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Daily Exposure (daily + exposure)
Selected AbstractsPrinciples of risk assessment for determining the safety of chemicals: Recent assessment of residual solvents in drugs and di(2-ethylhexyl) phthalateCONGENITAL ANOMALIES, Issue 2 2004Ryuichi Hasegawa ABSTRACT Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose,response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose,response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established ,safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity. [source] Postnatal stress in mice: Does "stressing" the mother have the same effect as "stressing" the pups?DEVELOPMENTAL PSYCHOBIOLOGY, Issue 4 2004A. Moles Abstract Short- and long-term effects of brief maternal separation, maternal exposure to novel male odor, and standard rearing were compared in NMRI mice. The first condition consisted of 15 min of daily exposure of pups to clean bedding (CB), and the second condition consisted of 15 min of mothers' exposure to the odor of strange males (SM), for 14 days after birth starting from postnatal Day 1. Thus, both conditions entailed the same period of maternal separation. A control mother,offspring group was left undisturbed (nonhandled, N-H). Corticosterone levels of mothers and pups were measured at the end of the last manipulation session. Corticosterone levels were higher in SM mothers, differing from both those of CB and of control dams; CB pups showed the highest corticosterone levels in comparison with the pups belonging to the other groups. Maternal behavior observed as furthest as possible from the daily separation session did not differ among the three groups. The behavioral response to 0.5 mg/kg of apomorphine in 15-day-old pups was enhanced in both CB and SM animals, which suggests an alteration of dopaminergic functioning. Finally, adult CB and SM male mice showed an increase in the percentage of time and entries into the open arms of the plus-maze in comparison to nonhandled males. This study indicates that exposure to ecologically relevant stimuli elicited a stress response in lactating dams. This "social stress" brings about short- and long-term effects in the offspring, even in the absence of any direct manipulation of the pups. © 2004 Wiley Periodicals, Inc. Dev Psychobiol 44: 230,237, 2004. [source] Oral toxicity of the cyanobacterial toxin cylindrospermopsin in mice: Long-term exposure to low dosesENVIRONMENTAL TOXICOLOGY, Issue 6 2006A. Sukenik Abstract The hepatotoxin cylindrospermopsin, a sulfated-guanidinium alkaloid with substituted dioxypyrimidine (uracil) moiety, was isolated from several cyanobacteria species. The acute toxicity of cylindrospermopsin was well established based on intraperitoneal and oral exposure; however, only a few long-term subacute exposure studies were performed to permit a reliable guideline value for cylindrospermopsin in drinking water. In the study reported herein, female and male mice were exposed to cylindrospermopsin in their drinking water. Cylindrospermopsin-containing, Aphanizomenon ovalisporum (cyanobacterium)-free medium was provided as the only source of drinking water, whereas a control group was given a fresh medium for cyanobacteria as drinking water. Over a period of 42 weeks, experiment groups were exposed to cylindrospermopsin concentration, gradually increased from 100 to 550 ,g L,1 (daily exposure ranged between 10 and 55 ,g kg,1 day,1). Body and organ weights were recorded, and serum and hematology analyses were performed 20 and 42 weeks after the beginning of the experiment. The most pronounced effect of cylindrospermopsin was elevated hematocrit levels in both male and female mice after 16 weeks of exposure to cylindrospermopsin. The observed changes in the hematocrit level were accompanied by deformation of red blood cells, which were changed into acanthocyte. Based on these results, a daily cylindrospermopsin dose of 20 ,g kg,1 day,1 (equivalent to 200 ,g L,1) is proposed as the lowest-observed-adverse-effect level for both male and female mice. © 2006 Wiley Periodicals, Inc. Environ Toxicol 21: 575,582, 2006. [source] Stochastic modelling of global solar radiation measured in the state of KuwaitENVIRONMETRICS, Issue 7 2002S. A. Al-Awadhi Abstract Two stochastic models that capture the main features of daily exposure of global radiation in Kuwait are proposed. The development of these models is based on removing the annual periodicity and seasonal variation of solar radiation. Thus the daily radiation is decomposed as the sum of the trend component and a stochastic component. In many situations, there are dramatic changes in the radiation series through the year due to the condition of the weather, as is the case of the data from Kuwait. This would affect the accuracy of the model, and