Journal of Toxicology http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Acute Methotrexate Ingestions in Adults: A Report of Serious Clinical Effects and Treatments Wed, 16 Apr 2014 07:01:33 +0000 http://www.hindawi.com/journals/jt/2014/214574/ Objective. Limited reported data have reports effects after acute ingestion of methotrexate. Treatment recommendations do not differentiate between exposure routes. Our objective was to determine the frequency of significant toxicity effects and use of therapy after methotrexate ingestion in adults. Methods. We performed a retrospective study on adult cases reported to 6 poison centers over 6 years (2000–2005) which exceed 180,000 exposures/year. Variables collected included demographics, dosages ingested, coingestions, clinical effects, and therapies with outcomes. Results. Sixty-three patients examined over the 6-year period met inclusion criteria. No patient in the series received dialysis or died. The mean dose ingested for all patients was 24 mg (range 2.5–100 mg) and the mean dose for suicidal ingestions was 47.5 mg (12.5–100 mg). The most common clinical effects were abdominal pain, oral irritation, throat irritation, nausea, dizziness, and headache. Nine patients received folinic acid and 3 patients received sodium bicarbonate. No patient developed renal failure, bone marrow suppression, seizure, or coma. No patient died or received dialysis. Conclusion. In our series of patients from 6 poison centers over six years, 63 cases of acute adult methotrexate ingestions were reported. Methotrexate toxicity from ingestion in adults was uncommon and rarely toxic. Vikhyat S. Bebarta, Matthew D. Hensley, and Douglas J. Borys Copyright © 2014 Vikhyat S. Bebarta et al. All rights reserved. Safety Evaluation of Artocarpus altilis as Pharmaceutical Agent in Wistar Rats Wed, 02 Apr 2014 11:58:40 +0000 http://www.hindawi.com/journals/jt/2014/980404/ This study was designed to elucidate the acute toxicity of Artocarpus altilis leaf and bark extracts. In acute toxicity study, no mortality or any toxic reaction was recorded in any group after 14 days of administering the extracts (2000 mg Kg−1 BW). The extracts (ALA, ABA, ALM, and ABM) did not cause any behavioural or physical changes in experimental rats. There was no significant () difference in the biochemical parameters analysed between the groups. Slight elevation in activities of AST and ALT in extract treated groups was observed, but this did not exert any deleterious effect on the normal metabolism which was supported by the histopathology of liver. Histopathological studies showed no remarkable changes after 14 days of oral administration of ALA, ABA, ALM, and ABM extracts. The study contributes to establishing the nontoxic quality parameters of Artocarpus altilis leaf and bark parts and the results suggest the safety of the extracts in therapeutic uses. Sudha Sairam and Asna Urooj Copyright © 2014 Sudha Sairam and Asna Urooj. All rights reserved. Acute Toxicity and Determination of the Active Constituents of Aqueous Extract of Uncaria tomentosa Bark in Hyphessobrycon eques Thu, 06 Mar 2014 08:23:13 +0000 http://www.hindawi.com/journals/jt/2014/412437/ Uncaria tomentosa is a medicinal plant used in folk medicine by Amazon tribes. In this study the constituents of aqueous extract of U. tomentosa bark were quantified by chromatographic technique and its lethal concentration 50 (48 h) in Hyphessobrycon eques was determined. The chromatography showed high levels of oxindole alkaloids, quinovic acid glycosides, and low molecular weight polyphenols. The CL50 48 h was 1816 mg/L. Fish showed behavior changes at concentrations above 2000 mg/L, accompanied by a significant decrease of dissolved oxygen. At the highest concentration 100% mortality was observed attributed to oxygen reduction by the amount of oxindole alkaloids, polyphenols accumulation of the extract in the gills, and the interaction of these compounds with dopamine. In conclusion, the aqueous extract of U. tomentosa did not alter the chemical components and it was shown that U. tomentosa has low toxicity to H. eques; therefore, it can be used safely in this species. Jefferson Yunis Aguinaga, Gustavo S. Claudiano, Paulo F. Marcusso, Cynthia Ikefuti, George G. Ortega, Silas F. Eto, Claudinei da Cruz, Juliet R. E. Moraes, Flávio R. Moraes, and João B. K. Fernandes Copyright © 2014 Jefferson Yunis Aguinaga et al. All rights reserved. Botulinum Toxin Suppression of CNS Network Activity In Vitro Wed, 12 Feb 2014 13:56:39 +0000 http://www.hindawi.com/journals/jt/2014/732913/ The botulinum toxins are potent agents which disrupt synaptic transmission. While the standard method for BoNT detection and quantification is based on the mouse lethality assay, we have examined whether alterations in cultured neuronal network activity can be used to detect the functional effects of BoNT. Murine spinal cord and frontal cortex networks cultured on substrate integrated microelectrode arrays allowed monitoring of spontaneous spike and burst activity with exposure to BoNT serotype A (BoNT-A). Exposure to BoNT-A inhibited spike activity in cultured neuronal networks where, after a delay due to toxin internalization, the rate of activity loss depended on toxin concentration. Over a 30 hr exposure to BoNT-A, the minimum concentration detected was 2 ng/mL, a level consistent with mouse lethality studies. A small proportion of spinal cord networks, but not frontal cortex networks, showed a transient increase in spike and burst activity with exposure to BoNT-A, an effect likely due to preferential inhibition of inhibitory synapses expressed in this tissue. Lastly, prior exposure to human-derived antisera containing neutralizing antibodies prevented BoNT-A induced inhibition of network spike activity. These observations suggest that the extracellular recording from cultured neuronal networks can be used to detect and quantify functional BoNT effects. Joseph J. Pancrazio, Kamakshi Gopal, Edward W. Keefer, and Guenter W. Gross Copyright © 2014 Joseph J. Pancrazio et al. All rights reserved. Concentration of Cd, Pb, Hg, and Se in Different Parts of Human Breast Cancer Tissues Tue, 11 Feb 