Single-grain dose-distribution measurements by optically stimulated luminescence using an integrated EMCCD-based system

We report on the feasibility of assessing single-grain dose-distributions by using an EMCCD-based imaging system with complementary analysis software. Automated image-processing was successfully applied to compensate sample motion and for automated grain identification. Following a dose recovery test, 74 % of the grains were recognized successfully, and 44 % exhibited a suitable OSL dose response behavior to interpolate an equivalent dose value and a central dose recovery ratio of 1.038 was obtained.Comment: 30 pages, 6 figures, 2 table

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Observational-Interventional Priors for Dose-Response Learning

Controlled interventions provide the most direct source of information for learning causal effects. In particular, a dose-response curve can be learned by varying the treatment level and observing the corresponding outcomes. However, interventions can be expensive and time-consuming. Observational data, where the treatment is not controlled by a known mechanism, is sometimes available. Under some strong assumptions, observational data allows for the estimation of dose-response curves. Estimating such curves nonparametrically is hard: sample sizes for controlled interventions may be small, while in the observational case a large number of measured confounders may need to be marginalized. In this paper, we introduce a hierarchical Gaussian process prior that constructs a distribution over the dose-response curve by learning from observational data, and reshapes the distribution with a nonparametric affine transform learned from controlled interventions. This function composition from different sources is shown to speed-up learning, which we demonstrate with a thorough sensitivity analysis and an application to modeling the effect of therapy on cognitive skills of premature infants

Phase i study of \u27dose-dense\u27 pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.

BACKGROUND: This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC). METHODS: Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles. RESULTS: Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients. CONCLUSIONS: Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC

A Short Investigation of the Luminescence Properties of Talc

This report presents results of a short study of the thermoluminescence TL properties of talc. Talc is a magnesium silicate mineral utilised widely in industrial and pharmaceutical applications. It occurs in well defined geological situations with several known formation processes, and is extracted by quarrying and mining. The use in foods and dietary supplements is mainly as a filler. The work was initiated to address questions as to the possible impact of talc on application of EN1788 methods to detect irradiated foods. Authentic samples were obtained from extraction and processing facilities in France and Italy. Supplementary samples from Sardinia, China, Mexico and Australia were obtained indirectly. Irradiated pharmaceutical grade talc was obtained from a UK commercial source for comparison. All samples were characterised by TL analysis after initial preparation, and also following irradiation to a 200 Gy dose. The dose response and behaviour under storage at ambient and elevated temperatures and in a light box, were investigated for two samples in detail. Exploratory kinetic analysis was performed to provide first order estimates of trap parameters. All samples of talc exhibited measurable TL response in the 0-500°C region, with at least four recognisable TL peaks present in response to radiation. Sensitivities vary by some 3 or more orders of magnitude from sample to sample, accompanied by less pronounced changes in glow shape following radiation. The dose response increases progressively in the 100-6400 Gy range investigated. At higher dose levels the response is non-linear with the onset of saturation occurring in the kGy region for the majority of signals. Radiation induced signals from all four peaks were stable at ambient temperatures over the duration of the study. Samples stored at 50°C showed some thermal erosion of the low temperature signals. This observation together with analysis of the distribution of natural TL and the kinetic analyses confirms that lower temperature signals have comparable stability with other silicates, and that higher temperature signals are the dominant components of geologically induced signals. The stability requirements to explain natural signals in terms of simple production mechanisms have been defined. Exploratory kinetic analysis confirms that there are multi-trap contributions to the main TL peaks, but provides broad support for a simple explanation of the natural TL. The TL response following high dose irradiation can be distinguished from geological signals by 1-2 orders of magnitude in low temperature peaks. There may be scope for further investigation of phototransfer effects, but these would clearly be overtaken by bleaching in prolonged exposures to light. Thermal processing of pharmaceutical grades of talc reduces residual low temperature signals by some 1-2 orders of magnitude leading to product with negligible low temperature natural signals. TL could in principle be used to verify the effectiveness of such thermal treatment, and potentially to authenticate commercial products. It can also quite clearly be used to identify irradiated talc, providing the amount of prior exposure to light is limited. In samples containing talc in extreme dilution with other unirradiated products, there might be ambiguity in interpretation of glow curves with minor low temperature peaks dominated by high temperature signals. Care would be needed in interpreting EN1788 results of this sort

Advanced Methods for Dose-Response Assessment: Bayesian Approaches—Final Report

Resources for the Future (RFF), in conjunction with the U.S. Environmental Protection Agency, the Society for Risk Analysis, and the Electric Power Research Institute, held a workshop September 18–20, 2000, at the RFF Conference Center in Washington, D.C. The intent was to discuss how Bayesian approaches could be useful in improving techniques for estimating exposure–response functions. Ten distinguished scholars from a range of fields (medical biostatistics, decision sciences, environmental engineering, and toxicology) served as faculty. Approximately 80 people attended the workshop. Bayesian methods have been applied to a variety of problems in biomedical research and environmental risk analysis, including design of clinical trials, estimation of exposures to humans and local environments, and, in a few cases, estimation of exposure–response functions. Bayesian methods offer two signal advantages: their use requires careful analysis of problem logic, which has intrinsic utility, and disparate data can be incorporated into calculations. Although application of formal Bayesian analysis can be computationally challenging, widely available computer programs now greatly reduce this burden. Participants identified several factors that may impede the dissemination of Bayesian approaches among practitioners of dose–response assessment and made some recommendations for overcoming these hurdles. EPA, other regulatory agencies that use dose–response assessment as part of their processes, and the private sector all should take steps to foster the use of Bayesian approaches. EPA and other agencies should work to persuade professional societies (for example, Society for Risk Analysis, Society of Toxicology) to seek out and recognize meritorious analyses that use Bayesian approaches. EPA and private-sector organizations should consider sponsoring research into using Bayesian approaches, demonstration analyses that use them, and using the results of this work to help educate peers in the risk analysis and toxicology professions. EPA should request all staff and contractor scientists who develop mathematical models to use Bayesian techniques to calibrate models. EPA should consider ways to inform its staff, contractors, and the research community as to the utility of Bayesian analyses. EPA should consider improving its research planning by making use of Bayesian techniques (including value-of-information analyses).Bayesian analysis, dose–response, regulation, risk assessment, arsenic