Mouse Peripheral Blood Erythrocytes Research Articles

Toxicity study of Stachybotrys chartarum (CASRN 67892-26-6) administered by inhalation to B6C3F1/N mice.

Stachybotrys chartarum, also known as "black mold," is a cellulolytic saprophyte with a worldwide distribution. Public concern for potential illnesses associated with water-damaged indoor environments has been heightened since the report of pediatric acute idiopathic pulmonary hemorrhage/hemosiderosis cases in the United States and following recent natural disasters. Although mycotoxicosis and pulmonary immunological endpoints have been previously examined, the systemic toxicity following subchronic inhalation of viable S. chartarum remains undercharacterized. To evaluate the toxicological responses to S. chartarum, B6C3F1/N mice were exposed to viable S. chartarum conidia (spores) twice a week for 3 months. All in-life procedures, including inhalation exposure, test article preparation, and hematology analysis, were completed by the National Institute for Occupational Safety and Health (NIOSH, Morgantown, WV). Battelle (Columbus, OH) conducted terminal necropsies, measured terminal body and organ weights, and evaluated gross lesions onsite at the NIOSH facility. Tissue processing and histopathology were completed at Battelle. Genetic toxicology studies on mouse peripheral blood erythrocytes were conducted by Integrated Laboratory Systems, LLC (Research Triangle Park, NC). (Abstract Abridged).

Toxicology and carcinogenesis studies of sodium tungstate dihydrate in Sprague Dawley (Hsd:Sprague Dawley SD) rats and B6C3F1/N mice (drinking water studies).

Sodium tungstate dihydrate (ST) is present naturally in the environment and can enter waterways through the weathering of rocks and soils. ST also is a high-production volume compound that is used in a variety of commercial applications including fire- and waterproofing fabrics, in the preparation of complex compounds (e.g., phosphotungstate and silicotungstate), as a reagent for biological products, and as a precipitant for alkaloids. Tungsten was nominated to the National Toxicology Program (NTP) by the Centers for Disease Control and Prevention to evaluate its potential to cause chronic toxicity and carcinogenicity because of concern about potential human exposure via contaminated drinking water (e.g., in the form of salts like tungstate) and inadequate data to assess human health implications of elevated exposures. ST was selected for study because it is the most prevalent water-soluble form of tungsten. In these studies, Sprague Dawley (Hsd:Sprague Dawley SD) rat dams were exposed to ST in drinking water from gestation day (GD) 6 through lactation day (LD) 20. Their pups were exposed to the same exposure concentrations in drinking water from postnatal day (PND) 12 through 3 months or 2 years. Adult male and female B6C3F1/N mice were exposed to ST in drinking water for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, rat and mouse peripheral blood erythrocytes, and cells from liver, kidney, and ileum; peripheral blood leukocytes from rats and mice also were assessed for DNA damage. (Abstract Abridged).

Toxicity studies of Aspergillus fumigatus administered by inhalation to B6C3F1/N mice (revised).

Aspergillus fumigatus is a thermotolerant, soil-borne fungal species that is ubiquitous in the environment. Mold was nominated to the National Toxicology Program (NTP) by a private individual due to suspected adverse health effects associated with personal exposure in indoor and occupational settings. A. fumigatus is of particular concern in the biowaste industry as the species can contaminate self-heating compost piles. Because of this potential for personal and occupational exposure and the lack of available toxicity data, toxicity studies were conducted in which male and female B6C3F1/N mice were exposed to A. fumigatus conidia (spores) two times a week for 3 months. All in-life procedures, including inhalation exposure, test article preparation, and hematology analysis, were completed by the National Institute for Occupational Safety and Health (NIOSH, Morgantown, WV). Battelle (Columbus, OH) conducted terminal necropsies, measured terminal body and organ weights, and evaluated gross lesions on-site at NIOSH. Tissue processing and histopathology were completed at Battelle. Grocott's methenamine silver (GMS) staining was performed at NIOSH. Genetic toxicology studies on mouse peripheral blood erythrocytes were conducted by Integrated Laboratory Systems, LLC (Research Triangle Park, NC). (Abstract Abridged).

Toxicity studies of myristicin administered by gavage to F344/NTac rats and B6C3F1/N mice.

