Myeloprotection with activated carbon in doxorubicin-treated rats.

Chemotherapy can often cause a variety of side effects including bone marrow (BM) suppression, termed as myelosuppression. Accordingly, facile and effective management of chemotherapy-induced myelosuppression is currently a pivotal task for experimental pathologists and oncologists. Here, we chose to use activated carbon (AC) with an extensive surface area for studying its possible protective effectiveness with respect to BM in doxorubicin (DOX)-treated rats. Spherical AC with an extended surface area up to 4490 m2/g was prepared for per os (p/o) delivery, whereas for intraperitoneal (i/p) delivery we used the powdered form of AC that was derived from the aforementioned spherical AC. During the monthly treatment of animals with AC and DOX these two components were delivered alternately (not in the same day). After treatment, BM cells were isolated from femurs of sacrificed animals, stained with acridine orange (AO) and analyzed by flow cytometry. Regardless of the route of AC delivery (p/o or i/p), apparent myeloprotection with a possible regenerative effect was observed in animals that received DOX, as evidenced by recovery of the populations of total nucleated cells (TNC) and polychromatic (immature) erythrocytes accompanied by a considerable reduction of the number of apoptotic/dead cells among TNC (≤2.0%). Moreover, as a result of AC administrations, there was a significant increase of AO green and far-red fluorescence intensities in the population of TNC, which is suggestive of the ongoing quantitative and conformational changes in DNA and RNA associated with cell recovery and proliferation. Thus, AC preparations under the present experimental conditions can effectively tackle DOX-induced myelosuppression via mechanisms not necessarily associated with adsorptive detoxification.

Methylated and ethylated dialkylphosphate metabolites of organophosphate pesticides: DNA damage in bone marrow cells of Balb/c mice.

Dialkylphosphates (DAPs), metabolites of organophosphate (OP) pesticides, are widely distributed in the environment and are often used as biomarkers of OP exposure. Recent reports indicate that DAPs may be genotoxic, both in vitro and in vivo. We have examined the genotoxicity of the methylated DAPs dimethyldithiophosphate (DMDTP) and dimethylphosphate (DMTP) and the ethylated DAPs diethyldithiophosphate (DEDTP) and diethylphosphate (DETP), in comparison with their parental compounds, malathion and terbufos, respectively, in bone marrow polychromatic erythrocytes (PCE) of male and female Balb/c mice. We also compared DNA damage (comet assay) induced by DMDTP and dimethyl phosphate (DMP) in human cell lines. Both DMDTP and DMP caused DNA damage in peripheral blood mononuclear cells, HeLa cells, and the hepatic cell lines HepG2 and WRL-68. In the in vivo micronucleus assay, methylated and ethylated DAPs increased micronucleated PCE cells in both male and female mice. Female mice were more susceptible to DNA damage. In comparison to their parental compounds, methylated DAPs, particularly DMTP, were more genotoxic than malathion; DEDTP, DETP, and terbufos were similar in potency. These results suggest that DAPs may contribute to DNA damage associated with OP pesticide exposure.

In vivo treatment with a subacute low dose of 3-nitropropionic acid does not induce genotoxicity or mutagenicity in rats.

3-nitropropionic acid (3-NP) is a toxin that causes neural damage in the striatum and can lead to the development of Huntington's disease manifestations in animal models. Several studies have shown genotoxicity related to the 3-NP treatment. This study investigated potential genotoxicity and mutagenicity that was induced by a low dose (6.25 mg/kg i. p.) 3-NP subacute treatment (daily, over 6 days) in a rat model. The arterial blood and the frontal cortex were analyzed by the comet assay and the bone marrow by micronucleus. Surprisingly, the 3-NP subacute treatment with the low dose did not show genotoxic or mutagenic effects.

Safety assessment of a novel thermostable phytase.

A novel 6-phytase (Phytase TSP, trade name OptiPhos® PLUS) with improved thermostability has been developed for use in animal feed. The safety of the new phytase was evaluated by testing for genotoxicity and subchronic toxicity. In in vitro and in vivo genotoxicity assays Phytase TSP concentrate was not mutagenic and did not induce biologically or statistically significant increases in the frequency of micronucleated polychromatic erythrocytes. In a subchronic toxicity study, male and female rats administered 100, 500 or 1000 mg/kg body weight/day of Phytase TSP concentrate via oral gavage for 90 days had no mortalities, and no treatment-related effects on body weight, food consumption, clinical observations or ophthalmology. Furthermore, there were no changes in haematology, clinical chemistry, urinalysis, gross pathology, organ weights or histopathology that could be attributed to the test article. Several endpoints exhibited statistically significant effects, but none was dose-related or considered to be of toxicological relevance. Based on these results, Phytase TSP concentrate (OptiPhos® PLUS) was not genotoxic and the No Observed Adverse Effect Level (NOAEL) for male and female rats was 1000 mg/kg body weight/day.

