Science.gov

Sample records for dose-response efeitos biologicos

  1. Implicit dose-response curves.

    PubMed

    Pérez Millán, Mercedes; Dickenstein, Alicia

    2015-06-01

    We develop tools from computational algebraic geometry for the study of steady state features of autonomous polynomial dynamical systems via elimination of variables. In particular, we obtain nontrivial bounds for the steady state concentration of a given species in biochemical reaction networks with mass-action kinetics. This species is understood as the output of the network and we thus bound the maximal response of the system. The improved bounds give smaller starting boxes to launch numerical methods. We apply our results to the sequential enzymatic network studied in Markevich et al. (J Cell Biol 164(3):353-359, 2004) to find nontrivial upper bounds for the different substrate concentrations at steady state. Our approach does not require any simulation, analytical expression to describe the output in terms of the input, or the absence of multistationarity. Instead, we show how to extract information from effectively computable implicit dose-response curves, with the use of resultants and discriminants. We moreover illustrate in the application to an enzymatic network, the relation between the exact implicit dose-response curve we obtain symbolically and the standard hysteresis diagram provided by a numerical ode solver. The setting and tools we propose could yield many other results adapted to any autonomous polynomial dynamical system, beyond those where it is possible to get explicit expressions. PMID:25008963

  2. Dose response signal detection under model uncertainty.

    PubMed

    Dette, Holger; Titoff, Stefanie; Volgushev, Stanislav; Bretz, Frank

    2015-12-01

    We investigate likelihood ratio contrast tests for dose response signal detection under model uncertainty, when several competing regression models are available to describe the dose response relationship. The proposed approach uses the complete structure of the regression models, but does not require knowledge of the parameters of the competing models. Standard likelihood ratio test theory is applicable in linear models as well as in nonlinear regression models with identifiable parameters. However, for many commonly used nonlinear dose response models the regression parameters are not identifiable under the null hypothesis of no dose response and standard arguments cannot be used to obtain critical values. We thus derive the asymptotic distribution of likelihood ratio contrast tests in regression models with a lack of identifiability and use this result to simulate the quantiles based on Gaussian processes. The new method is illustrated with a real data example and compared to existing procedures using theoretical investigations as well as simulations. PMID:26228796

  3. Dose-Response Analysis Using R

    PubMed Central

    Ritz, Christian; Baty, Florent; Streibig, Jens C.; Gerhard, Daniel

    2015-01-01

    Dose-response analysis can be carried out using multi-purpose commercial statistical software, but except for a few special cases the analysis easily becomes cumbersome as relevant, non-standard output requires manual programming. The extension package drc for the statistical environment R provides a flexible and versatile infrastructure for dose-response analyses in general. The present version of the package, reflecting extensions and modifications over the last decade, provides a user-friendly interface to specify the model assumptions about the dose-response relationship and comes with a number of extractors for summarizing fitted models and carrying out inference on derived parameters. The aim of the present paper is to provide an overview of state-of-the-art dose-response analysis, both in terms of general concepts that have evolved and matured over the years and by means of concrete examples. PMID:26717316

  4. Inferring mechanisms from dose-response curves

    PubMed Central

    Chow, Carson C.; Ong, Karen M.; Dougherty, Edward J.; Simons, S. Stoney

    2011-01-01

    The steady state dose-response curve of ligand-mediated gene induction usually appears to precisely follow a first-order Hill equation (Hill coefficient equal to 1). Additionally, various cofactors/reagents can affect both the potency and the maximum activity of gene induction in a gene-specific manner. Recently, we have developed a general theory for which an unspecified sequence of steps or reactions yields a first-order Hill dose-response curve (FHDC) for plots of the final product vs. initial agonist concentration. The theory requires only that individual reactions “dissociate” from the downstream reactions leading to the final product, which implies that intermediate complexes are weakly bound or exist only transiently. We show how the theory can be utilized to make predictions of previously unidentified mechanisms and the site of action of cofactors/reagents. The theory is general and can be applied to any biochemical reaction that has a FHDC. PMID:21187235

  5. The Dose Response Relationship for Radiation Carcinogenesis

    NASA Astrophysics Data System (ADS)

    Hall, Eric

    2008-03-01

    Recent surveys show that the collective population radiation dose from medical procedures in the U.S. has increased by 750% in the past two decades. It would be impossible to imagine the practice of medicine today without diagnostic and therapeutic radiology, but nevertheless the widespread and rapidly increasing use of a modality which is a known human carcinogen is a cause for concern. To assess the magnitude of the problem it is necessary to establish the shape of the dose response relationship for radiation carcinogenesis. Information on radiation carcinogenesis comes from the A-bomb survivors, from occupationally exposed individuals and from radiotherapy patients. The A-bomb survivor data indicates a linear relationship between dose and the risk of solid cancers up to a dose of about 2.5 Sv. The lowest dose at which there is a significant excess cancer risk is debatable, but it would appear to be between 40 and 100 mSv. Data from the occupation exposure of nuclear workers shows an excess cancer risk at an average dose of 19.4 mSv. At the other end of the dose scale, data on second cancers in radiotherapy patients indicates that cancer risk does not continue to rise as a linear function of dose, but tends towards a plateau of 40 to 60 Gy, delivered in a fractionated regime. These data can be used to estimate the impact of diagnostic radiology at the low dose end of the dose response relationship, and the impact of new radiotherapy modalities at the high end of the dose response relationship. In the case of diagnostic radiology about 90% of the collective population dose comes from procedures (principally CT scans) which involve doses at which there is credible evidence of an excess cancer incidence. While the risk to the individual is small and justified in a symptomatic patient, the same is not true of some screening procedures is asymptomatic individuals, and in any case the huge number of procedures must add up to a potential public health problem. In the

