychotropic effects of N. lotus. The evaluation of neurobiochemistry revealed consistent rise of brain cholesterol by 44.05 %; 158.10 % and 147.62 % respectively in male rats treated with the doses of 200, 400 and 600 mg/kg. In female rats, these levels were significantly increased (p<0.001) only at the dose of 600 mg/kg compared to control. This trend persisted after 14 days withdrawal. Brain potassium and calcium concentrations were increased in all rats compared to their respective control receiving distilled water, suggesting transmembrane current stabilizing properties of brain cells by our extract. Further, serum biochemical analysis demonstrated that 28-day administration of N. lotus flowers increased depending on the dose and sex, the levels of serum urea, proteins, creatinine and bilirubin and reduced γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) activities. These results suggest liver alterations that are endowed by lower liver relative weight and histology damages observed in female rats treated with the dose of 600 mg/kg of our extract. We also observed a rise in the low-density lipoprotein (LDL) fraction and AI of male rats undergoing N. lotus treatment. In female rats, the latter remains unaltered, confirming the dose- and sex-dependent response of our extract. The levels of white blood cells (WBC) and granulocytes were higher in male irrespective to their control, revealing stimulatory properties of the male hematopoietic system. Such variations (sex- and dose-dependent) are without biological relevance for the majority of the biochemical parameters evaluated, indicating a wide margin of safety for the traditional use of N. lotus. The alkaloids, nitrites and phytosterols contained in N. lotus flowers extract may probably account for its neuroprotective, anti-oxidant, and immunoboosting properties. Conclusions N. lotus do not possesses neurotoxicity but is able to induce behavioral changes in rats. Therefore, the application of this plant as either drug or supplementary food should be carefully considered.

Toxicity study of dimethylethoxysilane (DMSES), the waterproofing agent for the Orbiter heat protective system

NASA Technical Reports Server (NTRS)

Lam, Chiu-Wing; James, John T.; Dodd, Darol; Stuart, Bruce; Rothenberg, Simon; Kershaw, Mary Ann; Thilagar, A.

1993-01-01

DMES, a volatile liquid, is used by NASA to waterproof the Orbiter thermal protective system. During waterproofing operations at the Oribter Processing Facility at KSC, workers could be exposed to DMES vapor. To assess the toxicity of DMES, acute and subchronic (2-week and 13-week) inhalation studies were conducted with rats. Studies were also conducted to assess the potential of DMES. Inhalation exposure concentrations ranged from 40 ppm to 4000 ppm. No mortality was observed during the studies. Exposures to 2100 ppm produced narcosis and ataxia. Post-exposure recovery from these CNS effects was rapid (less than 1 hr). These effects were concentration-dependent and relatively independent of exposure length. Exposure to 3000 ppm for 2 weeks (5 h/d, 5 d/wk) produced testicular toxicity. The 13-week study yielded similar results. Results from the genotoxicity assays (in vivo/in vitro unscheduled DNA synthesis in rat primary heptaocytes, chromosomal aberrations in rat bone marrow cells; reverse gene mutation in Salmonella typhimurium; and forward mutation in Chinese hamster culture cells) were negative. These studies indicated that DMES is mildly to moderately toxic but not a multagen.

Effect of exposure routes on the relationships of lethal toxicity to rats from oral, intravenous, intraperitoneal and intramuscular routes.

PubMed

Ning, Zhong H; Long, Shuang; Zhou, Yuan Y; Peng, Zi Y; Sun, Yi N; Chen, Si W; Su, Li M; Zhao, Yuan H

2015-11-01

The lethal toxicity values (log 1/LD(50)) of 527 aliphatic and aromatic compounds in oral, intravenous, intramuscular and intraperitoneal routes were used to investigate the relationships of log 1/LD(50) from different exposure routes. Regression analysis shows that the log 1/LD(50) values are well correlated between intravenous and intraperitoneal or intramuscular injections. However, the correlations between oral and intravenous or intraperitoneal routes are relatively poor. Comparison of the average residuals indicates that intravenous injection is the most sensitive exposure route and oral administration is the least sensitive exposure route. This is attributed to the difference in kinetic process of toxicity testing. The toxic effect of a chemical can be similar or significantly different between exposure routes, depending on the absorption rates of chemicals into blood. Inclusion of hydrophobic parameter and fractions of ionic forms can improve the correlations between intravenous and intraperitoneal or oral routes, but not between intraperitoneal and oral routes. This is due to the differences of absorption rate in different exposure environments from different routes. Several factors, such as experimental uncertainty, metabolism and toxic kinetics, can affect the correlations between intravenous and intraperitoneal or oral routes. Copyright © 2015 Elsevier Inc. All rights reserved.

Development of quantitative parameters to assess in-vivo optical coherence tomography images of late oral radiation toxicity patients

NASA Astrophysics Data System (ADS)

Davoudi, Bahar; Damodaran, Vani; Bizheva, Kostadinka; Yang, Victor; Dinniwell, Robert; Levin, Wilfred; Vitkin, Alex

2013-03-01

Late oral radiation toxicity is a common condition occurring in a considerable percentage of head and neck cancer patients after radiation therapy which reduces their quality of life. The current examination of these patients is based on a visual inspection of the surface of the oral cavity; however, it is well known that many of the complications start in the subsurface layers before any superficial manifestation. Considering the currently suboptimal examination techniques, we address this clinical problem by using optical coherence tomography (OCT) to monitor the subsurface oral layers with micron-scale resolution images. A spectral-domain OCT system and a specialized oral imaging probe were designed and built for a clinical study to image late oral radiation toxicity patients. In addition to providing qualitative 2D and 3D images of the subsurface oral layers, quantitative metrics were developed to assess the back-scattering and thickness properties of different layers. Metric derivations are explained and preliminary results from late radiation toxicity patients and healthy volunteers are presented and discussed.

Sub-chronic toxicity study in rats orally exposed to nanostructured silica

PubMed Central

2014-01-01

Background Synthetic Amorphous Silica (SAS) is commonly used in food and drugs. Recently, a consumer intake of silica from food was estimated at 9.4 mg/kg bw/day, of which 1.8 mg/kg bw/day was estimated to be in the nano-size range. Food products containing SAS have been shown to contain silica in the nanometer size range (i.e. 5 – 200 nm) up to 43% of the total silica content. Concerns have been raised about the possible adverse effects of chronic exposure to nanostructured silica. Methods Rats were orally exposed to 100, 1000 or 2500 mg/kg bw/day of SAS, or to 100, 500 or 1000 mg/kg bw/day of NM-202 (a representative nanostructured silica for OECD testing) for 28 days, or to the highest dose of SAS or NM-202 for 84 days. Results SAS and NM-202 were extensively characterized as pristine materials, but also in the feed matrix and gut content of the animals, and after in vitro digestion. The latter indicated that the intestinal content of the mid/high-dose groups had stronger gel-like properties than the low-dose groups, implying low gelation and high bioaccessibility of silica in the human intestine at realistic consumer exposure levels. Exposure to SAS or NM-202 did not result in clearly elevated tissue silica levels after 28-days of exposure. However, after 84-days of exposure to SAS, but not to NM-202, silica accumulated in the spleen. Biochemical and immunological markers in blood and isolated cells did not indicate toxicity, but histopathological analysis, showed an increased incidence of liver fibrosis after 84-days of exposure, which only reached significance in the NM-202 treated animals. This observation was accompanied by a moderate, but significant increase in the expression of fibrosis-related genes in liver samples. Conclusions Although only few adverse effects were observed, additional studies are warranted to further evaluate the biological relevance of observed fibrosis in liver and possible accumulation of silica in the spleen in the NM-202 and SAS exposed animals respectively. In these studies, dose-effect relations should be studied at lower dosages, more representative of the current exposure of consumers, since only the highest dosages were used for the present 84-day exposure study. PMID:24507464

Amended final report on the safety assessment of polyacrylamide and acrylamide residues in cosmetics.

PubMed

2005-01-01

Polyacrylamide is a polymer of controllable molecular weight formed by the polymerization of acrylamide monomers available in one of three forms: solid (powder or micro beads), aqueous solution, or inverse emulsions (in water droplets coated with surfactant and suspended in mineral oil). Residual acrylamide monomer is likely an impurity in most Polyacrylamide preparations, ranging from <1 ppm to 600 ppm. Higher levels of acrylamide monomers are present in the solid form compared to the other two forms. Polyacrylamide is reportedly used in 110 cosmetic formulations, at concentrations ranging from 0.05% to 2.8%. Residual levels of acrylamide in Polyacrylamide can range from <.01% to 0.1%, although representative levels were reported at 0.02% to 0.03%. Because of the large sizes of Polyacrylamide polymers, they do not penetrate the skin. Polyacrylamide itself is not significantly toxic. For example, an acute oral toxicity study of Polyacrylamide in rats reported that a single maximum oral dose of 4.0 g/kg body weight was tolerated. In subchronic oral toxicity studies, rats and dogs treated with Polyacrylamide at doses up to 464 mg/kg body weight showed no signs of toxicity. Several 2-year chronic oral toxicity studies in rats and dogs fed diets containing up to 5% Polyacrylamide had no significant adverse effects. Polyacrylamide was not an ocular irritant in animal tests. No compound-related lesions were noted in a three-generation reproductive study in which rats were fed 500 or 2000 ppm Polyacrylamide in their diet. Polyacrylamide was not carcinogenic in several chronic animal studies. Human cutaneous tolerance tests performed to evaluate the irritation of 5% (w/w) Polyacrylamide indicated that the compound was well tolerated. Acrylamide monomer residues do penetrate the skin. Acrylamide tested in a two-generation reproductive study at concentrations up to 5 mg/kg day(- 1) in drinking water, was associated with prenatal lethality at the highest dose, with evidence of parental toxicity. The no adverse effects level was close to the 0.5 mg/kg day(- 1) dose. Acrylamide tested in a National Toxicology Program (NTP) reproductive and neurotoxicity study at 3, 10, and 30 ppm produced no developmental or female reproductive toxicity. However, impaired fertility in males was observed, as well as minimal neurotoxic effects. Acrylamide neurotoxicity occurs in both the central and peripheral nervous systems, likely through microtubule disruption, which has been suggested as a possible mechanism for genotoxic effects of acrylamide in mammalian systems. Acrylamide was genotoxic in mammalian in vitro and in vivo assays. Acrylamide was a tumor initiator, but not an initiator/promoter, in two different mouse strains at a total dose of 300 mg/kg (6 doses over 2 weeks) resulting in increased lung adenomas and carcinomas without promotion. Acrylamide was tested in two chronic bioassays using rats. In one study, increased incidence of mammary gland tumors, glial cell tumors, thyroid gland follicular tumors, oral tissue tumors, uterine tumors and clitoral gland tumors were noted in female rats. In male rats, the number of tumors in the central nervous system (CNS), thyroid gland, and scrotum were increased with acrylamide exposure. In the second study, using higher doses and a larger number of female rats, glial cell tumors were not increased, nor was there an increase in mammary gland, oral tissue, clitoral gland, or uterine tumors. Tumors of the scrotum in male rats were confirmed, as were the thyroid gland follicular tumors in males and females. Taken together, there was a dose-dependent, but not statistically significant, increase in the number of astrocytomas. Different human lifetime cancer risk predictions have resulted, varying over three orders of magnitude from 2 x 10(- 3) to 1.9 x 10(- 6). In the European Union, acrylamide has been limited to 0.1 ppm for leave-on cosmetic products and 0.5 ppm for other cosmetic products. An Australian risk assessment suggested negligible health risks from acrylamide in cosmetics. The Cosmetic Ingredient Review (CIR) Expert Panel acknowledged that acrylamide is a demonstrated neurotoxin in humans and a carcinogen in animal tests, but that neurotoxic levels could not be attained by use of cosmetics. Although there are mechanisms of action of acrylamide that have been proposed for tumor types seen in rat studies that suggest they may be unique to the rat, the Panel was not convinced that these results could be disregarded as a species-specific finding with no relevance to human health and safety. Based on the genotoxicity and carcinogenicity data, the Panel does not believe that acrylamide is a genotoxic carcinogen in the usual manner and that several of the risk assessment approaches have overestimated the human cancer risk. The Panel did conclude, however, that it was appropriate to limit acrylamide levels to 5 ppm in cosmetic formulations.

Acute and subchronic administration of anandamide or oleamide increases REM sleep in rats.

PubMed

Herrera-Solís, Andrea; Vásquez, Khalil Guzmán; Prospéro-García, Oscar

2010-03-01

Anandamide and oleamide, induce sleep when administered acutely, via the CB1 receptor. Their subchronic administration must be tested to demonstrate the absence of tolerance to this effect, and that the sudden withdrawal of these endocannabinoids (eCBs) does not affect sleep negatively. The sleep-waking cycle of rats was evaluated for 24h, under the effect of an acute or subchronic administration of eCBs, and during sudden eCBs withdrawal. AM251, a CB1 receptor antagonist (CB1Ra) was utilized to block eCBs effects. Our results indicated that both acute and subchronic administration of eCBs increase REMS. During eCBs withdrawal, rats lack the expression of an abstinence-like syndrome. AM251 was efficacious to prevent REMS increase caused by both acute and subchronic administration of these eCBs, suggesting that this effect is mediated by the CB1 receptor. Our data further support a role of the eCBs in REMS regulation. (c) 2009 Elsevier Inc. All rights reserved.

Male rats treated with subchronic PCP show intact olfaction and enhanced interest for a social odour in the olfactory habituation/dishabituation test.

PubMed

Tarland, Emilia; Brosda, Jan

2018-06-01

The olfactory system participates in many sensory processes, and olfactory endophenotypes appear in a variety of neurological disorders such as Alzheimer's and Parkinson's disease, depression and schizophrenia. Social withdrawal is a core negative symptom of schizophrenia and animal models have proven to be invaluable for studying the neurobiological mechanisms and cognitive processes behind the formation of social relationships. The subchronic phencyclidine (PCP) rat model is a validated model for negative symptoms of schizophrenia, such as impaired sociability. However, the complete range of social behaviour and deficits in the model are still not fully understood. Intact rodent olfaction is essential for a wide range of social behaviour and disrupted olfactory function could have severe effects on social communication and recognition. In order to examine the olfactory ability of male rats treated with subchronic PCP, we conducted an olfactory habituation/dishabituation test including both non-social and social odours. The subchronic PCP-treated rats successfully recognized and discriminated among the odours, indicative of intact olfaction. Interestingly, the subchronic PCP-treated rats showed greater interest for a novel social odour compared to the saline-treated rats and the rationale remains to be elucidated. Our data indicate that subchronic PCP treatment does not disrupt olfactory function in male rats. By ruling out impaired olfaction as cause for the poor social interaction performance in subchronic PCP-treated rats, our data supports the use of NMDA receptor antagonists to model the negative symptoms of schizophrenia. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Subchronic MK-801 treatment and post-weaning social isolation in rats: differential effects on locomotor activity and hippocampal long-term potentiation.

PubMed

Ashby, Donovan M; Habib, Diala; Dringenberg, Hans C; Reynolds, James N; Beninger, Richard J

2010-09-01

Subchronic NMDA receptor antagonist treatment and post-weaning social isolation are two animal models of schizophrenia symptoms. However, behavioral and physiological changes following a combination of these two procedures have not been investigated. Thus, we examined effects of a novel, "double hit" model combining these two treatments, comparing them to standard models involving only NMDA antagonist treatment or social isolation. Male, Sprague-Dawley rats were either group-housed or maintained in social isolation (starting at postnatal day [PD] 21 and continuing throughout the study). Each housing condition was further subdivided into two groups, receiving either subchronic treatment with either saline or MK-801 (0.5mg/kg, i.p., 2xday for seven days starting at PD 56). Post-weaning social isolation increased locomotor activity (assessed at PD 70) in response to a novel environment and an acute amphetamine injection, while subchronic MK-801 increased only amphetamine induced locomotor activity. Subsequent electrophysiological experiments (under urethane anesthesia) assessing changes in plasticity of hippocampal synapses showed that subchronic MK-801 treatment resulted in an increase in long-term potentiation in area CA1 in response to high frequency stimulation of the contralateral CA3 area, while housing condition had no effect. No other changes in hippocampal electrophysiology (input-output curves, paired-pulse facilitation) were observed. These data are the first to demonstrate an enhancement in hippocampal long-term plasticity in vivo following subchronic MK-801 administration, an effect that may be related to the well-characterized changes in glutamatergic and GABAergic systems seen after subchronic NMDA receptor blockade. That lack of additive or synergistic effects in the "double hit model" suggests that combining isolation and subchronic MK-801 treatment does not necessarily produce greater behavioral or physiological dysfunction than that seen with either treatment alone. Copyright 2010 Elsevier B.V. All rights reserved.

The genotoxic effect of oxcarbazepine on mice blood lymphocytes.

PubMed

Akbar, Huma; Khan, Ajmal; Mohammadzai, Imdadullah; Khisroon, Muhammad; Begum, Ilham

2018-04-01

This study was conducted to assess the amount of DNA damage caused by Oxcarbazepine (OXC) through single cell gel electrophoresis (SCGE) technique/comet assay. OXC derived from dibenzazepine series is an effective second generation antiepileptic drug (AED) for both children and adults. Side effects like genotoxic effects of AEDs are of prime importance resulting from toxic metabolites, free radicals and reactive oxygen species (ROS). Forty Eight adult male Bagg's albino mice (BALB/c) were randomly classified into eight groups, each comprising of six animals. Two of these groups were control and six were tested groups. Control groups were injected with 1% tween 80 while tested groups were injected with 10, 20, and 40 mg/kg-day OXC for seven days (acute therapy) and 28 days (subchronic therapy) in peritoneal cavity. Blood samples were collected by cardiac puncture and subjected to comet assay for the analysis of DNA damage. Per sample 100 cells were scored and classified according to comet tail length. The results showed that OXC in acute and long term therapies had significantly higher (p < 0.05) genotoxicity in treated groups as compared to control groups. Our study suggests that OXC may cause significant DNA damage in both acute as well as in subchronic therapies.

Modulation of antipyrine clearance by polysaccharide peptide (PSP) isolated from Coriolus versicolor in the rat.

PubMed

Chan, Siu-Lung; Yeung, John H K

2006-09-01

Polysaccharide peptide (PSP), isolated from Coriolus versicolor COV-1, has been previously shown to have immuno-stimulatory, anti-tumour and analgesic effects in animal models. When used as an adjunct in cancer chemotherapy in clinical trials carried out in China, PSP improved the quality of life in the patients by improving appetite and alleviating symptoms associated with cancer chemotherapy. In this study, the effects of non-toxic doses of PSP on phase I metabolism was investigated in the rat, using the conventional probe antipyrine. Acute PSP (3-5 micromol/kg, i.p.) treatment did not produce significant changes in antipyrine clearance. Sub-chronic treatment with PSP (1-3 micromol/kg/day, i.p., 3 days) decreased the antipyrine clearance (30-35%), with an increase in the plasma half-life (T1/2) by 55% and an increase in the area under concentration-time curve (AUC) by 61%. Total hepatic cytochrome P450 (P450) was dose-dependently decreased (32-54%) after sub-chronic, but not the acute treatment of PSP. Given that PSP can affect phase I metabolism and hepatic cytochrome P450 content, the concomitant use of PSP with other therapeutic agents that undergo phase I metabolism should be carefully monitored.

Recovery by N-acetylcysteine from subchronic exposure to Imidacloprid-induced hypothalamic-pituitary-adrenal (HPA) axis tissues injury in male rats.

PubMed

Annabi, Alya; Dhouib, Ines Bini; Lamine, Aicha Jrad; El Golli, Nargès; Gharbi, Najoua; El Fazâa, Saloua; Lasram, Mohamed Montassar

2015-01-01

Imidacloprid is the most important example of the neonicotinoid insecticides known to target the nicotinic acetylcholine receptor in insects, and potentially in mammals. N-Acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the recovery effect of NAC against Imidacloprid-induced oxidative stress and cholinergic transmission alteration in hypothalamic-pituitary-adrenal (HPA) axis of male rats following subchronic exposure. About 40 mg/kg of Imidacloprid was administered daily by intragastric intubation and 28 days later, the rats were sacrificed and HPA axis tissues were removed for different analyses. Imidacloprid increased adrenal relative weight and cholesterol level indicating an adaptive stage of the general alarm reaction to stress. Moreover, Imidacloprid caused a significant increase in malondialdehyde level, the antioxidants catalase, superoxide dismutase and glutathione-S-transferase showed various alterations following administration and significant depleted thiols content was only recorded in hypothalamic tissue. Furthermore, the hypothalamic and pituitary acetylcholinesterase activity and calcium level were significantly increased highlighting the alteration of cholinergic activity. The present findings revealed that HPA axis is a sensitive target to Imidacloprid (IMI). Interestingly, the use of NAC for only 7 days post-exposure to IMI showed a partial therapeutic effect against Imidacloprid toxicity.

A subchronic feeding study of dicamba-tolerant soybean with the dmo gene in Sprague-Dawley rats.

PubMed

Wang, Xiaoyun; He, Xiaoyun; Zou, Shiyin; Xu, Wentao; Jia, Xin; Zhao, Bo; Zhao, Changhui; Huang, Kunlun; Liang, Zhihong

2016-06-01

The dicamba-tolerant soybean MON87708 expresses the dicamba mono-oxygenase (DMO) enzyme that is encoded by the dmo gene. In order to evaluate the safety of this soybean, a 90-day subchronic feeding toxicity study (13 weeks) was conducted on Sprague-Dawley rats. A total of 140 rats were divided into 7 groups (10/sex/group), including a standard commercial diet control group. The genetically modified (GM) soybean MON87708 and the near isogenic non-GM soybean A3525 were respectively processed to unhulled, full-fat, and heat-treated powder, then mixed into the diet at levels of 7.5%, 15%, and 30% (wt/wt) with the main nutrients of the various diets balanced and then fed to 6 groups. The remaining group of rats fed with a commercial rat diet served as blank control. Some isolated parameters indicated statistically significant differences in body weight, feed consumption/utilization, hematology, serum biochemistry, and relative organ weights. These differences were not consistent across gender or test-diet dose, which were attributed to incidental and biological variability. In conclusion, the results demonstrated that the transgenic soybean MON87708 containing DMO was as safe as non-transgenic isogenic counterpart with historical safe use. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute oral toxicity of chemicals in terrestrial life stages of amphibians: Comparisons to birds and mammals.

PubMed

Crane, Mark; Finnegan, Meaghean; Weltje, Lennart; Kosmala-Grzechnik, Sylwia; Gross, Melanie; Wheeler, James R

2016-10-01

Amphibians are currently the most threatened and rapidly declining group of vertebrates and this has raised concerns about their potential sensitivity and exposure to plant protection products and other chemicals. Current environmental risk assessment procedures rely on surrogate species (e.g. fish and birds) to cover the risk to aquatic and terrestrial life stages of amphibians, respectively. Whilst a recent meta-analysis has shown that in most cases amphibian aquatic life stages are less sensitive to chemicals than fish, little research has been conducted on the comparative sensitivity of terrestrial amphibian life stages. Therefore, in this paper we address the questions "What is the relative sensitivity of terrestrial amphibian life stages to acute chemical oral exposure when compared with mammals and birds?" and "Are there correlations between oral toxicity data for amphibians and data for mammals or birds?" Identifying a relationship between these data may help to avoid additional vertebrate testing. Acute oral amphibian toxicity data collected from the scientific literature and ecotoxicological databases were compared with toxicity data for mammals and birds. Toxicity data for terrestrial amphibian life stages are generally sparse, as noted in previous reviews. Single-dose oral toxicity data for terrestrial amphibian life stages were available for 26 chemicals and these were positively correlated with LD50 values for mammals, while no correlation was found for birds. Further, the data suggest that oral toxicity to terrestrial amphibian life stages is similar to or lower than that for mammals and birds, with a few exceptions. Thus, mammals or birds are considered adequate toxicity surrogates for use in the assessment of the oral exposure route in amphibians. However, there is a need for further data on a wider range of chemicals to explore the wider applicability of the current analyses and recommendations. Copyright © 2016 Elsevier Inc. All rights reserved.