The Influence of High and Low Doses of Acrylamide on Porcine Erythropoiesis.

INTRODUCTION: Due to the widespread occurrence of acrylamide in the environment, its likely carcinogen status, and the suitability of the pig model as a human analogue, the authors decided to evaluate the impact of high and low doses of this compound on the processes of erythropoiesis in swine bone marrow. MATERIAL AND METHODS: The experiment was carried out on Danish Landrace pigs at the age of eight weeks and body weight about 20 kg. The animals were divided into three equal groups consisting of five pigs in each. Control animals received empty gelatin capsules (placebos). Animals from the first experimental group received a low dose of acrylamide of 0.5 µg/kg b.w./day (> 99% purity; Sigma-Aldrich, Poland), and animals from the second experimental group received a dose 10 times higher. Placebos and acrylamide capsules were administered with feed every morning for 28 days. After anaesthetisation of the animals, bone marrow from the femur was collected into tubes without an anticoagulant on days 0 and 28. After drying and staining, bone marrow smears were subjected to detailed cytological evaluation using a light microscope. RESULTS: This study showed that high and low doses of acrylamide affected the process of porcine erythropoiesis. The cytotoxic effect of acrylamide on this process was demonstrated in a change of the polychromatic erythroblasts/normochromatic erythroblasts ratio. CONCLUSION: Both doses of acrylamide caused a decrease in the number of ortho- and polychromatic erythroblasts.

A toxicological evaluation of a fulvic and humic acids preparation.

Humic substances are ubiquitous in soils and waters. These complex superstructures are derived from the decomposition of dead plant and animal matter and are vital to soil health. Their heterogenous composition is specific to their site of origin and is comprised of weakly bound aggregates of small organic compounds that can sequester minerals and make them available to plants. As such, they may possess potential nutritional value for humans, and extractions of fulvic and humic acids can be produced that could be suitable for such purposes. For this reason, we evaluated the toxicological profile of a specific preparation (blk. 333) of fulvic and humic acids derived from a lignite deposit in Alberta, Canada and found it to lack genotoxic potential in a bacterial reverse mutation test, in vitro mammalian chromosomal aberration test, and in vivo mammalian micronucleus test. No general or organ toxicity was observed in Wistar rats following 90 days of continuous exposure, and a no observed adverse effect level (NOEAL) was determined at 2000 mg/kg bw/day, the highest tested dose. Our results suggest the feasibility of further evaluation for development of the preparation as a nutritional supplement in food.

Solid-state fermentation of ammoniated corn straw to produce feed protein and toxicological assessment of the product.

Solid-state fermentation (SSF) of ammoniated corn straw was used to produce feed protein, followed by a toxicological assessment of the fermentation product. Results showed that through ammonification at 35 °C for 9 days and the subsequent SSF by the two fungi Penicillium sp. and Torula allii at 30 °C for 5 days, the contents of real protein and crude protein of the corn straw reached 29.66% and 35.41%, respectively. Toxicological assessment in mice showed that there were no significant differences (P > 0.05) for micronucleated polychromatic erythrocytes (Mn-PCEs) and sperm abnormality between dose groups and the control group. Malondialdehyde (MDA) levels and activities of superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) also showed no significant difference (P > 0.05) between tissues (heart, liver, spleen, stomach, kidney, and brain), which indicates that the fermentation product did not induce toxic effects and is safe to use as ruminant feed.

Attenuation of potassium dichromate and sodium arsenite toxicities by methanol extract of Rauvolfia vomitoria in mice.