  6. Dose-Response Relationships in Human Experimental Exposure to Solvents

    PubMed Central

    Iavicoli, Ivo; Carelli, Giovanni; Marinaccio, Alessandro

    2006-01-01

    Previous studies carried out in the field of experimental toxicology have shown evidence of biphasic dose-response relationships for different experimental models, endpoints and chemicals tested. As these studies excluded humans as the experimental model, we have examined the literature of the last three decades in order to verify data concerning human experimental exposure with the aim of highlighting possible biphasic dose-response relationships. The substances used for experimental exposures included hydrocarbons, esters, alcohols, ketones, ethers, glycoethers, halogenated hydrocarbons, and carbon sulphide; the absorption route was inhalation. We did not detect any biphasic dose-response relationship and, in the studies reviewed, our examination revealed major methodological limitations that prevented us making a more detailed examination of experimental data. We concluded that the experimental data available did not allow us to support evidence of biphasic dose-response relationships in human experimental exposure to the above-mentioned chemical substances. PMID:18648639

  7. Dose-response relationships for carcinogens: a review.

    PubMed Central

    Zeise, L; Wilson, R; Crouch, E A

    1987-01-01

    We review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Our major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so we pay special attention to experimentally observed and theoretically expected nonlinearities. There are few experimental examples of nonlinear dose-response relations in humans, but this may simply be due to the limitations in the data. The several examples in rodents, even though for high dose data, suggest that nonlinearity is common. In some cases such nonlinearities may be rationalized on the basis of the pharmacokinetics of the test compound or its metabolites. PMID:3311725

  8. DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY: III. STATISTICAL MODELS

    EPA Science Inventory

    Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. Recently, statistical models appropriate for developmental toxicity testing have been developed and applied (Rai...

  9. Curious cases: Altered dose-response relationships in addiction genetics.

    PubMed

    Uhl, George R; Drgonova, Jana; Hall, F Scott

    2014-03-01

    Dose-response relationships for most addictive substances are "inverted U"-shaped. Addictive substances produce both positive features that include reward, euphoria, anxiolysis, withdrawal-relief, and negative features that include aversion, dysphoria, anxiety and withdrawal symptoms. A simple model differentially associates ascending and descending limbs of dose-response curves with rewarding and aversive influences, respectively. However, Diagnostic and Statistical Manual (DSM) diagnoses of substance dependence fail to incorporate dose-response criteria and don't directly consider balances between euphoric and dysphoric drug effects. Classical genetic studies document substantial heritable influences on DSM substance dependence. Linkage and genome-wide association studies identify modest-sized effects at any locus. Nevertheless, clusters of SNPs within selected genes display 10(-2)>p>10(-8) associations with dependence in many independent samples. For several of these genes, evidence for cis-regulatory, level-of-expression differences supports the validity of mouse models in which levels of expression are also altered. This review documents surprising, recently defined cases in which convergent evidence from humans and mouse models supports central influences of altered dose-response relationships in mediating the impact of relevant genomic variation on addiction phenotypes. For variation at loci for the α5 nicotinic acetylcholine receptor, cadherin 13, receptor type protein tyrosine phosphatase Δ and neuronal cell adhesion molecule genes, changed dose-response relationships conferred by gene knockouts in mice are accompanied by supporting human data. These observations emphasize desirability of carefully elucidating dose-response relationships for both rewarding and aversive features of abused substances wherever possible. They motivate consideration of individual differences in dose-response relationships in addiction nosology and therapeutics. PMID:24189489

  10. Dose-Response Calculator for ArcGIS

    USGS Publications Warehouse

    Hanser, Steven E.; Aldridge, Cameron L.; Leu, Matthias; Nielsen, Scott E.

    2011-01-01

    The Dose-Response Calculator for ArcGIS is a tool that extends the Environmental Systems Research Institute (ESRI) ArcGIS 10 Desktop application to aid with the visualization of relationships between two raster GIS datasets. A dose-response curve is a line graph commonly used in medical research to examine the effects of different dosage rates of a drug or chemical (for example, carcinogen) on an outcome of interest (for example, cell mutations) (Russell and others, 1982). Dose-response curves have recently been used in ecological studies to examine the influence of an explanatory dose variable (for example, percentage of habitat cover, distance to disturbance) on a predicted response (for example, survival, probability of occurrence, abundance) (Aldridge and others, 2008). These dose curves have been created by calculating the predicted response value from a statistical model at different levels of the explanatory dose variable while holding values of other explanatory variables constant. Curves (plots) developed using the Dose-Response Calculator overcome the need to hold variables constant by using values extracted from the predicted response surface of a spatially explicit statistical model fit in a GIS, which include the variation of all explanatory variables, to visualize the univariate response to the dose variable. Application of the Dose-Response Calculator can be extended beyond the assessment of statistical model predictions and may be used to visualize the relationship between any two raster GIS datasets (see example in tool instructions). This tool generates tabular data for use in further exploration of dose-response relationships and a graph of the dose-response curve.