Improving reptile ecological risk assessment: oral and dermal toxicity of pesticides to a common lizard species (Sceloporus occidentalis).

PubMed

Weir, Scott M; Yu, Shuangying; Talent, Larry G; Maul, Jonathan D; Anderson, Todd A; Salice, Christopher J

2015-08-01

Reptiles have been understudied in ecotoxicology, which limits consideration in ecological risk assessments. The goals of the present study were 3-fold: to improve oral and dermal dosing methodologies for reptiles, to generate reptile toxicity data for pesticides, and to correlate reptile and avian toxicity. The authors first assessed the toxicity of different dosing vehicles: 100 μL of water, propylene glycol, and acetone were not toxic. The authors then assessed the oral and dermal toxicity of 4 pesticides following the up-and-down procedure. Neither brodifacoum nor chlorothalonil caused mortality at doses ≤ 1750 μg/g. Under the "neat pesticide" oral exposure, endosulfan (median lethal dose [LD50] = 9.8 μg/g) was more toxic than λ-cyhalothrin (LD50 = 916.5 μg/g). Neither chemical was toxic via dermal exposure. An acetone dosing vehicle increased λ-cyhalothrin toxicity (oral LD50 = 9.8 μg/g; dermal LD50 = 17.5 μg/g), but not endosulfan. Finally, changes in dosing method and husbandry significantly increased dermal λ-cyhalothrin LD50s, which highlights the importance of standardized methods. The authors combined data from the present study with other reptile LD50s to correlate with available avian data. When only definitive LD50s were used in the analysis, a strong correlation was found between avian and reptile toxicity. The results suggest it is possible to build predictive relationships between avian and reptile LD50s. More research is needed, however, to understand trends associated with chemical classes and modes of action. © 2015 SETAC.

Acute and sub-acute oral toxicity of Dracaena cinnabari resin methanol extract in rats.

PubMed

Al-Afifi, Nashwan Abdullah; Alabsi, Aied Mohammed; Bakri, Marina Mohd; Ramanathan, Anand

2018-02-05

Dracaena cinnabari (DC) is a perennial tree that located on the Southern coast of Yemen native to the Socotra Island. This tree produces a deep red resin known as the Dragon's blood, the Twobrother's Blood or Damm Alakhwain. The current study performed to evaluate the safety of the DC resin methanol extract after a single or 28 consecutive daily oral administrations. In assessing the safety of DC resin methanol extract, acute and sub-acute oral toxicity tests performed following OECD guidelines 423 and 407, respectively, with slight modifications. In acute oral toxicity test, DC resin methanol extract administered to female Sprague Dawley rats by oral gavage at a single dose of 300 and 2000 mg/kg body weight. Rats observed for toxic signs for 14 days. In sub-acute oral toxicity test, DC resin methanol extract administered to the rats by oral gavage at 500, 1000, and 1500 mg/kg body weight daily up to 28 days to male and female Spradgue Dawley rats. The control and high dose in satellite groups were also maintained and handled as the previous groups to determine the late onset toxicity of DC resin methanol extract. At the end of each test, hematological and biochemical analysis of the collected blood were performed as well as gross and microscopic pathology. In acute oral toxicity, no treatment-related death or toxic signs were observed. It revealed that the DC resin methanol extract could be well tolerated up to the dose 2000 mg/kg body weight and could be classified as Category 5. The sub-acute test observations indicated that there are no treatment-related changes up to the high dose level compared to the control. Food consumption, body weight, organ weight, hematological parameters, biochemical parameters and histopathological examination (liver, kidney, heart, spleen and lung) revealed no abnormalities. Water intake was significantly higher in the DC resin methanol extract treated groups compared to the control. This study demonstrates tolerability of DC resin methanol extract administered daily for 28 days up to 1500 mg/kg dose.

Extensive review of fish embryo acute toxicities for the prediction of GHS acute systemic toxicity categories.

PubMed

Scholz, Stefan; Ortmann, Julia; Klüver, Nils; Léonard, Marc

2014-08-01

Distribution and marketing of chemicals require appropriate labelling of health, physical and environmental hazards according to the United Nations global harmonisation system (GHS). Labelling for (human) acute toxicity categories is based on experimental findings usually obtained by oral, dermal or inhalative exposure of rodents. There is a strong societal demand for replacing animal experiments conducted for safety assessment of chemicals. Fish embryos are considered as alternative to animal testing and are proposed as predictive model both for environmental and human health effects. Therefore, we tested whether LC50s of the fish embryo acute toxicity test would allow effectively predicting of acute mammalian toxicity categories. A database of published fish embryo LC50 containing 641 compounds was established. For these compounds corresponding rat oral LD50 were identified resulting in 364 compounds for which both fish embryo LC50 and rat LD50 was available. Only a weak correlation of fish embryo LC50 and rat oral LD50 was obtained. Fish embryos were also not able to effectively predict GHS oral acute toxicity categories. We concluded that due to fundamental exposure protocol differences (single oral dose versus water-borne exposure) a reverse dosimetry approach is needed to explore the predictive capacity of fish embryos. Copyright © 2014 Elsevier Inc. All rights reserved.

Selected endocrine disrupting compounds (vinclozolin, flutamide, ketoconazole and dicofol): effects on survival, occurrence of males, growth, molting and reproduction of Daphnia magna.

PubMed

Haeba, Maher H; Hilscherová, Klára; Mazurová, Edita; Bláha, Ludek

2008-05-01

Pollution-induced endocrine disruption in vertebrates and invertebrates is a worldwide environmental problem, but relatively little is known about effects of endocrine disrupting compounds (EDCs) in planktonic crustaceans (including Daphnia magna). Aims of the present study were to investigate acute 48 h toxicity and sub-chronic (4-6 days) and chronic (21 days) effects of selected EDCs in D. magna. We have investigated both traditional endpoints as well as other parameters such as sex determination, maturation, molting or embryogenesis in order to evaluate the sensitivity and possible use of these endpoints in ecological risk assessment. We have studied effects of four model EDCs (vinclozolin, flutamide, ketoconazole and dicofol) on D. magna using (i) an acute 48 h immobilization assay, (ii) a sub-chronic, 4-6 day assay evaluating development and the sex ratio of neonates, and (iii) a chronic, 21 day assay studying number of neonates, sex of neonates, molting frequency, day of maturation and the growth of maternal organisms. Acute EC50 values in the 48 h immobilization test were as follows (mg/L): dicofol 0.2, ketoconazole 1.5, flutamide 2.7, vinclozolin >3. Short-term, 4-6 day assays with sublethal concentrations showed that the sex ratio in Daphnia was modulated by vinclozolin (decreased number of neonate males at 1 mg/L) and dicofol (increase in males at 0.1 mg/L). Flutamide (up to 1 mg/L) had no effect on the sex of neonates, but inhibited embryonic development at certain stages during chronic assay, resulting in abortions. Ketoconazole had no significant effects on the studied processes up to 1 mg/L. Sex ratio modulations by some chemicals (vinclozolin and dicofol) corresponded to the known action of these compounds in vertebrates (i.e. anti-androgenicity and anti-oestrogenicity, respectively). Our study revealed that some chemicals known to affect steroid-regulated processes in vertebrates can also affect sublethal endpoints (e.g. embryonic sex determination and/or reproduction) in invertebrates such as D. magna. A series of model vertebrate endocrine disrupters affected various sub-chronic and chronic parameters in D. magna including several endpoints that have not been previously studied in detail (such as sex determination in neonates, embryogenesis, molting and maturation). Evaluations of traditional reproduction parameters (obtained from the 21 day chronic assay). as well as the results from a rapid, 4-6 day, sub-chronic assay provide complementary information on non-lethal effects of suspected organic endocrine disrupters. It seems that there are analogies between vertebrates and invertebrates in toxicity mechanisms and in vivo effects of endocrine disruptors. However, general physiological status of organisms may also indirectly affect endpoints that are traditionally considered 'hormone regulated' (especially at higher effective concentrations as observed in this study) and these factors should be carefully considered. Further research of D. magna physiology and comparative studies with various EDCs will help to understand mechanisms of action as well as ecological risks of EDCs in the environment.

Tretinoin: a review of the nonclinical developmental toxicology experience.

PubMed

Kochhar, D M; Christian, M S

1997-03-01

Tretinoin has been thoroughly evaluated for its potential as an embryofetal developmental toxicant. Oral tretinoin produces developmental anomalies in animal models; the minimal teratogenic dose is consistently 2.5 to 10 mg/kg. In contrast, topical application does not induce developmental malformations in laboratory animals. A structurally related compound, isotretinoin, is a potent toxicant in humans and animals; the lowest systemic dose that induces fetal anomalies varies more than 100-fold depending on the model. Oral isotretinoin is a more potent developmental toxicant than oral tretinoin in monkeys. Between-drug differences in the metabolism and transplacental transfer of the two retinoids account for the differences in toxicant potency. Pharmacokinetic studies reveal that absorption of tretinoin from the skin is poor and yields maternal plasma concentrations below the developmentally toxic threshold established after oral administration. Analysis of outcomes of developmental toxicology and pharmacokinetic studies suggests that the human risk of fetal anomalies is negligible after therapeutic application of topical tretinoin.

Oral acute toxic class method: a successful alternative to the oral LD50 test.

PubMed

Schlede, Eva; Genschow, Elke; Spielmann, Horst; Stropp, Gisela; Kayser, Detlev

2005-06-01

The oral acute toxic class method (ATC method) was developed as an alternative to replace the oral LD50 test. The ATC method is a sequential testing procedure using only three animals of one sex per step at any of the defined dose levels. Depending on the mortality rate three but never more than six animals are used per dose level. This approach results in the reduction of numbers of animals used in comparison to the LD50 test by 40-70%. The principle of the oral ATC method is based on the Probit model and it was first evaluated on a biometric basis before a national and subsequently an international ring study were conducted. The results demonstrated an excellent agreement between the toxicity and the animal numbers predicted biometrically and observed in the validation studies. The oral ATC method was adopted as an official test guideline by OECD in 1996 and was slightly amended in 2001. The ATC method has been successfully used in Germany and in 2003 >85% of all tests on acute oral toxicity testing was conducted as oral ATC tests. In member states of the European Union the ATC method is used in the range of 50% of all tests conducted. Meanwhile the oral LD50 test has been deleted by OECD, by the European Union and by the USA, making the use of alternatives to the oral LD50 test mandatory.

Comparison of oral toxicological properties of botulinum neurotoxin serotypes A and B.

PubMed

Cheng, Luisa W; Henderson, Thomas D

2011-07-01

Botulinum neurotoxins (BoNTs) are among the most potent biological toxins for humans. Of the seven known serotypes (A-G) of BoNT, serotypes A, B and E cause most of the foodborne intoxications in humans. BoNTs in nature are associated with non-toxic accessory proteins known as neurotoxin-associated proteins (NAPs), forming large complexes that have been shown to play important roles in oral toxicity. Using mouse intraperitoneal and oral models of botulism, we determined the dose response to both BoNT/B holotoxin and complex toxins, and compared the toxicities of BoNT/B and BoNT/A complexes. Although serotype A and B complexes have similar NAP composition, BoNT/B formed larger-sized complexes, and was approximately 90 times more lethal in mouse oral intoxications than BoNT/A complexes. When normalized by mean lethal dose, mice orally treated with high doses of BoNT/B complex showed a delayed time-to-death when compared with mice treated with BoNT/A complex. Furthermore, we determined the effect of various food matrices on oral toxicity of BoNT/A and BoNT/B complexes. BoNT/B complexes showed lower oral bioavailability in liquid egg matrices when compared to BoNT/A complexes. In summary, our studies revealed several factors that can either enhance or reduce the toxicity and oral bioavailability of BoNTs. Dissecting the complexities of the different BoNT serotypes and their roles in foodborne botulism will lead to a better understanding of toxin biology and aid future food risk assessments. Published by Elsevier Ltd.

Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and neuronal density in the prefrontal cortex, striatum and hippocampus in sub-chronic phencyclidine administration rat model of schizophrenia.

PubMed

Wetchateng, Thanitsara; Piyabhan, Pritsana

2015-03-01

Cognitive deficit is a significant problem, which finally occurs in all schizophrenic patients. It can not be attenuated by any antipsychotic drugs. It is well known that changes of neuronal density are correlated with learning and memory deficits. Bacopa monnieri (Brahmi), popularly known as a cognitive enhancer; might be a novel therapeutic agentfor cognitive deficit in schizophrenia by changing cerebral neuronal density. The objective of this study was to determine the effects of Brahmi on attenuation at cognitive deficit and on the neuronal density in the prefrontal cortex, striatum and cornu ammonis subfield 1 (CA1) and 2/3 (CA2/3) of hippocampus in sub-chronic phencyclidine (PCP) rat model of schizophrenia. Rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: PCP + Brahmi. Rats were testedfor cognitive ability by using the novel object recognition test. Neuronal density from a serial Nissl stain sections ofthe prefrontal cortex, striatum and hippocampus ofrat model ofschizophrenia were measured by using Image ProPlus software and manual counting. Sub-chronic administration of PCP results in cognitive deficits in novel object recognition task. This occurred alongside significantly increased neuronal density in CA1. The cognitive deficit was recovery to normal in PCP + Brahmi group and it occurred alongside significantly decreased neuronal density in CA1. On the other hand, significantly increased neuronal density was observed in CA2/3 of PCP + Brahmi group compared with PCP alone. Brahmi is a potential cognitive enhancer against schizophrenia. It reduces neuronal density, most likely glutamatergic neuron, which results in neuronal toxicity and cognitive deficit. Therefore, Brahmi has cognitive enhancement effect by reducing glutamatergic neuron in CAI. Moreover, it also has neurogenesis effect in CA2/3, which is needed to be investigated in the further study.

Effects of environmentally relevant sub-chronic atrazine concentrations on African clawed frog (Xenopus laevis) survival, growth and male gonad development.

PubMed

Rimayi, Cornelius; Odusanya, David; Weiss, Jana M; de Boer, Jacob; Chimuka, Luke; Mbajiorgu, Felix

2018-06-01

Sub-chronic toxicity of environmentally relevant atrazine concentrations on exposed tadpoles and adult male African clawed frogs (Xenopus laevis) was evaluated in a quality controlled laboratory for 90 days. The aim of this study was to determine the effects of atrazine on the survival, growth and gonad development of African clawed frogs. After exposure of tadpoles to atrazine concentrations of 0 (control), 0.01, 200 and 500 μg L -1 in water, mortality rates of 0, 0, 3.3 and 70% respectively were recorded for the 90 day exposure period. Morphometry showed significantly reduced tadpole mass in the 500 μg L -1 atrazine exposed tadpoles (p < 0.05). Light microscopy on testes of adult frogs exposed to the same atrazine concentrations using hematoxylin and eosin (H&E) and Van Gieson staining techniques revealed gonadal atrophy, disruption of germ cell lines, seminiferous tubule structure damage and formation of extensive connective tissue around seminiferous tubules of frogs exposed to 200 μg L -1 and 500 μg L -1 atrazine concentrations. Ultrastructural analysis of the cellular organelles using transmission electron microscopy (TEM) revealed significant amounts of damaged mitochondria in testosterone producing Leydig cells as well as Sertoli cells. Biochemical analysis revealed reduced serum testosterone levels in adult frogs at all exposure levels as well as presence of six atrazine metabolites in frog serum and liver. The results indicate that atrazine concentrations greater than the calculated LC50 of 343.7 μg L -1 cause significant mortality in tadpoles, while concentrations ≥200 μg L -1 adversely affect reproductive health of adult frogs and development of tadpoles sub-chronically exposed to atrazine. Copyright © 2018 Elsevier B.V. All rights reserved.

Protective Effect of Morocco Carob Honey Against Lead-Induced Anemia and Hepato-Renal Toxicity.

PubMed

Fihri, Aicha Fassi; Al-Waili, Noori S; El-Haskoury, Redouan; Bakour, Meryem; Amarti, Afaf; Ansari, Mohammad J; Lyoussi, Badiaa

2016-01-01

Natural honey has many biological activities including protective effect against toxic materials. The aim of this study was to evaluate the protective effect of carob honey against lead-induced hepato-renal toxicity and lead-induced anemia in rabbits. Twenty four male rabbits were allocated into four groups six rabbits each; group 1: control group, received distilled water (0.1 ml / kg.b.wt /daily); group 2: received oral lead acetate (2 g/kg.b.wt/daily); group 3: treated with oral honey (1g /kg.b.wt/daily) and oral lead (2 g/kg.b.wt/daily), and group 4: received oral honey (1 g/kg.b.wt/daily). Honey and lead were given daily during 24 days of experimentation. Laboratory tests and histopathological evaluations of kidneys were done. Oral administration of lead induced hepatic and kidney injury and caused anemia during three weeks of the exposure. Treatment with honey prevented hepato-renal lead toxicity and ameliorated lead-induced anemia when honey was given to animals during lead exposure. It might be concluded that honey has a protective effect against lead-induced blood, hepatic and renal toxic effects. © 2016 The Author(s) Published by S. Karger AG, Basel.

Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Porter, J.B.; Morgan, J.; Hoyes, K.P.

1990-12-01

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown bymore » a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02).« less

Subchronic (13-week) toxicity and prenatal developmental toxicity studies of dietary astaxanthin in rats.

PubMed

Vega, Katherine; Edwards, James; Beilstein, Paul

2015-12-01

Two studies examined the effects of dietary astaxanthin on Hanlbm Wistar (SPF) rats. Male and female rats receiving astaxanthin concentrations up to 1.52% of the feed for 13 weeks showed no evidence of toxicity; no effects were noted in the offspring of female rats exposed to astaxanthin at up to 1.39% of the feed during the period of organogenesis (GD 7-16). Discoloration of the feces and yellow pigmentation of adipose tissue was seen in the 13-week study, an intrinsic property of the substance, and not a sign of toxicity. Differences between the control and astaxanthin groups, some of which reached statistical significance, were generally sporadic (i.e., transient and/or not related to astaxanthin concentration) and not considered of biological or toxicological significance. Blood cholesterol levels, for example, were greater in animals receiving astaxanthin for 13 weeks, but remained within the normal range. The highest dietary concentration of astaxanthin in each of the studies is proposed as a no-observable-adverse-effect level (NOAEL). Specifically, 1.52% for the 13-week study, corresponding to a mean intake of 1033 mg/kg bw/day (range: 880-1240 mg/kg bw/day), and 1.39% for the developmental toxicity study, corresponding to a mean intake of approximately 830 mg/kg bw/day (range: 457-957 mg/kg bw/day). Copyright © 2015 Elsevier Inc. All rights reserved.

Predictive Modeling of Apical Toxicity Endpoints Using Data ...

EPA Pesticide Factsheets

The US EPA and other regulatory agencies face a daunting challenge of evaluating potential toxicity for tens of thousands of environmental chemicals about which little is currently known. The EPA’s ToxCast program is testing a novel approach to this problem by screening compounds using a variety of in vitro assays and using the results to prioritize chemicals for further, more detailed testing. Phase I of ToxCast is testing 320 chemicals (mainly pesticide active ingredients) against ~400 cell-based and biochemical assays. In order to anchor these studies, we are using in vivo guideline study data for subchronic, chronic, cancer, reproductive and developmental endpoints. This data is compiled in the EPA toxicity reference database, ToxRefDB. The main goal of ToxCast is the discovery and validation of “signatures” linking in vitro assay data to in vivo toxicity endpoints. These signatures will be collections of assays that are correlated with particular endpoints. These assay collections should also help define molecular-and cellular-level mechanisms of toxicity. This talk will discuss our strategy to use a combination of statistical and machine learning methods, coupled with biochemical network or systems biology approaches. Our initial examples will focus signatures for endpoints from 2 year rodent cancer bioassays. Most of the data we have analyzed is in dose or concentration response series, so to effectively use this data we have developed novel appro

Nickel exposure alters behavioral parameters in larval and adult zebrafish.

PubMed

Nabinger, Débora Dreher; Altenhofen, Stefani; Bitencourt, Paula Eliete Rodrigues; Nery, Laura Roesler; Leite, Carlos Eduardo; Vianna, Mônica Ryff Moreira Roca; Bonan, Carla Denise

2018-05-15

Nickel is a heavy metal that, at high concentrations, leads to environmental contamination and causes health problems. We evaluated the effects of NiCl 2 exposure on cognition and behavior in larval and adult zebrafish. Larval and adult zebrafish were exposed to NiCl 2 concentrations (0.025, 2.0, 5.0, and 15.0mg/L) or water (control) in two treatment regimens: acute and subchronic. Larvae were exposed to NiCl 2 for 2h (acute treatment: 5-day-old larvae treated for 2h, tested after treatment) or 11days (subchronic treatment: 11-day-old larvae treated since fertilization, tested at 5, 8 and 11days post-fertilization, dpf). Adults were exposed for 12h (acute treatment) or 96h (subchronic treatment) and were tested after the treatment period. In both regimens, exposed zebrafish showed concentration-dependent increases in body nickel levels compared with controls. For larvae, delayed hatching, decreased heart rate and morphological alterations were observed in subchronically treated zebrafish. Larvae from subchronic treatment tested at 5dpf decrease distance and mean speed at a low concentration (0.025mg/L) and increased at higher concentrations (5.0 and 15.0mg/L). Subchronic treated larvae decrease locomotion at 15.0mg/L at 8 and 11dpf, whereas decreased escape responses to an aversive stimulus was observed at 2.0, 5.0 and 15.0mg/L in all developmental stages. For adults, the exploratory behavior test showed that subchronic nickel exposure induced anxiogenic-like behavior and decrease aggression, whereas impaired memory was observed in both treatments. These results indicate that exposure to nickel in early life stages of zebrafish leads to morphological alterations, avoidance response impairment and locomotor deficits whereas acute and subchronic exposure in adults resulst in anxiogenic effects, impaired memory and decreased aggressive behavior. These effects may be associated to neurotoxic actions of nickel and suggest this metal may influence animals' physiology in doses that do not necessarily impact their survival. Copyright © 2017 Elsevier B.V. All rights reserved.

Overview of ToxCast™ | Science Inventory | US EPA

EPA Pesticide Factsheets

In 2007, EPA launched ToxCast™ in order to develop a cost-effective approach for prioritizing the toxicity testing of large numbers of chemicals in a short period of time. Using data from state-of-the-art high throughput screening (HTS) bioassays developed in the pharmaceutical industry, ToxCast™ is building computational models to forecast the potential human toxicity of chemicals. These hazard predictions will provide EPA regulatory programs with science-based information helpful in prioritizing chemicals for more detailed toxicological evaluations, and lead to more efficient use of animal testing. In its first phase, ToxCast™ is profiling over 300 well-characterized chemicals (primarily pesticides) in over 400 HTS endpoints. These endpoints include biochemical assays of protein function, cell-based transcriptional reporter assays, multi-cell interaction assays, transcriptomics on primary cell cultures, and developmental assays in zebrafish embryos. Almost all of the compounds being examined in Phase 1 of ToxCast™ have been tested in traditional toxicology tests, including developmental toxicity, multi-generation studies, and sub-chronic and chronic rodent bioassays. ToxRefDB, a relational database being created to house this information, will contain nearly $1B worth of toxicity studies in animals when completed. ToxRefDB is integrated into a more comprehensive data management system developed by NCCT called ACToR (Aggregated Computational Toxicology

Influence of Study Design on Developmental and Reproductive Toxicology Study Outcomes.