2014 00:00:00 +0000 http://www.hindawi.com/journals/jt/2014/413870/ Breast cancer is the major cause of cancer morbidity and mortality between women in the world. Metals involved in environmental toxicology are closely related to tumor growth and cancer. On the other hand, some metals such as selenium have anticarcinogenic properties. The aim of this study is to determine the concentration of cadmium, lead, mercury, and selenium in separated parts of tegmen, tumor, tumor adiposity, and tegmen adiposity of 14 breast cancer tissues which have been analyzed by graphite furnace atomic absorption (AA-670) and ICP-OES (ULTIMA 2CE). Our results show that Se and Hg have maximum and minimum concentration, respectively. Statistical analysis reveals no significant differences between metal accumulations in different parts of cancer tissues and this observation might be due to the close relation of separated parts of fatty breast organ. Thus, we could conclude that a high level of these heavy metals is accumulated in Iranian cancerous breasts and their presence can be one of the reasons of cancer appearance. Mehrnoosh Mohammadi, Alireza Riyahi Bakhtiari, and Saber Khodabandeh Copyright © 2014 Mehrnoosh Mohammadi et al. All rights reserved. Sanitary Risks Connected to the Consumption of Infusion from Senna rotundifolia L. Contaminated with Lead and Cadmium in Cotonou (Benin) Wed, 29 Jan 2014 11:33:57 +0000 http://www.hindawi.com/journals/jt/2014/376503/ This study carried out an assessment of sanitary risks connected to the consumption of Senna rotundifolia Linn. contaminated with lead and cadmium. This plant was collected and analyzed by atomic absorption spectrophotometry. The results revealed a contamination of plants from markets of Dantokpa, Vossa, and Godomey with heavy metals. Senna from Vossa was higher in cadmium and lead levels (Pb: 2.733 mg/kg ± 0.356 mg/kg; Cd: 0.58 mg/kg ± 0.044 mg/kg) compared to the two other places (Pb: 1.825 mg/kg ± 0.133 mg/kg, Cd: 0.062 mg/kg ± 0.015 mg/kg and Pb: 1.902 mg/kg ± 0.265 mg/kg, Cd: 0.328 mg/kg ± 0.024 mg/kg), respectively, for Dantokpa and Godomey. In terms of risk assessment through the consumption of Senna, the values recorded for lead were nine times higher with children and six times higher with adults than the daily permissive intake (Pb: 3.376 × 10−2 mg/kg/day for children and 2.105 × 10−2 mg/kg/day for adults versus 3.6 × 10−3 mg/kg/day for DPI). With respect to cadmium, there was no significant difference between the recorded values and the DPI (Cd: 1 × 14 10−3 mg/ kg/day for children and Cd: 0.71 × 10−3 mg/ kg/day for adults versus Cd: 1 × 10−3 mg/kg/day for adults). This exposure of the population to lead and cadmium through the consumption of antimalarial healing plants could pose public health problems. S. A. Montcho, K. Koudouvo, A. P. E. Yehouenou, P. Guedenon, L. Koumolou, M. Oke Sopoh, V. Dougnon, Mensavi F. Gbéassor, E. E. Creppy, M. Boko, and A. P. Edorh Copyright © 2014 S. A. Montcho et al. All rights reserved. Toxicological Study of Ocimum sanctum Linn Leaves: Hematological, Biochemical, and Histopathological Studies Wed, 29 Jan 2014 00:00:00 +0000 http://www.hindawi.com/journals/jt/2014/135654/ The present study was aimed to study the acute and subacute toxicity studies with orally administered 50% ethanolic leaves extract of Ocimum sanctum Linn (OSE). In acute toxicity tests, four groups of mice were orally treated with doses of 200, 600, and 2000 mg/kg, and general behavior, adverse effects, and mortality were recorded for up to 14 days. In subacute toxicity study, rats received OSE by gavage at the doses of 200, 400, and 800 mg/kg/day for 28 days, and biochemical, hematological, and histopathological changes in tissues (liver, kidney, spleen, heart, and testis/ovary) were determined. OSE did not produce any hazardous symptoms or death and CNS and ANS toxicities in the acute toxicity test. Subacute treatment with OSE did not show any change in body weight, food and water consumption, and hematological and biochemical profiles. In addition, no change was observed both in macroscopic and microscopic aspects of vital organs in rats. Our result showed that Ocimum sanctum extract could be safe for human use. M. K. Gautam and R. K. Goel Copyright © 2014 M. K. Gautam and R. K. Goel. All rights reserved. Cyclosporine and Herbal Supplement Interactions Sun, 12 Jan 2014 00:00:00 +0000 http://www.hindawi.com/journals/jt/2014/145325/ Cyclosporine (CyA) is a well-known immunosuppressant with a narrow therapeutic window. Its bioavailability is affected by many other traditional drugs and herbal extracts. Cytochrome P-450 isoenzymes CYP3A4 and CYP3A5 and protein P-glycoprotein (P-gp) are involved in CyA bioavailability. Interactions of CyA with herbal extracts are not well known, but, given their increased concomitant use, it is important to know which extracts, many of which are commonly self-prescribed, can affect CyA blood concentrations. Decreased CyA blood concentration has been shown with St John’s wort in case reports and, in vivo animal studies, with ginger, liquorice, scutellariae radix, and quercetin. Increased CyA concentration has been reported in patients with grapefruit juice, chamomile, or berberine, and with cannabidiol or resveratrol in animal studies. Effects of Echinacea and Serenoa repens on CyA levels have not been shown consistently, but concomitant use should be avoided. Although findings from animal studies cannot be directly translated into humans, avoiding concomitant use of herbal extracts is prudent until human clinical studies have ruled out any possible interaction. Clinicians should interview their patients carefully about their use of herbal supplements before CyA administration, and those receiving CyA should be warned about possible interactions between herbal preparations and CyA. D. Colombo, L. Lunardon, and G. Bellia Copyright © 2014 D. Colombo et al. All rights reserved. Influence of Exposure to Benzo[a]pyrene on Mice Testicular Germ Cells during Spermatogenesis Mon, 23 Dec 2013 09:47:11 +0000 http://www.hindawi.com/journals/jt/2013/387850/ The objective of this study was to assess the toxicological effect of exposure to