Myristicin is derived from the tropical evergreen tree Myristica fragrans. It is a major constituent in essential oil extracted from either the seed, which is the source of the spice nutmeg, or the aril covering the seed, which is the source of the spice mace. Myristicin was nominated for study by the National Cancer Institute due to widespread human exposure from natural sources and extensive consumer exposure. Male and female F344/NTac rats and B6C3F1/N mice received myristicin (greater than 94% pure) in corn oil by gavage at doses of 0, 10, 30, 100, 300, or 600 mg/kg body weight 5 days per week for 13 weeks. Additional groups of 10 male and 10 female clinical pathology study rats were administered the same doses for 21 days. Genetic toxicology studies were conducted in Salmonella typhimurium and in rat and mouse peripheral blood erythrocytes. (Abstract Abridged).

Toxicology and carcinogenesis studies in B6C3F1/N mice exposed to whole-body radio frequency radiation at a frequency (1,900 MHz) and modulations (GSM and CDMA) used by cell phones.

The predominant source of human exposure to radio frequency radiation (RFR) occurs through usage of cellular phone handsets. The Food and Drug Administration nominated cell phone RFR emission for toxicology and carcinogenicity testing in 1999. At that time, animal experiments were deemed crucial because meaningful human exposure health data from epidemiological studies were not available. Male and female B6C3F1/N mice were exposed to time-averaged whole-body specific absorption rates of 0 (sham control), 5, 10, or 15 W/kg Global System for Mobile Communications (GSM)- or Code Division Multiple Access (CDMA)-modulated cell phone RFR at 1,900 MHz for 28 days or 0, 2.5, 5, or 10 W/kg GSM- or CDMA-modulated cell phone RFR for up to 2 years. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes and leukocytes, brain cells, and liver cells. (Abstract Abridged).

Toxicity studies of triethylamine administered by inhalation to F344/N rats and B6C3F1/N mice.

Triethylamine is used primarily as a catalyst to cure the resin systems incorporated into sand cores for foundry molds. It is also used as a curing catalyst in phenol-formaldehyde particle board adhesives, for the precipitation and purification of penicillin and cephalosporin antibiotics, and in the interfacial polymerization process for the production of polycarbonate resins. Triethylamine was nominated by the United Auto Workers Union for long-term toxicity and carcinogenicity studies based on its high production volume, the large number of occupationally exposed workers, and the lack of carcinogenicity data. Male and female F344/N rats and B6C3F1/N mice were exposed to triethylamine (greater than 99% pure) by whole body inhalation for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. (Abstract Abridged).

Toxicology studies of indole-3-carbinol in F344/N rats and B6C3F1/N mice and toxicology and carcinogenesis studies of indole-3-carbinol in Harlan Sprague Dawley rats and B6C3F1/N mice (gavage studies).

Indole-3-carbinol is sold as a sole ingredient in dietary supplements or as a combination nutraceutical along with a variety of herbs and/or vitamins. It is marketed for its potential ability to prevent cancer and provide other health benefits, such as detoxifying the liver and boosting the immune system. Indole-3-carbinol is a naturally formed breakdown product of glucosinolate glucobrassicin, a component found in cruciferous vegetables of the Brassica genus, including broccoli, brussels sprouts, cauliflower, cabbage, kale, kohlrabi, and turnips. Exposure to indole-3-carbinol occurs through the oral route through the ingestion of Brassica vegetables or dietary supplements. Indole-3-carbinol was nominated by the National Cancer Institute for toxicity and carcinogenicity testing because of its occurrence in natural products and for its potential use as a breast cancer chemopreventive agent. Male and female F344/N rats and Harlan Sprague Dawley rats received indole-3-carbinol in corn oil by gavage for 3 months or 2 years, respectively. Male and female B6C3F1/N mice received indole-3-carbinol in corn oil gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, rat bone marrow cells, and mouse peripheral blood erythrocytes. (Abstract Abridged).

Interactions between ethanol and cigarette smoke in a mouse lung carcinogenesis model.

Both ethanol and cigarette smoke are classified as human carcinogens. They can synergize, especially in tissues of the upper aerodigestive tract that are targeted by both agents. The main objective of the present study was to evaluate the individual and combined effects of ethanol and smoke in the respiratory tract, either following transplacental exposure and/or postnatal exposure. We designed two consecutive studies in mouse models by exposing Swiss H mice to oral ethanol and/or inhaled mainstream cigarette smoke for up to 4 months, at various prenatal and postnatal life stages. Clastogenic effects and histopathological alterations were evaluated after 4 and 8 months, respectively. Ethanol was per se devoid of clastogenic effects in mouse peripheral blood erythrocytes. However, especially in mice exposed both transplacentally throughout pregnancy and in the postnatal life, ethanol administration was associated not only with liver damage but also with pro-angiogenetic effects in the lung by stimulating the proliferation of blood vessels. In addition, these mice developed pulmonary emphysema, alveolar epithelial hyperplasias, microadenomas, and benign tumors. On the other hand, ethanol interfered in the lung carcinogenesis process resulting from the concomitant exposure of mice to smoke. In fact, ethanol significantly attenuated some smoke-related preneoplastic and neoplastic lesions in the respiratory tract, such as alveolar epithelial hyperplasia, microadenomas, and even malignant tumors. In addition, ethanol attenuated cigarette smoke clastogenicity. In conclusion, preclinical studies provide evidence that, in spite of its pulmonary toxicity, ethanol may mitigate some noxious effects of cigarette smoke in the respiratory tract.