PubMed

Foster, Paul M D

2017-01-01

Regulatory studies of developmental and reproductive toxicity (DART) studies have remained largely unchanged for decades, with exposures occurring at various phases of the reproductive cycle and toxicity evaluations at different ages/times depending on the study purpose. The National Toxicology Program has conducted studies examining the power to detect adverse effects where there is a prenatal exposure, but evaluations occur postnatally. In these studies, examination is required of only 1 male and female pup from each litter beyond weaning. This provides poor resolving power to detect rare events (e.g., reproductive tract malformations). If an adverse effect is detected, there is little confidence in the shape of the dose-response curve (and the Benchmark Dose or No Observed Adverse Effect Level [NOAEL]). We have developed a new protocol to evaluate DART, the modified one generation study, with exposure commencing with pregnant animals and retention of 4 males and females from each litter beyond weaning to improve statistical power. These animals can be allocated to specific cohorts that examine subchronic toxicity, teratology, littering, and neurobehavioral toxicity in the same study. This approach also results in a reduction in animal numbers used, compared with individual stand-alone studies, and offers increased numbers of end points evaluated compared with recent Organization for Economic Cooperation and Development proposals.

Evaluation of the inhalation toxicity of diethylethanolamine (DEEA) in rats.

PubMed

Hinz, J P; Thomas, J A; Ben-Dyke, R

1992-04-01

Diethylethanolamine (DEEA), an industrial anticorrosive additive, was evaluated in rats for its potential toxicity. A 2-week inhalation exposure to 10 ppm revealed no signs of toxicity. At 56 ppm, rats exhibited signs of nasal irritation and corneal opacities. Significant mortality (males, 90%; females, 50%) occurred at 301 ppm. Histopathology revealed inflammatory cell infiltrations of the nasal turbinate mucosa and squamous metaplasia after exposure to 56 ppm. In the 14-week subchronic study, rats were exposed to 0, 11, 25, or 76 ppm. During exposure to DEEA, transient signs of mild to moderate respiratory irritation (noises or rales) were observed with a frequency and severity that was dose dependent. These signs usually cleared within 1 hr post-exposure. However, at 76 ppm some rats continued to exhibit these respiratory signs overnight. There were no significant DEEA-induced changes in either blood chemistry or neurobehavioral parameters. Nasal cavities of rats exposed to 25 or 76 ppm revealed evidence of inflammatory cell infiltration, focal hyperplasia, and squamous metaplasia in the respiratory epithelium of the anterior nasal turbinates. Hypertrophic goblet cells, focal necrosis, and exudate in the nasal lumen were also seen at 76 ppm. DEEA vapors failed to produce persistent ocular or respiratory tract toxicity below 26 ppm. The no-observed-effect-level in this study was 10 ppm.

Plants used in Guatemala for the treatment of protozoal infections. I. Screening of activity to bacteria, fungi and American trypanosomes of 13 native plants.

PubMed

Cáceres, A; López, B; González, S; Berger, I; Tada, I; Maki, J

1998-10-01

Extracts were prepared from 13 native plants used for the treatment of protozoal infections. Activity against bacteria and fungi was demonstrated by dilution procedures; Trypanosoma cruzi was evaluated in vitro against epimastigote and trypomastigotes and in vivo against trypomastigotes. In active extracts, toxicity was evaluated by Artemia salina nauplii, oral acute toxicity (1-5 g/kg) and oral and intraperitoneal subacute toxicity in mice (500 mg/kg). From the plants screened, six showed activity (< or = 2 mg/ml) against bacteria, three against yeasts, five against Microsporum gypseum and five against T. cruzi in vitro and/or in vivo. In vitro and in vivo activity was demonstrated by Neurolaena lobata and Solanum americanum; in vitro or in vivo activity was shown by Acalypha guatemalensis, Petiveria alliacea and Tridax procumbens. Toxicity studies showed that extracts from S. americanum are toxic to A. salina (aqueous, 160 ppm). None showed acute or oral toxicity to mice; S. americanum showed intraperitoneal subacute toxicity.

Bioactive natural constituents from lemongrass tea and erythropoiesis boosting effects: potential use in prevention and treatment of anemia.

PubMed

Ekpenyong, Christopher E; Daniel, Nyebuk E; Antai, Atim B

2015-01-01

This study assessed the effects of lemongrass (Cymbopogon citratus) tea on hematologic indices in human volunteers. One hundred five subjects (55 men and 50 women), aged 18 to 35 years, were randomly assigned to groups set to orally receive infusion prepared from 2, 4, or 8 g of C. citratus leaves once daily for 30 days. Assessment of hematologic indices (hemoglobin concentration [Hb], packed cell volume [PCV], red blood cell [RBC] count, mean cell Hb [MCH], mean cell volume [MCV], mean cell Hb concentration [MCHC], total white blood cell [WBC-total] and differentials, and platelets) were performed 1 day before (baseline), and at 10 (acute) and 30 days (subchronic phase) after the initiation of treatment. Results obtained on days 10 and 30 were compared with baseline values. Infusions prepared from C. citratus leaf powder, which tested positive for tannins, saponins, alkaloids, flavonoids, macro- and micronutrients, significantly increased PCV, Hb, and RBC (P<.05) in all subjects, particularly in the subchronic phase of the study. MCH, MCV, and MCHC were not significantly different from baseline values in both the sexes. WBCs and differentials significantly decreased (P<.05) with the exception of neutrophils and lymphocytes, which significantly increased in some or all groups (P<.05), respectively. C. citratus leaf infusion appears to exert an erythropoiesis boosting effect, likely due to some nutritional constituents and its antioxidant and pharmacologic properties.

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

PubMed Central

Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan

2015-01-01

Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression. PMID:26114099

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression.

PubMed

Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan; Cheng, Tain-Junn; Chuu, Jiunn-Jye

2015-01-01

Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

Acute oral and percutaneous toxicity of pesticides to mallards: Correlations with mammalian toxicity data

USGS Publications Warehouse

Hudson, R.H.; Haegele, M.A.; Tucker, R.K.

1979-01-01

Acute oral (po) and 24-hr percutaneous (perc) LD50 values for 21 common pesticides (19 anticholinesterases, of which 18 were organophosphates, and one was a carbamate; one was an organochlorine central nervous system stimulant; and one was an organonitrogen pneumotoxicant) were determined in mallards (Anas platyrhynchos). Three of the pesticides tested were more toxic percutaneously than orally. An index to the percutaneous hazard of a pesticide, the dermal toxicity index (DTI = po LD50/perc LD50 ? 100), was also calculated for each pesticide. These toxicity values in mallards were compared with toxicity data for rats from the literature. Significant positive correlations were found between log po and log percutaneous LD50 values in mallards (r = 0.65, p 0.10). Variations in percutaneous methodologies are discussed with reference to interspecies variation in toxicity values. It is recommended that a mammalian DTI value approaching 30 be used as a guideline for the initiation of percutaneous toxicity studies in birds, when the po LD50 and/or projected percutaneous LD50 are less than expected field exposure levels.

FDA toxicity databases and real-time data entry.

PubMed

Arvidson, Kirk B

2008-11-15

Structure-searchable electronic databases are valuable new tools that are assisting the FDA in its mission to promptly and efficiently review incoming submissions for regulatory approval of new food additives and food contact substances. The Center for Food Safety and Applied Nutrition's Office of Food Additive Safety (CFSAN/OFAS), in collaboration with Leadscope, Inc., is consolidating genetic toxicity data submitted in food additive petitions from the 1960s to the present day. The Center for Drug Evaluation and Research, Office of Pharmaceutical Science's Informatics and Computational Safety Analysis Staff (CDER/OPS/ICSAS) is separately gathering similar information from their submissions. Presently, these data are distributed in various locations such as paper files, microfiche, and non-standardized toxicology memoranda. The organization of the data into a consistent, searchable format will reduce paperwork, expedite the toxicology review process, and provide valuable information to industry that is currently available only to the FDA. Furthermore, by combining chemical structures with genetic toxicity information, biologically active moieties can be identified and used to develop quantitative structure-activity relationship (QSAR) modeling and testing guidelines. Additionally, chemicals devoid of toxicity data can be compared to known structures, allowing for improved safety review through the identification and analysis of structural analogs. Four database frameworks have been created: bacterial mutagenesis, in vitro chromosome aberration, in vitro mammalian mutagenesis, and in vivo micronucleus. Controlled vocabularies for these databases have been established. The four separate genetic toxicity databases are compiled into a single, structurally-searchable database for easy accessibility of the toxicity information. Beyond the genetic toxicity databases described here, additional databases for subchronic, chronic, and teratogenicity studies have been prepared.

Past, present and emerging toxicity issues for jet fuel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mattie, David R., E-mail: david.mattie@wpafb.af.mil; Sterner, Teresa R.

2011-07-15

The US Air Force wrote the specification for the first official hydrocarbon-based jet fuel, JP-4, in 1951. This paper will briefly review the toxicity of the current fuel, JP-8, as compared to JP-4. JP-8 has been found to have low acute toxicity with the adverse effects being slight dermal irritation and weak dermal sensitization in animals. JP-4 also has low acute toxicity with slight dermal irritation as the adverse effect. Respiratory tract sensory irritation was greater in JP-8 than in JP-4. Recent data suggest exposure to jet fuel may contribute to hearing loss. Subchronic studies for 90 days with JP-8more » and JP-4 showed little toxicity with the primary effect being male rat specific hydrocarbon nephropathy. A 1-year study was conducted for JP-4. The only tumors seen were associated with the male rat specific hydrocarbon nephropathy. A number of immunosuppressive effects have been seen after exposure to JP-8. Limited neurobehavioral effects have been associated with JP-8. JP-8 is not a developmental toxicant and has little reproductive toxicity. JP-4 has not been tested for immune, neurobehavioral or reproductive endpoints. JP-8 and JP-4 were negative in mutagenicity tests but JP-4 showed an increase in unscheduled DNA synthesis. Currently, JP-8 is being used as the standard for comparison of future fuels, including alternative fuels. Emerging issues of concern with jet fuels include naphthalene content, immunotoxicity and inhalation exposure characterization and modeling of complex mixtures such as jet fuels.« less

Past, present and emerging toxicity issues for jet fuel.

PubMed

Mattie, David R; Sterner, Teresa R

2011-07-15

The US Air Force wrote the specification for the first official hydrocarbon-based jet fuel, JP-4, in 1951. This paper will briefly review the toxicity of the current fuel, JP-8, as compared to JP-4. JP-8 has been found to have low acute toxicity with the adverse effects being slight dermal irritation and weak dermal sensitization in animals. JP-4 also has low acute toxicity with slight dermal irritation as the adverse effect. Respiratory tract sensory irritation was greater in JP-8 than in JP-4. Recent data suggest exposure to jet fuel may contribute to hearing loss. Subchronic studies for 90 days with JP-8 and JP-4 showed little toxicity with the primary effect being male rat specific hydrocarbon nephropathy. A 1-year study was conducted for JP-4. The only tumors seen were associated with the male rat specific hydrocarbon nephropathy. A number of immunosuppressive effects have been seen after exposure to JP-8. Limited neurobehavioral effects have been associated with JP-8. JP-8 is not a developmental toxicant and has little reproductive toxicity. JP-4 has not been tested for immune, neurobehavioral or reproductive endpoints. JP-8 and JP-4 were negative in mutagenicity tests but JP-4 showed an increase in unscheduled DNA synthesis. Currently, JP-8 is being used as the standard for comparison of future fuels, including alternative fuels. Emerging issues of concern with jet fuels include naphthalene content, immunotoxicity and inhalation exposure characterization and modeling of complex mixtures such as jet fuels. Copyright © 2011 Elsevier Inc. All rights reserved.

An Update on ToxCast™ | Science Inventory | US EPA

EPA Pesticide Factsheets

In its first phase, ToxCast™ is profiling over 300 well-characterized chemicals (primarily pesticides) in over 400 HTS endpoints. These endpoints include biochemical assays of protein function, cell-based transcriptional reporter assays, multi-cell interaction assays, transcriptomics on primary cell cultures, and developmental assays in zebrafish embryos. Almost all of the compounds being examined in Phase 1 of ToxCast™ have been tested in traditional toxicology tests, including developmental toxicity, multi-generation studies, and sub-chronic and chronic rodent bioassays Lessons learned to date for ToxCast: Large amounts of quality HTS data can be economically obtained. Large scale data sets will be required to understand potential for biological activity. Value in having multiple assays with overlapping coverage of biological pathways and a variety of methodologies Concentration-response will be important for ultimate interpretation Data transparency will be important for acceptance. Metabolic capabilities and coverage of developmental toxicity pathways will need additional attention. Need to define the gold standard Partnerships are needed to bring critical mass and expertise.

Acute Oral Toxicity of Trimethylolethane Trinitrate (TMETN) in Sprague- Dawley Rats

DTIC Science & Technology

1989-07-01

classification scheme of Hodge and Steiner, these results indicate that TMETN is a slightly toxic compound.1 20. ON-RIBUTION /AVAILABILITY OF ABSTRACT 21. ABSTRACT...the classification scheme of Hodge and Sterner, these results indcate that TMETN is a slightly toxic compound. KEY WORDS: Acute Oral Toxicit-y...Dawley rats and 1027.4 63.7 mg/kg in female Sprague-Dawley rats. These MLD values place TMETN in the "slightly toxic" range by the system of Hodge and

Oral toxicity of fipronil insecticide against the stingless bee Melipona scutellaris (Latreille, 1811).

PubMed

Lourenço, Clara Tavares; Carvalho, Stephan Malfitano; Malaspina, Osmar; Nocelli, Roberta Cornélio Ferreira

2012-10-01

For a better evaluation of the model using Apis mellifera in toxicology studies with insecticides, the oral acute toxicity of the insecticide fipronil against the stingless bee Melipona scutellaris was determined. The results showed that fipronil was highly toxic to M. scutellaris, with a calculated LC(50) (48 h) value of 0.011 ng a.i./μL of sucrose solution and an estimated oral LD(50) (48 h) of 0.6 ng a.i./bee. Our results showed that M. scutellaris bee is more sensitive to fipronil than the model specie A. mellifera.

Changes in the levels of p-ERK, p-CREB, and c-fos in rat mesocorticolimbic dopaminergic system after morphine-induced conditioned place preference: the role of acute and subchronic stress.

PubMed

Haghparast, Abbas; Fatahi, Zahra; Alamdary, Shabnam Zeighamy; Reisi, Zahra; Khodagholi, Fariba

2014-03-01

ERK pathway plays a critical role in the cellular adaptive responses to environmental changes. Stressful conditions can induce the activation of activate ERK, and its downstream targets, CREB and c-fos, in neural cells. Exposure to opioids has the same effect. In this study, we investigated the effects of morphine-induced conditioned place preference (CPP) on p-ERK/ERK ratio, p-CREB/CREB ratio and c-fos level in the mesocorticolimbic dopaminergic system including the nucleus accumbens (NAc), amygdala (AMY), striatum (Str), and prefrontal cortex (PFC).Our aim was to determine if acute and subchronic stress would affect these alterations. Male Wistar rats were divided into two saline- and morphine-treated groups. Each group contained of control, acute stress, and subchronic stress subgroups. The CPP procedure was performed for all of the rats. We dissected out the NAc, AMY, Str, and PFC regions and measured the mentioned ratios and c-fos level by Western blot analysis. The results revealed that in saline-treated animals, all factors enhanced significantly after performing acute and subchronic stress while there was an exception in p-ERK/ERK ratio in the Str and PFC; the changes were not significant during acute stress. Conditioning score decreased after applying the subchronic but not acute stress. In morphine-treated animals, all factors were increased after application of acute and subchronic stress, and conditioning scores also decreased after stress. Our findings suggest that in saline- or morphine-treated animals, acute and subchronic stress increases p-ERK, p-CREB, and c-fos levels in the mesocorticolimbic system. It has been shown that morphine induces the enhancement of the mentioned factors; on the other hand, our result demonstrates that stress can amplify these changes.

Toxicological assessment of green petroleum coke.

PubMed

McKee, Richard H; Herron, Deborah; Beatty, Patrick; Podhasky, Paula; Hoffman, Gary M; Swigert, James; Lee, Carol; Wong, Diana

2014-01-01

Green petroleum coke is primarily inorganic carbon with some entrained volatile hydrocarbon material. As part of the petroleum industry response to the high production volume challenge program, the potential for reproductive effects was assessed in a subchronic toxicity/reproductive toxicity screening test in rats (OECD 421). The repeated-dose portion of the study provided evidence for dust accumulation and inflammatory responses in rats exposed to 100 and 300 mg/m(3) but there were no effects at 30 mg/m(3). In the reproductive toxicity screen, the frequency of successful matings was reduced in the high exposure group (300 mg/m(3)) and was not significantly different from control values but was outside the historical experience of the laboratory. The postnatal observations (external macroscopic examination, body weight, and survival) did not indicate any treatment-related differences. Additional tests conducted to assess the potential hazards to aquatic (fish, invertebrates, and algae) and soil dwelling organisms (earthworms and vascular plants) showed few effects at the maximum loading rates of 1000 mg coke/L in aquatic studies and 1000 mg coke/kg soil in terrestrial studies. The only statistically significant finding was an inhibition of algal growth measured as either biomass or growth rate.

Testicular effects of sub-chronic administration of Hibiscus sabdariffa calyx aqueous extract in rats.

PubMed

Orisakwe, Orish Ebere; Husaini, Danladi Chiroma; Afonne, Onyenmechi Johnson

2004-01-01

The sub-chronic effect of Hibiscus sabdariffa (HS) calyx aqueous extract on the rat testes was investigated with a view to evaluate the pharmacological basis for the use of HS calyx extract as an aphrodisiac. Three test groups received different doses of 1.15, 2.30, and 4.60 g/kg based on the LD(50). The extracts were dissolved in the drinking water. The control group was given equivalent volume of water only. The animals were allowed free access to drinking solution during the 12-week period of exposure. At the expiration of the treatment period, animals were sacrificed, testes excised and weighed, and epididymal sperm number recorded. The testes were processed for histological examination. Results did not show any significant (P>0.05) change in the absolute and relative testicular weights. There was, however, a significant (P<0.05) decrease in the epididymal sperm counts in the 4.6 g/kg group, compared to the control. The 1.15 g/kg dose group showed distortion of tubules and a disruption of normal epithelial organization, while the 2.3 g/kg dose showed hyperplasia of testis with thickening of the basement membrane. The 4.6 g/kg dose group, on the other hand, showed disintegration of sperm cells. The results indicate that aqueous HS calyx extract induces testicular toxicity in rats.

Endometrial damage and apoptosis in rats induced by dichlorvos and ameliorating effect of antioxidant vitamins E and C.

PubMed

Oral, Baha; Guney, Mehmet; Demirin, Hilmi; Ozguner, Meltem; Giray, Seren Gülsen; Take, Gulnur; Mungan, Tamer; Altuntas, Irfan

2006-11-01

We aimed to investigate the effect of subchronic administration of dichlorvos (DDVP) on endometrium and to evaluate ameliorating effects of a combination of Vitamins E and C against DDVP toxicity in the rat. Three groups of rats were used in the experiment. The first group was treated with 4 mg/kg DDVP; the second group was treated with 4 mg/kg body weight DDVP plus Vitamins E and C (DDVP+Vit); the third group was given only corn oil (control). DDVP and DDVP+Vit groups were given DDVP by gavage 5 days a week for 4 weeks at a dose level of 4 mg/kg day by using corn oil as the vechicle. Vitamins E and C were injected at doses of 50 mg/kg i.m. and 20 mg/kg body weight i.p. Histopathological and immunohistochemical examinations for caspase-3 and caspase-9 were accomplished in the endometrium. The level of malondialdehyde (MDA) increased significantly in the DDVP group compared with the control group (p<0.05). MDA significantly decreased in the DDVP+Vit group compared with the DDVP group (p<0.05). Administration of Vitamins E and C along with DDVP significantly reduced the histopathological changes and the extent of apoptosis. In conclusion, subchronic DDVP administration caused endometrial damage and that treatment with a combination of Vitamins E and C reduced endometrial damage caused by DDVP.

Decreased Hippocampal Neuroplasticity and Behavioral Impairment in an Animal Model of Inhalant Abuse

PubMed Central

Malloul, Hanaa; Bennis, Mohammed; Bonzano, Sara; Gambarotta, Giovanna; Perroteau, Isabelle; De Marchis, Silvia; Ba-M'hamed, Saadia

2018-01-01

Thinners are highly toxic chemicals widely employed as organic solvents in industrial and domestic use. They have psychoactive properties when inhaled, and their chronic abuse as inhalants is associated with severe long-term health effects, including brain damage and cognitive-behavioral alterations. Yet, the sites and mechanisms of action of these compounds on the brain are far from being fully understood. Here, we investigated the consequences of paint thinner inhalation in adult male mice. Depression-like behaviors and an anxiolytic effect were found following repeated exposure in chronic treatments lasting 12 weeks. Both subchronic (6 weeks) and chronic treatments impaired learning and memory functions, while no changes were observed after acute treatment. To investigate possible molecular/structural alterations underlying such behavioral changes, we focused on the hippocampus. Notably, prolonged, but not acute thinner inhalation strongly affected adult neurogenesis in the dentate gyrus (DG), reducing progenitor cell proliferation after chronic treatments and impairing the survival of newborn neurons following both chronic and subchronic treatments. Furthermore, a down-regulation in the expression of BDNF and NMDA receptor subunits as well as a reduction in CREB expression/phosphorylation were found in the hippocampi of chronically treated mice. Our findings demonstrate for the first time significant structural and molecular changes in the adult hippocampus after prolonged paint thinner inhalation, indicating reduced hippocampal neuroplasticity and strongly supporting its implication in the behavioral dysfunctions associated to inhalant abuse. PMID:29472835

Subchronic arsenic exposure through drinking water alters vascular redox homeostasis and affects physical health in rats.

PubMed

Waghe, Prashantkumar; Sarath, Thengumpallil Sasindran; Gupta, Priyanka; Kutty, Harikumar Sankaran; Kandasamy, Kannan; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

2014-12-01

We evaluated whether arsenic can alter vascular redox homeostasis and modulate antioxidant status, taking rat thoracic aorta as a model vascular tissue. In addition, we evaluated whether the altered vascular biochemical homeostasis could be associated with alterations in the physical indicators of toxicity development. Rats were exposed to arsenic as 25, 50, and 100 ppm of sodium arsenite through drinking water for 90 consecutive days. Body weight, food intake, and water consumption were recorded weekly. On the 91st day, rats were sacrificed; vital organs and thoracic aorta were collected. Lipid peroxidation, reactive oxygen species generation, and antioxidants were assessed in the thoracic aorta. Arsenic increased aortic lipid peroxidation and hydrogen peroxide generation while decreased reduced glutathione content in a dose-dependent manner. The activities of the enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were decreased. Further, arsenic at 100 ppm decreased feed intake, water consumption, and body weight from the 11th week onward. At this concentration, arsenic increased the relative weights of the liver and kidney. The results suggest that arsenic causes dose-dependent oxidative stress, reduction in antioxidative defense systems, and body weight loss with alteration in hepato-renal organosomatic indices. Overall, subchronic arsenic exposure through drinking water causes alteration in vascular redox homeostasis and at high concentration affects physical health.

E-submission Format for Sub-chronic and Chronic Studies

EPA Pesticide Factsheets

The purpose of this document is to suggest the format for final reports and to provide instructions for creation of Adobe PDF electronic submission documents for electronic submission of sub-chronic and chronic studies for pesticides.

Experiences and coping strategies of oncology patients undergoing oral chemotherapy: First steps of a grounded theory study.

PubMed

Gassmann, Catherine; Kolbe, Nina; Brenner, Andrea

2016-08-01

Chemotherapies are increasingly available for oral application. Previous studies have focussed on differences between orally and intravenously administered chemotherapies, mostly following quantitative designs surveying patients' preferences and adherence. The lived experience of patients undergoing oral chemotherapy has been rarely explored. Therefore, this study investigates how patients experience oral chemotherapy. We conducted open interviews with six patients and two spouses. Recruitment took place in the outpatient clinic of an urban Swiss hospital. Data collection and analysis followed the principles of Straussian grounded theory. The participants reported physical and emotional reluctance towards oral chemotherapy as well as toxic side effects. Feeling responsible emerged as a core phenomenon. All participants intended to adhere to the therapy although this was challenging because of the complex medication regimen. Belief in the effectiveness of the therapy was a strengthening factor. All participants reported to be highly adherent to oral chemotherapy. Although they experienced some toxic side effects, they did not react. Monitoring toxicities and support in everyday life should be a core feature of care. Copyright © 2016 Elsevier Ltd. All rights reserved.