benzo(a)pyrene, B[a]P, on germ cells during spermatogenesis. Mice were exposed to B[a]P at 1, 10, 50, and 100 mg/kg/day for 30 days via oral ingestion. Germ cells, including spermatogonia, spermatocytes, pachytene spermatocytes, and round spermatids, were recovered from testes of mice exposed to B[a]P, while mature spermatozoa were isolated from vas deferens. Reproductive organs were collected and weighed. Apoptotic response of germ cells and mature spermatozoa were qualified using the terminal deoxynucleotidyl transferase mediated deoxy-UTP nick end labeling (TUNEL) assay. B[a]P exposure at ≤10 mg/kg/day for 30 days did not significantly alter concentrations of germ cells and mature spermatozoa and apoptotic response in germ cells and mature spermatozoa. Exposure to B[a]P at 50 and 100 mg/kg/day induced testicular atrophy and yielded a significant reduction in the concentrations of spermatogonia, spermatocytes, pachytene spermatocytes, and round spermatid cells as compared with the control. Also, mature spermatozoa experienced decreased concentrations and viability. B[a]P-exposed mice experienced a significant increase in apoptotic germ cells as compared to the control mice. However, the mice dose concentrations were not relevant for comparison to human exposure. Hueiwang Anna Jeng and Silvina M. Bocca Copyright © 2013 Hueiwang Anna Jeng and Silvina M. Bocca. All rights reserved. Prenatal and Postnatal Polycyclic Aromatic Hydrocarbon Exposure, Airway Hyperreactivity, and Beta-2 Adrenergic Receptor Function in Sensitized Mouse Offspring Thu, 12 Dec 2013 08:44:20 +0000 http://www.hindawi.com/journals/jt/2013/603581/ Despite data associating exposure to traffic-related polycyclic aromatic hydrocarbons (PAH) in asthma, mechanistic support has been limited. We hypothesized that both prenatal and early postnatal exposure to PAH would increase airway hyperreactivity (AHR) and that the resulting AHR may be insensitive to treatment with a β2AR agonist drug, procaterol. Further, we hypothesized that these exposures would be associated with altered β2AR gene expression and DNA methylation in mouse lungs. Mice were exposed prenatally or postnatally to a nebulized PAH mixture versus negative control aerosol 5 days a week. Double knockout β2AR mice were exposed postnatally only. Prenatal exposure to PAH was associated with reduced β2AR gene expression among nonsensitized mice offspring, but not increases in DNA methylation or AHR. Postnatal exposure to PAH was borderline associated with increased AHR among sensitized wildtype, but not knockout mice. In the first study that delivers PAH aerosols to mice in a relatively physiological manner, small effects on AHR and β2AR gene expression, but not β2AR agonist drug activity, were observed. If confirmed, the results may suggest that exposure to PAH, common ambient urban pollutants, affects β2AR function, although the impact on the efficacy of β2AR agonist drugs used in treating asthma remains uncertain. Sophie Chu, Hanjie Zhang, Christina Maher, Jacob D. McDonald, Xiang Zhang, Shuk-Mei Ho, Beizhan Yan, Steven Chillrud, Frederica Perera, Phillip Factor, and Rachel L. Miller Copyright © 2013 Sophie Chu et al. All rights reserved. The Aryl-Hydrocarbon Receptor Protein Interaction Network (AHR-PIN) as Identified by Tandem Affinity Purification (TAP) and Mass Spectrometry Thu, 05 Dec 2013 10:06:40 +0000 http://www.hindawi.com/journals/jt/2013/279829/ The aryl-hydrocarbon receptor (AHR), a ligand activated PAS superfamily transcription factor, mediates most, if not all, of the toxicity induced upon exposure to various dioxins, dibenzofurans, and planar polyhalogenated biphenyls. While AHR-mediated gene regulation plays a central role in the toxic response to dioxin exposure, a comprehensive understanding of AHR biology remains elusive. AHR-mediated signaling starts in the cytoplasm, where the receptor can be found in a complex with the heat shock protein of 90 kDa (Hsp90) and the immunophilin-like protein, aryl-hydrocarbon receptor-interacting protein (AIP). The role these chaperones and other putative interactors of the AHR play in the toxic response is not known. To more comprehensively define the AHR-protein interaction network (AHR-PIN) and identify other potential pathways involved in the toxic response, a proteomic approach was undertaken. Using tandem affinity purification (TAP) and mass spectrometry we have identified several novel protein interactions with the AHR. These interactions physically link the AHR to proteins involved in the immune and cellular stress responses, gene regulation not mediated directly via the traditional AHR:ARNT heterodimer, and mitochondrial function. This new insight into the AHR signaling network identifies possible secondary signaling pathways involved in xenobiotic-induced toxicity. Dorothy M. Tappenden, Hye Jin Hwang, Longlong Yang, Russell S. Thomas, and John J. LaPres Copyright © 2013 Dorothy M. Tappenden et al. All rights reserved. Metabolic Effects of Sucralose on Environmental Bacteria Tue, 03 Dec 2013 10:47:16 +0000 http://www.hindawi.com/journals/jt/2013/372986/ Sucralose was developed as a low cost artificial sweetener that is nonmetabolizable in humans. Sucralose can withstand changes in pH and temperature and is not degraded by the wastewater treatment process. Since the molecule can withstand heat, acidification, and microbial degradation, it is accumulating in the environment and has been found in wastewater, estuaries, rivers, and the Gulf Stream. Environmental isolates were cultured in the presence of sucralose looking for potential sucralose metabolism or growth acceleration responses. Sucralose was found to be nonnutritive and demonstrated bacteriostatic effects on all six isolates. This growth inhibition was directly proportional to the concentration of sucralose exposure, and the amount of the growth inhibition appeared to be species-specific. The bacteriostatic effect may be due to a decrease in sucrose uptake by bacteria exposed to sucralose. We have determined that sucralose inhibits invertase and sucrose permease. These enzymes cannot catalyze hydrolysis or be effective in transmembrane transport of the sugar