therefore the series is divided into two regimes: one corresponds to clear days where the value of the global radiation would be normal and the other to non-clear days where the value of global radiation would be very low. Then the trend component is expressed as a Fourier series taking into account such apparent breaks in the series. The stochastic component is first tested for linearity and Gaussianity and it is found that it does not satisfy these assumptions. Therefore, a linear time series model (ARMA modeling) may not be adequate and, to overcome this problem, a bilinear time series is used to model the stochastic component of daily global radiation in Kuwait. The method proposed considers first fitting an AR model to the data and then seeing whether a further reduction in the mean sum of squares can be achieved by introducing extra bilinear terms. The Akaike Information Criterion (AIC) is used to select the best model. Copyright © 2002 John Wiley & Sons, Ltd. [source] Protective effects of quercetin on ultraviolet A light-induced oxidative stress in the blood of ratJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2002Ahmet Kahraman Abstract The oxidative effects of ultraviolet A (UVA) light (320,400 nm) and the antioxidant effects of quercetin were examined in rat blood. For this purpose, rats were divided into three groups: control, ultraviolet (UV) and ultraviolet + quercetin (UV + Q). The UV and UV + Q groups were irradiated for 4 h a day with UVA light (1.25 mW cm2) during periods of 3, 6 and 9 days. Quercetin (50 mg kg,1 body wt.) was administered intraperitoneally in the UV + Q group rats before irradiation periods. Blood was taken 3, 6 and 9 days post-treatment. Plasma malondialdehyde (MDA) levels significantly increased after 9 days of daily exposure to UVA. Whole blood glutathione (GSH) levels significantly declined after 3,9 days of irradiation. Glutathione peroxidase activity on days 6 and 9 and glutathione reductase activities on days 3, 6 and 9 post-irradiation were diminished significantly. Superoxide dismutase and catalase activities decreased significantly 3,9 days post-irradiation. The administration of quercetin before the 9-day period of irradiation significantly reduced the increase in plasma MDA value. Whole blood GSH levels significantly decreased with the administration of quercetin on all days. Quercetin significantly increased antioxidant enzymes diminished by UVA irradiation. Exposure of rats to UVA light leads to oxidative stress, reflected by increased MDA and reduced antioxidant enzyme levels. The administration of quercetin appears to be a useful approach to reduce the damage produced by UVA radiation. Copyright © 2002 John Wiley & Sons, Ltd. [source] Renal, vascular and cardiac fibrosis in rats exposed to passive smoking and industrial dust fibre amositeJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 11-12 2009Peter Boor Abstract Passive smoking is an independent risk factor for cardiovascular diseases. Industrial fibrous dust, e.g. the asbestos group member, amosite, causes lung cancer and fibrosis. No data are available on renal involvement after inhalational exposure to these environmental pollutants or of their combination, or on cardiovascular and renal toxicity after exposure to amosite. Male Wistar rats were randomized into four groups (n= 6): control and amosite group received initially two intratracheal instillations of saline and amosite solution, respectively. Smoking group was subjected to standardized daily exposure to tobacco smoke for 2 hrs in a concentration resembling human passive smoking. Combined group was exposed to both amosite and cigarette smoke. All rats were killed after 6 months. Rats exposed to either amosite or passive smoking developed significant glomerulosclerosis and tubulointerstitial fibrosis. Combination of both exposures had additive effects. Histomorphological changes preceded the clinical manifestation of kidney damage. In both groups with single exposures, marked perivascular and interstitial cardiac fibrosis was detected. The additive effect in the heart was less pronounced than in the kidney, apparent particularly in changes of vascular structure. Advanced oxidation protein products, the plasma marker of the myeloperoxidase reaction in activated monocytes/macrophages, were increased in all exposed groups, whereas the inflammatory cytokines did not differ between the groups. In rats, passive smoking or amosite instillation leads to renal, vascular and cardiac fibrosis potentially mediated via increased myeloperoxidase reaction. Combination of both pollutants shows additive effects. Our data should be confirmed in subjects exposed to these environmental pollutants, in particular if combined. [source] Brand specific responses to smokeless tobacco in a rat lip canal modelJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 6 2010Joel L. Schwartz J Oral Pathol Med (2010) 39: 453,459 Background:, Different compositions of smokeless tobacco (ST) are widely thought to cause oral carcinoma at different rates but there is little direct evidence for this hypothesis. Methods:, We used a rat lip canal model to examine the mucosal changes induced by chronic daily exposure to four different brands of ST: Skoal, Copenhagen, Ettan Swedish Snus, and Stonewall, differing in measured levels of: tobacco specific nitrosamines (TSNAs), unprotonated nicotine, moisture, and pH. Results:, Exposure to the lip canal for 12 months produced changes in the mucosa marked by increases in S phase and M phase cells for the Skoal and Copenhagen exposed rats. This correlated with the high level of TSNAs and nicotine in these products. All the tobacco products, to different degrees, induced sites of moderate to severe dysplasia some with extensive rete peg outgrowth from the oral mucosa not seen in the controls. Many of these sites showed a loss of p16 expression. Conclusions:, While all ST products caused dysplasia, the products with lower levels of TSNAs and unprotonated nicotine caused less, consistent with the model that tobacco with low levels of nitrosamines might potentially induce fewer carcinomas in human users. [source] A full-UV spectrum absorbing daily use cream protects human skin against biological changes occurring in photoagingPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 4 2000S. Seité Background: There is overwhelming evidence that exposure of human skin to ultraviolet radiations (UVR) leads to the development of cutaneous photoaging and eventually to neoplasia. This study was designed to evaluate in humans the protection afforded by a daily use cream containing a photostable combination of UVB and UVA absorbers (Uvinul® N539, Parsol® 1789 and Mexoryl® SX) providing a continuous absorption through the entire UV spectrum, against damages induced by repeated daily exposure to solar simulated radiation (SSR). Methods: Buttock skin of 12 healthy volunteers was exposed 5 days per week for 6 weeks to one minimal erythema dose of solar simulated radiation per exposure. The following parameters in treated and untreated skin were evaluated: erythema, pigmentation, skin hydration, skin microtopography, histology and immunochemistry, and collagen and metalloproteinase (MMP) mRNA levels. Results: In SSR exposed unprotected skin sites, we observed melanization and changes in the skin hydration and microtopography. The epidermis revealed a significant increase in stratum corneum and stratum granulosum thickness. In the dermis, an enhanced expression of tenascin and a reduced expression of type I pro-collagen were evidenced just below the dermal epidermal junction. Although we were unable to visualize any change in elastic fibers in exposed buttock skin, a slightly increased deposition of lysozyme and alpha 1 antitrypsin on these fibers was observed using immunofluorescence techniques. Furthermore, types I and III collagen mRNA were slightly increased and a significant enhancement (up to 2.8-fold) of MMP-2 mRNA level was observed. The daily use cream was shown to prevent all these biological changes. Conclusion: Our results show in vivo that an appropriate full-UV spectrum product significantly reduces the solar-UV-induced skin damage, demonstrating the benefit of daily photoprotection. [source] No interaction between methyl jasmonate and ozone in Pima cotton: growth and allocation respond independently to bothPLANT CELL & ENVIRONMENT, Issue 5 2010D. A. GRANTZ ABSTRACT Ozone (O3) is damaging to plants, inducing signalling pathways involving antagonism between jasmonates and ethylene. These pathways mediate O3 responses, particularly to acute exposure, and their manipulation protected several species against acute and chronic O3. We use chronic daily exposure of up to 163 ppb O3, and twice weekly application of up to 320 µg plant,1 methyl jasmonate (MeJA) to test two hypothesizes: 1) a low rate of MeJA does not affect growth but increases O3 sensitivity; 2) a high rate inhibits growth but reduces O3 sensitivity. Both hypotheses were rejected. Growth declined with increases in both MeJA and O3. MeJA at 40 µg plant,1 caused no direct effect, and at 160 µg plant,1 reduced growth similarly at all O3. Neither rate altered O3 sensitivity. These additive responses are not consistent with protection by MeJA in this system. They may reflect inter-specific differences in signalling, since O3 concentrations used here exceeded some reported acute exposures. Alternatively, parallel responses to O3 and MeJA may suggest that O3 -induced jasmonates play a developmental role in chronic response but no protective role in the absence of lesions characteristic of acute exposure. MeJA appears useful