Iron overload prevents oxidative damage to rat brain after chlorpromazine administration.

PubMed

Piloni, Natacha E; Caro, Andres A; Puntarulo, Susana

2018-05-15

The hypothesis tested is that Fe administration leads to a response in rat brain modulating the effects of later oxidative challenges such as chlorpromazine (CPZ) administration. Either a single dose (acute Fe overload) or 6 doses every second day (sub-chronic Fe overload) of 500 or 50 mg Fe-dextran/kg, respectively, were injected intraperitoneally (ip) to rats. A single dose of 10 mg CPZ/kg was injected ip 8 h after Fe treatment. DNA integrity was evaluated by quantitative PCR, lipid radical (LR · ) generation rate by electron paramagnetic resonance (EPR), and catalase (CAT) activity by UV spectrophotometry in isolated brains. The maximum increase in total Fe brain was detected after 6 or 2 h in the acute and sub-chronic Fe overload model, respectively. Mitochondrial and nuclear DNA integrity decreased after acute Fe overload at the time of maximal Fe content; the decrease in DNA integrity was lower after sub-chronic than after acute Fe overload. CPZ administration increased LR · generation rate in control rat brain after 1 and 2 h; however, CPZ administration after acute or sub-chronic Fe overload did not affect LR · generation rate. CPZ treatment did not affect CAT activity after 1-4 h neither in control rats nor in acute Fe-overloaded rats. However, CPZ administration to rats treated sub-chronically with Fe showed increased brain CAT activity after 2 or 4 h, as compared to control values. Fe supplementation prevented brain damage in both acute and sub-chronic models of Fe overload by selectively activating antioxidant pathways.

Characterization of the dinophysistoxin-2 acute oral toxicity in mice to define the Toxicity Equivalency Factor.

PubMed

Abal, Paula; Louzao, M Carmen; Cifuentes, José Manuel; Vilariño, Natalia; Rodriguez, Ines; Alfonso, Amparo; Vieytes, Mercedes R; Botana, Luis M

2017-04-01

Ingestion of shellfish with dinophysistoxin-2 (DTX2) can lead to diarrheic shellfish poisoning (DSP). The official control method of DSP toxins in seafood is the liquid chromatography-mass spectrometry analysis (LC-MS). However in order to calculate the total toxicity of shellfish, the concentration of each compound must be multiplied by individual Toxicity Equivalency Factor (TEF). Considering that TEFs caused some controversy and the scarce information about DTX2 toxicity, the aim of this study was to characterize the oral toxicity of DTX2 in mice. A 4-Level Up and Down Procedure allowed the characterization of DTX2 effects and the estimation of DTX2 oral TEF based on determination of the lethal dose 50 (LD50). DTX2 passed the gastrointestinal barrier and was detected in urine and feces. Acute toxicity symptoms include diarrhea and motionless, however anatomopathology study and ultrastructural images restricted the toxin effects to the gastrointestinal tract. Nevertheless enterocytes microvilli and tight junctions were not altered, disconnecting DTX2 diarrheic effects from paracellular epithelial permeability. This is the first report of DTX2 oral LD 50 (2262 μg/kg BW) indicating that its TEF is about 0.4. This result suggests reevaluation of the present TEFs for the DSP toxins to better determine the actual risk to seafood consumers. Copyright © 2017 Elsevier Ltd. All rights reserved.

SUBCHRONIC ENDOTOXIN INHALATION CAUSES PERSISTENT AIRWAY DISEASE

EPA Science Inventory

ABSTRACT

The endotoxin component of organic dusts causes acute reversible airflow obstruction and airway inflammation. To test the hypothesis that endotoxin alone causes airway remodeling, we have compared the response of two inbred mouse strains to subchronic endotoxin ...

Acute oral toxicity of Pereskia bleo and Pereskia grandifolia in mice

PubMed Central

Sim, K. S.; Sri Nurestri, A. M.; Sinniah, S. K.; Kim, K. H.; Norhanom, A. W.

2010-01-01

Pereskia bleo and Pereskia grandifolia, belonging to the botanical family Cactaceae, have been traditionally used by the locals in Malaysia for treatment of various ailments. The current study reports the outcome of acute oral toxicity investigation of Pereskia bleo and Pereskia grandifolia, on ICR mice. No mortalities or evidence of adverse effects have been observed in ICR mice following acute oral administration at the highest dose of 2500 mg/ kg crude extracts of Pereskia bleo and Pereskia grandifolia. This is the first report on the acute oral toxicity of Pereskia bleo and Pereskia grandifolia and the findings of this study are in agreement with those of in vitro experiments and thus provide scientific validation on the use of the leaves of Pereskia bleo and Pereskia grandifolia. PMID:20548939

Combined treatment with subchronic lithium and acute intracerebral mirtazapine microinjection into the median raphe nucleus exerted an anxiolytic-like effect synergistically.

PubMed

An, Yan; Inoue, Takeshi; Kitaichi, Yuji; Chen, Chong; Nakagawa, Shin; Wang, Ce; Kusumi, Ichiro

2016-07-15

Although preclinical and clinical studies have established the efficacy of lithium augmentation of antidepressant drugs, the mechanism of action of lithium augmentation is not fully understood. Our previous study reported that subchronic lithium treatment enhanced the anxiolytic-like effect of systemic mirtazapine. In the present study, we examined the effect of subchronic lithium in combination with acute local intracerebral injection of mirtazapine on fear-related behaviors in a contextual fear conditioning test in rats to clarify the target brain region of lithium augmentation of mirtazapine. After conditioning by footshock, diet (food pellets) containing Li2CO3 at a concentration of 0.2% was administered for 7 days. Ten min before testing and 7 days after conditioning, mirtazapine (3μg/site) in a volume of 0.5µl was acutely injected into the median raphe nucleus (MRN), hippocampus or amygdala. The combination of subchronic lithium and acute mirtazapine microinjection into the MRN but not the hippocampus or the amygdala reduced fear expression synergistically. These results suggest that intra-MRN mirtazapine treatment with subchronic lithium exerts the anxiolytic-like effect through the facilitation of the MRN-5HT pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

Combinatorial QSAR Modeling of Rat Acute Toxicity by Oral Exposure

EPA Science Inventory

Quantitative Structure-Activity Relationship (QSAR) toxicity models have become popular tools for identifying potential toxic compounds and prioritizing candidates for animal toxicity tests. However, few QSAR studies have successfully modeled large, diverse mammalian toxicity end...

Subchronic mercury exposure in coturnix and a method of hazard evaluation

USGS Publications Warehouse

Hill, E.F.; Soares, J.H.

1984-01-01

The sublethal toxicity of inorganic (HgCI 2) and organic (CH3HgCI) mercury chloride was studied in coturnix (Corurnix japonica) by feeding them mercuric compounds (CH3HgCI at concentrations of 0.125,0.5,2 and 8 ppm; HgCI2 at 0.5, 2, 8 and 32 ppm) in ad libitum diets from hatching to adulthood. Differences of response to the mercurials were compared on the basis of selected indicator enzymes and plasma chemistries. Comparisons of response to equivalent concentrations of the two mercurials and dose-response relationships were made at 1,3,5,7 and 9 weeks. Changes of activity were detected for brain acetylcholinesterase (AChE) and the plasma enzymes aspartate aminotransferase (ASA T), butyrylcholinesterase (BChE), lactate dehydrogenase (LDH) and ornithine carbamoyl transferase (OCT). Changes of ASA T, LDH and OCT were then quantified by probit analysis and the mercurials were compared through their median effective concentrations (EC50). This quantal procedure was based on the establishment of normal control values for each enzyme and then classifying mercury-treated outliers (more than + 2 SD) as respondents. The EC50 values at 9 weeks for ASA T, LDH and OCT, respectively, were 9, 3 and 63 ppm for HgCl 2, and 5, 1 and 4 ppm for CH3HgCI. These results provided the basis for two hazard indices that were calculated by dividing the EC50 into the oral LD50 and the 5-d dietary LC50. Mercury also had contradictory effects on gonadal maturation in both sexes.

Oral exposure to cylindrospermopsin in pregnant rats: reproduction and foetal toxicity studies.

PubMed

Sibaldo de Almeida, Cristhiano; Costa de Arruda, Andrea Caroline; Caldas de Queiroz, Erika; Matias de Lima Costa, Haline Tereza; Barbosa, Patrícia Fernandes; Araújo Moura Lemos, Telma Maria; Oliveira, Cláudia Nunes; Pinto, Ernani; Schwarz, Aline; Kujbida, Paula

2013-11-01

Cylindrospermopsin (CYN) induces toxicity in pregnant mice when administered intraperitoneally. This study investigated whether oral exposure to CYN (0.03, 0.3 and 3 μg/kg) during pregnancy causes toxic effects and impairs gestation in rats. The results of reproductive performance and teratology studies were similar between the control and experimental dams. Our findings suggest that CYN consumption within the guideline values for drinking water is not able to promote foetal toxicity or alterations in rat reproductive performance. Copyright © 2013 Elsevier Ltd. All rights reserved.

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

PubMed Central

Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-01-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day. PMID:25874036

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

PubMed

Nam, Chunja; Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-03-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

Single, 14-Day, and 13-Week Repeated Dose Toxicity Studies of Daily Oral Gelidium elegans Extract Administration to Rats.

PubMed

Choi, Jia; Ryu, Su-Jung; Kim, Kui-Jin; Kim, Hyung-Min; Chung, Hee-Chul; Lee, Boo-Yong

2018-01-20

Gelidium elegans extract (GEE) is derived from a red alga from the Asia-Pacific region, which has antioxidant, anti-adipogenic, and anti-hyperglycemic effects. However, detailed studies of the toxicology of GEE have not been performed. We evaluated the single oral dose toxicity of GEE in male and female Sprague-Dawley (CD) rats. GEE did not cause deaths or have toxic effects at dosages of 5000 mg/kg/day, although compound-colored stools and diarrhea were observed in both sexes, which lasted <2 days. Therefore, the LD 50 of GEE is likely to be >5000 mg/kg. We next evaluated the repeated oral dose toxicity of GEE in CD rats over 14 days and 13 weeks. GEE did not induce any significant toxicological changes in either sex at 2000 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects, in terms of clinical signs, mortality, body mass, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy, organ masses, or histopathology, at dosages of 500, 1000, or 2000 mg/kg/day. The no observed adverse effect level (NOAEL) for GEE is thus likely to be >2000 mg/kg/day, and no pathology was identified in potential target organs. Therefore, this study indicates that repeated oral dosing with GEE is safe in CD rats.

Amelioration of cadmium- and mercury-induced liver and kidney damage in rats by genetically engineered probiotic Escherichia coli Nissle 1917 producing pyrroloquinoline quinone with oral supplementation of citric acid.

PubMed

Raghuvanshi, Ruma; Chaudhari, Archana; Kumar, G Naresh

2016-01-01

Antioxidants, chelating agents, and probiotics are used to manage the toxic effects of cadmium (Cd) and mercury (Hg). The aim of this study was to investigate the combined effects of antioxidants, chelating agents, and probiotics against heavy metal toxicity. Genetically modified probiotic Escherichia coli Nissle 1917 (EcN-20) producing a potent water soluble antioxidant pyrroloquinoline quinone (PQQ) was supplemented with oral citric acid and compared with another genetically modified probiotic EcN-21 producing PQQ and citric acid against oxidative stress induced by Cd and Hg. Rats were independently given 100 ppm Cd and 80 ppm Hg in drinking water for 4 wk. EcN-20 was found to be more effective than EcN-2 (EcN strain with genomic integration of vgb and gfp genes) with orally given PQQ against oxidative stress induced by Cd and Hg. EcN-20 supplemented with oral citric acid was more effective against Cd and Hg toxicity compared with EcN-2+citric acid (oral), EcN-2+PQQ (oral), EcN-2+PQQ (oral)+citric acid (oral), EcN-20, and EcN-21. However, protection shown by EcN-21 was similar to EcN-20. The combination therapy involving probiotic EcN-20 producing PQQ with citric acid given orally was found to be a moderately effective strategy against toxicity induced by Cd and Hg, whereas the protective effect of EcN-21 was the same as EcN-20. Copyright © 2016 Elsevier Inc. All rights reserved.

Evidence for oral agmatine sulfate safety--a 95-day high dosage pilot study with rats.

PubMed

Gilad, Gad M; Gilad, Varda H

2013-12-01

Agmatine, decarboxylated arginine, exerts beneficial effects in various experimental disease models. Clinical trials indicate the safety and effectiveness of short-term (up to 21 days) high dose regimens of oral agmatine sulfate, but longer term studies are lacking. This pilot study undertook to assess the safety of a longer term high dosage oral agmatine sulfate in laboratory rats. Adult Wistar rats consumed 5.3 g/l agmatine sulfate in their drinking water for 95 days, a regimen estimated to result in a daily dosage of absorbed agmatine of about 100mg/kg. Animals' body weight, water consumption and blood pressure were periodically measured, and general cage behavior, fur appearance, urination and feces appearance monitored. These parameters were also determined at 20 days after treatment cessation (day 115). On days 95 and 115, animals were euthanized for gross necropsy assessment. Agmatine-treated rats showed slight, but significant reductions in body weight and blood pressure, and reduced water consumption during treatment, which recovered completely within 20 days after treatment cessation. Otherwise, no abnormal behaviors or organ pathologies were observed. These findings are first to suggest apparent safety of sub-chronic high dosage dietary agmatine sulfate in laboratory rats, thus lending further support to the therapeutic applications of agmatine. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bioaccumulation, morphological changes, and induction of metallothionein gene expression in the digestive system of the freshwater crab Sinopotamon henanense after exposure to cadmium.

PubMed

Wu, Hao; Li, Yingjun; Lang, Xingping; Wang, Lan

2015-08-01

To study the responses of digestive system of the freshwater crab Sinopotamon henanense to the exposure with cadmium (Cd), crabs were acutely exposed to 7.25, 14.50, and 29.00 mg/l Cd for 96 h and subchronically exposed to 0.725, 1.450, and 2.900 mg/l for 21 days. Cd bioaccumulation in the hepatopancreas and digestive tract (esophagus and intestine) was examined. Furthermore, histopathological alterations of the esophagus, midgut, hindgut, and hepatopancreas were assessed in animals from the 29.0 and 2.90 mg/l Cd treatment groups, and expression of metallothionein messenger RNA (MT mRNA) in the hepatopancreas and intestine was measured in all treatment groups. The results showed difference in the middle and high concentrations between acute and subchronic treatment groups. Cd content in digestive tract after acute 14.5 and 29.0 mg/l Cd exposure was significantly higher than that at subchronic 1.45 and 2.90 mg/l exposure, but Cd levels in hepatopancreas were not significantly different under the same condition. Acute exposure to Cd induced greater morphological damage than subchronic exposure: large areas of epithelial cells were necrotic in hepatopancreas and midgut, which detached from the basal lamina. Vacuolated muscle cells were observed in the hindgut of animals from the acute exposure group, but the changes of esophageal morphology were not obvious after acute or subchronic treatments. The expression of MT mRNA increased with increasing Cd concentration, and MT mRNA level in acute exposure groups was significantly lower when compared to the subchronic exposure groups. Higher Cd content and lower MT mRNA expression in the acutely exposed groups may be responsible for more severe damage of digestive system in these exposure groups.

Overview of Chronic Oral Toxicity Values for Chemicals Present in Hydraulic Fracturing Fluids, Flowback and Produced Waters

EPA Science Inventory

As the use of hydraulic fracturing has increased, concerns have been raised about potential public health effects that may arise if hydraulic fracturing-related chemicals were to impact drinking water resources. This study presents an overview of the chronic oral toxicity values—...

Consensus Modeling of Oral Rat Acute Toxicity

EPA Science Inventory

An acute toxicity dataset (oral rat LD50) with about 7400 compounds was compiled from the ChemIDplus database. This dataset was divided into a modeling set and a prediction set. The compounds in the prediction set were selected so that they were present in the modeling set used...

Antimicrobial, antioxidative, and insect repellent effects of Artemisia absinthium essential oil.

PubMed

Mihajilov-Krstev, Tatjana; Jovanović, Boris; Jović, Jovana; Ilić, Budimir; Miladinović, Dragoljub; Matejić, Jelena; Rajković, Jelena; Dorđević, Ljubiša; Cvetković, Vladimir; Zlatković, Bojan

2014-12-01

In this paper, the chemical composition and biological activity of the essential oil of Artemisia absinthium was studied. The aim of this study was to investigate the potential of ethnopharmacological uses of this plant species in the treatment of gastrointestinal diseases and wounds, and as an insect repellent. The aerial part of the plant was hydrodistilled, and the chemical composition of the essential oil was analyzed by gas chromatography and gas chromatography/mass spectrometry. Forty-seven compounds, corresponding to 94.65 % of the total oil, were identified, with the main constituents being sabinene (24.49 %), sabinyl acetate (13.64 %), and α-phellandrene (10.29 %). The oil yield was 0.23 % (v/w). The antimicrobial activity of the oil was investigated against ten bacterial isolates (from patients wounds and stools) and seven American Type Culture Collection strains using a microwell dilution assay. The minimal inhibitory/bactericidal concentration of the oil ranged from < 0.08 to 2.43 mg/mL and from 0.08 to 38.80 mg/mL, respectively. The antioxidant activity of the essential oil was evaluated using 2,2-diphenyl-1-picrylhydrazil and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical-scavenging methods and assessed as significant. Skin irritation potential and acute toxicity of the oil were also investigated. Results of the skin irritant reaction showed that none of the 30 volunteers developed a positive skin irritant reaction to undiluted A. absinthium essential oil. Acute oral exposure to the essential oil did not cause mortality in the treated mice, but it did cause neurological, muscle, and gastrointestinal problems. A subchronic toxicity test on Drosophila melanogaster showed that the essential oil of A. absinthium is toxic for developing insect larvae. Starting with the concentration of 0.38 % of essential oil in medium, significant mortality of larvae exposed to the oil was noted when compared to the control. Probit analysis revealed that the LC50 value of A. absinthium essential oil for D. melanogaster larvae after 15 days of exposure was 6.31 % (49 mg/mL). The essential oil also affected the development of D. melanogaster larvae and significantly delayed achievement of the pupa stadium. Georg Thieme Verlag KG Stuttgart · New York.

FDA toxicity databases and real-time data entry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arvidson, Kirk B.

Structure-searchable electronic databases are valuable new tools that are assisting the FDA in its mission to promptly and efficiently review incoming submissions for regulatory approval of new food additives and food contact substances. The Center for Food Safety and Applied Nutrition's Office of Food Additive Safety (CFSAN/OFAS), in collaboration with Leadscope, Inc., is consolidating genetic toxicity data submitted in food additive petitions from the 1960s to the present day. The Center for Drug Evaluation and Research, Office of Pharmaceutical Science's Informatics and Computational Safety Analysis Staff (CDER/OPS/ICSAS) is separately gathering similar information from their submissions. Presently, these data are distributedmore » in various locations such as paper files, microfiche, and non-standardized toxicology memoranda. The organization of the data into a consistent, searchable format will reduce paperwork, expedite the toxicology review process, and provide valuable information to industry that is currently available only to the FDA. Furthermore, by combining chemical structures with genetic toxicity information, biologically active moieties can be identified and used to develop quantitative structure-activity relationship (QSAR) modeling and testing guidelines. Additionally, chemicals devoid of toxicity data can be compared to known structures, allowing for improved safety review through the identification and analysis of structural analogs. Four database frameworks have been created: bacterial mutagenesis, in vitro chromosome aberration, in vitro mammalian mutagenesis, and in vivo micronucleus. Controlled vocabularies for these databases have been established. The four separate genetic toxicity databases are compiled into a single, structurally-searchable database for easy accessibility of the toxicity information. Beyond the genetic toxicity databases described here, additional databases for subchronic, chronic, and teratogenicity studies have been prepared.« less

Murine pulmonary responses after sub-chronic exposure to aluminum oxide-based nanowhiskers

PubMed Central

2012-01-01

Background Aluminum oxide-based nanowhiskers (AO nanowhiskers) have been used in manufacturing processes as catalyst supports, flame retardants, adsorbents, or in ceramic, metal and plastic composite materials. They are classified as high aspect ratio nanomaterials. Our aim was to assess in vivo toxicity of inhaled AO nanowhisker aerosols. Methods Primary dimensions of AO nanowhiskers specified by manufacturer were 2–4 nm x 2800 nm. The aluminum content found in this nanomaterial was 30% [mixed phase material containing Al(OH)3 and AlOOH]. Male mice (C57Bl/6 J) were exposed to AO nanowhiskers for 4 hrs/day, 5 days/wk for 2 or 4 wks in a dynamic whole body exposure chamber. The whiskers were aerosolized with an acoustical dry aerosol generator that included a grounded metal elutriator and a venturi aspirator to enhance deagglomeration. Average concentration of aerosol in the chamber was 3.3 ± 0.6 mg/m3 and the mobility diameter was 150 ± 1.6 nm. Both groups of mice (2 or 4 wks exposure) were necropsied immediately after the last exposure. Aluminum content in the lung, heart, liver, and spleen was determined. Pulmonary toxicity assessment was performed by evaluation of bronchoalveolar lavage (BAL) fluid (enumeration of total and differential cells, total protein, activity of lactate dehydrogenase [LDH] and cytokines), blood (total and differential cell counts), lung histopathology and pulmonary mechanics. Results Following exposure, mean Al content of lungs was 0.25, 8.10 and 15.37 μg/g lung (dry wt) respectively for sham, 2 wk and 4 wk exposure groups. The number of total cells and macrophages in BAL fluid was 2-times higher in animals exposed for 2 wks and 6-times higher in mice exposed for 4 wks, compared to shams (p < 0.01, p < 0.001, respectively). However no neutrophilic inflammation in BAL fluid was found and neutrophils were below 1% in all groups. No significant differences were found in total protein, activity of LDH, or cytokines levels (IL-6, IFN-γ, MIP-1α, TNF-α, and MIP-2) between shams and exposed mice. Conclusions Sub-chronic inhalation exposures to aluminum-oxide based nanowhiskers induced increased lung macrophages, but no inflammatory or toxic responses were observed. PMID:22713230

Murine pulmonary responses after sub-chronic exposure to aluminum oxide-based nanowhiskers.

PubMed

Adamcakova-Dodd, Andrea; Stebounova, Larissa V; O'Shaughnessy, Patrick T; Kim, Jong Sung; Grassian, Vicki H; Thorne, Peter S

2012-06-19

Aluminum oxide-based nanowhiskers (AO nanowhiskers) have been used in manufacturing processes as catalyst supports, flame retardants, adsorbents, or in ceramic, metal and plastic composite materials. They are classified as high aspect ratio nanomaterials. Our aim was to assess in vivo toxicity of inhaled AO nanowhisker aerosols. Primary dimensions of AO nanowhiskers specified by manufacturer were 2-4 nm x 2800 nm. The aluminum content found in this nanomaterial was 30% [mixed phase material containing Al(OH)3 and AlOOH]. Male mice (C57Bl/6 J) were exposed to AO nanowhiskers for 4 hrs/day, 5 days/wk for 2 or 4 wks in a dynamic whole body exposure chamber. The whiskers were aerosolized with an acoustical dry aerosol generator that included a grounded metal elutriator and a venturi aspirator to enhance deagglomeration. Average concentration of aerosol in the chamber was 3.3 ± 0.6 mg/m3 and the mobility diameter was 150 ± 1.6 nm. Both groups of mice (2 or 4 wks exposure) were necropsied immediately after the last exposure. Aluminum content in the lung, heart, liver, and spleen was determined. Pulmonary toxicity assessment was performed by evaluation of bronchoalveolar lavage (BAL) fluid (enumeration of total and differential cells, total protein, activity of lactate dehydrogenase [LDH] and cytokines), blood (total and differential cell counts), lung histopathology and pulmonary mechanics. Following exposure, mean Al content of lungs was 0.25, 8.10 and 15.37 μg/g lung (dry wt) respectively for sham, 2 wk and 4 wk exposure groups. The number of total cells and macrophages in BAL fluid was 2-times higher in animals exposed for 2 wks and 6-times higher in mice exposed for 4 wks, compared to shams (p < 0.01, p < 0.001, respectively). However no neutrophilic inflammation in BAL fluid was found and neutrophils were below 1% in all groups. No significant differences were found in total protein, activity of LDH, or cytokines levels (IL-6, IFN-γ, MIP-1α, TNF-α, and MIP-2) between shams and exposed mice. Sub-chronic inhalation exposures to aluminum-oxide based nanowhiskers induced increased lung macrophages, but no inflammatory or toxic responses were observed.