  11. Dose-response relationship for supraglottic laryngeal carcinoma

    SciTech Connect

    Peters, L.J.; Thomas, H.D. Jr.

    1983-03-01

    In this editorial, two important issues in the treatment of cancers of the supraglottic larynx which had been raised by other authors, Harwood et al., are discussed. The first is the technique of elective irradiation of clinically uninvolved neck nodes. The second is the question of dose-response relationships for local control of tumors of this site. The present authors do not believe that the data of Harwood et al. can be construed as convincing evidence against a dose-response relationship, because of the heterogeneity of the clinical material and the narrow range of doses represented.(KRM)

  12. A Bayesian Semiparametric Model for Radiation Dose-Response Estimation.

    PubMed

    Furukawa, Kyoji; Misumi, Munechika; Cologne, John B; Cullings, Harry M

    2016-06-01

    In evaluating the risk of exposure to health hazards, characterizing the dose-response relationship and estimating acceptable exposure levels are the primary goals. In analyses of health risks associated with exposure to ionizing radiation, while there is a clear agreement that moderate to high radiation doses cause harmful effects in humans, little has been known about the possible biological effects at low doses, for example, below 0.1 Gy, which is the dose range relevant to most radiation exposures of concern today. A conventional approach to radiation dose-response estimation based on simple parametric forms, such as the linear nonthreshold model, can be misleading in evaluating the risk and, in particular, its uncertainty at low doses. As an alternative approach, we consider a Bayesian semiparametric model that has a connected piece-wise-linear dose-response function with prior distributions having an autoregressive structure among the random slope coefficients defined over closely spaced dose categories. With a simulation study and application to analysis of cancer incidence data among Japanese atomic bomb survivors, we show that this approach can produce smooth and flexible dose-response estimation while reasonably handling the risk uncertainty at low doses and elsewhere. With relatively few assumptions and modeling options to be made by the analyst, the method can be particularly useful in assessing risks associated with low-dose radiation exposures. PMID:26581473

  13. PREDICTIVE BAYESIAN PATHOGEN DOSE-RESPONSE MODEL FORMS

    EPA Science Inventory

    The use of predictive Bayesian methods in dose-response assessment will be investigated. The predictive Bayesian approach offers an alternative to current approaches in that it does not require the selection of a specific confidence limit, yet provides an answer that is more cons...

  14. A Framework for "Fit for Purpose" Dose Response Assessment

    EPA Science Inventory

    The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose-response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two ...

  15. Computer Simulation of Quantal Dose-Response Relationships.

    ERIC Educational Resources Information Center

    McGilliard, Kip L.

    1985-01-01

    Describes a program which simulates animal pharmacology experiments involving "all-or-none" responses. Use of the Applesoft BASIC program in the pharmacology teaching laboratory provides students with a rapid and economical way to gain experience in the design and statistical analysis of quantal dose-response experiments. Information on obtaining…

  16. Radiation Dose-Response Relationships and Risk Assessment

    SciTech Connect

    Strom, Daniel J.

    2005-07-05

    The notion of a dose-response relationship was probably invented shortly after the discovery of poisons, the invention of alcoholic beverages, and the bringing of fire into a confined space in the forgotten depths of ancient prehistory. The amount of poison or medicine ingested can easily be observed to affect the behavior, health, or sickness outcome. Threshold effects, such as death, could be easily understood for intoxicants, medicine, and poisons. As Paracelsus (1493-1541), the 'father' of modern toxicology said, 'It is the dose that makes the poison.' Perhaps less obvious is the fact that implicit in such dose-response relationships is also the notion of dose rate. Usually, the dose is administered fairly acutely, in a single injection, pill, or swallow; a few puffs on a pipe; or a meal of eating or drinking. The same amount of intoxicants, medicine, or poisons administered over a week or month might have little or no observable effect. Thus, before the discovery of ionizing radiation in the late 19th century, toxicology ('the science of poisons') and pharmacology had deeply ingrained notions of dose-response relationships. This chapter demonstrates that the notion of a dose-response relationship for ionizing radiation is hopelessly simplistic from a scientific standpoint. While useful from a policy or regulatory standpoint, dose-response relationships cannot possibly convey enough information to describe the problem from a quantitative view of radiation biology, nor can they address societal values. Three sections of this chapter address the concepts, observations, and theories that contribute to the scientific input to the practice of managing risks from exposure to ionizing radiation. The presentation begins with irradiation regimes, followed by responses to high and low doses of ionizing radiation, and a discussion of how all of this can inform radiation risk management. The knowledge that is really needed for prediction of individual risk is presented

  17. Dose-response relationship of fibrous dusts in intraperitoneal studies.

    PubMed Central

    Roller, M; Pott, F; Kamino, K; Althoff, G H; Bellmann, B

    1997-01-01

    The relationship between the number of fibers injected intraperitoneally and the occurrence of peritoneal mesotheliomas in rats was investigated using data from a series of carcinogenicity studies with several fibrous dusts. Based on observed tumor incidences ranging between 10 and 90%, the hypothesis of a common slope of dose-response relationships (parallel probit lines in probit analysis) cannot be rejected. In general, parallelism of probit lines is considered an indication of a common mode of action. Analysis of the shape of the dose-response relationship, with one apparent exception, shows virtually linear or superlinear behavior, i.e., from these data, there is no indication of a decrease in carcinogenic potency of an elementary carcinogenic unit at lower doses. PMID:9400733

  18. Bayesian multimodel inference for dose-response studies

    USGS Publications Warehouse

    Link, W.A.; Albers, P.H.

