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Our understanding of the etiology of cancer has developed significantly over the past fifty years, beginning with a single-hit linear no-threshold (LNT) conceptual model based on early studies conducted in Drosophila. Over the past several decades, multiple lines of evidence have accumulated to support a contemporary model of chemical carcinogenesis: a multi-hit model involving a prolonged stress environment that over time may drive the mutation of multiple cells into an injured state that ultimately could lead to uncontrolled proliferation via clonal expansion of mutation-carrying daughter cells. Arsenic carcinogenicity offers a useful case study for further exploration of advanced conceptual models for chemical carcinogenesis. A threshold for arsenic carcinogenicity is supported by its mode of action, characterized by repeating cycles of cytotoxicity and cellular regeneration. Furthermore, preliminary meta-analyses of epidemiology dose-response data for inorganic arsenic (iAs) and bladder cancer, correlated to dose-response data measured in vitro, support a threshold of effect in humans on the order of 50-100 µg/L in drinking water. In light of recent developments in our understanding of cancer etiology, we urge strong consideration of the existing mode-of-action evidence supporting a threshold of effect for arsenic carcinogenicity, as well as consideration of the potential methodological pitfalls in evaluating epidemiology dose-response data that could potentially bias in the direction of low-dose linearity.

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A decreasing number of new therapeutic drugs reaching the clinic has led to the publication of regulatory guidelines on human microdosing trials by the European Medicines Agency in 2004 and the US Food and Drug Administration in 2006. Microdosing trials are defined by the administration of 1/100th of the therapeutic dose and designed to investigate basic drug properties. This review investigates the current application of phase 0 trials in medical research. Thirty-three studies found in PubMed and EMBASE were systematically reviewed for aim and analytical method. Pharmacokinetic studies have been a major focus of phase 0 trials, but drug distribution, drug-drug interactions, imaging and pharmacogenomics have also been investigated. Common analytical methods were tandem mass liquid chromatography, accelerator mass spectrometry and positron emission tomography. New ongoing trials are investigating the pharmacodynamics and chemoresistance of marketed drugs, suggesting that the application of phase 0 trials is still evolving.

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AIM: The present study was to investigate the use of MOSFET as an vivo dosimeter for the application of Ir-192 HDR brachytherapy treatments. MATERIAL AND METHODS: MOSFET was characterized for dose linearity in the range of 50-1000 cGy, depth dose dependence from 2 to 7 cm, angular dependence. Signal fading was checked for two weeks. RESULT AND DISCUSSION: Dose linearity was found to be within 2% in the dose range (50-1000 cGy). The response varied within 8.07% for detector-source distance of 2-7 cm. The response of MOSFET with the epoxy side facing the source (0 degree) is the highest and the lowest response was observed at 90 and 270 degrees. Signal was stable during the study period. CONCLUSION: The detector showed high dose linearity and insignificant fading. But due to angular and depth dependence, care should be taken and corrections must be applied for clinical dosimetry.

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BACKGROUND: Carvedilol is a third-generation ß-blocker indicated for congestive heart failure and high blood pressure. The aim of this study was to investigate the dose proportionality of the carvedilol sustained-release (SR) formulation in healthy male subjects. METHODS: An open-label, single dose-ascending, 10-sequence, 3-period balanced incomplete block study was performed using healthy male subjects. In varying sequences, each subject received three of five carvedilol SR formulations (8, 16, 32, 64, or 128 mg once). The treatment periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 h after dosing. The plasma concentrations of carvedilol were determined by using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters including the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time (AUClast), AUC extrapolated to infinity (AUCinf), and the measured peak plasma concentration (C max) were obtained by noncompartmental analysis. Dose proportionality was evaluated if the ln-ln plots of AUClast, AUCinf, and C max versus dose were linear and the 90% confidence intervals (CIs) of the slopes were within 0.9195 and 1.0805. Tolerability was assessed by vital signs, electrocardiogram, clinical laboratory tests, and monitoring of adverse events (AEs) throughout the study. RESULTS: A total of 31 subjects were enrolled, and 30 completed the study. The assessment of dose proportionality meets the statistical criteria; the point estimates of slope were 1.0104 (90% CI: 0.9849-1.0359) for AUClast, 1.0003 (90% CI: 0.9748-1.0258) for AUCinf, and 0.9901 (90% CI: 0.9524-1.0277) for C max, respectively. All AEs were mild, and none of the subjects dropped out due to AEs. CONCLUSION: In this study, exposure to carvedilol was proportional over the therapeutic dose range of 8-128 mg. The carvedilol SR formulation was well tolerated.