SUBCHRONIC INHALATION EXPOSURE OF RATS TO LIBBY AMPHIBOLE AND AMOSITE ASBESTOS

EPA Science Inventory

Exposure to Libby amphibole (LA) is associated with significant increases in asbestosis, lung cancer, and mesothelioma. To support biological potency assessment and dosimetry model development, a subchronic nose-only inhalation exposure study (6 hr/d, 5 d/wk, 13 wk) was conducted...

Toxicity study of a rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats.

PubMed

Saitoh, M; Umemura, T; Kawasaki, Y; Momma, J; Matsushima, Y; Sakemi, K; Isama, K; Kitajima, S; Ogawa, Y; Hasegawa, R; Suzuki, T; Hayashi, M; Inoue, T; Ohno, Y; Sofuni, T; Kurokawa, Y; Tsuda, M

1999-07-01

2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid toxicity in rats and is a candidate as an environmental endocrine disrupter. 2-Mercaptomethylbenzimidazoles (a 1:1 mixture of 4-methyl and 5-methyl isomers, MMBIs), are also employed industrially as rubber antioxidants and are suspected to exert antithyroid toxicity such as 2-MBI. In this investigation, acute and subacute oral toxicity studies of MMBIs in Wistar rats were conducted. The clinical signs of acute oral toxicity were observed including decreased spontaneous movement, a paralytic gait, salivation and lacrimation, and adoption of prone and lateral positions. The LD50 was estimated to be 330 mg/kg. In the subacute oral toxicity study, male and female rats were treated with MMBIs by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg for 28 consecutive days followed by a 2-week recovery period for the control and highest dose groups. Body weight and food consumption, clinical signs, organ weights, clinical biochemistry and haematological parameters including clotting times and micronuclei induction in bone marrow erythropoeitic cells, and histopathology were examined. Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MMBIs exhibited a 1.8-fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level. The antithyroid toxicity of MMBIs in rats was estimated to be one-tenth that of 2-MBI. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study.

Mutagenicity and Acute Oral Toxicity Test for Herbal Poultry Feed Supplements.

PubMed

Srinivasa Rao, Boddapati; Chandrasekaran, C V; Srikanth, H S; Sasikumar, Murugan; Edwin Jothie, R; Haseena, Begum; Bharathi, Bethapudi; Selvam, Ramasamy; Prashanth, D'Souza

2018-01-01

Herbal products are being used and trusted globally for thousands of years for their health benefits and limited side effects. Globally, a general belief amongst the consumers is that herbal supplements are always safe because they are "natural." But later, research reveals that they may not be safe. This raises concern on their safety and implications for their use as feed supplement or medicine. Toxicity testing can reveal some of the risks that may be associated with use of herbs, therefore avoiding potential harmful effects. The present study was designed to investigate five poultry feed supplements (PFS), EGMAX® (to revitalize ovarian activity), FEED-X ™ (feed efficiency enhancer), KOLIN PLUS ™ (natural replacer of synthetic choline chloride), PHYTOCEE® (natural defence enhancer), and STODI® (to prevent and control loose droppings), for their possible mutagenicity and toxicity. Bacterial reverse mutation (BRMT) and acute oral toxicity tests were employed to assess the PFS for their possible mutagenicity and toxicity. Results indicated that the PFS were devoid of mutagenic effects in BRMT and showed higher safety profile in rodent acute oral toxicity test.

Safety of Pochonia chlamydosporia var catenulata in acute oral and dermal toxicity/pathogenicity evaluations in rats and rabbits.

PubMed

García, Liseth; Bulnes, Carlos; Melchor, Gleiby; Vega, Ernesto; Ileana, Miranda; de Oca, Nivian Montes; Hidalgo, Leopoldo; Marrero, Eva

2004-10-01

The nematophagous fungus, Pochonia chlamydosporia var. catenulata (Kamyschlco ex Barron & Onions) Zare & W-Gams, was investigated as a potential biocontrol agent in integrated pest management strategy for Meloidogyne incognita (Kofoid and White) Chitwood in vegetable crops in Cuba. An acute oral and dermal toxicity/patogenicity study was performed to determine the safety of this fungus in non-target organisms. In the first study, a 1-dose level of 5 x 10(8) units of the microbial pest control agent/treated rat was used. Mortality or clinical signs were not evident and no adverse effects on body weight, hematology, microbiology and gross or microscopic pathology were observed. Food and water consumption was not significantly different between control and treated groups. In the acute dermal toxicity study, there was neither mortality nor clinical signs of toxicity, and no toxic effects in gross and microscopic pathology were detected. Thus, Pochonia chlamydosporia var. catenulate (Vcc-108, IMI SD 187), administered oral and dermally to rats and rabbits respectively, was safe in toxicity/pathogenicity studies.

Tavaborole, a Novel Boron-Containing Small Molecule Pharmaceutical Agent for Topical Treatment of Onychomycosis: I. Reproductive and Developmental Toxicity Studies.

PubMed

Ciaravino, Vic; Coronado, Dina; Lanphear, Cheryl; Hoberman, Alan; Chanda, Sanjay

2016-09-01

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. As part of the nonclinical development program, reproductive and developmental toxicity studies were conducted (rat oral fertility and early embryonic development, rat (oral) and rabbit (dermal) embryo-fetal development). There were no effects on fertility or reproductive performance at doses up to 300 mg/kg/d (107 times the maximum recommended human dose [MRHD] based on mean area under the plasma concentration-time curve comparisons). In the rat embryo-fetal development toxicity studies, teratogenicity was not observed at doses up to 100 mg/kg/d (29 times the MRHD). However, several treatment-related skeletal malformations and variations were observed at 300 mg/kg/d (570 times the MRHD). In rabbit embryo-fetal development toxicity studies dosed via oral or dermal administration, the no observable adverse effect level for maternal toxicity and embryo-fetal toxicity was 50 mg/kg/d (16 times the MRHD) and 5% (26 times the MRHD), respectively. © The Author(s) 2016.

Effects of Persea americana Mill (Lauraceae) ["Avocado"] ethanolic leaf extract on blood glucose and kidney function in streptozotocin-induced diabetic rats and on kidney cell lines of the proximal (LLCPK1) and distal tubules (MDBK).

PubMed

Gondwe, M; Kamadyaapa, D R; Tufts, M A; Chuturgoon, A A; Ojewole, J A O; Musabayane, C T

2008-01-01

Extracts of Persea americana Mill (Lauraceae) ("Avocado") have been traditionally used to treat hypertension and diabetes mellitus. Accordingly, we studied the hypoglycaemic and renal function effects of P. americana leaf ethanolic extracts (PAE) in STZ-induced diabetic rats. Oral glucose tolerance responses to various doses of PAE were monitored in fasted rats following a glucose load. Rats treated with deionized water or standard hypoglycaemic drugs acted as untreated and treated positive controls, respectively. Acute renal effects of PAE were investigated in anesthetized rats challenged with 0.077 M NaCl after a 3.5-h equilibration for 4 h comprising 1 h control, 1.5 h treatment and 1.5 h recovery periods. PAE was added to the infusate during the treatment period. Hepatic glycogen concentration was measured after 6 weeks of daily treatment with PAE. PAE induced dose-dependent hypoglycaemic responses in STZ-induced diabetic rats while subchronic PAE treatment additionally increased hepatic glycogen concentrations. Acute PAE infusion decreased urine flow and electrolyte excretion rates, whilst subchronic treatment reduced plasma creatinine and urea concentrations. These results indicate not only the basis of the ethnomedicinal use of P. americana leaf extract in diabetes management, but also of need for further studies to identify and evaluate the safety of PAE's bioactive compounds. (c) 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

Acute and Subacute Toxicity of Safranal, a Constituent of Saffron, in Mice and Rats

PubMed Central

Hosseinzadeh, Hossein; Sadeghi Shakib, Saied; Khadem Sameni, Abbas; Taghiabadi, Elahe

2013-01-01

The acute and sub-acute toxicity of safranal were studied in rat and mice within 2 and 21 days after exposure, respectively. For subacute toxicity, changes in weight as well as biochemical, hematological and pathological parameters were studied. The intraperitoneal LD50 values of safranal were 1.48 mL/kg in male mice, 1.88 mL/kg in female mice and 1.50 mL/kg in male rats. Oral LD50 values were 21.42 mL/kg in male mice, 11.42 mL/kg in female mice and 5.53 mL/kg in male rats. For subacute toxicity, safranal was administered orally to male rats once daily for 21 days. In hematological tests, a significant decrease in RBC counts, hematocrit, hemoglobin and platelets were observed. Safranal decreased cholesterol, triglyceride and alkalin phosphatase. Lactate dehydrogenase and serum urea nitrogen were increased by safranal. Histological studies indicated that safranal did not have any toxic effect on the heart, liver and spleen. However, pathological changes were seen in the kidney and lung. According to LD50 values, safranal was low-toxic in acute intraperitoneal route and practically non-toxic in acute oral administration in both mice and rats. In subacute toxicity, safranal changed some hematological and biochemical parameters. PMID:24250576

BEHAVIORAL ASSESSMENTS OF LONG EVANS RATS FOLLOWING A 13 WEEK SUBCHRONIC TOLUENE EXPOSURE.

EPA Science Inventory

Whereas the acute effects of volatile organic compounds (VOCs) are relatively well understood, there is some controversy regarding the potential for persistent effects following long-term exposure. The current study sought to develop an animal model of subchronic exposure to VOCs...

Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making.

PubMed

Broos, Nienke; Loonstra, Rhianne; van Mourik, Yvar; Schetters, Dustin; Schoffelmeer, Anton N M; Pattij, Tommy; De Vries, Taco J

2015-07-01

Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the reduction of impulsive decision making. Therefore, this study explored whether subchronic atomoxetine treatment can reduce relapse vulnerability by reducing impulsive decision making. Rats were trained in the delayed reward task and were subjected to 3 weeks of cocaine self-administration. Following drug self-administration, animals were divided to different experimental groups and received the noradrenaline transporter inhibitor and attention-deficit/hyperactivity disorder drug atomoxetine or vehicle subchronically for 20 days. On days 1 and 10 after treatment cessation, a context-induced reinstatement test was performed. Throughout the entire experiment, changes in impulsive decision making were continuously monitored. Subchronic treatment with atomoxetine reduced context-induced reinstatement both 1 and 10 days after treatment cessation, only in animals receiving no extinction training. Interestingly, neither subchronic nor acute atomoxetine treatments affected impulsive decision making. Our data indicate that the enduring reduction in relapse sensitivity by atomoxetine occurred independent of a reduction in impulsive decision making. Nonetheless, repeated atomoxetine administration seems a promising pharmacotherapeutical strategy to prevent relapse to cocaine seeking in abstinent drug-dependent subjects. © 2014 Society for the Study of Addiction.

Effects of MDMA on olfactory memory and reversal learning in rats

PubMed Central

Hawkey, Andrew; April, L. Brooke; Galizio, Mark

2014-01-01

The effects of acute and sub-chronic MDMA were assessed using a procedure designed to test rodent working memory capacity: the odor span task (OST). Rats were trained to select an odor that they had not previously encountered within the current session, and the number of odors to remember was incremented up to 24 during the course of each session. In order to separate drug effects on the OST from more general performance impairment, a simple olfactory discrimination was also assessed in each session. In Experiment 1, acute doses of MDMA were administered prior to select sessions. MDMA impaired memory span in a dose-dependent fashion, but impairment was seen only at doses (1.8 and 3.0 mg/kg) that also increased response omissions on both the simple discrimination and the OST. In Experiment 2, a sub-chronic regimen of MDMA (10.0 mg/kg, twice daily over four days) was administered after OST training. There was no evidence of reduced memory span following sub-chronic MDMA, but a temporary increase in omission errors on the OST was observed. In addition, rats exposed to sub-chronic MDMA showed delayed learning when the simple discrimination was reversed. Overall, the disruptive effects of both acute and sub-chronic MDMA appeared to be due to non-mnemonic processes, rather than effects on specific memory functions. PMID:25017644

Antidepressant-like effects of the acute and chronic administration of nicotine in the rat forced swimming test and its interaction with fluoxetine [correction of flouxetine].

PubMed

Vázquez-Palacios, G; Bonilla-Jaime, H; Velázquez-Moctezuma, J

2004-05-01

An antidepressant action of nicotine (NIC) has recently been suggested. Flouxetine, a selective serotonin reuptake inhibitor, is currently the most widely used antidepressant. In the present study, we analyzed the effects of the administration of NIC, fluoxetine (FLX), and the combination of both drugs given acutely, subchronically, and chronically as well as 7 days after chronic administration of these drugs on the forced swim test. Results showed that NIC induced a significant reduction of the time in immobility during the forced swim test (antidepressant effect), with a concomitant increase in swimming activity (serotonergic activation), after acute administration. These effects remain the same after subchronic and chronic administration. FLX failed to induce any effect after acute administration but did induce a significant decrease of immobility and an increase of swimming after subchronic administration. The effect of the chronic administration was significantly larger compared to subchronic administration. The combination of both drugs induced a larger effect than that observed after a single administration but only after subchronic treatment. No effect was observed after the end of the 7-day treatments. Data suggest that NIC has an antidepressant action that is expressed faster than FLX but remains the same later. Thus, cholinergic-serotonergic interactions could play an important role in the treatment of depression.

Diphenyl ditelluride intoxication triggers histological changes in liver, kidney, and lung of mice.

PubMed

da Luz, Sônia Cristina Almeida; Daubermann, Melissa Falster; Thomé, Gustavo Roberto; Dos Santos, Matheus Mülling; Ramos, Angelica; Torres Salazar, Gerson; da Rocha, João Batista Teixeira; Barbosa, Nilda Vargas

2015-01-01

Tellurium compounds may be cytotoxic to different cells types. Thus, this work evaluated the effect of diphenyl ditelluride ((PhTe)2), an organotellurium commonly used in organic synthesis, on the morphology of liver, kidney, and lung. Adult mice were acutely (a subcutaneous single dose: 250 μmol/kg) or subchronically (one daily subcutaneous dose: 10 or 50 μmol/kg for 7 and 14 days) exposed to (PhTe)2. Afterwards, the histological analyses of liver, kidney, and lungs were performed. Liver histology revealed that the hepatocytes of mice subchronically exposed to (PhTe)2 presented cytoplasmic vacuolization, hydropic degeneration, and hyperchromatic nuclei. Subchronic exposure to 50 μmol/kg (PhTe)2 also caused hepatic necrosis. Microvesicular and macrovesicular steatosis were identified in liver of mice acutely exposed to (PhTe)2. Acute and subchronic intoxication with (PhTe)2 induced changes on epithelial cells of renal tubules, namely, loss of brush border and cytoplasmatic vacuolization. Atrophy and hypertrophy, cast proteinaceous formation, and acute tubular necrosis were also identified in renal tissue. Mice subchronically exposed to 50 μmol/kg (PhTe)2 developed intra-alveolar edema and alveolar wall congestion in some areas of lungs. Acute exposure to (PhTe)2 did not cause histological changes in lungs. Our data show that (PhTe)2 may be considered a histotoxic agent for liver, kidney, and lung.

Toxicological analysis and antihyperalgesic, antidepressant, and anti-inflammatory effects of Campomanesia adamantium fruit barks.

PubMed

de Souza, Juliane C; Piccinelli, Ana Cláudia; Aquino, Diana F S; de Souza, Vanessa V; Schmitz, Wanderlei O; Traesel, Giseli K; Cardoso, Claudia A L; Kassuya, Candida A L; Arena, Arielle C

2017-01-01

This study evaluates the anti-inflammatory, antihyperalgesic, and antidepressive potential of the hydroalcoholic extract of Campomanesia adamantium fruit barks (CAE) on rodents and determines the safety of this plant. The acute toxicity of CAE was evaluated by oral administration to female rats as single doses of 0, 500, 1000, or 2000 mg/kg body weight. General behavior and toxic symptoms were observed for 14 days. In the subacute toxicity test, male and female rats received 125 or 250 mg/kg body weight of CAE for 28 days. The oral anti-inflammatory activity of CAE was evaluated in carrageenan-induced pleurisy in male mice. The effect of treatment with CAE (100 mg/kg) for 15 days was evaluated in mechanical hyperalgesia (electronic von Frey), depressive behavior (forced swimming test), and cold hypersensitivity in spared nerve injury (SNI) model in rats. No clinical signs of toxicity were observed in animals from the experimental groups during acute and subacute exposure to CAE. At pleurisy test, the oral administration of CAE significantly inhibited leukocyte migration and protein leakage at all doses tested when compared to control. Oral administration of CAE for 3-15 days significantly inhibited SNI-induced mechanical hyperalgesia and increased immobility in the forced swim test. Finally, on the 15th day, oral treatment with CAE prevented the increase in sensitivity to a cold stimulus induced by SNI. The present study shows that C. adamantium extract has anti-inflammatory, antihyperalgesic, and antidepressive properties in rodents without causing toxicity.

EFFECTS OF SUBCHRONIC EXPOSURES TO CONCENTRATED AMBIENT PARTICLES: VII. DEGENERATION OF DOPAMINERGIC NEURONS IN APO E-/- MICE.

EPA Science Inventory

This research describes the neuropathological consequences of subchronic exposure to particulate matter. A genetically modified animal strain (Apo E-/-) which expresses high levels of oxidative stress was exposed to ambient NYC air for 4-6 months. The brains of these animals were...

BEHAVIORAL ASSESSMENTS OF LONG EVANS RATS FOLLOWING A 13-WEEK SUBCHRONIC TOLUENE EXPOSURE.

EPA Science Inventory

The current study sought to develop an animal model of the neurotoxicity of long-term exposure to volatile organic compounds (VOCs) which may be used to predict the effects of chronic exposure to VOCs on public health. The effects of Subchronic inhalation exposure to toluene (0,...

Huperzine A attenuates cognitive deficits and hippocampal neuronal damage after transient global ischemia in gerbils.

PubMed

Zhou, J; Zhang, H Y; Tang, X C

2001-11-09

The protective effects of huperzine A on transient global ischemia in gerbils were investigated. Five min of global ischemia in gerbils results in working memory impairments shown by increased escape latency in a water maze and reduced time spent in the target quadrant. These signs of dysfunction are accompanied by delayed degeneration of pyramidal hippocampal CA1 neurons and by decrease in acetylcholinesterase activity in the hippocampus. Subchronic oral administration of huperzine A (0.1 mg/kg, twice per day for 14 days) after ischemia significantly reduced the memory impairment, reduced neuronal degeneration in the CA1 region, and partially restored hippocampal choline acetyltransferase activity. The ability of huperzine A to attenuate memory deficits and neuronal damage after ischemia might be beneficial in cerebrovascular type dementia.

Single oral dose toxicity test of polycalcium, a mixed composition of polycan and calcium lactate-gluconate 1:9 (G/G) in SD rat.

PubMed

Kim, Joo-Wan; Choi, Jae-Suk; Ha, Yu-Mi; Choi, In Soon; Kim, Ki-Young; Cho, Hyung-rae; Rha, Chae-hun; Ku, Sae-Kwang

2013-11-01

The object of this study was to obtain acute oral toxicity information of Polycalcium, a mixed composition of Polycan and Calcium lactate-gluconate 1:9 (g/g), in Sprague-Dawely (SD) rats. In order to investigate the toxicity and identify target organs, Polycalcium were once orally administered to female and male SD rats at dose levels of 2000, 1000, 500 and 0 (control) mg/kg body weights. The mortality, changes on body weight and clinical signs were monitored during 14 days after treatment with gross observation, changes on the organ weights and histopathology of principle organs and treatment sites based on the recommendation of KFDA Guidelines [2009-116, 2009]. As the results of single oral treatment of Polycalcium, no treatment related mortalities were observed within 14 days after end of treatment up to 2000 mg/kg, the limited dosage of rodents in the both genders. In addition, no Polycalcium treatment related changes on the body and organ weights, clinical signs, necropsy and histopathological findings were detected. The results obtained in this study suggest that the Polycalcium is non-toxic in rats. The LD50 and approximate LD in rats after single oral dose of Polycalcium were considered over 2000 mg/kg in both female and male, respectively.

[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (1)--Single oral and intravenous dose toxicity studies in rats].

PubMed

Yahara, I; Furukawa, H; Sato, K; Nishimura, K; Harihara, A; Yabuuchi, K; Miyauchi, H; Kii, Y; Muraoka, Y; Kitamura, T; Kato, I

2001-05-01

A single oral dose toxicity study of Cefmatilen hydrochloride hydrate (S-1090) and a single intravenous dose toxicity study of its sodium salt (S-1090-Na) were conducted in rats. One dose level of 2000 mg potency/kg was set in both studies. Single oral dose toxicity study of S-1090 No deaths occurred. Diarrhea occurred on the dosing day and slightly soft feces lasted until 6 days after administration. These changes were considered to result from changes of intestinal flora induced by the antibiotic activity of S-1090. Reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were also observed until the next day after administration. Body weights increased favorably, and no S-1090-related pathological changes were observed. The oral lethal dose of S-1090 was estimated to be more than 2000 mg potency/kg. Single intravenous dose toxicity study of S-1090-Na No deaths occurred. The rats showed characteristic clinical signs such as hypoactivity, abnormal gait and hypopnea immediately after dosing, and some rats showed prone position or paleness of eyeballs and ear auricles in due course. These signs disappeared by 4 hr after administration. Slightly soft feces and reddish-brown feces were observed much the same as in the orally-treated rats. Body weights increased favorably. In the pathological examinations, slight cecal enlargement and increased basophilia, dilatation and calcification of the renal tubules in the kidney were observed. The intravenous lethal dose of S-1090-Na was estimated to be more than 2000 mg potency/kg.

Acute and chronic toxicities of Bacopa monnieri extract in Sprague-Dawley rats.

PubMed

Sireeratawong, Seewaboon; Jaijoy, Kanjana; Khonsung, Parirat; Lertprasertsuk, Nirush; Ingkaninan, Kornkanok

2016-07-27

Bacopa monnieri is a medicinal plant which has long been used in Ayurvedic medicines to augment brain function and to improve memory. The purpose of our study was to identify and evaluate possible toxic effects of B. monnieri extract in rats by assessing hematological, biochemical, and histopathological parameters. Acute oral toxicity of Bacopa monnieri extract was studied in female rats by giving a single orally administered dose at a level of 5,000 mg/kg. The rats were monitored for toxic signs for 14 days. In the chronic toxicity test, groups of both female and male rats were given daily oral doses of B. monnieri extract at dose levels of either 30, 60, 300 or 1,500 mg/kg for 270 days. The behavior and health of the animals was then monitored. At the end of the observation period, the body and organ weights of the rats in each group were measured. Blood was collected and necropsy was performed to evaluate their hematology, blood clinical chemistry, and microanatomy. The acute toxicity test found no significant differences between the experimental and the control group rats. In the chronic toxicity test, animal behavior and health of the experimental groups were normal, just as in the control rats. All values of other parameters assessed remained within the normal range. A single oral administration of B. monnieri extract at the dose of 5,000 mg/kg did not cause any serious undesirable effects. B. monnieri extract at doses of 30, 60, 300 and 1,500 mg/kg given for 270 days did not produce any toxicity in rats.