    2007-01-01

    Statistical inference in dose?response studies is model-based: The analyst posits a mathematical model of the relation between exposure and response, estimates parameters of the model, and reports conclusions conditional on the model. Such analyses rarely include any accounting for the uncertainties associated with model selection. The Bayesian inferential system provides a convenient framework for model selection and multimodel inference. In this paper we briefly describe the Bayesian paradigm and Bayesian multimodel inference. We then present a family of models for multinomial dose?response data and apply Bayesian multimodel inferential methods to the analysis of data on the reproductive success of American kestrels (Falco sparveriuss) exposed to various sublethal dietary concentrations of methylmercury.

  19. Total dose responses and reliability issues of 65 nm NMOSFETs

    NASA Astrophysics Data System (ADS)

    Dezhao, Yu; Qiwen, Zheng; Jiangwei, Cui; Hang, Zhou; Xuefeng, Yu; Qi, Guo

    2016-06-01

    In this paper, total dose responses and reliability issues of MOSFETs fabricated by 65 nm CMOS technology were examined. “Radiation-induced narrow channel effect” is observed in a narrow channel device. Similar to total dose responses of NMOSFETs, narrow channel NMOSFEs have larger hot-carrier-induced degradation than wide channel devices. Step Time-Dependent Dielectric Breakdown (TDDB) stresses are applied, and narrow channel devices have higher breakdown voltage than wide channel devices, which agree with “weakest link” theory of TDDB. Experimental results show that linear current, transconductance, saturated drain current and subthreshold swing are superposed degenerated by total dose irradiation and reliability issues, which may result in different lifetime from that considering total dose irradiation reliability issues separately. Project supported by “Light of West China” Program of CAS (No. XBBS201219).

  20. Summary of Dose-Response Modeling for Developmental Toxicity Studies

    PubMed Central

    Hunt, Daniel L.; Rai, Shesh N.; Li, Chin-Shang

    2008-01-01

    Developmental toxicity studies are an important area in the field of toxicology. Endpoints measured on fetuses include weight and indicators of death and malformation. Binary indicator measures are typically summed over the litter and a discrete distribution is assumed to model the number of adversely affected fetuses. Additionally, there is noticeable variation in the litter responses within dose groups that should be taken into account when modeling. Finally, the dose-response pattern in these studies exhibits a threshold effect. The threshold dose-response model is the default model for non-carcinogenic risk assessment, according to the USEPA, and is encouraged by the agency for the use in the risk assessment process. Two statistical models are proposed to estimate dose-response pattern of data from the developmental toxicity study: the threshold model and the spline model. The models were applied to two data sets. The advantages and disadvantages of these models, potential other models, and future research possibilities will be summarized. PMID:19088901

  1. Biphasic Dose Response in Low Level Light Therapy

    PubMed Central

    Huang, Ying-Ying; Chen, Aaron C.-H.; Carroll, James D.; Hamblin, Michael R.

    2009-01-01

    The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response. PMID:20011653

  2. Quantitative dose-response curves from subcellular lipid multilayer microarrays.

    PubMed

    Kusi-Appiah, A E; Lowry, T W; Darrow, E M; Wilson, K A; Chadwick, B P; Davidson, M W; Lenhert, S

    2015-08-21

    The dose-dependent bioactivity of small molecules on cells is a crucial factor in drug discovery and personalized medicine. Although small-molecule microarrays are a promising platform for miniaturized screening, it has been a challenge to use them to obtain quantitative dose-response curves in vitro, especially for lipophilic compounds. Here we establish a small-molecule microarray assay capable of controlling the dosage of small lipophilic molecules delivered to cells by varying the sub-cellular volumes of surface supported lipid micro- and nanostructure arrays fabricated with nanointaglio. Features with sub-cellular lateral dimensions were found necessary to obtain normal cell adhesion with HeLa cells. The volumes of the lipophilic drug-containing nanostructures were determined using a fluorescence microscope calibrated by atomic-force microscopy. We used the surface supported lipid volume information to obtain EC-50 values for the response of HeLa cells to three FDA-approved lipophilic anticancer drugs, docetaxel, imiquimod and triethylenemelamine, which were found to be significantly different from neat lipid controls. No significant toxicity was observed on the control cells surrounding the drug/lipid patterns, indicating lack of interference or leakage from the arrays. Comparison of the microarray data to dose-response curves for the same drugs delivered liposomally from solution revealed quantitative differences in the efficacy values, which we explain in terms of cell-adhesion playing a more important role in the surface-based assay. The assay should be scalable to a density of at least 10,000 dose response curves on the area of a standard microtiter plate. PMID:26167949

  3. Quantitative Dose-Response Curves from Subcellular Lipid Multilayer Microarrays

    PubMed Central

    Kusi-Appiah, A. E.; Lowry, T. W.; Darrow, E. M.; Wilson, K.; Chadwick, B. P.; Davidson, M. W.; Lenhert, S.