Toxicology and carcinogenesis studies of TRIM VX in Wistar Han [Crl:WI (Han)] rats and B6C3F1/N mice (inhalation studies).

TRIM VX is a metalworking fluid used as a lubricant and coolant liquid and for cleaning tools and parts during cutting, drilling, milling, and grinding. The metalworking fluid class was nominated by the National Institute for Occupational Safety and Health (NIOSH) for study by the National Toxicology Program because of high production volumes, the large number of occupationally exposed workers, the lack of carcinogenicity and chronic toxicology data, and because epidemiologic data indicate an increased incidence of laryngeal cancer in workers exposed to metalworking fluids. TRIM VX was selected as an example soluble oil metalworking fluid following chemical analysis and collaboration with NIOSH. Male and female Wistar Han [Crl:WI (Han)] rats and B6C3F1/N mice were exposed to TRIM VX by inhalation for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and rat and mouse peripheral blood erythrocytes. (Abstract Abridged).

Toxicity studies of octahydro-tetramethyl-naphthalenyl-ethanone (OTNE) administered dermally to F344/NTac rats and B6C3F1/N mice.

Octahydro-tetramethyl-naphthalenyl-ethanone (OTNE) is a fragrance ingredient that is formed as a mixture of isomers with a basic unsaturated alkyl cyclic ketone structure. The main isomer is 1-(1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)ethanone (β-isomer). Two other predominant isomers within the mixture are 1-(1,2,3,4,6,7,8,8a-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)ethanone (α-isomer) and 1-(1,2,3,5,6,7,8,8a-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)ethanone (γ-isomer). OTNE is used as a perfume ingredient in soap, shampoo, cologne, liquid detergent compounds, and malodor-reducing compounds. Male and female F344/NTac rats and B6C3F1/N mice were administered OTNE (greater than 92.3% pure with respect to the 3 prominent isomers) dermally for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and rat and mouse peripheral blood erythrocytes. (Abstract Abridged).

Toxicity studies of α-pinene administered by inhalation to F344/N rats and B6C3F1/N mice.

α-Pinene is the main component in turpentine and is used as a fragrance and flavoring ingredient. Due to widespread exposure potential and a lack of available toxicity data, male and female F344/N rats and B6C3F1/N mice were exposed to α-pinene (96% pure) by inhalation for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. (Abstract Abridged).

Toxicology studies of cobalt metal in F344/N rats and B6C3F1/N mice and toxicology and carcinogenesis studies of cobalt metal in F344/NTac rats and B6C3F1/N mice (inhalation studies).

Widespread exposure to cobalt metal dust occurs occupationally through the production of alloys, in the manufacture of cobalt salts, and in nuclear technology. It is an effective catalyst for many organic reactions, particularly in hydrotreating catalysts, which have molybdenum and cobalt sulfides as active components. Concerns have been raised about the occurrence of occupational disease, i.e. hard metal disease, associated with exposure to cobalt and its compounds, including cobalt metal-tungsten carbide. Cobalt metal is also widely dispersed in low concentrations in the environment and the general population may be exposed by breathing air, drinking water, or skin contact with soil, water, cobalt alloys, or other substances that contain cobalt. In addition, cobalt metal is an essential trace element as a component of cyanocobalamin (vitamin B12). Cobalt metal dust was nominated for toxicology and carcinogenesis studies by the United Auto Workers and the Cobalt Development Institute based on the widespread occupational exposure and limited availability of data on chronic toxicity and carcinogenic potential of inhaled insoluble cobalt compounds, particularly cobalt metal dust. Inhalation was selected as the route of exposure because this is the most common route of exposure to cobalt metal dust in occupational settings in humans. Male and female F344/N or F344/NTac rats and B6C3F1/N mice were exposed to cobalt metal by inhalation for 2 weeks, 3 months, or 2 years (F344/NTac rats). In addition, genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. (Abstract Abridged).

Toxicology and carcinogenesis studies of β-picoline in F344/N rats and B6C3F1/N mice (drinking water studies).