Mechanical-chemical analyses and sub-chronic systemic toxicity of chemical treated organic bovine bone.

PubMed

Lee, Kwang-il; Lee, Jung-soo; Lee, Keun-soo; Jung, Hong-hee; Ahn, Chan-min; Kim, Young-sik; Shim, Young-bock; Jang, Ju-woong

2015-12-01

Sequentially chemical-treated bovine bone was not only evaluated by mechanical and chemical analyses but also implanted into the gluteal muscles of rats for 12 weeks to investigate potential local pathological effects and systemic toxicities. The test (chemical treated bone) and control (heat treated bone) materials were compared using scanning electron microscope (SEM), x-ray diffraction pattern, inductively coupled plasma analysis, and bending strength test. In the SEM images, the micro-porous structure of heat-treated bone was changed to sintered ceramic-like structure. The structure of bone mineral from test and control materials was analyzed as100% hydroxyapatite. The ratio of calcium (Ca) to potassium (P), the main inorganic elements, was same even though the Ca and P percentages of the control material was relatively higher than the test material. No death or critical symptoms arose from implantation of the test (chemical treated bone) and control (physiological saline) materials during 12 weeks. The implanted sites were macroscopically examined, with all the groups showing non-irritant results. Our results indicate that chemical processed bovine bone has a better mechanical property than the heat treated bone and the implantation of this material does not produce systemic or pathological toxicity. Copyright © 2015 Elsevier Inc. All rights reserved.

Toxicological evaluation of Terminalia paniculata bark extract and its protective effect against CCl4-induced liver injury in rodents.

PubMed

Talwar, Sahil; Jagani, Hitesh V; Nayak, Pawan G; Kumar, Nitesh; Kishore, Anoop; Bansal, Punit; Shenoy, Rekha R; Nandakumar, Krishnadas

2013-06-06

Based on the reported antioxidant and anti-inflammatory potential of Terminalia paniculata, the bark aqueous extract (TPW) was investigated against liver damage. Intrinsic cytotoxicity was tested on normal human liver (Chang) cell lines, followed by acute and sub-chronic toxicity studies in mice. TPW was then evaluated against CCl4-induced liver toxicity in rats. Liver enzymes (AST, ALT, and ALP) and antioxidant markers were assessed. The effect of TPW on isolated hepatic cells, post-CCl4 administration, was assessed by isolated mitochondrial membrane staining. The actions of TPW on apoptotic pathway in CCl4-treated Chang cells were also elucidated. TPW was found to be safe at all doses tested in both in vitro and in vivo toxicity studies. TPW (400 mg/kg, p.o.) significantly (*p <0.05) improved liver enzyme activity as compared to CCl4. Also, it improved antioxidant status (GSH, GST, MDA and total thiol) and preserved hepatic cell architecture. TPW pre-treatment significantly attenuated the levels of phospho-p53, p53, cleaved caspase-3, phospho-Bad, Bad and cleaved PARP in CCl4-treated Chang cells, improving the viability considerably. The findings support a protective role for Terminalia paniculata in pathologies involving oxidative stress.

Neurotoxic effects of subchronic intratracheal Mn nanoparticle exposure alone and in combination with other welding fume metals in rats.

PubMed

Máté, Zsuzsanna; Horváth, Edina; Papp, András; Kovács, Krisztina; Tombácz, Etelka; Nesztor, Dániel; Szabó, Tamás; Szabó, Andrea; Paulik, Edit

2017-04-01

Manganese (Mn) is a toxic heavy metal exposing workers in various occupational settings and causing, among others, nervous system damage. Metal fumes of welding, a typical source of Mn exposure, contain a complex mixture of metal oxides partly in nanoparticle form. As toxic effects of complex substances cannot be sufficiently understood by examining its components separately, general toxicity and functional neurotoxicity of a main pathogenic welding fume metal, Mn, was examined alone and combined with iron (Fe) and chromium (Cr), also frequently found in fumes. Oxide nanoparticles of Mn, Mn + Fe, Mn + Cr and the triple combination were applied, in aqueous suspension, to the trachea of young adult Wistar rats for 4 weeks. The decrease of body weight gain during treatment, caused by Mn, was counteracted by Fe, but not Cr. At the end of treatment, spontaneous and evoked cortical electrical activity was recorded. Mn caused a shift to higher frequencies, and lengthened evoked potential latency, which were also strongly diminished by co-application of Fe only. The interaction of the metals seen in body weight gain and cortical activity were not related to the measured blood and brain metal levels. Fe might have initiated protective, e.g. antioxidant, mechanisms with a more general effect.

Toxicological evaluation of 6'-sialyllactose (6'-SL) sodium salt.

PubMed

Gurung, Rit Bahadur; Kim, Dae Hee; Kim, Lila; Lee, Albert W; Wang, Zhenhua; Gao, Yonglin

2018-06-01

We performed a series of toxicity studies on the safety of 6'-sialyllactose (6'-SL) sodium salt as a food ingredient. 6'-SL sodium salt, up to a maximum dose of 5000 μg/plate, did not increase the number of revertant colonies in five strains of Salmonella typhimurium in the presence or absence of S9 metabolic activation. A chromosomal aberration assay (using Chinese hamster lung cells) found no clastogenic effects at any concentration of 6'-SL sodium salt in the presence or absence of S9 metabolic activation. An in vivo bone marrow micronucleus test in Kunming mice showed no clastogenic activities with 6'-SL sodium salt doses up to 2000 mg/kg body weight (bw). In an acute toxicity study, the mean lethal dose of 6'-SL sodium salt was greater than 20 g/kg bw in rats. In a 13-week subchronic toxicity investigation, no effects were found at doses up to 5.0 g/kg bw of 6'-SL sodium salt in food consumption, body weight, clinical signs, blood biochemistry and hematology, urinalysis, or ophthalmic and histological macroscopic examination of organs. The no-observed-adverse-effect level (NOAEL) was 5.0 g/kg bw/day in rats. Copyright © 2018 Elsevier Inc. All rights reserved.

Preclinical development of a non-toxic oral formulation of monoethanolamine, a lipid precursor, for prostate cancer treatment

PubMed Central

Saxena, Roopali; Yang, Chunhua; Rao, Mukkavilli; Turaga, Ravi Chakra; Garlapati, Chakravarthy; Gundala, Sushma Reddy; Myers, Kimberly; Ghareeb, Ahmed; Bhattarai, Shristi; Kamilinia, Golnaz; Bristi, Sangina; Su, Dan; Gadda, Giovanni; Rida, Padmashree C. G.; Cantuaria, Guilherme H.; Aneja, Ritu

2018-01-01

Purpose Most currently-available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly-dividing normal cells resulting in toxic side-effects. This non-specificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less-toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel non-toxic orally-deliverable anticancer formulation of monoethanolamine (Etn), for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis. Experimental Design We first evaluated GI-tract stability, drug-drug interaction liability, pharmacokinetic and toxicokinetic properties of Etn to evaluate its suitability as a non-toxic orally-deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action. Results Our data demonstrate that Etn exhibits excellent bioavailability, GI-tract stability, and no drug-drug interaction liability. Remarkably, orally-fed Etn inhibited tumor growth in four weeks by ~67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death. Conclusions Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose non-toxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management. PMID:28167510

Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration.

PubMed Central

Van Os, E C; Zins, B J; Sandborn, W J; Mays, D C; Tremaine, W J; Mahoney, D W; Zinsmeister, A R; Lipsky, J J

1996-01-01

BACKGROUND: 6-Mercaptopurine and its prodrug azathioprine are effective medications for refractory inflammatory bowel disease. However, use of these drugs has been limited by concerns about their toxicity. Colonic delivery of azathioprine may reduce its systemic bioavailability and limit toxicity. AIM: To determine the bioavailability of 6-mercaptopurine after administration of azathioprine via three colonic delivery formulations. METHODS: Twenty four healthy human subjects each received 50 mg of azathioprine by one of four delivery formulations (each n = 6): oral; delayed release oral; hydrophobic rectal foam; and hydrophilic rectal foam. All subjects also received a 50 mg dose of intravenous azathioprine during a separate study period. Plasma concentrations of 6-mercaptopurine were determined by high pressure liquid chromatography. RESULTS: The bioavailabilities of 6-mercaptopurine after colonic azathioprine administration via delayed release oral, hydrophobic rectal foam, and hydrophilic rectal foam (7%, 5%, 1%; respectively) were significantly lower than the bioavailability of 6-mercaptopurine after oral azathioprine administration (47%) by Wilcoxon rank sum pairwise comparison. CONCLUSIONS: Azathioprine delivered to the colon by delayed release oral and rectal foam formulations considerably reduced systemic 6-mercaptopurine bioavailability. The therapeutic potential of these colonic delivery methods, which can potentially limit toxicity by local delivery of high doses of azathioprine, should be investigated in patients with inflammatory bowel disease. PMID:8881811

40 CFR 799.9310 - TSCA 90-day oral toxicity in rodents.

Code of Federal Regulations, 2011 CFR

2011-07-01

... REQUIREMENTS Health Effects Test Guidelines § 799.9310 TSCA 90-day oral toxicity in rodents. (a) Scope. This... a test substance for a period of 90 days. This study is not capable of determining those effects... exposure. (b) Source. The source material used in developing this TSCA test guideline is the Office of...

40 CFR 799.9310 - TSCA 90-day oral toxicity in rodents.

Code of Federal Regulations, 2014 CFR

2014-07-01

... REQUIREMENTS Health Effects Test Guidelines § 799.9310 TSCA 90-day oral toxicity in rodents. (a) Scope. This... a test substance for a period of 90 days. This study is not capable of determining those effects... exposure. (b) Source. The source material used in developing this TSCA test guideline is the Office of...

40 CFR 799.9310 - TSCA 90-day oral toxicity in rodents.

Code of Federal Regulations, 2010 CFR

2010-07-01

... REQUIREMENTS Health Effects Test Guidelines § 799.9310 TSCA 90-day oral toxicity in rodents. (a) Scope. This... a test substance for a period of 90 days. This study is not capable of determining those effects... exposure. (b) Source. The source material used in developing this TSCA test guideline is the Office of...

40 CFR 799.9310 - TSCA 90-day oral toxicity in rodents.

Code of Federal Regulations, 2013 CFR

2013-07-01

... REQUIREMENTS Health Effects Test Guidelines § 799.9310 TSCA 90-day oral toxicity in rodents. (a) Scope. This... a test substance for a period of 90 days. This study is not capable of determining those effects... exposure. (b) Source. The source material used in developing this TSCA test guideline is the Office of...

40 CFR 799.9310 - TSCA 90-day oral toxicity in rodents.

Code of Federal Regulations, 2012 CFR

2012-07-01

... REQUIREMENTS Health Effects Test Guidelines § 799.9310 TSCA 90-day oral toxicity in rodents. (a) Scope. This... a test substance for a period of 90 days. This study is not capable of determining those effects... exposure. (b) Source. The source material used in developing this TSCA test guideline is the Office of...

ORAL TOXICITY OF 1,3-DICHLOROPROPANE: ACUTE, SHORT-TERM, AND LONG-TERM STUDIES IN RATS

EPA Science Inventory

The objective of this investigation was to characterize the acute and short- and long-term toxic potency of orally administered 1,2-dichloropropane (DCP). In the acute and short-term studies, male rats of 250-300 g were gavaged with 0, 100, 250, 500, or 1000 mg DCP/kg in corn oil...

Normal anatomy and histology of the adult zebrafish.

PubMed

Menke, Aswin L; Spitsbergen, Jan M; Wolterbeek, Andre P M; Woutersen, Ruud A

2011-08-01

The zebrafish has been shown to be an excellent vertebrate model for studying the roles of specific genes and signaling pathways. The sequencing of its genome and the relative ease with which gene modifications can be performed have led to the creation of numerous human disease models that can be used for testing the potential and the toxicity of new pharmaceutical compounds. Many pharmaceutical companies already use the zebrafish for prescreening purposes. So far, the focus has been on ecotoxicity and the effects on embryonic development, but there is a trend to expand the use of the zebrafish with acute, subchronic, and chronic toxicity studies that are currently still carried out with the more conventional test animals such as rodents. However, before we can fully realize the potential of the zebrafish as an animal model for understanding human development, disease, and toxicology, we must first greatly advance our knowledge of normal zebrafish physiology, anatomy, and histology. To further this knowledge, we describe, in the present article, location and histology of the major zebrafish organ systems with a brief description of their function.

Toxicological evaluation of Grains of Paradise (Aframomum melegueta) [Roscoe] K. Schum

PubMed Central

Ilic, Nebojsa; Schmidt, Barbara M.; Poulev, Alexander; Raskin, Ilya

2013-01-01

Ethnopharmacological relevance Grains of Paradise (Aframomum melegueta [Roscoe] K. Schum.) seeds are used in West Africa as a remedy for variety of ailments such as stomachache, snakebite, diarrhea and they have reported anti-inflammatory properties. Additionally, the seeds contain gingerols and related compounds that may be useful against cardiovascular disease, diabetes, and inflammation. Aim of study A 28-day sub-chronic toxicity study in male and female Sprague Dawley rats was conducted to evaluate the safety of a Grains of Paradise extract. Materials and methods An ethanolic extract of the seeds was evaluated for toxicological effect on rats. Results A dose-related increase in absolute and relative liver weights was observed in males and females dosed with 450 and 1500 mg/kg. There was a corresponding increase in alkaline phosphatase with no signs of steatosis or cirrhosis. At the same doses, there was a significant decrease in blood glucose in male rats. Conclusions This study shows that Grains of Paradise extract may be useful as a treatment for diabetes, however liver toxicity should be considered. PMID:19883745

Calculating LOAEL/NOAEL uncertainty factors for wildlife species in ecological risk assessments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suedel, B.C.; Clifford, P.A.; Ludwig, D.F.

1995-12-31

Terrestrial ecological risk assessments frequently require derivation of NOAELs or toxicity reference values (TRVS) against which to compare exposure estimates. However, much of the available information from the literature is LOAELS, not NOAELS. Lacking specific guidance, arbitrary factors of ten are sometimes employed for extrapolating NOAELs from LOAELs. In this study, the scientific literature was searched to obtain chronic and subchronic studies reporting NOAEL and LOAEL data for wildlife and laboratory species. Results to date indicate a mean conversion factor of 4.0 ({+-} 2.61 S.D.), with a minimum of 1. 6 and a maximum of 10 for 106 studies acrossmore » several classes of compounds (I.e., metals, pesticides, volatiles, etc.). These data suggest that an arbitrary factor of 10 conversion factor is unnecessarily restrictive for extrapolating NOAELs from LOAELs and that a factor of 4--5 would be more realistic for deriving toxicity reference values for wildlife species. Applying less arbitrary and more realistic conversion factors in ecological risk assessments will allow for a more accurate estimate of NOAEL values for assessing risk to wildlife populations.« less

Disposition of [14C]N,N-dimethyl-p-toluidine in F344 rats and B6C3F1 mice.

PubMed

Dix, Kelly J; Ghanbari, Katayoon; Hedtke-Weber, Briana M

2007-05-15

N,N-Dimethyl-p-toluidine (DMPT) is used as a polymerization accelerator, in industrial glues, and as an intermediate in dye and pesticide synthesis. There is potential for human exposure to DMPT. The disposition of oral and intravenous (i.v.) doses of [14C]DMPT in F344 rats and B6C3F1 mice was investigated. A single i.v. (2.5 mg/kg) or oral (2.5, 25, or 250 mg/kg) dose of [14C]DMPT (1-25 microCi) was administered in an aqueous vehicle to male rats and mice. The 25-mg/kg oral dose was administered to females to investigate possible gender differences in disposition. However, no striking gender differences were observed. Since toxicity studies conducted elsewhere used a corn oil vehicle, the 250-mg/kg oral dose also was administered in corn oil to male rats; disposition was not dependent on vehicle. Excreta (through 24 h) and tissues collected at sacrifice were analyzed for total radioactivity. Dose-dependent differences in toxicity and disposition were observed. Toxicity at the 250-mg/kg oral dose to male mice was consistent with acute renal failure. At the same dose, male rats exhibited clinical signs of toxicity through 12 h but were clinically normal by 24 h. At lower oral doses, [14C]DMPT-derived radioactivity was well absorbed and rapidly excreted, primarily in urine.

Acute oral toxicity and biodistribution study of zinc-aluminium-levodopa nanocomposite

NASA Astrophysics Data System (ADS)

Kura, Aminu Umar; Saifullah, Bullo; Cheah, Pike-See; Hussein, Mohd Zobir; Azmi, Norazrina; Fakurazi, Sharida

2015-03-01

Layered double hydroxide (LDH) is an inorganic-organic nano-layered material that harbours drug between its two-layered sheets, forming a sandwich-like structure. It is attracting a great deal of attention as an alternative drug delivery (nanodelivery) system in the field of pharmacology due to their relative low toxic potential. The production of these nanodelivery systems, aimed at improving human health through decrease toxicity, targeted delivery of the active compound to areas of interest with sustained release ability. In this study, we administered zinc-aluminium-LDH-levodopa nanocomposite (ZAL) and zinc-aluminium nanocomposite (ZA) to Sprague Dawley rats to evaluate for acute oral toxicity following OECD guidelines. The oral administration of ZAL and ZA at a limit dose of 2,000 mg/kg produced neither mortality nor acute toxic signs throughout 14 days of the observation. The percentage of body weight gain of the animals showed no significant difference between control and treatment groups. Animal from the two treated groups gained weight continuously over the study period, which was shown to be significantly higher than the weight at the beginning of the study ( P < 0.05). Biochemical analysis of animal serum showed no significant difference between rats treated with ZAL, ZA and controls. There was no gross lesion or histopathological changes observed in vital organs of the rats. The results suggested that ZAL and ZA at 2,000 mg/kg body weight in rats do not induce acute toxicity in the animals. Elemental analysis of tissues of treated animals demonstrated the wider distribution of the nanocomposite including the brain. In summary, findings of acute toxicity tests in this study suggest that zinc-aluminium nanocomposite intercalated with and the un-intercalated were safe when administered orally in animal models for short periods of time. It also highlighted the potential distribution ability of Tween-80 coated nanocomposite after oral administration.

Tissue-specific in vivo genetic toxicity of nine polycyclic aromatic hydrocarbons assessed using the Muta™Mouse transgenic rodent assay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Long, Alexandra S., E-mail: alexandra.long@hc-sc.gc.ca; Mechanistic Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON; Lemieux, Christine L.

Test batteries to screen chemicals for mutagenic hazard include several endpoints regarded as effective for detecting genotoxic carcinogens. Traditional in vivo methods primarily examine clastogenic endpoints in haematopoietic tissues. Although this approach is effective for identifying systemically distributed clastogens, some mutagens may not induce clastogenic effects; moreover, genotoxic effects may be restricted to the site of contact and/or related tissues. An OECD test guideline for transgenic rodent (TGR) gene mutation assays was released in 2011, and the TGR assays permit assessment of mutagenicity in any tissue. This study assessed the responses of two genotoxicity endpoints following sub-chronic oral exposures ofmore » male Muta™Mouse to 9 carcinogenic polycyclic aromatic hydrocarbons (PAHs). Clastogenicity was assessed via induction of micronuclei in peripheral blood, and mutagenicity via induction of lacZ transgene mutations in bone marrow, glandular stomach, small intestine, liver, and lung. Additionally, the presence of bulky PAH-DNA adducts was examined. Five of the 9 PAHs elicited positive results across all endpoints in at least one tissue, and no PAHs were negative or equivocal across all endpoints. All PAHs were positive for lacZ mutations in at least one tissue (sensitivity = 100%), and for 8 PAHs, one or more initial sites of chemical contact (i.e., glandular stomach, liver, small intestine) yielded a greater response than bone marrow. Five PAHs were positive in the micronucleus assay (sensitivity = 56%). Furthermore, all PAHs produced DNA adducts in at least one tissue. The results demonstrate the utility of the TGR assay for mutagenicity assessment, especially for compounds that may not be systemically distributed. - Highlights: • The Muta™Mouse is a reliable tool for in vivo mutagenicity assessment of PAHs. • All 9 PAHs induced lacZ transgene mutations in small intestine. • Only 5 of 9 PAHs induced lacZ mutations and micronuclei in haematopoietic tissue. • Tissue-specific results are likely related to metabolism, repair, and proliferation. • For oral exposures, it is important to examine effects at the site-of-contact.« less

SUBCHRONIC ENDOTOXIN INHALATION CAUSES CHRONIC AIRWAY DISEASE IN ENDOTOXIN-SENSITIVE BUT NOT ENDOTOXIN-RESISTANT MICE

EPA Science Inventory

SUBCHRONIC ENDOTOXIN INHALATION CAUSES CHRONIC AIRWAY DISEASE IN ENDOTOXIN-SENSITIVE BUT NOT ENDOTOXIN-RESISTANT MICE. D. M. Brass, J. D. Savov, *S. H. Gavett, ?C. George, D. A. Schwartz. Duke Univ Medical Center Durham, NC, *U.S. E.P.A. Research Triangle Park, NC, ?Univ of Iowa,...

Comparative In Vitro Toxicity Evaluation of Heavy Metals (Lead, Cadmium, Arsenic, and Methylmercury) on HT-22 Hippocampal Cell Line.

PubMed

Karri, Venkatanaidu; Kumar, Vikas; Ramos, David; Oliveira, Eliandre; Schuhmacher, Marta

2018-07-01

Heavy metals are considered some of the most toxic environmental pollutants. Exposure to heavy metals including lead (Pb), cadmium (Cd), arsenic (As), and methyl mercury (MeHg) has long been known to cause damage to human health. Many recent studies have supported the hippocampus as the major target for these four metals for inflicting cognitive dysfunction. In the present study, we proposed hippocampal relevant in vitro toxicity of Pb, Cd, As, and MeHg in HT-22 cell line. This study reports, initially, cytotoxic effects in acute, subchronic, chronic exposures. We further investigated the mechanistic potency of DNA damage and apoptosis damage with the observed cytotoxicity. The genotoxicity and apoptosis were measured by using the comet assay, annexin-V FTIC / propidium iodide (PI) assay, respectively. The results of cytotoxicity assay clearly demonstrated significant concentration and time-dependent effects on HT-22 cell line. The genotoxic and apoptosis effects also concentration-dependent fashion with respect to their potency in the range of IC 10 -IC 30, maximal level of damage observed in MeHg. In conclusion, the obtained result suggests concentration and potency-dependent response; the maximal level of toxicity was observed in MeHg. These novel findings support that Pb, Cd, As, and MeHg induce cytotoxic, genotoxic, and apoptotic effects on HT-22 cells in potency-dependent manner; MeHg> As> Cd> Pb. Therefore, the toxicity of Pb, Cd, As, and MeHg could be useful for knowing the common underlying molecular mechanism, and also for estimating the mixture impacts on HT-22 cell line.

Effects of acute and subchronic AT1 receptor blockade on cardiovascular, hydromineral and neuroendocrine responses in female rats.