substitute. Current environmental concentrations should not have much of an effect on environmental bacteria since the bacteriostatic effect seems to be consecration based; however, as sucralose accumulates in the environment, we must consider it a contaminant, especially for microenvironments. Arthur Omran, Gregory Ahearn, Doria Bowers, Janice Swenson, and Charles Coughlin Copyright © 2013 Arthur Omran et al. All rights reserved. Effect of Aqueous Stem Bark Extract of Khaya senegalensis on Some Biochemical, Haematological, and Histopathological Parameters of Rats Mon, 18 Nov 2013 15:40:33 +0000 http://www.hindawi.com/journals/jt/2013/803835/ The subchronic effect of aqueous stem bark extract of Khaya senegalensis on some biochemical, haematological, and histopathological parameters of rats was investigated. The rats were divided into six groups of five rats per group. Groups I to VI were administered graded doses of 0, 400, 800, 1200, 1600, and 2000 mg/kg bw, respectively. The result of study revealed that administration of the Khaya senegalensis for twenty-eight days at the experimental dose resulted in significant () increase in urea, electrolytes (Na+, K+), and creatinine levels. The extract also significantly () increased serum activity of ALT, AST, and ALP. The levels of protein, albumin, and bilirubin were significantly changed when compared to their control values, but they were not dose dependent. The hematological indices assayed in this study were not significantly affected at the experimental dose when compared to the control values. Histological studies of the liver showed cellular degeneration and necrosis and bile duct hyperplasia and fibrosis with lymphocytic infiltration of the hepatocyte, providing supportive evidence for discussing the biochemical findings, indicative of functional derangement. The histological architecture of the kidney and that of the heart were however preserved. The result of this study indicates that the aqueous stem bark extract of K. senegalensis may affect the cellular integrity of vital organs of the body. A. Onu, Y. Saidu, M. J. Ladan, L. S. Bilbis, A. A. Aliero, and S. M. Sahabi Copyright © 2013 A. Onu et al. All rights reserved. Acetaldehyde Content and Oxidative Stress in the Deleterious Effects of Alcohol Drinking on Rat Uterine Horn Sun, 17 Nov 2013 14:57:58 +0000 http://www.hindawi.com/journals/jt/2013/161496/ After alcohol exposure through a standard Lieber and De Carli diet for 28 days, a severe atrophy in the rat uteirne horn was observed, accompanied by significant alterations in its epithelial cells. Microsomal pathway of acetaldehyde production was slightly increased. Hydroxyl radicals were detected in the cytosolic fraction, and this was attributed to participation of xanthine oxidoreductase. They were also observed in the microsomal fraction in the presence of NADPH generating system. No generation of 1-hydroxyethyl was evidenced. The t-butylhydroperoxide-induced chemiluminescence analysis of uterine horn homogenates revealed a significant increase in the chemiluminiscence emission due to ethanol exposure. In the animals repeatedly exposed to alcohol, sulfhydryl content from uterine horn proteins was decreased, but no significant changes were observed in the protein carbonyl content from the same samples. Minor but significant decreasing changes were observed in the GSH content accompanied by a tendency to decrease in the GSH/GSSG ratio. A highly significant finding was the diminished activity content of glutathione peroxidase. Results suggest that acetaldehyde accumulation plus the oxidative stress may play an additional effect to the alcohol-promoted hormonal changes in the uterus reported by others after chronic exposure to alcohol. Lara Romina Buthet, María Eugenia Maciel, Leandro Néstor Quintans, Carmen Rodríguez de Castro, Martín Hernán Costantini, Silvia Laura Fanelli, José Alberto Castro, and Gerardo Daniel Castro Copyright © 2013 Lara Romina Buthet et al. All rights reserved. Alterations in Sensitivity to Estrogen, Dihydrotestosterone, and Xenogens in B-Lymphocytes from Children with Autism Spectrum Disorder and Their Unaffected Twins/Siblings Wed, 06 Nov 2013 14:19:49 +0000 http://www.hindawi.com/journals/jt/2013/159810/ It has been postulated that androgen overexposure in a susceptible person leads to excessive brain masculinization and the autism spectrum disorder (ASD) phenotype. In this study, the responses to estradiol (E2), dihydrotestosterone (DHT), and dichlorodiphenyldichloroethylene (DDE) on B-lymphocytes from ASD subjects and controls are compared. B cells were obtained from 11 ASD subjects, their unaffected fraternal twins, and nontwin siblings. Controls were obtained from a different cell bank. Lactate dehydrogenase (LDH) and sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction levels were measured after incubation with different concentrations of E2, DHT, and DDE. XTT/LDH ratio, representative of mitochondria number per cell, was calculated. E2, DHT, and DDE all cause “U”-shaped growth curves, as measured by LDH levels. ASD B cells show less growth depression compared to siblings and controls (). They also have reduced XTT/LDH ratios () when compared to external controls, whereas siblings had values of XTT/LDH between ASD and external controls. B-lymphocytes from people with ASD exhibit a differential response to E2, DHT, and hormone disruptors in regard to cell growth and mitochondrial upregulation when compared to non-ASD siblings and external controls. Specifically, ASD B-lymphocytes show significantly less growth depression and less mitochondrial upregulation when exposed to these effectors. A mitochondrial deficit in ASD individuals is implied. Martyn A. Sharpe, Taylor L. Gist, and David S. Baskin Copyright © 2013 Martyn A. Sharpe et al. All rights reserved. The Benefits and Risks of Consuming Brewed Tea: Beware of Toxic Element Contamination Wed, 23 Oct 2013 18:42:50 +0000 http://www.hindawi.com/journals/jt/2013/370460/ Background. Increasing concern is evident about contamination of foodstuffs and natural health products. Methods. Common off-the-shelf varieties of black, green, white, and oolong teas sold in tea bags