β-Picoline is used as a solvent in the synthesis of pharmaceuticals, resins, dyes, rubber accelerators, and insecticides. β-Picoline was nominated by the National Institute of Environmental Health Sciences for toxicological evaluation and carcinogenicity studies based on its high production volume and potential for human exposure. Male and female F344/N rats and B6C3F1/N mice were exposed to β-picoline (greater than 96% pure) in drinking water for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. (Abstract Abridged).

Methylphenidate lacks genotoxic effects in mouse peripheral blood erythrocytes

Methylphenidate (MPH; Ritalin®; Novartis Pharmaceuticals, Inc., Basel, Switzerland) has been prescribed to treat attention deficit/hyperactivity disorder (ADHD) since its approval by the U.S. Food and Drug Administration over 50 years ago. Due to concerns that MPH might induce cytogenetic alterations in children, treatment with this drug has been a controversial issue. In the present study, we assessed the frequency of micronucleated erythrocytes (MNEs), micronucleated polychromatic erythrocytes (MNPCEs), and polychromatic erythrocytes (PCEs) in peripheral blood samples from mice treated with three different doses of MPH (30, 60, or 125 mg/kg). We found no evidence of increased MNEs or MNPCEs, nor did PCEs decline. These results add to the accumulating evidence that MPH does not induce genotoxic or cytotoxic damage.

Effect of masticadienonic acid on the induction of micronuclei in polychromatic erythrocytes in mouse peripheral blood

The bark of Amphipterygium adstringens Schiede ex Schltdl. is widely used in the traditional Mexican medicine for treating ailments such as gastric ulcers, gastritis and stomach cancer. The masticadienonic acid was isolated from the bark of this species. In previous papers have been informed that this compound possess anti-inflammatory and cytotoxic activities [1, 2]. Now we describe cytotoxic and genotoxic effects of this compound. The cytotoxic and genotoxic effects of masticadienonic acid on CD1 male mice were determined with micronucleus assay at 24, 48 and 72h after oral administration of doses of 250, 500 and 1000mg/kg. Peripheral blood samples were drawn from the caudal vein and analyzed by Giemsa-stained technique. The results showed that the ratios of polychromatic erythrocytes (PCE) to normochromatic erythrocytes (NCE) in mice treated with 250, 500 and 1000mg/kg were not statistically different compared with their negative control animals at 0, 24 and 72h. PCE/NCE ratios were increased at 48h at all doses. The masticadienonic acid showed cytotoxic activity at 48h after administered at all doses. The test compound do not increased the frequency of micronucleated polychromatic erythrocytes; this compound may not lead to chromosome damage at the evaluated doses.

Effect of 6-nonadecyl salicylic acid and its methyl ester on the induction of micronuclei in polychromatic erythrocytes in mouse peripheral blood

The bark of Amphipterygium adstringens is widely used in the traditional Mexican medicine for treating ailments such as gastric ulcers, gastritis and stomach cancer. The 6-nonadecyl salicylic acid (anacardic acid) was isolated from the bark of this species. In previous papers have been informed that the anacardic acids possess anti-tumour, antimicrobial, antiacne, antibacterial and many others medicinal properties. Now we describe cytotoxic and genotoxic effects of this compound and its methyl ester. The cytotoxic and genotoxic effects of 6-nonadecyl salicylic acid (6NDSA) and its methyl ester (ME6NDSA) on CD1 male mice were determined with micronucleus assay at 24, 48 and 72 h after oral administration of doses of 0.75, 2.5, 5.0 and 10.0 mg/kg. Peripheral blood samples were drawn from the caudal vein and analyzed by Giemsa-stained technique. The results obtained showed that the ratios of polychromatic erythrocytes (PCE) to normochromatic erythrocytes (NCE) in mice treated with 10 mg/kg of 6NDSA were statistically lower after 24 h compared with its negative control animals, and that after 72 h, PCE/NCE ratios were reduced in animals treated with 6NDSA at all tested dose levels. The methyl ester ME6NDSA showed no such cytotoxic activity. Neither of the test compounds increased the frequency of micronucleated polychromatic erythrocytes from which it appears that administration of 6NDSA and ME6NDSA may not lead to chromosome damage at the evaluated doses.