as a probe of these mechanisms. [source] Daily computer usage correlated with undergraduate students' musculoskeletal symptoms,AMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 6 2007Che-hsu (Joe) Chang PT Abstract Background A pilot prospective study was performed to examine the relationships between daily computer usage time and musculoskeletal symptoms on undergraduate students. Methods For three separate 1-week study periods distributed over a semester, 27 students reported body part-specific musculoskeletal symptoms three to five times daily. Daily computer usage time for the 24-hr period preceding each symptom report was calculated from computer input device activities measured directly by software loaded on each participant's primary computer. General Estimating Equation models tested the relationships between daily computer usage and symptom reporting. Results Daily computer usage longer than 3 hr was significantly associated with an odds ratio 1.50 (1.01,2.25) of reporting symptoms. Odds of reporting symptoms also increased with quartiles of daily exposure. Conclusions These data suggest a potential dose,response relationship between daily computer usage time and musculoskeletal symptoms. Am. J. Ind. Med. 50:481,488, 2007. © 2007 Wiley-Liss, Inc. [source] Influence of Co-Medication with Sirolimus or Cyclosporine on Mycophenolic Acid Pharmacokinetics in Kidney TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2005D. Cattaneo The pharmacokinetics of mycophenolic acid (MPA),the active metabolite of mycophenolate mofetil (MMF),is significantly influenced by co-medications. The impact of sirolimus on daily MPA exposure, however, has not been investigated so far. As a part of the study aimed at investigating the efficacy of Campath-1H induction therapy in a steroid-free regimen in kidney transplantation, MPA plasma levels were serially measured in 21 patients treated with low-dose sirolimus (SRL) or low-dose CsA both in addition to low-dose MMF over 12 months post-operatively. Full pharmacokinetic profiles were compared at month 6 and 12 post-surgery. Mean dose-adjusted MPA trough levels were 4.4-fold higher in patients on combined SRL and MMF than in those given CsA and MMF. Pharmacokinetic studies demonstrated that mean MPA Cmax and Tmax were comparable in the two groups, while mean MPA AUC0-12 was higher in SRL than CsA treated patients. The pharmacokinetic profile of SRL- but not of CsA-group showed a second peak consistent with the enterohepatic recirculation of MPA. These findings suggest that SRL and CsA have different effects on MPA metabolism and/or excretion eventually affecting its immunosuppressive property and/or toxicity. CsA, but not SRL, inhibits MPA enterohepatic recirculation, reducing MPA daily exposure. [source] Exposure to inhomogeneous static magnetic field ceases mechanical allodynia in neuropathic pain in miceBIOELECTROMAGNETICS, Issue 6 2009Miklós Antal Abstract Magnetic therapy as a self-care intervention has led to the conduct of numerous human trials and animal experiments. Results concerning the analgesic efficacy of magnetic exposure, however, are inconsistent. By using a magnetic device generating an inhomogeneous static magnetic field (iSMF), here we studied how the whole-body exposure to iSMF may influence the mechanical withdrawal threshold (MWT) of the hind paw in different stages of neuropathic pain evoked by partial ligation of the sciatic nerve in mice. It was found that iSMF exposure did not prevent the decrease of MWT in the first postoperative week. A 2-week long iSMF treatment that was started just after the nerve ligation elevated MWT values to a modest extent. However, the effectiveness of a daily exposure to iSMF was much more prominent when it was applied between postoperative days 15 and 28. In this case, MWT was already noticeably increased after the first treatment and it practically reached the control values by the end of the 2-week long exposure period. The results suggest that exposure to iSMF cannot prevent the development of mechanical allodynia, but can inhibit processes that maintain the increased sensitivity to mechanical stimuli in neuropathic pain. Bioelectromagnetics 30:438,445, 2009. © 2009 Wiley-Liss, Inc. [source] Strategies to improve efficacy and safety of a novel class of antiviral hyper-activation-limiting therapeutic agents: the VS411 model HIV/AIDSBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2010D De Forni BACKGROUND AND PURPOSE Antiviral hyper-activation-limiting therapeutic agents (AV-HALTs) are a novel experimental drug class designed to both decrease viral replication and down-regulate excessive immune system activation for the treatment of chronic infections, including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. VS411, a first-in-class AV-HALT, is a single-dosage