were used for analysis in this study. Toxic element testing was performed on 30 different teas by analyzing (i) tea leaves, (ii) tea steeped for 3-4 minutes, and (iii) tea steeped for 15–17 minutes. Results were compared to existing preferred endpoints. Results. All brewed teas contained lead with 73% of teas brewed for 3 minutes and 83% brewed for 15 minutes having lead levels considered unsafe for consumption during pregnancy and lactation. Aluminum levels were above recommended guidelines in 20% of brewed teas. No mercury was found at detectable levels in any brewed tea samples. Teas contained several beneficial elements such as magnesium, calcium, potassium, and phosphorus. Of trace minerals, only manganese levels were found to be excessive in some black teas. Conclusions. Toxic contamination by heavy metals was found in most of the teas sampled. Some tea samples are considered unsafe. There are no existing guidelines for routine testing or reporting of toxicant levels in “naturally” occurring products. Public health warnings or industry regulation might be indicated to protect consumer safety. Gerry Schwalfenberg, Stephen J. Genuis, and Ilia Rodushkin Copyright © 2013 Gerry Schwalfenberg et al. All rights reserved. In Silico Risk Assessment of HLA-A*02:06-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Caused by Cold Medicine Ingredients Sat, 12 Oct 2013 12:43:15 +0000 http://www.hindawi.com/journals/jt/2013/514068/ Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug hypersensitivities with high mortality. Typical over-the-counter drugs of cold medicines are suggested to be causative. As multiple ingredients are generally contained in cold medicines, it is of particular interest to investigate which ingredients are responsible for SJS/TEN. However, experimental examination of causal relationships between SJS/TEN and a particular drug molecule is not straightforward. Significant association between HLA-A*02:06 and SJS/TEN with severe ocular surface complications has been observed in the Japanese. In the present study, we have undertaken in silico docking simulations between various ingredients contained in cold medicines available in Japan and the HLA-A*02:06 molecule. We use the composite risk index (CRI) that is the absolute value of the binding affinity multiplied by the daily dose to assess the potential risk of the adverse reactions. The drugs which have been recognized as causative drugs of SJS/TEN in Japan have revealed relatively high CRI, and the association between SJS/TEN and HLA-A*02:06 has been qualitatively verified. The results have also shown that some drugs whose links to SJS/TEN have not been clinically recognized in Japan show the high CRI and suggested that attention should be paid to their adverse drug reactions. Hideto Isogai, Hiroko Miyadera, Mayumi Ueta, Chie Sotozono, Shigeru Kinoshita, Katsushi Tokunaga, and Noriaki Hirayama Copyright © 2013 Hideto Isogai et al. All rights reserved. The Effects of Eucheuma cottonii on Signaling Pathway Inducing Mucin Synthesis in Rat Lungs Chronically Exposed to Particulate Matter 10 (PM10) Coal Dust Tue, 08 Oct 2013 12:54:22 +0000 http://www.hindawi.com/journals/jt/2013/528146/ This study was aimed at investigating the effects of Eucheuma cottonii (EC) in oxidative stress and the signaling for mucin synthesis in rat lungs chronically exposed to coal dust. Coal dust with concomitant oral administration of ethanolic extract of EC at doses of 150 (EC150) or 300 mg/kg BW (EC300) compared to exposed to PM10 coal dust at doses of 6.25 (CD6.25), 12.5 (CD12.5), or 25 mg/m3 (CD25) (an hour daily for 6 months) and nonexposure group (control). The malondialdehyde (MDA), epidermal growth factor (EGF), transforming growth factor (TGF)-α, epidermal growth factor receptor (EGFR), and MUC5AC levels were determined in the lung. The administration of EC300 significantly (p < 0.05) reduced the MDA levels in groups exposed to all doses of coal dust compared to the respective coal dust-exposed nonsupplemented groups. Although not statistically significant,EC reduced the EGF levels and EGFR expressions in CD12.5 and CD25 groups and decreased the TGF-α, level and MUC5AC expression in CD25 group compared to the respective coal dust-exposed nonsupplemented groups. EC was able to decrease oxidative stress and was also able to decrease signaling for mucin synthesis, at least a part, via reducing the ligand in chronic coal dust exposure. Nia Kania, Elly Mayangsari, Bambang Setiawan, Dian Nugrahenny, Frans Tony, Endang Sri Wahyuni, and M. Aris Widodo Copyright © 2013 Nia Kania et al. All rights reserved. In Vitro Toxicity Evaluation of Engineered Cadmium-Coated Silica Nanoparticles on Human Pulmonary Cells Mon, 30 Sep 2013 09:11:56 +0000 http://www.hindawi.com/journals/jt/2013/931785/ Cytotoxicity of cadmium-containing silica nanoparticles Cd-SiO2NPs (0.05–100 µg/mL) versus SiO2NPs and CdCl2 was evaluated by an in vitro test battery in A549 by assessing (i) mitochondrial function, (ii) membrane integrity/cell morphology, (iii) cell growth/proliferation, (iv) apoptotic pathway, (v) oxidative stress, after short- (24–48 h) and long-term (10 days) exposure. Both Cd-SiO2NPs and CdCl2 produced dose-dependent cytotoxic effects: (i) MTT-assay: similar cytotoxicity pattern was observed at both 24 and 48 h, with a more Cd-SiO2NPs pronounced effect than CdCl2. Cd-SiO2NPs induced mortality (about 50%) at 1 μg/mL, CdCl2 at 25 μg/mL; (ii) calcein-AM/PI staining: decrease in cell viability, noticeable at 25 μg/mL, enhanced markedly at 50 and 100 μg/mL, after 24 h. Cd-SiO2NPs induced higher mortality than CdCl2 (25% versus 4%, resp., at 25 μg/mL) with further exacerbation after 48h; (iii) clonogenic assay: exposure for longer period (10 days) compromised the A549 proliferative capacity at very low dose (0.05 μg/mL); (iv) a progressive activation of caspase-3 immunolabelling was detected already at 1 μg/mL; (v) GSH intracellular level was modified by all compounds. In summary, in vitro data demonstrated that both Cd-SiO2NPs and CdCl2 affected all investigated endpoints, more markedly after Cd-SiO2NPs, while SiO2NPs influenced GSH only. Uliana De Simone, Luigi Manzo, Antonella