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The concept of microdosing has been around for more than a decade. It consists of the subpharmacologic administration of an investigational drug (1% of the pharmacologic dose or 100 µg, whichever is lower) to human subjects to attain pre-phase 1 pharmacokinetics (PK) in humans. The major concern with microdosing has been the potential for nonlinear PK between doses, but methods are emerging to evaluate the potential for nonlinear PK prior to conducting a study. Currently, approximately 80% of drugs tested by the oral route and 100% by the intravenous route have exhibited scalable PK between a microdose and a therapeutic dose (within a factor of 2). Over the past few years microdosing has found utility in pediatrics, protein-based therapeutics, and a new application known as intra-arterial microdosing that focuses more on localized pharmacodynamics than PK. Compared with other PK predictive methods, such as physiologically based pharmacokinetic modeling, allometry, and in vitro-in vivo extrapolation, microdosing appears to provide a significantly better understanding of PK prior to phase 1, albeit within what is currently a limited database.

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ED001-study data on increased liver and stomach tumor risks in >40,000 trout fed dibenzo[a,l]pyrene (DBP), one of the most potently mutagenic chemical carcinogens known, provide the greatest low-dose dose-response resolution of any experimentally induced tumor data set to date. Although multistage somatic mutation/clonal-expansion cancer theory predicts that genotoxic carcinogens increase tumor risk in linear no-threshold proportion to dose at low doses, ED001 tumor data curiously exhibit substantial low-dose nonlinearity. To explore the role that nongenotoxic mechanisms may have played to yield such nonlinearity, the liver and stomach tumor data sets were each fit by two models that each assume a genotoxic and a nongenotoxic pathway to increased tumor risk: the stochastic 2-stage (MVK) cancer model, and a model implementing the more recent dysregulated adaptive hyperplasia (DAH) theory of tumorigenesis. MVK and DAH fits to the data sets were each excellent, but unexpectedly each MVK fit implies that DBP acts to increase tumor risk by entirely non-mutagenic mechanisms. Given that DBP is such a potent mutagen, the MVK-model fits obtained appear to be biologically implausible, whereas the DAH-model fits reflect that model's assumption that chemical-induced tumorigenesis typically is driven by elevated repair-cell populations rather than mutations per se.

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Dose linearity studies on conventional linear accelerators show a linearity error at low monitor units (MUs). The purpose of this study was to establish the dose linearity and MU stability characteristics of a cyberknife (Accuray Inc., USA) stereotactic radiosurgery system. Measurements were done at a depth of 5 cm in a stereotactic dose verification phantom with a source to surface distance of 75 cm in a Generation 4 (G4) type cyberknife system. All the 12 fixed-type collimators starting from 5 to 60 mm were used for the dose linearity study. The dose linearity was examined in small (1-10), medium (15-100) and large (125-1000) MU ranges. The MU stability test was performed with 60 mm collimator for 10 MU and 20 MU with different combinations. The maximum dose linearity error of -38.8% was observed for 1 MU with 5 mm collimator. Dose linearity error in the small MU range was considerably higher than in the medium and large MU ranges. The maximum error in the medium range was -2.4%. In the large MU range, the linearity error varied between -0.7% and 1.2%. The maximum deviation in the MU stability was -3.03%.

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The 2009 National Research Council report, Science and Decisions, proposes harmonizing dose-response approaches for cancer and non-cancer endpoints, and for non-cancer quantitative risk assessment, this would usually take the form of a low-dose linear no-threshold dose-response curve. The soundness of this recommendation has been questioned, but I focus on its consequences if adopted, many of them apparently unintended. If most endpoints for most agents are assumed to have non-zero low-dose risks, then the critical-effect concept, choosing the one endpoint on which to calculate acceptable doses, loses its basis. All regulatory decisions, since they entail substituting some exposures (and their attendant risks) for others, become risk-risk trade-off decisions, and equity questions are raised since risk transfer is inevitably involved. A valid basis for estimating low-dose linear components is not evident, and upper-bound approaches fail to be reliably public health-protective owing to the risk trade-off decisions that need to be faced.

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Gamma irradiator is widely used for cell, animal experiment, irradiation for blood, dose measurement, and education. Biobeam8000 gamma irradiator (STS Steuerungstechnik &. Strahlenschutz GmbH, Braunschweig, Germany, Cs137, 81.4 TBq) that KIRAMS (Korea Institute of Radiological and Medical Science) has is a irradiation device that enables to be used in large-capacity of 7.5 L and extensive area. Cs-137 source moves range of 24 cm back-and-forth in a regular cycle in beaker for uniform irradiation and a beaker that puts a specimen like existing radiation irradiator such as Gammacell3000 rotates 360degrees during irradiation. Precise dose information according to the location of radiation source would be needed because of the movement of radiation source, whereas radiation could be uniformly irradiated in comparison with existing gamma irradiator. In this study, dose distribution of the inside beaker located in Biomeam8000 gamma irradiator was measured using glass dosimeter, and dose evaluation and distribution regarding dose linearity and dose reproducibility were implemented based on measurement results. This aims to show guideline for efficient use of irradiator based on measurement result when doing experiment or radiation exposure.

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