    2015-01-01

    The dose-dependent bioactivity of small molecules on cells is a crucial factor in drug discovery and personalized medicine. Although small-molecule microarrays are a promising platform for miniaturized screening, it has been a challenge to use them to obtain quantitative dose-response curves in vitro, especially for lipophilic compounds. Here we establish a small-molecule microarray assay capable of controlling the dosage of small lipophilic molecules delivered to cells by varying the sub-cellular volumes of surface supported lipid micro- and nanostructure arrays fabricated with nanointaglio. Features with sub-cellular lateral dimensions were found necessary to obtain normal cell adhesion with HeLa cells. The volumes of the lipophilic drug-containing nanostructures were determined using a fluorescence microscope calibrated by atomic-force microscopy. We used the surface supported lipid volume information to obtain EC-50 values for the response of HeLa cells to three FDA-approved lipophilic anticancer drugs, docetaxel, imiquimod and triethylenemelamine, which were found to be significantly different from neat lipid controls. No significant toxicity was observed on the control cells surrounding the drug/lipid patterns, indicating lack of interference or leakage from the arrays. Comparison of the microarray data to dose-response curves for the same drugs delivered liposomally from solution revealed quantitative differences in the efficacy values, which we explain in terms of cell-adhesion playing a more important role in the surface-based assay. The assay should be scalable to a density of at least 10,000 dose response curves on the area of a standard microtiter plate. PMID:26167949

  4. Modeling Effective Dosages in Hormetic Dose-Response Studies

    PubMed Central

    Belz, Regina G.; Piepho, Hans-Peter

    2012-01-01

    Background Two hormetic modifications of a monotonically decreasing log-logistic dose-response function are most often used to model stimulatory effects of low dosages of a toxicant in plant biology. As just one of these empirical models is yet properly parameterized to allow inference about quantities of interest, this study contributes the parameterized functions for the second hormetic model and compares the estimates of effective dosages between both models based on 23 hormetic data sets. Based on this, the impact on effective dosage estimations was evaluated, especially in case of a substantially inferior fit by one of the two models. Methodology/Principal Findings The data sets evaluated described the hormetic responses of four different test plant species exposed to 15 different chemical stressors in two different experimental dose-response test designs. Out of the 23 data sets, one could not be described by any of the two models, 14 could be better described by one of the two models, and eight could be equally described by both models. In cases of misspecification by any of the two models, the differences between effective dosages estimates (0–1768%) greatly exceeded the differences observed when both models provided a satisfactory fit (0–26%). This suggests that the conclusions drawn depending on the model used may diverge considerably when using an improper hormetic model especially regarding effective dosages quantifying hormesis. Conclusions/Significance The study showed that hormetic dose responses can take on many shapes and that this diversity can not be captured by a single model without risking considerable misinterpretation. However, the two empirical models considered in this paper together provide a powerful means to model, prove, and now also to quantify a wide range of hormetic responses by reparameterization. Despite this, they should not be applied uncritically, but after statistical and graphical assessment of their adequacy. PMID

  5. The Radiation Dose-Response of the Human Spinal Cord

    SciTech Connect

    Schultheiss, Timothy E.

    2008-08-01

    Purpose: To characterize the radiation dose-response of the human spinal cord. Methods and Materials: Because no single institution has sufficient data to establish a dose-response function for the human spinal cord, published reports were combined. Requisite data were dose and fractionation, number of patients at risk, number of myelopathy cases, and survival experience of the population. Eight data points for cervical myelopathy were obtained from five reports. Using maximum likelihood estimation correcting for the survival experience of the population, estimates were obtained for the median tolerance dose, slope parameter, and {alpha}/{beta} ratio in a logistic dose-response function. An adequate fit to thoracic data was not possible. Hyperbaric oxygen treatments involving the cervical cord were also analyzed. Results: The estimate of the median tolerance dose (cervical cord) was 69.4 Gy (95% confidence interval, 66.4-72.6). The {alpha}/{beta} = 0.87 Gy. At 45 Gy, the (extrapolated) probability of myelopathy is 0.03%; and at 50 Gy, 0.2%. The dose for a 5% myelopathy rate is 59.3 Gy. Graphical analysis indicates that the sensitivity of the thoracic cord is less than that of the cervical cord. There appears to be a sensitizing effect from hyperbaric oxygen treatment. Conclusions: The estimate of {alpha}/{beta} is smaller than usually quoted, but values this small were found in some studies. Using {alpha}/{beta} = 0.87 Gy, one would expect a considerable advantage by decreasing the dose/fraction to less than 2 Gy. These results were obtained from only single fractions/day and should not be applied uncritically to hyperfractionation.

  6. Dose-response model for teratological experiments involving quantal responses

    SciTech Connect

    Rai, K.; Van Ryzin, J.