PubMed

Araujo, Iracema Gomes; Elias, Lucila Leico Kagohara; Antunes-Rodrigues, José; Reis, Luís Carlos; Mecawi, Andre Souza

2013-10-02

Female Wistar rats were ovariectomized (OVX) and separated into two groups that received either estradiol cypionate (EC, 40 μg/kg, sc; OVX-EC) or vehicle (corn oil, sc; OVX-oil) for 14 consecutive days. On the 7th day of treatment, a subset of animals from both the OVX-oil and OVX-EC groups was subjected to subchronic losartan (AT1 receptor antagonist) treatment (0.1g/L in drinking water; ~15 mg/kg/day) for 7 days. Other group of OVX-oil and OVX-EC rats was submitted to an acute losartan injection (100mg/kg, ip) on the 14th day of hormone replacement. In both protocols, the following parameters were measured: I) mean arterial pressure (MAP) and heart rate (HR); II) water and 0.3M saline intake; III) angiotensin II (ANG II), atrial natriuretic peptide (ANP), vasopressin (AVP) and oxytocin (OT) plasma concentrations; and IV) urinary and plasma sodium concentrations. Acute AT1 blockade induced a significant reduction in the MAP in the OVX rats, resulting in increased HR and water intake, which were attenuated by estradiol therapy. Acute AT1 blockade also increased ANG II and OT and reduced ANP plasma concentrations, with no changes in AVP secretion. In addition, acute hypotension was accompanied by a decrease in natriuresis, which was unaltered by estradiol. Subchronic AT1 blockade induced a significant decrease in MAP without changing HR in both groups. Additionally, subchronic losartan treatment induced sodium appetite in OVX rats. Prolonged AT1 blockade increased ANG II and AVP and reduced ANP plasma concentrations. Moreover, it increased natriuresis but did not alter plasma OT concentrations. Finally, estradiol treatment attenuated the increase in salt intake and plasma ANG II concentrations induced by subchronic AT1 blockade. In conclusion, our results suggest differential adaptive responses to the acute or subchronic losartan treatment in OVX and OVX-EC rats. © 2013.

Acute oral toxicity and brine shrimp lethality of Elaeis guineensis Jacq., (oil palm leaf) methanol extract.

PubMed

Syahmi, Abdul Rani Muhamad; Vijayarathna, Soundararajan; Sasidharan, Sreenivasan; Latha, Lachimanan Yoga; Kwan, Yuet Ping; Lau, Yee Ling; Shin, Lai Ngit; Chen, Yeng

2010-11-10

Elaeis guineensis (Arecaceae) is widely used in West African traditional medicine for treating various ailments. An evaluation on the toxicity of extracts of this plant is crucial to support the therapeutic claims. The acute oral toxicity and brine shrimp lethality of a methanolic extract of this plant was tested. Oral administration of crude extract at the highest dose of 5,000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that E. guineensis is nontoxic. Normal behavioral pattern, clinical signs and histology of vital organs confirm this evidence. The E. guineensis extracts screened for toxicity against brine shrimp had 50% lethal concentration (LC₅₀) values of more than 1.0 mg/mL (9.00 and 3.87 mg/mL, at 6 and 24 h, respectively), confirming that the extract was not toxic. Maximum mortalities occurred at 100 mg/mL concentration while the least mortalities happened to be at 0.195 mg/mL concentration. The results of both tests confirm that E. guineensis is nontoxic and hence safe for commercial utilization.

The effects of a standardized Acanthopanax koreanum extract on stress-induced behavioral alterations in mice.

PubMed

Jung, Jun Man; Park, Se Jin; Lee, Young Woo; Lee, Hyung Eun; Hong, Sung In; Lew, Jae Hwan; Hong, Eunyoung; Shim, Jae Seok; Cheong, Jae Hoon; Ryu, Jong Hoon

2013-07-30

The roots and stem bark of Acanthopanax koreanum Nakai (Araliaceae), a well-known herbal medicine in Jeju Island, Korea, has been used as a tonic agent in treating stress-related states. Despite its popular application, the anti-anxiety or anti-depressive action of Acanthopanax koreanum is not yet known. This study aimed to determine the effects of Acanthopanax koreanum on stress-induced behavioral alterations such as anxiety and depression. Mice in the acute stress group were exposed to immobilization stress for 2h followed by electric foot shocks (0.5 mA in 1 s duration with a 10 s inter-shock interval) for 2 min, while sub-chronically stressed mice were exposed to these stresses for 2 weeks, once per day. 70% ethanolic extract of Acanthopanax koreanum (EEAK) (25, 50, 100, or 200 mg/kg) was administered once or sub-chronically (for 2 weeks) 1h prior to stress induction. Anxiety- or depression-like behavioral changes were evaluated using the elevated plus-maze (EPM) test and the forced swimming test (FST) a day after the final stress induction. Corticosterone levels and spleen weight were measured after conducting all the behavioral assays. The numbers of BrdU- or DCX-immunopositive cells in the hippocampal region of sub-chronically stressed mice were measured 2 days after EEAK treatment. The percentage of time spent in the open arms was decreased in both the acutely and chronically stressed mice. In the FST, the immobility time was increased by only chronic stress, but not by acute stress. Acute or sub-chronic administration of EEAK significantly prevented the anxiety- or depression-like behavioral changes caused by stress. EEAK also attenuated stress-induced decrease and increase of spleen weight and corticosterone levels, respectively. Furthermore, the sub-chronic administration of EEAK (100 or 200 mg/kg, for 2 weeks) increased the number of BrdU-, doublecortin-, and neuropeptide Y-positive cells in the hippocampal region of the sub-chronically stressed mice. EEAK attenuated the behavioral and biochemical changes in acute or sub-chronic stressed mice. These results suggest the therapeutic potential of Acanthopanax koreanum for the treatment of stress-related neuropsychiatric disorders including anxiety disorders or major depressive disorder. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform

DOE Office of Scientific and Technical Information (OSTI.GOV)

Philip, Binu K.; Anand, Sathanandam S.; Palkar, Prajakta S.

2006-10-01

Protection offered by pre-exposure priming with a small dose of a toxicant against the toxic and lethal effects of a subsequently administered high dose of the same toxicant is autoprotection. Although autoprotection has been extensively studied with diverse toxicants in acute exposure regimen, not much is known about autoprotection after priming with repeated exposure. The objective of this study was to investigate this concept following repeated exposure to a common water contaminant, chloroform. Swiss Webster (SW) mice, exposed continuously to either vehicle (5% Emulphor, unprimed) or chloroform (150 mg/kg/day po, primed) for 30 days, were challenged with a normally lethalmore » dose of chloroform (750 mg chloroform/kg po) 24 h after the last exposure. As expected, 90% of the unprimed mice died between 48 and 96 h after administration of the lethal dose in contrast to 100% survival of mice primed with chloroform. Time course studies indicated lower hepato- and nephrotoxicity in primed mice as compared to unprimed mice. Hepatic CYP2E1, glutathione levels (GSH), and covalent binding of {sup 14}C-chloroform-derived radiolabel did not differ between livers of unprimed and primed mice after lethal dose exposure, indicating that protection in liver is neither due to decreased bioactivation nor increased detoxification. Kidney GSH and glutathione reductase activity were upregulated, with a concomitant reduction in oxidized glutathione in the primed mice following lethal dose challenge, leading to decreased renal covalent binding of {sup 14}C-chloroform-derived radiolabel, in the absence of any change in CYP2E1 levels. Buthionine sulfoximine (BSO) intervention led to 70% mortality in primed mice challenged with lethal dose. These data suggest that higher detoxification may play a role in the lower initiation of kidney injury observed in primed mice. Exposure of primed mice to a lethal dose of chloroform led to 40% lower chloroform levels (AUC{sub 15-360min}) in the systemic circulation. Exhalation of {sup 14}C-chloroform was unchanged in primed as compared to unprimed mice (AUC{sub 1-6h}). Urinary excretion of {sup 14}C-chloroform was higher in primed mice after administration of the lethal dose. However, neither slightly higher urinary elimination nor unchanged expiration can account for the difference in systemic levels of chloroform. Liver and kidney regeneration was inhibited by the lethal dose in unprimed mice leading to progressive injury, organ failure, and 90% mortality. In contrast, sustained and highly stimulated compensatory hepato- and nephrogenic repair prevented the progression of injury resulting in 100% survival of primed mice challenged with the lethal dose. These findings affirm the critical role of tissue regeneration and favorable detoxification (only in kidney) of the lethal dose of chloroform in subchronic chloroform priming-induced autoprotection.« less

Development of methods for avian oil toxicity studies using the double crested cormorant (Phalacrocorax auritus).

PubMed

Cunningham, Fred; Dean, Karen; Hanson-Dorr, Katie; Harr, Kendal; Healy, Kate; Horak, Katherine; Link, Jane; Shriner, Susan; Bursian, Steven; Dorr, Brian

2017-07-01

Oral and external dosing methods replicating field exposure were developed using the double crested cormorant (DCCO) to test the toxicity of artificially weathered Deepwater Horizon Mississippi Canyon 252 oil. The majority of previous oil dosing studies conducted on wild-caught birds used gavage methods to dose birds with oil and determine toxicity. However, rapid gut transit time of gavaged oil likely reduces oil absorption. In the present studies, dosing relied on injection of oil into live feeder fish for oral dosing of these piscivorous birds, or applying oil to body contour feathers resulting in transdermal oil exposure and oral exposure through preening. Both oral and external oil dosing studies identified oil-related toxicity endpoints associated with oxidative stress such as hemolytic anemia, liver and kidney damage, and immuno-modulation or compromise. External oil application allowed for controlled study of thermoregulatory stress as well. Infrared thermal images indicated significantly greater surface temperatures and heat loss in treated birds following external oil applications; however, measurements collected by coelomically implanted temperature transmitters showed that internal body temperatures were stable over the course of the study period. Birds exposed to oil externally consumed more fish than control birds, indicating metabolic compensation for thermal stress. Conversely, birds orally dosed with oil experienced hypothermia and consumed less fish compared to control birds. Published by Elsevier Inc.

Acute oral toxicity of the ethyl acetate fraction of Orostachys japonicus in mice.

PubMed

Kim, Seon-Hee; Ryu, Deok-Seon; Lee, Hyeong-Seon; Shin, Hye-Ryoung; Kwon, Ji-Hye; Lee, Dong-Seok

2014-10-01

Orostachys japonicus (Crassulaceae) is referred to as Wa-song in Korea. It is used as an anti-inflammatory, antifebrile, hemostatic, and anti cancer agent, and as an antidote. The purpose of this study was to evaluate the acute toxicity of the ethyl acetate fraction of O. japonicus (OJE) after the oral administration in Balb/c mice of both sexes. Mice were oral administered a single doses of 500, 1000, and 2000 mg/kg of body weight and were monitored for 14 d. Biochemical parameters [aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total protein (TP), globulin (GB), total cholesterol (TC), triglyceride (TG), blood urea nitrogen (BUN), and creatinine (CR)] and histopathological examination of liver were performed. No animals died and no toxic changes were observed in clinical signs, body weight, and organ weight. The LD50 of orally administered OJE was higher than 2000 mg/kg/d in both sexes. No toxicological findings were found in biochemical parameters. In histophathological examination, neutrophilic infiltration was observed at a dose of 2000 mg/kg group in both sexes. These finding suggest that oral administration of OJE does not produce acute toxicity. Therefore, these results could provide satisfactory preclinical evidence of safety to launch clinical trials on standardized formulation of OJE to be a biohealth product.

Comparison of subchronic immunotoxicity of four different types of aluminum-based nanoparticles.

PubMed

Park, Eun-Jung; Lee, Sang Jin; Lee, Gwang-Hee; Kim, Dong-Wan; Yoon, Cheolho; Lee, Byoung-Seok; Kim, Younghun; Chang, Jaerak; Lee, Kyuhong

2018-04-01

Nanoparticles (NPs) have recently emerged as an inhalable pollutant, owing to their applications, aluminum-based NPs (Al-NPs) have been prioritized for toxicity testing. In the current study, we compared the pulmonary biopersistence and subsequent toxicity of four different types of Al-NPs (two rod-type aluminum oxide NPs [AlONPs] with different aspect ratios [short (S)- and long (L)-AlONPs], spherical aluminum cerium oxide NPs [AlCeO 3 , AlCeONPs] and spherical γ-aluminum oxide hydroxide nanoparticles [AlOOHNPs]) 13weeks after a single intratracheal instillation, considering the importance of their properties in their toxicity. We found that the pulmonary biopersistence of Al-NPs was strengthened by a high aspect ratio in the rod-type AlONPs and by the presence of hydroxyl groups in the spherical-type Al-NPs. The highest toxicity was observed in the mice treated with AlOOHNPs, which showed low biostability. More importantly, we identified that the commercially available AlCeONPs were Al 2 O 3 -coated CeO 2 NPs, but not AlCeO 3 NPs, although they have been sold under the trade name of AlCeONPs. In conclusion, the aspect ratio and biostability may be important factors in the determination of the biopersistence of NPs and the subsequent biological response. In addition, the physicochemical properties of NPs should be examined in detail before their release into the market to prevent unexpected adverse health effects. Copyright © 2017 John Wiley & Sons, Ltd.

A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo.

PubMed

Das, Banibrata; Rajagopalan, Subramanian; Joshi, Gnanada S; Xu, Liping; Luo, Dan; Andersen, Julie K; Todi, Sokol V; Dutta, Aloke K

2017-09-01

Here, we report the characterization of a novel hybrid D 2 /D 3 agonist and iron (II) specific chelator, D-607, as a multi-target-directed ligand against Parkinson's disease (PD). In our previously published report, we showed that D-607 is a potent agonist of dopamine (DA) D 2 /D 3 receptors, exhibits efficacy in a reserpinized PD animal model and preferentially chelates to iron (II). As further evidence of its potential as a neuroprotective agent in PD, the present study reveals D-607 to be protective in neuronal PC12 cells against 6-OHDA toxicity. In an in vivo Drosophila melanogaster model expressing a disease-causing variant of α-synuclein (α-Syn) protein in fly eyes, the compound was found to significantly suppress toxicity compared to controls, concomitant with reduced levels of aggregated α-Syn. Furthermore, D-607 was able to rescue DAergic neurons from MPTP toxicity in mice, a well-known PD neurotoxicity model, following both sub-chronic and chronic MPTP administration. Mechanistic studies indicated that possible protection of mitochondria, up-regulation of hypoxia-inducible factor, reduction in formation of α-Syn aggregates and antioxidant activity may underlie the observed neuroprotection effects. These observations strongly suggest that D-607 has potential as a promising multifunctional lead molecule for viable symptomatic and disease-modifying therapy for PD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Some patterns of metallic nanoparticles' combined subchronic toxicity as exemplified by a combination of nickel and manganese oxide nanoparticles.

PubMed

Katsnelson, Boris A; Minigaliyeva, Ilzira A; Panov, Vladimir G; Privalova, Larisa I; Varaksin, Anatoly N; Gurvich, Vladimir B; Sutunkova, Marina P; Shur, Vladimir Ya; Shishkina, Ekaterina V; Valamina, Irene E; Makeyev, Oleg H

2015-12-01

Stable suspensions of NiO and/or Mn3O4 nanoparticles with a mean diameter of 16.7 ± 8.2 nm and 18.4 ± 5.4 nm, respectively, prepared by laser ablation of 99.99% pure metals in de-ionized water were repeatedly injected IP to rats at a dose of 0.50 mg or 0.25 mg 3 times a week up to 18 injections, either separately or in different combinations. Many functional indices as well as histological features of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The accumulation of Ni and Mn in these organs was measured with the help of AES and EPR methods. Both metallic nanoparticles proved adversely bio-active, but those of Mn3O4 were found to be more noxious in most of the non-specific toxicity manifestations. Moreover, they induced a more marked damaging effect in the neurons of the caudate nucleus and hippocampus which may be considered an experimental correlate of manganese-induced parkinsonism. Mathematical analysis based on the Response Surface Methodology (RSM) revealed a diversity of combined toxicity types depending not only on particular effects these types are assessed for but on their level as well. The prognostic power of the RSM model proved satisfactory. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluation of 90-day inhalation toxicity of petroleum and oil-shale diesel fuel marine (DFM). Final technical report, November 1977-January 1985

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaworski, C.L.; MacEwen, J.D.; Vernot, E.H.

1985-12-01

Subchronic 90-day inhalation toxicity studies were conducted to compare the toxicity of petroleum and oil-shale-derived diesel fuel marine (DFM). Beagle dogs, Fischer 344 rats, and C57BL/6 mice were continuously exposed to DFM at concentrations of 50 mg/cu. m and 300 mg/cu. m. Unexposed controls were also maintained. All dogs and a portion of each rodent group were sacrificed and examined at exposure termination. The remaining rodents were held for observation up to 21 months postexposure. Male rats exposed to DFM for 90 days developed nephrotoxic changes characterized by hyaline degeneration, necrosis, and intratubular cysts. Subsequently, male rats exposed to 300more » mg/cu. m DFM developed mineralization and papillary hyperplasia. These postexposure renal changes were generally less severe in male rats exposed to 50 mg/cu. m Shale DFM and were absent in male rats exposed to 50 mg/cu. m Petroleum DFM. Female rats as well as dogs and mice exposed to DFM were free of significant renal damage. Mild reductions in body-weight gains and erythrocyte parameters were also noted in male rats exposed to DFM. Neither material produced significant tumor formation in any species tested. The results of this study are consistent with the effects noted in other hydrocarbon-fuel toxicity studies. Comparison of the effects observed in these studies with petroleum or shale suggest only minor differences between the two materials.« less

Oral Toxicity and Intestinal Transport Mechanism of Colloidal Gold Nanoparticle-Treated Red Ginseng

PubMed Central

Bae, Song-Hwa; Yu, Jin; Go, Mi-Ran; Kim, Hyun-Jin; Hwang, Yun-Gu; Choi, Soo-Jin

2016-01-01

(1) Background: Application of nanotechnology or nanomaterials in agricultural food crops has attracted increasing attention with regard to improving crop production, quality, and nutrient utilization. Gold nanoparticles (Au-NPs) have been reported to enhance seed yield, germination rate, and anti-oxidant potential in food crops, raising concerns about their toxicity potential. In this study, we evaluated the oral toxicity of red ginseng exposed to colloidal Au-NPs during cultivation (G-red ginseng) in rats and their intestinal transport mechanism. (2) Methods: 14-day repeated oral administration of G-red ginseng extract to rats was performed, and body weight, hematological, serum biochemical, and histopathological values were analyzed. An in vitro model of human intestinal follicle-associated epithelium (FAE) and an intestinal epithelial monolayer system were used for intestinal transport mechanistic study. (3) Results: No remarkable oral toxicity of G-red ginseng extract in rats was found, and Au-NPs did not accumulate in any organ, although Au-NP transfer to G-red ginseng and some increased saponin levels were confirmed. Au-NPs were transcytozed by microfold (M) cells, but not by a paracellular pathway in the intestinal epithelium. (4) Conclusion: These findings suggest great potential of Au-NPs for agricultural food crops at safe levels. Further study is required to elucidate the functional effects of Au-NPs on ginseng and long-term toxicity. PMID:28335336

Toxicity studies of the water extract from the calyces of Hibiscus sabdariffa L. in rats.

PubMed

Sireeratawong, Seewaboon; Itharat, Arunporn; Khonsung, Parirat; Lertprasertsuke, Nirush; Jaijoy, Kanjana

2013-01-01

Acute and chronic toxicities of the water extract from calyces of Hibiscus sabdariffa were studied in male and female rats. After 14 days of a single oral administration of test substance 5,000 mg/kg body weight, measurement of the body and organ weights, necropsy and health monitoring were performed. No signs and differences of the weights or behaviour compared to the control rats were observed. The results indicated that the single oral administration of H. sabdariffa extract in the amount of 5,000 mg/kg body weight does not produce acute toxicity. The chronic toxicity was determined by oral feeding both male and female rats daily with the extract at the doses of 50, 100, and 200 mg/kg body weight for 270 days. The examinations of signs, animal behaviour and health monitoring showed no defects in the test groups compared to the control groups. Both test and control groups (day 270th) and satellite group (day 298th) were analysed by measuring their final body and organ weights, taking necropsy, and examining haematology, blood clinical chemistry, and microanatomy. Results showed no differences from the control groups. Overall, our study demonstrated that an oral administration of H. sabdariffa extract at the doses of 50, 100 and 200 mg/kg body weight for 270 days does not cause chronic toxicity in rat.

Subchronic inhalation exposure of rats to Libby amphibole and amosite asbestos: Effects at 1 and 3 months post exposure#

EPA Science Inventory

Increased asbestosis, lung cancer, and mesothelioma rates are evident in humans after exposures to Libby amphibole (LA). To support dosimetry model development and compare potency, a subchronic nose-only inhalation study (6 hr/d, 5 d/wk, 13 wk) was conducted in male F344 rats. Ra...

Subchronic Inhalation Exposure of Rats to Libby Amphibole and Amosite Asbestos: Effects at 18 Months Post Exposure###

EPA Science Inventory

Increased asbestosis, lung cancer, and mesothelioma rates are evident after exposures to Libby amphibole (LA). To support dosimetry model development and compare potency, a subchronic nose-only inhalation study (6 hr/d, 5 d/wk, 13 wk) was conducted in male F344 rats. Rats were ex...

Subchronic Inhalation Exposure of Rats to Libby Amphibole and Amosite Asbestos: Effects at 18 Months Post Exposure

EPA Science Inventory

Increased asbestosis, lung cancer, and mesothelioma rates are evident after exposures to Libby amphibole (LA). To support dosimetry model development and compare potency, a subchronic nose-only inhalation study (6 hr/d, 5 d/wk, 13 wk) was conducted in male F344 rats. Rats were ex...

Subchronic Inhalation Exposure of Rats to Libby Amphibole and Amosite Asbestos: Effects at 1 and 3 Months Post Exposure**

EPA Science Inventory

Increased asbestosis, lung cancer, and mesothelioma rates are evident after exposures to Libby amphibole (LA). To support dosimetry model development and compare potency, a subchronic nose-only inhalation exposure study (6 hr/d, 5 d/wk, 13 wk) was conducted in male F344 rats. Rat...

FORMATION OF 8-OXO-7, 8-DIHYDRO-2'-DEOXYGUANOSINE IN RAT LUNG FOLLOWING SUB-CHRONIC INHALATION OF CARBON BLACK

EPA Science Inventory

ABSTRACT
Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, an oxidative adduct in the lung DNA of rats following sub-chronic inhalation of carbon black. Gallagher, J., Sams II, R.L., Inmon, J., Gelein, R., Elder, A., Oberdorster, G., Prahalad, A. (2002). Toxicol. Appl. Pharm...

Acute Oral Toxicity Up-And-Down-Procedure

EPA Pesticide Factsheets

The Up-and-Down Procedure is an alternative acute toxicity test that provides a way to determine the toxicity of chemicals with fewer test animals by using sequential dosing steps. Find out about this test procedure.

Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice

PubMed Central

Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; Micale, Rosanna T; La Maestra, Sebastiano; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

2014-01-01

The anti-diabetic drug metformin is endowed with anti-cancer properties. Epidemiological and experimental studies, however, did not provide univocal results regarding its role in pulmonary carcinogenesis. We used Swiss H mice of both genders in order to detect early molecular alterations and tumors induced by mainstream cigarette smoke. Based on a subchronic toxicity study, oral metformin was used at a dose of 800 mg/kg diet, which is 3.2 times higher than the therapeutic dose in humans. Exposure of mice to smoke for 4 months, starting at birth, induced a systemic clastogenic damage, formation of DNA adducts, oxidative DNA damage, and extensive downregulation of microRNAs in lung after 10 weeks. Preneoplastic lesions were detectable after 7.5 months in both lung and urinary tract along with lung tumors, both benign and malignant. Modulation by metformin of 42 of 1281 pulmonary microRNAs in smoke-free mice highlighted a variety of mechanisms, including modulation of AMPK, stress response, inflammation, NFκB, Tlr9, Tgf, p53, cell cycle, apoptosis, antioxidant pathways, Ras, Myc, Dicer, angiogenesis, stem cell recruitment, and angiogenesis. In smoke-exposed mice, metformin considerably decreased DNA adduct levels and oxidative DNA damage, and normalized the expression of several microRNAs. It did not prevent smoke-induced lung tumors but inhibited preneoplastic lesions in both lung and kidney. In conclusion, metformin was able to protect the mouse lung from smoke-induced DNA and microRNA alterations and to inhibit preneoplastic lesions in lung and kidney but failed to prevent lung adenomas and malignant tumors induced by this complex mixture. PMID:24683044

Toxicology of haloacetonitriles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayes, J.R.; Condie, L.W. Jr.; Borzelleca, J.F.