Profumo, and Teresa Coccini Copyright © 2013 Uliana De Simone et al. All rights reserved. Hepatoprotective Potential of Some Local Medicinal Plants against 2-Acetylaminoflourene-Induced Damage in Rat Sun, 15 Sep 2013 15:36:54 +0000 http://www.hindawi.com/journals/jt/2013/272097/ The in vivo micronucleus assay was used to examine the anticlastogenic effects of crude extracts of Bridelia ferruginea, Vernonia amygdalina, Tridax procumbens, Ocimum gratissimum, and Lawsonia inermis in Wistar albino rats. Extracts of doses of 100 mg/kg body weight were given to rats in five groups for seven consecutive days followed by a single dose of 2-AAF (0.5 mmol/kg body weight). The rats were sacrificed after 24 hours and their bone marrow smears were prepared on glass slides stained with Giemsa. The micronucleated polychromatic erythrocyte cells (mPCEs) were thereafter recorded. The hepatoprotective effects of the plant extracts against 2-AAF-induced liver toxicity in rats were evaluated by monitoring the levels of alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and histopathological analysis. The results of the 2-AAF-induced liver toxicity experiments showed that rats treated with the plant extracts (100 mg/kg) showed a significant decrease in mPCEs as compared with the positive control. The rats treated with the plant extracts did not show any significant change in the concentration of ALP and GGT in comparison with the negative control group whereas the 2-AAF group showed a significant increase () in these parameters. Some of the leaf extracts also showed protective effects against histopathological alterations. This study suggests that the leaf extracts have hepatoprotective potential, thereby justifying their ethnopharmacological uses. Adewale Adetutu and Olubukola S. Olorunnisola Copyright © 2013 Adewale Adetutu and Olubukola S. Olorunnisola. All rights reserved. Assessment of Safety and Therapeutic Efficacy of Rosa damascena L. and Quercus infectoria on Cardiovascular Performance of Normal and Hyperlipidemic Rabbits: Physiologically Based Approach Thu, 12 Sep 2013 12:00:08 +0000 http://www.hindawi.com/journals/jt/2013/769143/ According to the use of Quercus infectoria (QI) and Rosa damascena L. (RD) for therapeutic purposes and lack of adequate information about their cardiovascular effects, we investigated the cardiovascular indices of rabbits which chronically pretreated with these agents. Animal groups were control group (CTL), RD and QI groups with normal chow plus 1.5 g RD and QI extracts, respectively, in each kg of the diet for 45 days; Hyperlipidemic (H) group received high-fat diet for 45 days; H+RD and H+QI groups received high fat diet plus QI and RD extracts, respectively. Blood pressure was greater in H+RD group than CTL, RD, and H groups. Left ventricular developed pressure and left ventricular systolic pressure increased significantly in H+RD group versus CTL and RD groups ( and , resp.) and in H+QI groups ( versus QI groups). Left ventricular end diastolic pressure (LVEDP) showed significant reduction in H+QI group versus H group. QI attenuated the values of total cholesterol, LDL, TG, and atherogenic indices of plasma when coadministrated with a high-fat diet. The results suggest the antilipidemic and antiatherogenic effects of QI. In addition, the use of RD along with a high-fat diet may increase the risk of hypertension in rabbits. Siyavash Joukar, Masoumeh Askarzadeh, Beydolah Shahouzehi, Hamid Najafipour, and Hossein Fathpour Copyright © 2013 Siyavash Joukar et al. All rights reserved. Clinical Validation of a Highly Sensitive GC-MS Platform for Routine Urine Drug Screening and Real-Time Reporting of up to 212 Drugs Wed, 10 Jul 2013 08:30:43 +0000 http://www.hindawi.com/journals/jt/2013/329407/ An important role of the clinical toxicology laboratory is to provide continuous diagnostic testing for patients with altered mental status and for other medical indications. To meet these needs, we have developed a new Gas Chromatography-Mass Spectrometry (GC-MS) platform that facilitates routine screening and automated reporting of 212 drugs by laboratory technologists around the clock without the need to sign out by an on-site mass spectrometry-trained toxicologist. The platform uses a programmable temperature vaporizer (PTV) injector for large sample volume injection and the free software Automated Mass Spectral Deconvolution and Identification System (AMDIS) for data reduction and spectral matching that facilitates rapid library searching and analyte identification. Method comparison with 118 patient samples demonstrated that this platform and data searching algorithm independently provided improvements in sensitivity compared to an established GC-MS platform. Further examination of the role of the data processing software and the in-house databases used in the established versus the new platform demonstrated that the improved analytical sensitivity of the new platform was attributed to both the technical superiority of the new GC-MS instrumentation and the use of AMDIS in conjunction with the newly generated in-house library for data processing. Hari Nair, Fred Woo, Andrew N. Hoofnagle, and Geoffrey S. Baird Copyright © 2013 Hari Nair et al. All rights reserved. Scorpion Peptides: Potential Use for New Drug Development Sat, 15 Jun 2013 13:30:23 +0000 http://www.hindawi.com/journals/jt/2013/958797/ Several peptides contained in scorpion fluids showed diverse array of biological activities with high specificities to their targeted sites. Many investigations outlined their potent effects against microbes and showed their potential to modulate various biological mechanisms that are involved in immune, nervous, cardiovascular, and neoplastic diseases. Because of their important structural and functional diversity, it is projected that scorpion-derived peptides could be used to develop new specific drugs. This review summarizes relevant findings improving their use as valuable tools for new drugs development. BenNasr Hmed, Hammami Turky Serria, and Zeghal Khaled Mounir Copyright © 2013 BenNasr Hmed et al. All rights reserved. Effect of the Antibiotic Neomycin on the Toxicity of the Glycoside Vicine