Induction of Micronucleated Erythrocytes in Mouse Peripheral Blood After Cutaneous Application of 5-Fluorouracil

Background For topically applied drugs such as 5-fluorouracil (5-FU), dosage is not as precise as for other drug administration pathways. Consequently, quantity of drug delivered may differ among individuals and applications. 5-FU is used in treatment of different diseases and has been reported as a clastogenic compound by micronucleus assay. Methods To determine whether 5-FU cream (5% 5-FU) absorbed through skin can produce genotoxic or cytotoxic effect in mouse bone marrow, induction of micronucleated erythrocytes (MNE) in mouse peripheral blood was examined after cutaneous application of 5-FU daily for 5 days. Results 5-FU cream induced significant micronuclei at doses of 37.5 mg (total weight of cream)/2 cm 2 and 75.0 mg/2 cm 2, as well as cytotoxic effects at doses of 150.0 and 300.0 mg/2 cm 2. Conclusions Cutaneous application of 5-FU increased number of MNE in mouse peripheral blood. These data emphasize the importance of using correct dose when applying drugs topically.

Genotoxicity study of a new tetraalkylammonium derivative of 6-methyluracil (agent No. 547).

Agent No. 547 (1,3-bis[omega-(diethyl-ortho-nitrobenzylammonio)-pentyl]-6-methyluracil dibromide), a newly synthesized inhibitor of mammalian-specific acetyltcholinesterase (EC 3.1.1.7) was investigated for genotoxicity using the DNA-repair test, Ames test and in vivo micronucleus test with mouse peripheral blood erythrocytes. Agent No. 547 did not cause significant changes in growth of repair-deficient Escherichia coli tester strains. The compound was non-mutagenic in Salmonella typhimurium strains TA98 and TA100 with and without rat microsomal activation mixture. However, we observed a marked increase in number of His(+) revertants for both tester strains in preincubation assays. The results obtained in the micronucleus test indicate that agent No. 547 possesses significant clastogenic activity. At the high dose tested (0.5 mg/kg), the compound induced a seven-fold increase in the number of micronuclei over the spontaneous background 48 h after treatment. The results suggest that further work should be promoted to identify the metabolic pathways involved in genotoxicity of agent No. 547 in mammalian cells and to evaluate the real risk of its exposure.

Effect of chlorophyllin on chromium trioxide-induced micronuclei in polychromatic erythrocytes in mouse peripheral blood

The effect of chlorophyllin on micronucleated polychromatic erythrocytes (MN-PCE) induction by chromium trioxide (CrO 3) exposure in peripheral blood of mice was studied. Animals were treated with a single intraperitoneal dose of chlorophyllin (CHL) (20 mg/kg), CrO 3 (20 mg/kg), and CHL (20 mg/kg) 4 h before (CHL–CrO 3) or 4 h before and 20 h after chromium treatments (20 mg/kg; CHL–CrO 3–CHL). Peripheral blood samples were drawn from the caudal vein at 0, 12 and 48 h, and analyzed by the acridine orange (AO) technique. The results obtained in present study shown that CHL injection did not modify the number of MN-PCE. CrO 3 treatment resulted in a significantly increases 12 and 48 h after the injection, reaching a four-fold increase 48 h after CrO 3 administration. Whereas treatment with 20 mg/kg of CHL prior to chromium, decreased the MN frequency induced by chromium in the 12 h samples. When the samples were analyzed 48 h after CrO 3 injection, no significant differences between CHL–CrO 3 and CHL–CrO 3–CHL in comparison with CrO 3 treatment, were observed. These results indicate that increase of MN-PCE by CrO 3 is CHL-blocked in both protocols used (CHL–CrO 3 and CHL–CrO 3–CHL) at 12 h after treatment, but it was unable to modify the frequency of MN-PCE measured 48 h after CrO 3 injection. The absence of a protective effect by CHL in the MN-PCE induction by CrO 3 at 48 h, show that CHL has action only on one of the times of MN induction and suggests the possible action of CrO 3 by two different mechanisms, and not by CHL time-limited in vivo.

Effects of extended low-dose-rate exposure to 137Cs detected by flow-cytometric enumeration of micronucleated erythrocytes in mouse peripheral blood.

An automated variant the of micronucleus assay for erythrocytes in mouse peripheral blood has recently been developed. The flow-cytometric technique used allows very large numbers of erythrocytes to be analysed with a relatively small effort. Here we report the potential of this method to detect a response to extended low-dose-rate exposure to gamma-irradiation. The mice were irradiated with a 137Cs source at a dose rate of 4.8 cGy/day for 26 days. Sampling was continued for another 39 days after irradiation. Elevated frequencies compared with the control group were found at days 2, 9 and 20 after the start of the irradiation for micronucleated polychromatic erythrocytes, and at days 9, 20, 29, 42, 51 and 65 for micronucleated normochromatic erythrocytes.