1986-11-01

Haloacetonitriles are by-products of water chlorination and may form in vivo from the reaction of residual chlorine with endogenous compounds such as amino acids. Dibromoacetonitrile (DBAN) was negative in selected mutagenic assays; dichloroacetonitrile (DCAN) was mutagenic in S. typhimurium, but not in S. cerevisiae. Both DBAN and DCAN may be carcinogenic. The studies described were conducted to determined the acute, subacute, and subchronic toxicity of DBAN and DCAN. The acute oral LD/sub 50/ values (mg/kg) in mice and rats are: DBAN, mice: 289 (M), 303 (F); DBAN, rats: 245 (M), 361 (F); DCAN, mice: 270 (M), 279 (F); DCAN, rats:more » 339 (M), 330 (F). Death was preceded by slowed respiration, depressed activity, prostration, and coma. There were no apparent compound-related gross pathological effects. DBAN (in corn oil) was administered by gavage to male and female CD rats for 14 or 90 days at levels of 23, 45, 90, and 180 mg/kg/day or 6, 23, and 45 mg/kg/day, respectively. No consistent, significant, adverse compound-related effects on any of the parameters evaluated were evident. Possible target organs might be spleen, thymus, and liver. The no-observed adverse-effect level (NOAEL) for 14 days was 45 mg/kg/day and for 90 days was 23 mg/kg/day. DCAN (in corn oil) was administered by gavage to male and female CD rats for 14 or 90 days at levels of 12, 23, 45, and 90 mg/kg/day or 8, 33, and 65 mg/kg/day, respectively. There were not deaths during the 14 day study. No consistent, significant adverse compound-related effects on any of the parameters evaluated were evident. The NOAEL for 14 days was 45 mg/kg/day and for 90 days was 9 mg/kg/day.« less

Development of water quality criteria and screening benchmarks for 2,4,6 trinitrotoluene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Talmage, S.S.; Opresko, D.M.

1995-12-31

Munitions compounds and their degradation products are present at many Army Ammunition Plant Superfund sites. Neither Water Quality Criteria (WQC) for aquatic organisms nor safe soil levels for terrestrial plants and animals have been developed for munitions compounds including trinitrotoluene (TNT). Data are available for the calculation of an acute WQC for TNT according to US EPA guidelines but are insufficient to calculate a chronic criterion. However, available data can be used to determine a Secondary Chronic Value (SCV) and to determine lowest chronic values for fish and daphnids (used by EPA in the absence of criteria). Based on datamore » from eight genera of aquatic organisms, an acute WOC of 0.566 mg/L was calculated. Using available data, a SCV of 0.137 mg/L was calculated. Lowest chronic values for fish and for daphnids are 0.04 mg/L and 1.03 mg/L, respectively. The lowest concentration that affected the growth of aquatic plants was 1.0 mg/L. For terrestrial animals, data from studies of laboratory animals can be extrapolated to derive screening benchmarks in the same way in which human toxicity values are derived from laboratory animal data. For terrestrial animals, a no-observed-adverse-effect-level (NOAEL) for reproductive effects of 1.60 mg/kg/day was determined from a subchronic laboratory feeding study with rats. By scaling the test NOAEL on the basis of differences in body size, screening benchmarks were calculated for oral intake for selected mammalian wildlife species. Screening benchmarks were also derived for protection of benthic organisms in sediment, for soil invertebrates, and for terrestrial plants.« less

Depletion of cellular adenosine triphosphate and hepatocellular damage in rat after subchronic exposure to leachate from anthropogenic recycling site.

PubMed

Akintunde, J K; Oboh, G

2015-11-01

One of the major hazards arising from recycling sites is the generation of leachate containing mixed metal. This study evaluated the toxic effects of leachate obtained from Elewi Odo municipal auto-battery recycling site (EOMABRSL) on male liver functions using hepatic indices and biomarker of cellular adenosine triphosphate (ATP) in rat via the oral route. Concentrations of heavy metals analysis showed that lead, cadmium, nickel, chromium, manganese, and iron were 1.5-, 2-, 2.5-, 1.36-, 19.61-, and 8.89-folds, respectively, higher than acceptable limits set by regulatory authority World Health Organization. Copper, zinc, and cobalt were 5.9-, 300-, and 1.02-folds, respectively, lower than permissible limits. The EOMABRSL was administered at 20, 40, 60, 80, and 100% concentrations to adult male rats for 60 days. Following exposure, plasma and livers were collected for several biochemistry assays. Exposure of animals to EOMABRSL resulted in 27.51, 28.14, 63.93, 28.42, and 40.16% increase in aspartate aminotransferase activity, whereas it elevated alanine aminotransferase activity by 5.35, 22.33, 88.68, 183.02, and 193.08%, respectively, when compared with the control. Similarly, γ-glutamyl transferase activity increased by 111.22, 114.19, 122.96, 573.14, and 437.02%, respectively, when compared with the control. EOMABRSL administration significantly decreased catalase activity and reduced glutathione level and superoxide dismutase with concomitant increase in malondialdehyde and hydrogen peroxide levels. Also, significant (p < 0.05) decrease in lactate dehydrogenase (LDH) activity (marker of cellular ATP) was observed. Taken together, the hepatotoxicity of EOMABRSL could be due to the depletion of LDH and induction of oxidative damage, which may suggest possible health hazards in subjects with occupational or environmental exposure. © The Author(s) 2015.

Toxicity of parathion to captive European starlings (Sturnus vulgaris)-absence of seasonal effects

USGS Publications Warehouse

Rattner, B.A.; Grue, C.E.

1990-01-01

The effects of season on the toxicity of the prototypic organophosphorus insecticide parathion was evaluated using adult European starlings (Sturnus vulgaris) housed in outdoor pens. Groups of birds received oral doses of parathion in the fall, winter, spring and summer. Median lethal dosage, and brain and plasma cholinesterase inhibition, were found to be quite similar among seasons. Parathion may have been more toxic during hot weather (winter vs. summer LD50 estimate: 160 vs. 118 mg/kg; p < 0.1). In view of previous reports in which ambient temperature extremes and harsh weather have enhanced organophosphorus insecticide toxicity to birds, it is concluded that circannual toxicity studies should include measures of sensitivity (acute oral exposure) and vulnerability (dietary exposure) to better predict responses of free-ranging birds.

Sub-chronic indomethacin treatment and its effect on the male reproductive system of albino rats: possible protective role of black tea extract.

PubMed

Bagoji, Ishwar B; Hadimani, Gavishiddappa A; Yendigeri, Saeed M; Das, Kusal K

2017-05-01

Indomethacin is commonly used as a nonsteroidal anti-inflammatory drug (NSAID) to treat inflammation, arthritis and joint pains. Unfortunately, it has a wide range of adverse effects on the physiological system, including gonads. This study aimed to assess possible beneficial effects of black tea extract (BTE) against indomethacin-induced alteration of gonadal hormone levels in male rats. Adult male rats were divided into Group I (control), Group II (indomethacin, 5 mg/kg body weight [bwt.]; i.p., 21 days), Group III (BTE, 2.5 g tea leaf/dL of water, i.e. 2.5% of aqueous BTE, orally, 21 days) and Group IV (indomethacin+BTE, 21 days). Sperm count and motility, serum luteinising hormone (LH), follicle-stimulating hormone (FSH) and testosterone, along with histopathology of testes were studied. One-way ANOVA, followed by post-hoc t-test were conducted. Indomethacin-treated rats showed significant decrease in testicular weight, sperm count, sperm motility, serum gonadotropins and testosterone concentrations. Histopathology of the testes showed tortuous and distorted seminiferous tubules, marked thickening of the tubular basement membrane, reduced spermatogenesis process (>30%) and marked decrease in the number of interstitial cells of Leydig in indomethacin-treated rats. Interestingly, rats supplemented with BTE showed remarkable improvements in testicular weight gain, sperm count and motility, serum gonadotropins and testosterone concentrations, along with testicular histopathology. The results suggest that BTE might have potential ameliorative effects against sub-chronic indomethacin-induced alteration of gonadal hormone levels in male albino rats.

In Vitro Comparison of Cytotoxic and Antibacterial Effects of 16 Commercial Toothpastes

PubMed Central

Ghapanchi, Jannan; Kamali, Fereshteh; Moattari, Afagh; Poorshahidi, Sara; Shahin, Esmaiel; Rezazadeh, Fahimeh; Khorshidi, Hooman; Jamshidi, Samira

2015-01-01

Background: Toothpastes are considered as one of the most common and usable cosmetic and hygienic materials. Such materials contain chemicals which may have an adverse effect on oral tissue in humans. The present study aimed to compare the toxic effect of current commercial toothpastes including Iranian products and imported types which are consumed globally on oral epithelial- and HeLa cells as well as to evaluate their antibacterial effect on Streptococcus mutans in Shiraz, Iran. Materials and Methods: In this experimental study, 16 types of commercial toothpastes were prepared, and their effect was determined on primer epithelial cells of the oral cavity and HeLa cells. Toothpastes anti streptococcal property and toxicity were examined in vitro in different intervals of 1, 2, and 5 min. Data collection and analysis were done using one-way analysis of variance. Results: All experimented toothpastes revealed variable toxic effects on cultured cells. Through an increase in the time of exposure with toothpastes, the toxicity of these materials substantially increased (P = 0.005). On the other hand, all tested toothpastes showed varying degrees of anti-streptococcal effect in the laboratory (P = 0.005). Conclusions: The most cytotoxic effect on primer epithelial cells of oral mucosa and HeLa cells, respectively, belongs to Bath, Daroogar2, Latifeh2, Crend, Sehat, Nasim and Aqua fresh toothpastes; however, the least cytotoxic effect on primer epithelial cells of oral mucosa and HeLa cells, respectively, belongs to Pronamel followed by Crest (sensitive), Close-up, Oral-B, Signal, Colgate, Paradent, and AME. PMID:25878477

Toxic corneal epitheliopathy after intravitreal methotrexate and its treatment with oral folic acid.

PubMed

Gorovoy, Ian; Prechanond, Tidarat; Abia, Maravillas; Afshar, Armin R; Stewart, Jay M

2013-08-01

To determine whether oral folic acid can ameliorate an iatrogenic, visually significant corneal epitheliopathy, which commonly occurs with intravitreal injections of methotrexate for the treatment of intraocular lymphoma. We report 2 cases of visually significant corneal epitheliopathy occurring after intravitreal injections of methotrexate for intraocular lymphoma. The first patient did not receive any treatment for the corneal disease, and the second patient with bilateral intraocular lymphoma received 1 mg of oral folic acid daily, a commonly used dosage for patients on systemic methotrexate. In the first patient without treatment, there was a complete regression of the corneal epithelial disease only when the frequency of intravitreal methotrexate was reduced from weekly to monthly as per a commonly used dosage regimen for methotrexate. In the second patient, the corneal disease improved 80% within 1 week of initiating oral folic acid for her eye already experiencing severe epitheliopathy during her weekly dosing regimen of methotrexate and also had significantly decreased epithelial disease in her second eye that started weekly intravitreal methotrexate several weeks after beginning oral folic acid. Currently, oral folic acid supplements are recommended for patients using systemic methotrexate to minimize drug toxicity. We suggest a similar use in patients undergoing intravitreal methotrexate injections to decrease toxic effects on the corneal epithelium.

Halloysite nanotubes-induced Al accumulation and oxidative damage in liver of mice after 30-day repeated oral administration.

PubMed

Wang, Xue; Gong, Jiachun; Gui, Zongxiang; Hu, Tingting; Xu, Xiaolong

2018-06-01

Halloysite (Al 2 Si 2 O 5 (OH) 4 ·nH 2 O) nanotubes (HNTs) are natural clay materials and widely applied in many fields due to their natural hollow tubular structures. Many in vitro studies indicate that HNTs exhibit a high level of biocompatibility, however the in vivo toxicity of HNTs remains unclear. The objective of this study was to assess the hepatic toxicity of the purified HNTs in mice via oral route. The purified HNTs were orally administered to mice at 5, 50, and 300 mg/kg body weight (BW) every day for 30 days. Oral administration of HNTs stimulated the growth of the mice at the low dose (5 mg/kg BW) with no liver toxicity, but inhibited the growth of the mice at the middle (50 mg/kg BW) and high (300 mg/kg BW) doses. In addition, oral administration of HNTs at the high dose caused Al accumulation in the liver but had no marked effect on the Si content in the organ. The Al accumulation caused significant oxidative stress in the liver, which induced hepatic dysfunction and histopathologic changes. These findings demonstrated that Al accumulation-induced oxidative stress played an important role in the oral HNTs-caused liver injury. © 2018 Wiley Periodicals, Inc.

Preparation of five 3-MCPD fatty acid esters and the effects of their chemical structures on acute oral toxicity in Swiss mice

USDA-ARS?s Scientific Manuscript database

Fatty acid esters of 3-monochloro-1, 2-propanediol (3-MCPDEs), including 1-stearic, 1-oleic, 1-linoleic, 1-linoleic-2-palmitic and 1-palmitic-2-linoleic acid esters, were synthetized and examined for their acute oral toxicities in Swiss mice. 3-MCPDEs were obtained through the reaction of 3-MCPD and...

An 'injury-time integral' model for extrapolating from acute to chronic effects of phosgene.

PubMed

Hatch, G; Kodavanti, U; Crissman, K; Slade, R; Costa, D

2001-06-01

The present study compares acute and subchronic episodic exposures to phosgene to test the applicability of the 'concentrationxtime' (CxT) product as a measure of exposure dose, and to relate acute toxicity and adaptive responses to chronic toxicity. Rats (male Fischer 344) were exposed (six hours/day) to air or 0.1, 0.2, 0.5 and 1.0 ppm of phosgene one time or on a repeated regimen for up to 12 weeks as follows: 0.1 ppm (five days/week), 0.2 ppm (five days/week), 0.5 ppm (two days/week), or 1.0 ppm (one day/week) (note that the CxT for the three highest exposures was the same). Animals were sacrificed at 4, 8, and 12 weeks during the exposure and after four weeks recovery. Bronchoalveolar lavage (BAL) was performed 18 hours after the last exposure for each time period and the BAL supernatant assayed for protein. Elevated BAL fluid protein was defined as 'acute injury', diminished response after repeated exposure was defined as 'adaptation', and increased lung hydroxyproline or trichrome staining for collagen was defined as 'chronic injury'. Results indicated that exposures that cause maximal chronic injury involve high exposure concentrations and longer times between exposures, not high CxT products. A conceptual model is presented that explains the lack of CxT correlation by the fact that adaptation reduces an 'injury-time integral' as phosgene exposure is lengthened from acute to subchronic. At high exposure concentrations, the adaptive response appears to be overwhelmed, causing a continued injury-time integral, which appears to be related to appearance of chronic injury. The adaptive response is predicted to disappear if the time between exposures is lengthened, leading to a continued high injury-time integral and chronic injury. It has generally been assumed that long, continuous exposures of rodents is a conservative approach for detecting possible chronic effects. The present study suggests that such an approach my not be conservative, but might actually mask effects that could occur under intermittent exposure conditions.

78 FR 22789 - Methyl Jasmonate; Exemption From the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-17

.... The acute toxicity data show virtual non-toxicity for all routes of exposure and suggest that any...) and confirmed virtual non-toxicity through the oral route of exposure. There were no observed... virtual non-toxicity through the dermal route of exposure. (MRID No. 48653902). Methyl jasmonate is...

Single oral dose safety of D-allulose in dogs.

PubMed

Nishii, Naohito; Nomizo, Toru; Takashima, Satoshi; Matsubara, Tatsuya; Tokuda, Masaaki; Kitagawa, Hitoshi

2016-07-01

Healthy dogs were administered acute oral doses of D-allulose (also called D-psicose) to evaluate its toxicity. Six dogs received oral doses of either a placebo or D-allulose solution (1 and 4 g/kg) on three different study days. One dog experienced vomiting, and five dogs showed transient diarrhea when 4 g/kg of D-allulose was administered. All dogs were active and had a good appetite throughout the study period. Blood glucose concentration slightly decreased without a rise in plasma insulin concentration 2 hr after D-allulose administration. Plasma alkaline phosphatase activities showed a mild increase between 12 and 48 hr after D-allulose administration. These data suggested that a single oral dose of D-allulose does not show severe toxicity in dogs.

Final report on the safety assessment of Lecithin and Hydrogenated Lecithin.

PubMed

Fiume, Z

2001-01-01

Lecithin is a naturally occurring mixture of the diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid, commonly called phosphatidylcholine. Hydrogenated Lecithin is the product of controlled hydrogenation of Lecithin. Bilayers of these phospholipids in water may form liposomes, a spherical structure in which the acyl chains are inside and not exposed to the aqueous phase. Lecithin and Hydrogenated Lecithin are used in a large number of cosmetic formulations as skin conditioning agents-miscellaneous and as surfactant-emulsifying agents. Hydrogenated Lecithin is also used as a suspending agent-nonsurfactant. Historical data on concentration of use of Lecithin reveals that 0.1% to 1.0% is the concentration range most frequently seen, with concentrations up to 50% reported for two moisturizing products. A solution of 65% Lecithin is currently reported to be used at concentrations up to 3% in cosmetics. Nonocclusive application of Lecithin-containing liposomes to murine skin resulted in 30% penetration to the subdermis. In piglet skin, the same application resulted in 99% accumulating in the stratum corneum. In general, liposomes are considered effective in capturing other compounds inside their spherical structure and delivering any such captured compound through the skin barrier. As a result, caution should be exhibited in formulating cosmetic products that contain these ingredients in combination with other ingredients whose safety is based on their lack of absorption or where dermal absorption is a concern. Lecithin is virtually nontoxic in acute oral studies, short-term oral studies, and subchronic dermal studies in animals. Lecithin is not a reproductive toxicant, nor is it mutagenic in several assays. In an oral carcinogenicity study, brain neoplasms were found in mice exposed to Lecithin. In a subcutaneous carcinogenicity study, no neoplasms were found in mice and rats exposed to Lecithin. Adverse reactions to Lecithin in a metered-dose inhaler have been reported. Lecithin and Hydrogenated Lecithin were generally nonirritating and nonsensitizing in animal and human skin. Based on the available data, Lecithin and Hydrogenated Lecithin are safe as used in rinse-off cosmetic products; they may be safely used in leave-on products at concentrations up to 15%, the highest concentration tested in clinical irritation and sensitization studies; but the safety of use could not be substantiated in cosmetic products likely to be inhaled. Because of the possibility of formation of nitrosamines, these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed.

Subacute (90 days) oral toxicity studies of Kombucha tea.

PubMed

Vijayaraghavan, R; Singh, M; Rao, P V; Bhattacharya, R; Kumar, P; Sugendran, K; Kumar, O; Pant, S C; Singh, R

2000-12-01

Kombucha tea (KT) is a popular health beverage and is used as an alternative therapy. KT is prepared by placing the kombucha culture in solution of tea and sugar and allowing to ferment. The inoculum is a fungus consisting of symbiotic colony of yeast and bacteria. KT is consumed in several countries and is believed to have prophylactic and therapeutic benefits in a wide variety of ailments, viz., intestinal disorders, arthritis, ageing and stimulation of immunological system. Though KT is used in several parts of the world its beneficial effects and adverse effects have not been scientifically evaluated. Since there are no animal toxicological data on KT, subacute oral toxicity study was carried out. Five groups of rats were maintained: (a) control group given tap water orally, (b) KT given 2 ml/kg orally, (c) plain tea (PT) given 2 ml/kg orally, (d) KT given in drinking water, 1% (v/v) and (e) PT given in drinking water, 1% (v/v). The rats were given this treatment daily for a period of 90 days. Weekly records of weight, feed intake, water intake and general behaviour were monitored. There was no significant difference in the growth of the animals as evidenced by the progressive body weight change. The organ to body weight ratio and histological evaluation did not show any toxic signs. The haematological and biochemical variables were within the clinical limits. The study indicates that rats fed KT for 90 days showed no toxic effects.

Implicit Versus Explicit Applications of the Tissue Residue Approach, Oral Presentation

EPA Science Inventory

Toxic effect models based on the relationship of toxic effects to chemical concentrations within receptor organism tissues can often be reformulated to describe the relationship of toxic effects to exposure concentrations without actual specification of the tissue concentrations....

Genomics Study of the Exposure Effect of Gymnodinium catenatum, a Paralyzing Toxin Producer, on Crassostrea gigas' Defense System and Detoxification Genes

PubMed Central

García-Lagunas, Norma; Romero-Geraldo, Reyna; Hernández-Saavedra, Norma Y.

2013-01-01

Background Crassostrea gigas accumulates paralytic shellfish toxins (PST) associated with red tide species as Gymnodinium catenatum. Previous studies demonstrated bivalves show variable feeding responses to toxic algae at physiological level; recently, only one study has reported biochemical changes in the transcript level of the genes involved in C. gigas stress response. Principal Findings We found that 24 h feeding on toxic dinoflagellate cells (acute exposure) induced a significant decrease in clearance rate and expression level changes of the genes involved in antioxidant defense (copper/zinc superoxide dismutase, Cu/Zn-SOD), cell detoxification (glutathione S-transferase, GST and cytochrome P450, CPY450), intermediate immune response activation (lipopolysaccharide and beta glucan binding protein, LGBP), and stress responses (glutamine synthetase, GS) in Pacific oysters compared to the effects with the non-toxic microalga Isochrysis galbana. A sub-chronic exposure feeding on toxic dinoflagellate cells for seven and fourteen days (30×103 cells mL−1) showed higher gene expression levels. A significant increase was observed in Cu/Zn-SOD, GST, and LGBP at day 7 and a major increase in GS and CPY450 at day 14. We also observed that oysters fed only with G. catenatum (3×103 cells mL−1) produced a significant increase on the transcription level than in a mixed diet (3×103 cells mL−1 of G. catenatum+0.75×106 cells mL−1 I. galbana) in all the analyzed genes. Conclusions Our results provide gene expression data of PST producer dinoflagellate G. catenatum toxic effects on C. gigas, a commercially important bivalve. Over expressed genes indicate the activation of a potent protective mechanism, whose response depends on both cell concentration and exposure time against these toxic microalgae. Given the importance of dinoflagellate blooms in coastal environments, these results provide a more comprehensive overview of how oysters respond to stress generated by toxic dinoflagellate exposure. PMID:24039751

Chronic toxicity and oncogenicity of decamethylcyclopentasiloxane in the Fischer 344 Rat.

PubMed

Jean, Paul A; Plotzke, Kathleen P; Scialli, Anthony R

2016-02-01

Decamethylcyclopentasiloxane (D5) is a cyclic polydimethylsiloxane used in the synthesis of silicon-based materials and as a component in consumer products. Male and female Fischer 344 rats were exposed to D5 vapor (0, 10, 40, 160 ppm; whole-body inhalation) for 6 h/d, 5 d/wk, for up to 104 weeks. Microscopic examination of tissues revealed test article effects at 160 ppm in the upper respiratory tract (hyaline inclusions in males and females at 6, 12, and 24 months) and an increased incidence of uterine endometrial adenocarcinoma at 24-months. The hyaline inclusions were considered a non-adverse tissue response for lack of any other respiratory tract non-neoplastic or neoplastic changes. Uterine endometrial adenocarcinoma was not anticipated. Toxicity testing (mutagenicity/genotoxicity, acute, sub-acute and sub-chronic descriptive toxicity) performed prior to the conduct of the chronic bioassay provided no indication that the uterus was a potential target organ. The target organ and tumor type specificity (adenocarcinoma is a common spontaneous tumor in the aged Fischer 344 rat) suggests the effect is associated with estrous cycle alteration. A robust assessment of potential mode(s) of action responsible for the uterine tumors and relevance to humans is addressed in a companion manuscript (Klaunig et al., 2015). Copyright © 2015 Elsevier Inc. All rights reserved.