    1985-03-01

    This paper introduces a dose-response model for teratological quantal response data where the probability of response for an offspring from a female at a given dose varies with the litter size. The maximum likelihood estimators for the parameters of the model are given as the solution of a nonlinear iterative algorithm. Two methods of low-dose extrapolation are presented, one based on the litter size distribution and the other a conservative method. The resulting procedures are then applied to a teratological data set from the literature.

  7. PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT

    EPA Science Inventory

    PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
    Dose-response analysis requires quantitatively linking infor...

  8. Maximum likelihood estimation for cytogenetic dose-response curves

    SciTech Connect

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

  9. Confidence bounds for nonlinear dose-response relationships.

    PubMed

    Baayen, C; Hougaard, P

    2015-11-30

    An important aim of drug trials is to characterize the dose-response relationship of a new compound. Such a relationship can often be described by a parametric (nonlinear) function that is monotone in dose. If such a model is fitted, it is useful to know the uncertainty of the fitted curve. It is well known that Wald confidence intervals are based on linear approximations and are often unsatisfactory in nonlinear models. Apart from incorrect coverage rates, they can be unreasonable in the sense that the lower confidence limit of the difference to placebo can be negative, even when an overall test shows a significant positive effect. Bootstrap confidence intervals solve many of the problems of the Wald confidence intervals but are computationally intensive and prone to undercoverage for small sample sizes. In this work, we propose a profile likelihood approach to compute confidence intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated using a public dataset and simulations based on the Emax and sigmoid Emax models. PMID:26112765

  10. Maximum likelihood estimation for cytogenetic dose-response curves

    SciTech Connect

    Frome, E.L.; DuFrain, R.J.

    1986-03-01

    In vitro dose-response curves are used to describe the relation between chromosome aberrations and radiation dose for human lymphocytes. The lymphocytes are exposed to low-LET radiation, and the resulting dicentric chromosome aberrations follow the Poisson distribution. The expected yield depends on both the magnitude and the temporal distribution of the dose. A general dose-response model that describes this relation has been presented by Kellerer and Rossi (1972, Current Topics on Radiation Research Quarterly 8, 85-158; 1978, Radiation Research 75, 471-488) using the theory of dual radiation action. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting dose-time-response models are intrinsically nonlinear in the parameters. A general-purpose maximum likelihood estimation procedure is described, and estimation for the nonlinear models is illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

  11. TESS-based dose-response using pediatric clonidine exposures

    SciTech Connect

    Benson, Blaine E. . E-mail: jebenson@salud.unm.edu; Spyker, Daniel A.; Troutman, William G.; Watson, William A. . E-mail: http://www.aapcc.org/

    2006-06-01

    Objective: The toxic and lethal doses of clonidine in children are unclear. This study was designed to determine whether data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) could be utilized to determine a dose-response relationship for pediatric clonidine exposure. Methods: 3458 single-substance clonidine exposures in children <6 years of age reported to TESS from January 2000 through December 2003 were examined. Dose ingested, age, and medical outcome were available for 1550 cases. Respiratory arrest cases (n = 8) were classified as the most severe of the medical outcome categories (Arrest, Major, Moderate, Mild, and No effect). Exposures reported as a 'taste or lick' (n = 51) were included as a dose of 1/10 of the dosage form involved. Dose ranged from 0.4 to 1980 (median 13) {mu}g/kg. Weight was imputed based on a quadratic estimate of weight for age. Dose certainty was coded as exact (26% of cases) or not exact (74%). Medical outcome (response) was examined via logistic regression using SAS JMP (release 5.1). Results: The logistic model describing medical outcome (P < 0.0001) included Log dose/kg (P 0.0000) and Certainty (P = 0.045). Conclusion: TESS data can provide the basis for a statistically sound description of dose-response for pediatric clonidine poisoning exposures.

  12. Appropriate statistical methods to compare dose responses of methionine sources.

    PubMed

    Kratzer, D D; Littell, R C

    2006-05-01

    Two sources of methionine (Met) activity are frequently used in commercial feed formulation: DL-2-hydroxy-4-(methylthio) butanoic acid (HMTBA), most commonly available as an 88% solution with 12% water; and DL-methionine (DLM, 99% powder). Despite the fact that both compounds have been in commercial use for over 50 yr, controversy and confusion remain with respect to their relative bioefficacy (RBE). This paper presents a review of the use of a nonlinear common plateau asymptotic regression technique (NLCPAR) that has been used to compare the 2 Met sources with particular emphasis on the validity of the basic assumptions of that model. The thesis of this paper is that the controversy is due, at least in part, to the misapplication of this regression technique to estimate the RBE of HMTBA and DLM. The NLCPAR model is a bioassay with the key dependent assumptions that HMTBA is a dilution of DLM, and that each follows dose-response curves of the same form and approach a common plateau. Because both provide Met activity, it may be considered reasonable to accept these assumptions; however, specifically testing them demonstrated that the assumption of a common dose-response is not supported by data. The common plateau assumption was tested with an alternative approach of fitting nonlinear separate plateaus asymptotic regression (NLSPAR) to a set of 13 published broiler studies in which the NLCPAR model had been used to estimate RBE of HMTBA and DLM. The hypothesis of a common plateau was rejected (P < 0.01), meaning that the conclusion that HMTBA had lower bioefficacy than DLM based on the NLCPAR methodology was not valid. An example using published data demonstrated that the NLSPAR model was a significantly better fit than the NLCPAR model, and showed that HMTBA and DLM followed different dose responses. Consequently, there was no single value for RBE for the entire dose range; rather, the RBE of the 2 compounds varied with use level. The evidence presented here

  13. A broadly applicable function for describing luminescence dose response

    SciTech Connect

    Burbidge, C. I.