OBJECTIVES: Exposure to arsenic and hexavalent chromium is a major public health concern especially in the developing part of the world and there is paucity of information on reliable treatment modalilities. It is in this regard that this study evaluates the efficacy of methanol leaf extract of Rauvolfia vomitoria (MRV) when used as pretreatment agent against potassium dichromate (K2Cr2O7) and sodium arsenite (NaAsO2) exposure. METHODS: Swiss albino mice between 7 and 10 weeks old were divided into eight cohorts of five animals each. Treatment groups consisted of a distilled water control, MRV alone (275 mg/kg po daily), K2Cr2O7 (12.0 mg/kg, single ip injection) +/- MRV pretreatment, NaAsO2 (2.5 mg/kg, single ip injection) +/- MRV pretreatment, Na2AsO2 + K2Cr2O7 +/- MRV pretreatment. MRV was given for seven consecutive days, while K2Cr2O7 and NaAsO2 were injected on day seven of the experiment. The frequency of micronucleated polychromatic erythrocytes (mPCEs) was determined in bone marrow cells, while aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were assessed in the plasma. Hepatic glutathione (GSH), malondialdehyde (MDA), catalase (CAT) and glutathione-S-transferase (GST) levels were also determined. RESULTS: The NaAsO2 and K2Cr2O7 significantly (p<0.05) increased mPCE formation, AST, ALT, and CAT when compared with the control. Simultaneous exposure to NaAsO2 and K2Cr2O7 further increased the levels of the markers. Furthermore, GSH and GST were significantly reduced by NaAsO2 or K2Cr2O7 or their combination. Pretreatment with MRV reversed the markers towards that of control. CONCLUSIONS: Methanol extract of Rauvolfia vomitoria may therefore ameliorate NaAsO2 and K2Cr2O7-induced toxicities via reduction of oxidative stress and fortification of anti-oxidant system.

Genotoxicity and subchronic toxicological study of a novel ginsenoside derivative 25-OCH3-PPD in beagle dogs.

BACKGROUND: Ginsenosides have been widely used clinically for many years and were regarded as very safe. However, a few researches on the toxicities of these kinds of agents showed that some ginsenosides may have side-effect on the rats or dogs. So it is extremely necessary to further clarify the potential toxicity of ginsenosides. This study was carried out to investigate long-term toxicity and genotoxicity of 25-methoxydammarane-3, 12, 20-triol (25-OCH3-PPD), a new derivative of ginsenoside, in beagle dogs. METHODS: Twenty-four beagle dogs were divided randomly into four treatment groups and repeatedly orally administered with 25-OCH3-PPD capsule at 60, 120, and 240 mg/kg/day for 91 consecutive days. Ames, micronucleus, and chromosomal aberration tests were established to analyze the possible genotoxicity of 25-OCH3-PPD. RESULTS: There was no 25-OCH3-PPD-induced systemic toxicity in beagle dogs at any doses. The level of 25-OCH3-PPD at which no adverse effects were observed was found to be 240 mg/kg/day. The result of Ames test showed that there was no significant increase in the number of revertant colonies of 25-OCH3-PPD administrated groups compared to the vehicle control group. There were also no significant differences between 25-OCH3-PPD administrated groups at all dose levels and negative group in the micronucleus test and chromosomal aberration assay. CONCLUSION: The highest dose level of 25-OCH3-PPD at which no adverse effects were observed was found to be 240 mg/kg per day, and it is not a genotoxic agent either in somatic cells or germs cells. 25-OCH3-PPD is an extremely safe candidate compound for antitumor treatment.

Toxicological Assessment of a Standardized Boswellia serrata Gum Resin Extract.

The acidic and non-acidic fractions of Boswellia serrata gum resin extracts were combined to prepare a unique product, LI13019F1 (Serratrin). The present series of studies evaluated LI13019F1 for acute and subchronic (28-day) toxicity in Wistar rats and acute dermal and eye irritation in New Zealand white rabbits. The mutagenicity and clastogenicity of LI13019F1 were evaluated in bacteria and mouse bone marrow erythrocytes, respectively. All studies were performed following the Organization for Economic Co-operation and Development guidelines. Acute oral and acute dermal toxicity studies did not show mortality or signs of toxicity in Wistar rats at a limit dose of 2,000 mg/kg LI13019F1. LI13019F1 did not cause irritation to the skin or the eyes of New Zealand white rabbits. In a repeated dose 28-day oral toxicity study, LI13019F1-treated Wistar rats did not show dose-related signs of toxicity on their body weights, organ weights, and on the hematology and clinical chemistry parameters. The estimated no observed adverse effect level for LI13019F1 was 1,000 mg/kg/day in both male and female rats. The bacterial reverse mutation test and a micronucleus assay in mouse bone marrow erythrocytes revealed that LI13019F1 was neither mutagenic nor clastogenic. Together, the present observations demonstrate a broad-spectrum safety of LI13019F1.

Toxicological assessment of Xanthigen® nutraceutical extract combination: Mutagenicity, genotoxicity and oral toxicity.