in Rats Wed, 12 Jun 2013 12:50:51 +0000 http://www.hindawi.com/journals/jt/2013/913128/ Vicine is hydrolyzed by microflora to highly reactive free radical generating compound divicine which causes mortality and other adverse effects. This study in the rats established the effect of a broad spectrum and poorly absorbed antibiotic, neomycin sulfate on the toxicity of vicine. The results showed extremely decrease in mortality rate in the group pretreated with neomycin. Hemoglobin (Hb) concentration, hematocrit (Hct) value, and red blood cells (RBCs) count were significantly decreased after injection of vicine and the improvement of these values in the group pretreated with neomycin. The same results were observed in white blood cells (WBCs). The results showed a significant decrease in glucose level and returned to normal in group pretreated with neomycin. Glutathione (GSH) was significantly decreased in the vicine group and returned to normal value in the group pretreated with neomycin. Lipid peroxide (TBARs) was significantly increased in the group treated with vicine and neomycin pretreated group decreased to the normal level. Glucose-6-phosphate dehydrogenase (G6-PD) activity was significantly decreased and returned to normal level in rats pretreated with neomycin. Serum protein and globulin were significantly decreased but serum albumin showed insignificant decrease in vicine and neomycin groups compared to control. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly decreased in the vicine group. The group pretreated with neomycin showed significantly increased activities of AST and ALT compared with vicine group. In conclusion, neomycin pretreatment of rats injected with glycoside vicine decreased to a great extent of its toxic and mortality effects and is useful in favism and hemolytic anemia. Mahmoud S. Arbid, Khaled M. M. Koriem, Gihan F. Asaad, and Hoda A. Megahed Copyright © 2013 Mahmoud S. Arbid et al. All rights reserved. B-Lymphocytes from a Population of Children with Autism Spectrum Disorder and Their Unaffected Siblings Exhibit Hypersensitivity to Thimerosal Sun, 09 Jun 2013 14:06:47 +0000 http://www.hindawi.com/journals/jt/2013/801517/ The role of thimerosal containing vaccines in the development of autism spectrum disorder (ASD) has been an area of intense debate, as has the presence of mercury dental amalgams and fish ingestion by pregnant mothers. We studied the effects of thimerosal on cell proliferation and mitochondrial function from B-lymphocytes taken from individuals with autism, their nonautistic twins, and their nontwin siblings. Eleven families were examined and compared to matched controls. B-cells were grown with increasing levels of thimerosal, and various assays (LDH, XTT, DCFH, etc.) were performed to examine the effects on cellular proliferation and mitochondrial function. A subpopulation of eight individuals (4 ASD, 2 twins, and 2 siblings) from four of the families showed thimerosal hypersensitivity, whereas none of the control individuals displayed this response. The thimerosal concentration required to inhibit cell proliferation in these individuals was only 40% of controls. Cells hypersensitive to thimerosal also had higher levels of oxidative stress markers, protein carbonyls, and oxidant generation. This suggests certain individuals with a mild mitochondrial defect may be highly susceptible to mitochondrial specific toxins like the vaccine preservative thimerosal. Martyn A. Sharpe, Taylor L. Gist, and David S. Baskin Copyright © 2013 Martyn A. Sharpe et al. All rights reserved. Determination of Pesticide Residues in Cannabis Smoke Sun, 12 May 2013 18:50:48 +0000 http://www.hindawi.com/journals/jt/2013/378168/ The present study was conducted in order to quantify to what extent cannabis consumers may be exposed to pesticide and other chemical residues through inhaled mainstream cannabis smoke. Three different smoking devices were evaluated in order to provide a generalized data set representative of pesticide exposures possible for medical cannabis users. Three different pesticides, bifenthrin, diazinon, and permethrin, along with the plant growth regulator paclobutrazol, which are readily available to cultivators in commercial products, were investigated in the experiment. Smoke generated from the smoking devices was condensed in tandem chilled gas traps and analyzed with gas chromatography-mass spectrometry (GC-MS). Recoveries of residues were as high as 69.5% depending on the device used and the component investigated, suggesting that the potential of pesticide and chemical residue exposures to cannabis users is substantial and may pose a significant toxicological threat in the absence of adequate regulatory frameworks. Nicholas Sullivan, Sytze Elzinga, and Jeffrey C. Raber Copyright © 2013 Nicholas Sullivan et al. All rights reserved. Cumulative Risk Assessment Toolbox: Methods and Approaches for the Practitioner Thu, 09 May 2013 16:16:24 +0000 http://www.hindawi.com/journals/jt/2013/310904/ The historical approach to assessing health risks of environmental chemicals has been to evaluate them one at a time. In fact, we are exposed every day to a wide variety of chemicals and are increasingly aware of potential health implications. Although considerable progress has been made in the science underlying risk assessments for real-world exposures, implementation has lagged because many practitioners are unaware of methods and tools available to support these analyses. To address this issue, the US Environmental Protection Agency developed a toolbox of cumulative risk resources for contaminated sites, as part of a resource document that was published in 2007. This paper highlights information for nearly 80 resources from the toolbox and provides selected updates, with practical notes for cumulative risk applications. Resources are organized according to the main elements of the assessment process: (1) planning, scoping, and problem formulation; (2) environmental fate and transport; (3) exposure analysis extending to human factors; (4) toxicity analysis; and (5) risk and uncertainty characterization, including presentation of results. In addition to providing online