    2015-07-28

    The basic form of luminescence dose response is investigated, with the aim of developing a single function to account for the appearance of linear, superlinear, sublinear, and supralinear behaviors and variations in saturation signal level and rate. A function is assembled based on the assumption of first order behavior in different major factors contributing to measured luminescence-dosimetric signals. Different versions of the function are developed for standardized and non-dose-normalized responses. Data generated using a two trap two recombination center model and experimental data for natural quartz are analyzed to compare results obtained using different signals, measurement protocols, pretreatment conditions, and radiation qualities. The function well describes a range of dose dependent behavior, including sublinear, superlinear, supralinear, and non-monotonic responses and relative response to α and β radiation, based on change in relative recombination and trapping probability affecting signals sourced from a single electron trap.

  14. Prediction of the mortality dose-response relationship in man

    SciTech Connect

    Morris, M.D.; Jones, T.D.

    1987-01-01

    Based upon an extensive data base including 100 separate animal studies, an estimate of the mortality dose-response relationship due to continuous photon radiation is predicted for 70 kg man. The model used in this prediction exercise includes fixed terms accounting for effects of body weight and dose rate, and random terms accounting for inter- and intra-species variation and experimental error. Point predictions and 95% prediction intervals are given for the LD/sub 05/, LD/sub 10/, LD/sub 25/, LD/sub 50/, LD/sub 75/, LD/sub 90/, and LD/sub 95/, for dose rates ranging from 1 to 50 R/min. 6 refs., 5 tabs.

  15. A broadly applicable function for describing luminescence dose response

    NASA Astrophysics Data System (ADS)

    Burbidge, C. I.

    2015-07-01

    The basic form of luminescence dose response is investigated, with the aim of developing a single function to account for the appearance of linear, superlinear, sublinear, and supralinear behaviors and variations in saturation signal level and rate. A function is assembled based on the assumption of first order behavior in different major factors contributing to measured luminescence-dosimetric signals. Different versions of the function are developed for standardized and non-dose-normalized responses. Data generated using a two trap two recombination center model and experimental data for natural quartz are analyzed to compare results obtained using different signals, measurement protocols, pretreatment conditions, and radiation qualities. The function well describes a range of dose dependent behavior, including sublinear, superlinear, supralinear, and non-monotonic responses and relative response to α and β radiation, based on change in relative recombination and trapping probability affecting signals sourced from a single electron trap.

  16. Bayesian Dose-Response Modeling in Sparse Data

    NASA Astrophysics Data System (ADS)

    Kim, Steven B.

    This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a

  17. The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.

    PubMed

    Simon, Ted W; Simons, S Stoney; Preston, R Julian; Boobis, Alan R; Cohen, Samuel M; Doerrer, Nancy G; Fenner-Crisp, Penelope A; McMullin, Tami S; McQueen, Charlene A; Rowlands, J Craig

    2014-08-01

    The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs. PMID:25070415

  18. Optimal dose-response relationships in voice therapy.

    PubMed

    Roy, Nelson

    2012-10-01

    Like other areas of speech-language pathology, the behavioural management of voice disorders lacks precision regarding optimal dose-response relationships. In voice therapy, dosing can presumably vary from no measurable effect (i.e., no observable benefit or adverse effect), to ideal dose (maximum benefit with no adverse effects), to doses that produce toxic or harmful effects on voice production. Practicing specific vocal exercises will inevitably increase vocal load. At ideal doses, these exercises may be non-toxic and beneficial, while at intermediate or high doses, the same exercises may actually be toxic or damaging to vocal fold tissues. In pharmacology, toxicity is a critical concept, yet it is rarely considered in voice therapy, with little known regarding "effective" concentrations of specific voice therapies vs "toxic" concentrations. The potential for vocal fold tissue damage related to overdosing on specific vocal exercises has been under-studied. In this commentary, the issue of dosing will be explored within the context of voice therapy, with particular emphasis placed on possible "overdosing". PMID:22574765

  19. Characterization of a developmental toxicity dose-response model.

    PubMed Central

    Faustman, E M; Wellington, D G; Smith, W P; Kimmel, C A

    1989-01-01

    The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose. PMID:2707204

  20. Dose-response in case-control studies.

    PubMed Central

    Berry, G

    1980-01-01

    The evidence provided by a case-control study on the association between a disease and some factor is strengthened if the extent of exposure to the factor is categorised into several groups or measured on a continuous scale. Then dose-response relationships can be estimated. The methods available are illustrated by application to data on lung cancer and chrysotile asbestos exposure from Quebec in which there were three matched controls for each case. Regression-type models were fitted assuming that the relative risk of lung cancer was linearly related to an exposure measure; a covariate, smoking, was also included in the analysis. The data were first analysed ignoring the matching and secondly taking account of the matching. The methodology for the latter analysis has only recently been developed; formerly, matched studies were of necessity analysed as unmatched. Although, in this particular example, the unmatched and matched analyses gave similar results, this is not always the case and it is argued that, now that the methodology is available, matched case-control studies should be analysed taking proper account of the matching. PMID:7441145

  1. Mutans Streptococci Dose Response to Xylitol Chewing Gum

    PubMed Central

    Milgrom, P.; Ly, K.A.; Roberts, M.C.; Rothen, M.; Mueller, G.; Yamaguchi, D.K.