Xanthigen® is a nutraceutical combination for weight management capable of increasing energy expenditure via uncoupling protein 1 (UCP-1) in white adipose tissue. It consists of brown seaweed Undaria pinnatifida extract, rich in the carotenoid fucoxanthin (FX) and pomegranate seed oil (PSO), rich in punicic acid. Xanthigen was screened to determine its genotoxicity and 90-days repeated oral toxicity. Genotoxicity was assessed with the Ames test (TA89, TA100, TA1535, TA1537, WP2), chromosomal aberration assay (Chinese hamster ovary cells) and mammalian micronucleus test (in mice). Xanthigen did not exhibit genotoxicity in any tested strain. Sub-chronic toxicity was evaluated with daily oral administration of 250, 500 and 1000 mg/kg/day doses of Xanthigen® to Sprague-Dawley rats over 90 days. No deaths and no deleterious effects were observed during the 90-day treatment, indicating an absence of sub-chronic toxicity and a no observed adverse effect level greater than 1000 mg/kg/day. A statistically significant decrease in bodyweight and food intake in Xanthigen® treated groups was attributed to the weight loss property of Xanthigen®. Overall, Xanthigen® shows no significant mutagenic or toxic effects.

28-day inhalation toxicity of 3-methoxybutyl chloroformate in rats.

The 28-day repeated inhalation study was applied for hazard assessment of 3-methoxybutyl chloroformate (3-MBCF) in Sprague Dawley rats. Groups of five rats per sex were exposed 6 h/day, 5 days per week for 4 weeks to test substance concentration (ranging from 3 to 12 ppm) using a whole-body exposure system. At the terminal sacrifice, following blood collection and gross pathological examination, organ weights were determined and fixed organs were examined. The micronucleus test was performed using bone marrow cells. Exposure of 3-MBCF induced mortality at concentrations above 6 ppm. Decreases in body weight and food intake, hematologic alterations, organ weight changes, and gross and microscopic findings were seen even at the lowest concentrations of 3 ppm. Histopathology revealed principal test substance exposure correlated with lesions in the respiratory tract in both male and female rats above 3 ppm. Groups of male rats exposed above 6 ppm show microscopic lesions in spleens, livers, testes and epididymides; however, the micronucleated polychromatic erythrocytes frequency in bone marrow cells was not changed. Based on histopathology of the respiratory tract and other organs, the no observed adverse effect level (NOAEL) of 3-MBCF in the present study was less than 3 ppm.

50% Ethanol extract of Orthosiphon stamineus modulates genotoxicity and clastogenicity induced by mitomycin C.

Herbal products contain a variety of compounds which may be useful in protecting against cellular damage caused by mutagens. Orthosiphon stamineus (O.s) also known as Cat whiskers. The herb has been shown anti-oxidative properties and can modulate key cellular proteins that have cytoprotective effect. The study aimed to evaluate the effects of different doses (250, 500 and 1000 mg kg-1) of 50% ethanol extract of O.s (Et. O.s) on micro-nucleated polychromatic erythrocytes (MNPCE), Polychromatic to normachromatic erythrocytes ratio (PCE/NCE), Mitotic index (MI), and Chromosomal aberration (CA) in Bab/c mice. Moreover, these parameters were used to evaluate the anti-genotoxic and clastogenic potencies of (Et. O.s) against mitomycin c (MMC) that interact with biological molecules and induce genotoxic and clastogenic disorders in non-tumor cells. MMC (4 mg kg-1) was injected intraperitoneally (i.p.) to the mice before and after treatment with three different doses of (Et. O.s). The results indicated that the extract at different doses did not show significant (p ≥ 0.05) differences in (MNPCE), (PCE/NCE) ratios, and (CA) values. The higher doses sowed high (MI) values compared with untreated control group. MMC showed significant increase (p ≤ 0.001) in (MNPCE), (CA) and reduce (PCE/NCE) and (MI) values compared with untreated control group. Treatment with (Et. O.s) at different doses before and after MMC injection showed to modulate MNPCE, PCE/NCE ratios, CA and MI values in mice bone marrow cells suggesting genoprotective potential of this plant extract.

Magnesium stearate, a widely-used food additive, exhibits a lack of in vitro and in vivo genotoxic potential.

