OBJECTIVE: 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.

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.

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.

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.

This mini-review aims to compare the differences in the kinetics of the induction of micronucleated polychromatic erythrocytes (MN-PCE) and cytotoxicity by distinct antineoplastic and genotoxic agents in murine peripheral blood in vivo and to correlate these kinetics with the underlying processes. Comparisons were carried out using our previously obtained data with nominal doses causing similar levels of cytotoxicity, as measured in terms reduction of PCE. The aneuploidogens caused the most rapid induction of MN-PCEs and had the highest rates of cytotoxicity and genotoxicity. The promutagens cyclophosphamide and dimethylnitrosamine showed the most delayed responses and had the lowest genotoxic and cytotoxic efficiencies. DNA crosslinking agents had a similar delay of 4-5 h, greater than those of aneuploidogens, but differed in their cytotoxic and genotoxic efficiencies. Methylnitrosourea and 5-aza-cytidine caused greater delays than crosslinking agents. These delays can be due to the methylnitrosourea-mediated induction of formation of mono alkyl adducts which are interpreted as mismatches during DNA duplication, whereas 5-aza-cytidine requires incorporation into the DNA to induce breakage. This review allows us to conclude that the requirement for metabolic activation and the mechanisms of DNA breakage and of micronucleus induction are the main factors that affect the time of maximal MN-PCE induction.

Chemotherapy remains an important approach in the fight against malaria. Artemether-lumefantrine combination is widely in use due to its effectiveness against Plasmodium falciparum. Misuse in the form of multiple repeated doses of this anti-malaria drug is rampant in Nigeria. This study was designed to assess the hepatotoxic and clastogenic potential of extreme misuse of artemether-lumefantrine in rats. Graded doses of artemether-lumefantrine (1-5 mg/kg body weight) were administered by oral gavage for 6 weeks, twice daily, for 3 consecutive days per week. Artemether-lumefantrine, at all doses, did not have significant effects on the body and relative liver weight of treated group compared to the negative control group. The mean γ-glutamyltransferase, alanine, and aspartate aminotransaminase activity in groups of artemether-lumefantrine treated rats were significantly higher (p < 0.05) than that of the negative control group indicating that repeated administration of artemether-lumefantrine may be hepatotoxic. Findings from histological analyses of liver cross-section support the enzyme pattern of hepatoxicity. In addition, the drug, at all experimental doses, significantly induced (p < 0.05) formation of micronucleated polychromatic erythrocytes in the bone marrow cells of the treated rats compared with the negative control indicating clastogenic potential of the drug when misused.

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).

We investigated whether combinations of ascorbic acid (AA) plus dietary polyphenols can protect in vivo against genotoxic damage induced by endogenous nitrosation. A nitrosation reaction mixture consisting of methylurea (MU) plus sodium nitrite (SN), which can react to form N-nitroso-N-methylurea in the stomach, was administered orally to mice, together with AA and one of the dietary polyphenols ferulic acid (FA), gallic acid (GA), chlorogenic acid (CA), or epigallocatechin gallate (EGCG). Genotoxic damage in bone marrow cells was assessed by measuring micronucleated polychromatic erythrocytes (Mn PCEs) and metaphase chromosome aberrations. When compared to damage induced by MU plus SN alone, co-administration with AA, FA, GA, CA, or EGCG resulted in significant protective effects. Combinations of AA plus EGCG or AA plus CA showed a further protective effect. Reduction in the frequency of Mn PCEs to the control level was obtained following co-administration of a combination of AA, FA, GA, and CA with MU plus SN. A similar trend was observed for metaphase chromosome aberrations. Co-administration of AA, FA, GA, or CA with N-nitroso-N-methylurea (MNU) did not show any significant reduction in genotoxicity, indicating the absence of a protective effect against a preformed N-nitroso compound. Our work demonstrates the protective effects of the \'antinitrosating\' combination of AA and dietary polyphenols FA, GA, or CA against genotoxic damage induced by an endogenously formed N-nitroso compound.

Achyrocline satureioides is widely consumed as infusion or aperitif and shows important therapeutic properties. Previously, we reported absence of genotoxicity of cold aqueous extract (CAE) of A. satureioides by Allium test. However, one test cannot predict the genotoxic effects of a substance. Thus, the aim of this work was to investigate cytotoxicity, genotoxicity and apoptotic ability of CAE of A. satureioides. In addition, CAE was chemically characterized. The cytotoxicity was evaluated by Trypan blue and MTT assays. The apoptotic capacity was evaluated by Hoechst staining and DNA fragmentation-analysis. The genotoxicity was studied by comet assay (CA) and micronucleus test. The identification and quantification of flavonoids were performed by HPLC-ESI-MS/MS. The cytotoxicity studies indicated low toxicity of CAE. In addition, CAE did not induce apoptotic effects on human PBMCs. CAE did not show genotoxicity in vitro against Vero cells, at 10-50 μg/mL. CAE did not induce in vivo genotoxic effects, but it showed at high concentrations cytotoxicity by micronucleus assay. CAE presented flavonoids such as quercetin, 3-O-methylquercetin and luteolin. In conclusion, A. satureioides at popularly concentrations used, in aperitif or infusion, can be consumed safely because did not show any cytotoxic or genotoxic effects.