access, plans for the toolbox include addressing nonchemical stressors and applications beyond contaminated sites and further strengthening resource accessibility to support evolving analyses for cumulative risk and sustainable communities. Margaret M. MacDonell, Lynne A. Haroun, Linda K. Teuschler, Glenn E. Rice, Richard C. Hertzberg, James P. Butler, Young-Soo Chang, Shanna L. Clark, Alan P. Johns, Camarie S. Perry, Shannon S. Garcia, John H. Jacobi, and Marcienne A. Scofield Copyright © 2013 Margaret M. MacDonell et al. All rights reserved. Differential Effects of Methyl-4-Phenylpyridinium Ion, Rotenone, and Paraquat on Differentiated SH-SY5Y Cells Wed, 20 Mar 2013 16:34:27 +0000 http://www.hindawi.com/journals/jt/2013/347312/ Paraquat (PQ), a cationic nonselective bipyridyl herbicide, has been used as neurotoxicant to modulate Parkinson’s disease in laboratory settings. Other compounds like rotenone (ROT), a pesticide, and 1-methyl-4-phenylpyridinium ion (MPP+) have been widely used as neurotoxicants. We compared the toxicity of these three neurotoxicants using differentiated dopaminergic SH-SY5Y human cells, aiming to elucidate their differential effects. PQ-induced neurotoxicity was shown to be concentration and time dependent, being mitochondrial dysfunction followed by neuronal death. On the other hand, cells exposure to MPP+ induced mitochondrial dysfunction, but not cellular lyses. Meanwhile, ROT promoted both mitochondrial dysfunction and neuronal death, revealing a biphasic pattern. To further elucidate PQ neurotoxic mechanism, several protective agents were used. SH-SY5Y cells pretreatment with tiron (TIR) and 2-hydroxybenzoic acid sodium salt (NaSAL), both antioxidants, and Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide synthase inhibitor, partially protected against PQ-induced cell injury. Additionally, 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenyl-propyl)piperazine (GBR 12909), a dopamine transporter inhibitor, and cycloheximide (CHX), a protein synthesis inhibitor, also partially protected against PQ-induced cell injury. In conclusion, we demonstrated that PQ, MPP+, and ROT exerted differential toxic effects on dopaminergic cells. PQ neurotoxicity occurred through exacerbated oxidative stress, with involvement of uptake through the dopamine transporter and protein synthesis. João Barbosa Martins, Maria de Lourdes Bastos, Félix Carvalho, and João Paulo Capela Copyright © 2013 João Barbosa Martins et al. All rights reserved. Differential Cytotoxicity Responses by Dog and Rat Hepatocytes to Phospholipogenic Treatments Wed, 13 Mar 2013 09:15:56 +0000 http://www.hindawi.com/journals/jt/2013/956404/ Dog and rat hepatocytes were treated with phospholipogenics to identify the more sensitive species and to determine whether lysosomal or mitochondrial changes were the primary cause of cytotoxicity. Endpoints included cell death, lysosome membrane integrity, mitochondrial membrane polarization, and fluorescent phospholipid (NBD-PE). Dog cells exhibited lower survival IC50 values than did rat cells with all phospholipogenic treatments and exhibited a lower capacity to accumulate NBD-PE in 4 of 5 phospholipogenic test conditions. The lysosomal modulator Bafilomycin A1 (Baf) rescued dog cells from cytotoxicity caused by 3 phospholipogenic 5HT1b antagonists and hydroxychloroquine, but not fluoxetine, and rescued rat cells from hydroxychloroquine and NMTMB, a 5HT1b antagonist. Following NMTMB treatment, rat mitochondrial membrane hyperpolarization was observed at modestly cytotoxic concentrations and depolarization at the highest concentration. At the highest test concentration, lysosomal loss of acridine orange occurred by 30 min, mitochondrial polarity changes by 1 hr, and NBD-PE accumulation by 2 hr, respectively. Baf shifted mitochondrial polarity from a depolarized state to a hyperpolarized state. These data demonstrate that (a) dog hepatocytes were generally less capable of mounting an adaptive, protective phospholipidotic response than rat hepatocytes, (b) effects on mitochondria and survival were preventable by lysosomal protection, and (c) destabilizing changes in both organelles are involved causally in cytotoxicity. James K. Morelli and Paul J. Ciaccio Copyright © 2013 James K. Morelli and Paul J. Ciaccio. All rights reserved. Expression of Glutathione Peroxidase and Glutathione Reductase and Level of Free Radical Processes under Toxic Hepatitis in Rats Mon, 11 Mar 2013 17:26:10 +0000 http://www.hindawi.com/journals/jt/2013/870628/ Correlation between intensity of free radical processes estimated by biochemiluminesce parameters, content of lipoperoxidation products, and changes of glutathione peroxidase (GP, EC 1.11.1.9) and glutathione reductase (GR, EC 1.6.4.2) activities at rats liver injury, after 12, 36, 70, 96, 110, and 125 hours & tetrachloromethane administration have been investigated. The histological examination of the liver sections of rats showed that prominent hepatocytes with marked vacuolisation and inflammatory cells which were arranged around the necrotic tissue are more at 96 h after exposure to CCl4. Moreover maximum increase in GR and GP activities, 2.1 and 2.5 times, respectively, was observed at 96 h after exposure to CCl4, what coincided with the maximum of free radical oxidation processes. Using a combination of reverse transcription and real-time polymerase chain reaction, expression of the glutathione peroxidase and glutathione reductase genes (Gpx1 and Gsr) was analyzed by the determination of their respective mRNAs in the rat liver tissue under toxic hepatitis conditions. The analyses of Gpx1 and Gsr expression revealed that the transcript levels increased in 2.5- and 3.0-folds, respectively. Western blot analysis revealed that the amounts of hepatic Gpx1 and Gsr proteins increased considerably after CCl4 administration. It can be proposed that the overexpression of these enzymes could be a mechanism of enhancement of hepatocytes tolerance to oxidative stress. Igor Y. Iskusnykh, Tatyana N. Popova, Aleksander A. Agarkov, Miguel Â. A. Pinheiro de Carvalho, and Stanislav G. Rjevskiy Copyright © 2013 Igor Y. Iskusnykh et al. All rights reserved.