Magnesium stearate is widely used in the production of dietary supplement and pharmaceutical tablets, capsules and powders as well as many food products, including a variety of confectionery, spices and baking ingredients. Although considered to have a safe toxicity profile, there is no available information regarding its potential to induce genetic toxicity. To aid safety assessment efforts, magnesium sulfate was evaluated in a battery of tests including a bacterial reverse mutation assay, an in vitro chromosome aberration assay, and an in vivo erythrocyte micronucleus assay. Magnesium stearate did not produce a positive response in any of the five bacterial strains tested, in the absence or presence of metabolic activation. Similarly, exposure to magnesium stearate did not lead to chromosomal aberrations in CHL/IU Chinese hamster lung fibroblasts, with or without metabolic activation, or induce micronuclei in the bone marrow of male CD-1 mice. These studies have been used by the Japanese government and the Joint FAO/WHO Expert Committee on Food Additives in their respective safety assessments of magnesium stearate. These data indicate a lack of genotoxic risk posed by magnesium stearate consumed at current estimated dietary exposures. However, health effects of cumulative exposure to magnesium via multiple sources present in food additives may be of concern and warrant further evaluation.

Methanol Extract of Adansonia digitata Leaf Protects Against Sodium Arsenite-induced Toxicities in Male Wistar Rats.

BACKGROUND: Human and animal population exposure to arsenic through the consumption of arsenic contaminated water is rampant in many parts of the world. Protective agents of medicinal plants origin could provide maximum protection against toxicities of various kinds. OBJECTIVE: The protective role of orally administered methanol extract of the leaves of Adansonia digitata (MELAD) on sodium arsenite (SA) - induced clastogenicity and hepatotoxicity in male Wistar rats was evaluated. MATERIALS AND METHODS: Thirty male Wistar rats divided into six Groups (1-6) of five animals each were used for the study. Group 1 (negative control) received distilled water and normal diet only, Groups 2-6 received the extract (at 250 or 500 mg/kg body weight) and/or SA at 2.5 mg/kg body weight. RESULTS: There was statistically significant (P < 0.05) increase in the number of micronucleated polychromatic erythrocytes and lipid peroxidation in the SA group as compared with the negative control and treated groups. Administration of the extract reduced the effects of SA on the above parameters. Activities of serum alanine and aspartate aminotransferases did not show statistically significant effects; however, the histological analyses revealed periportal cellular infiltration by mononuclear cells, whereas the MELAD treated groups show mild cellular infiltration and mild portal congestion. CONCLUSIONS: MELAD protect against SA-induced toxicities in rats, and it may offer protection in circumstances of co-exposure and cases of arsenicosis. SUMMARY: MELAD extract significantly reduce the lipid peroxidation induced by sodium arsenite in the liver of rats.MELAD did not show profound effects on the activities of serum alanine (ALT) and aspartate (AST) aminotranferases.MELAD offered significant protection against sodium arsenite-induced genotoxicity in the micronuclei induction assay.In the circumstances of co-exposure to arsenic contamination, MELAD may protect against sodium arsenite-induced toxicities. Abbreviations Used: MELAD: Methanol extract of the leaves of Adansonia digitata, SA: Sodium arsenite, nMPCEs: Number of micronucleated polychromatic erythocytes; ALT: Alanine aminotranferase; AST: Aspartate aminotranferase, TBARS: Thiobarbituric acid reactive substances, TBA: Thiobarbituric acid, MDA: malondialdehyde, Sodium arsenite (NaAsO2), IARC: International Agency for Research on Cancer.

Modulatory role of betulinic acid in N-nitrosodimethylamine-induced hepatorenal toxicity in male Wistar rats.

N-nitrosodimethylamine (NDMA) is a toxicant found in foods and drinking water. Several synthetic agents used in alleviation of NDMA toxicity have been associated with serious side effects. Therefore, a safe and less toxic agent is desirable. In this study, betulinic acid (BA), a triterpenoid antioxidant, is proposed as a better and alternative agent to modulate NDMA-induced toxicity. Twenty-four Wistar rats were assigned into four groups of six rats each and treated with normal saline (control), BA (25 mg/kg), NDMA (5 mg/kg) and (BA + NDMA). BA was given by oral gavage for 14 consecutive days, while NDMA was administered intraperitoneally on days 7 and 12. Results showed that administration of NDMA significantly ( p < 0.05) elevated the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase and gamma-glutamyl transferase by 51%, 48% and 81%, respectively. Also, NDMA intoxication significantly ( p < 0.05) increased the levels of serum urea and creatinine by 64% and 82%, respectively, and decreased urinary creatinine by 67%. In addition, administration of NDMA significantly ( p < 0.05) increased the levels of hepatic and renal DNA fragmentation by 44% and 61%, respectively, relative to control. The number of micronucleated polychromatic erythrocytes (mnPCEs) in NDMA-treated rats (11.1 ± 2.6 mnPCE/1000PCE) was significantly higher than control (4.3 ± 1.1 mnPCE/1000 PCE). Immunohistochemistry revealed strong expressions of Bcl-2 and nuclear p53 in NDMA-intoxicated rats. Interestingly, pretreatment with BA significantly ( p < 0.05) ameliorated NDMA-induced changes in serum biochemical indices, mnPCEs, DNA fragmentation and expressions of Bcl-2 and p53 proteins. These findings suggest that BA protects against NDMA-induced toxicity via anti-oxidative and anti-apoptotic activities.