form combining didanosine (ddI, 400 mg), an antiviral (AV), and hydroxyurea (HU, 600 mg), a cytostatic agent, designed to provide a slow release of ddI to reduce its maximal plasma concentration (Cmax) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the AV activity. EXPERIMENTAL APPROACH This was a pilot phase I, open-label, randomized, single-dose, four-way crossover trial to investigate the fasted and non-fasted residual variance of AUC, Cmax and the oral bioavailability of ddI and HU, co-formulated as VS411, and administered as two different fixed-dose combination formulations compared to commercially available ddI (Videx EC) and HU (Hydrea) when given simultaneously. KEY RESULTS Formulation VS411-2 had a favourable safety profile, displayed a clear trend for lower ddI Cmax (P= 0.0603) compared to Videx EC, and the 90% confidence intervals around the least square means ratio of Cmax did not include 100%. ddI AUC, was not significantly decreased compared to Videx EC. HU pharmacokinetic parameters were essentially identical to Hydrea, although there was a decrease in HU exposure under fed versus fasted conditions. CONCLUSIONS AND IMPLICATIONS A phase IIa trial utilizing VS411-2 formulation has been fielded to identify the optimal doses of HU plus ddI as an AV-HALT for the treatment of HIV disease. [source] Clinically relevant radioresistant cells efficiently repair DNA double-strand breaks induced by X-raysCANCER SCIENCE, Issue 4 2009Yoshikazu Kuwahara Radiotherapy is one of the major therapeutic modalities for eradicating malignant tumors. However, the existence of radioresistant cells remains one of the most critical obstacles in radiotherapy and radiochemotherapy. Standard radiotherapy for tumor treatment consists of approximately 2 Gy once a day, 5 days a week, over a period of 5,8 weeks. To understand the characteristics of radioresistant cells and to develop more effective radiotherapy, we established a novel radioresistant cell line, HepG2-8960-R with clinical relevance from parental HepG2 cells by long-term fractionated exposure to 2 Gy of X-rays. HepG2-8960-R cells continued to proliferate with daily exposure to 2 Gy X-rays for more than 30 days, while all parental HepG2 cells ceased. After exposure to fractionated 2 Gy X-rays, induction frequencies of micronuclei and remaining foci of ,-H2AX in HepG2-8960-R were less than those in HepG2. Flow cytometric analysis revealed that the proportion of cells in S- and G2/M-phase of the cell cycle was higher in HepG2-8960-R than in HepG2. These suggest that the response of clinically relevant radioresistant (CRR) cells to fractionated radiation is not merely an accumulated response to each fractionated radiation. This is the first report on the establishment of a CRR cell line from an isogenic parental cell line. (Cancer Sci 2009; 100: 747,752) [source] Effect of various stabilizing agents on Imperata cylindrica grass pollen allergen extractCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2003K. M. Bijli Summary Background Allergen extracts are unstable, heat labile or susceptible to proteases. Stability of allergen extracts is important for proper diagnosis and therapy of allergic disorders. Objective The present study was undertaken to determine the preservation and stabilization conditions of Imperata cylindrica (Ic) grass pollen extract. Methods The Ic extract was kept with 0.1 m,-aminocaproic acid (EACA), 0.75 m sucrose, 5% glycerol, 0.03% human serum albumin (HSA) or 0.4% phenol for different time periods. The extracts were stored for 3, 6 and 12 months each at 4 °C, 4 °C with daily exposure to room temperature (RT) for 1 h, and RT. The quality of extracts was analysed by SDS-PAGE, Western blot, ELISA, ELISA inhibition and skin test. Results Extracts kept with EACA and sucrose retained most of the protein bands followed by glycerol as determined by SDS-PAGE and Western blot during all storage periods and conditions in comparison with standard extracts. The extracts kept with HSA, phenol and without preservative (WP) showed protein degradation below 33 kDa after 3 months storage at all conditions. However, a 67-kDa allergen was stable in these extracts. EACA extract required 75 to 120 ng of protein for 50% inhibition in IgE binding under different conditions, whereas standard extract required 70 ng for the same. ELISA also demonstrated high allergenic reactivity of EACA extract. ID test on allergy patients with EACA extract demonstrated same allergenic potency as that of standard extract. Conclusion EACA is the best preservative/stabilizing agent of Ic pollen extract, followed by sucrose and glycerol. Ic extract kept with phenol, HSA and without preservative showed degradation within 3 months. EACA preserved extract is equally potent as that of standard extract up to 1 year's storage. [source] | |||||||||||||