Complementary pharmacological and toxicological characterization data on the pharmacological profile of N-(2,6-dichlorophenyl)-2-(4-methyl-1-piperidinyl) acetamide.

This text presents complementary data corresponding to pharmacological and toxicological characterization of N-(2,6-dichlorophenyl)-2-(4-methyl-1-piperidinyl)acetamide (LIA) compound. These data support our research article entitled "Pharmacological profile of N-(2,6-dichlorophenyl)-2-(4-methyl-1-piperidinyl)acetamide, a novel analog of lidocaine" Déciga-Campos M., Navarrete-Vázquez G., López-Muñoz F.J., Librowski T., Sánchez-Recillas A., Yañez-Pérez V., Ortiz-Andrade R. (2016) [1]. Toxicity was predicted through the ACD/ToxSuite software and evaluated in vivo using brine shrimp larvae (Artemia salina L.) and mice. Also, we used the micronucleus assay to determine genotoxicity. We used the platform admetSAR to predict absorption properties of LIA and lidocaine.

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.

A 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 (S6821, CAS 1119831-25-2) and 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-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.

Antigenotoxic effects of a polyherbal drug septilin against the genotoxicity of cyclophosphamide in mice.

Septilin (Spt) is a polyherbal drug formulation from Himalaya Drug Company, consisting of extracts from different medicinal plants and minerals. In the traditional system of medicine, septilin is being used as immunomodulatory, antioxidant and anti-inflammatory agent. In the present study, the protective effects of septilin against the genotoxicity of cyclophosphamide (CP) a widely used alkylating anticancer drug was evaluated by using in vivo micronucleus (MN) and sperm shape abnormality assays in Swiss albino mice. CP administered intraperitoneally at a dose of 50 mg/kg b.w. was used as positive mutagen. Different doses of septilin viz., 125, 250 and 500 mg/kg b.w. was orally administered for 5 consecutive days. CP was administered intraperitoneally on 5th day. MN and sperm preparations were made after 24 h and 35 days respectively. CP induced significant MN in both bone marrow and peripheral blood cells and also a high frequency of abnormal sperms. In septilin supplemented animals, no significant induction of MN and abnormal sperms was recorded. In septilin supplemented groups, a dose dependent significant decrease in CP induced clastogenicity was observed. Thus the current in vivo study revealed the antigenotoxic effects of septilin against CP induced damage, in both somatic and germ cells of Swiss albino mice.

Fluoranthene and phenantrene, two predominant PAHs in heat-prepared food, do not influence the frequency of micronucleated mouse erythrocytes induced by other PAHs.

Polycyclic aromatic hydrocarbons (PAHs) occur in complex mixtures present in the human environment. Because of the carcinogenic properties of some of these PAHs, they raise concerns regarding health and food safety. Because the occurrence of benzo[a]pyrene, chrysene, benz[a]anthracene, and benzo[b]fluoranthene (PAH4) are considered markers for other genotoxic PAHs in foodstuffs, the European Union has put a maximum level of PAH4 in some foodstuffs. Fluoranthene (Flu) and phenanthrene (Phe), two other PAHs, are not classified as genotoxic and are abundant at rather high concentrations in food. Inasmuch as PAH4, Flu, and Phe are metabolized by the same cytochrome P450 pathway system, it is important to clarify whether Phe and Flu influence the genotoxicity of PAH4. We have analyzed the genotoxic response of Phe and Flu, separately and together, as well as in combination with different low doses of PAH4. In all experiments we used the flow cytometer-based micronucleus test in vivo. Phe and Flu, when administered separately, did not show any dose-related effect on the frequency of micronucleated polychromatic erythrocytes (fMNPCE). Nor did a mixture of Phe and Flu change the fMNPCEs. Phe and Flu did not significantly change the fMNPCE of PAH4-exposed FVB and BALB/c mice.