    2008-01-01

    Xylitol is promoted in caries-preventive strategies, yet its effective dose range is unclear. This study determined the dose-response of mutans streptococci in plaque and unstimulated saliva to xylitol gum. Participants (n = 132) were randomized: controls (G1) (sorbitol/maltitol), or combinations giving xylitol 3.44 g/day (G2), 6.88 g/day (G3), or 10.32 g/day (G4). Groups chewed 3 pellets/4 times/d. Samples were taken at baseline, 5 wks, and 6 mos, and were cultured on modified Mitis Salivarius agar for mutans streptococci and on blood agar for total culturable flora. At 5 wks, mutans streptococci levels in plaque were 10x lower than baseline in G3 and G4 (P = 0.007/0.003). There were no differences in saliva. At 6 mos, mutans streptococci in plaque for G3 and G4 remained 10x lower than baseline (P = 0.007/0.04). Saliva for G3 and G4 was lower than baseline by 8 to 9x (P = 0.011/0.038). Xylitol at 6.44 g/day and 10.32 g/day reduces mutans streptococci in plaque at 5 wks, and in plaque and unstimulated saliva at 6 mos. A plateau effect is suggested between 6.44 g and 10.32 g xylitol/day. PMID:16434738

  2. Biological bases for cancer dose-response extrapolation procedures

    SciTech Connect

    Wilson, J.D. )

    1991-01-01

    The Moolgavkar-Knudson theory of carcinogenesis of 1981 incorporates the viable portions of earlier multistage theories and provides the basis for both the linearized multistage and biologically based dose-response extrapolation methodologies. This theory begins with the premise that cancer occurs because irreversible genetic changes (mutations) are required for transformation of normal cells to cancer cells; incidence data are consistent with only two critical changes begin required, but a small contribution from three or higher mutation pathways cannot be rules out. Events or agents that increase the rate of cell division also increase the probability that one of these critical mutations will occur by reducing the time available for repair of DNA lesions before mitosis. The DNA lesions can occur from background causes or from treatment with mutagenic agents. Thus, the equations describing incidence as a function of exposure to carcinogenic agents include two separate terms, one accounting for mutagenic and one for mitogenic stimuli. At high exposures these interact, producing synergism and high incidence rates, but at low exposures they are effectively independent. The multistage models that are now used include only terms corresponding to the mutagenic stimuli and this fail to adequately describe incidence at high dose rates. Biologically based models attempt to include mitogenic effects, as well; they are usually limited by data availability.

  3. A normal tissue dose response model of dynamic repair processes

    NASA Astrophysics Data System (ADS)

    Alber, Markus; Belka, Claus

    2006-01-01

    A model is presented for serial, critical element complication mechanisms for irradiated volumes from length scales of a few millimetres up to the entire organ. The central element of the model is the description of radiation complication as the failure of a dynamic repair process. The nature of the repair process is seen as reestablishing the structural organization of the tissue, rather than mere replenishment of lost cells. The interactions between the cells, such as migration, involved in the repair process are assumed to have finite ranges, which limits the repair capacity and is the defining property of a finite-sized reconstruction unit. Since the details of the repair processes are largely unknown, the development aims to make the most general assumptions about them. The model employs analogies and methods from thermodynamics and statistical physics. An explicit analytical form of the dose response of the reconstruction unit for total, partial and inhomogeneous irradiation is derived. The use of the model is demonstrated with data from animal spinal cord experiments and clinical data about heart, lung and rectum. The three-parameter model lends a new perspective to the equivalent uniform dose formalism and the established serial and parallel complication models. Its implications for dose optimization are discussed.

  4. Shared dosimetry error in epidemiological dose-response analyses

    DOE PAGESBeta

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J.; Boice, John; Beck, Harold; Till, John; Bouville, Andre; Zeeb, Hajo

    2015-03-23

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takesmore » up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed.« less

  5. Shared dosimetry error in epidemiological dose-response analyses

    SciTech Connect

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J.; Boice, John; Beck, Harold; Till, John; Bouville, Andre; Zeeb, Hajo

    2015-03-23

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed.

  6. Shared dosimetry error in epidemiological dose-response analyses.

    PubMed

    Stram, Daniel O; Preston, Dale L; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J; Boice, John; Beck, Harold; Till, John; Bouville, Andre

    2015-01-01

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed. PMID:25799311

  7. Dose-response relationship between light exposure and cycling performance.

    PubMed

    Knaier, R; Meister, S; Aeschbacher, T; Gemperle, D; Rossmeissl, A; Cajochen, C; Schmidt-Trucksäss, A

    2016-07-01

    Light has a stimulating effect on physical performance if scheduled according to the chronotype, but dose-dependent effects on performance have not yet been examined. Three groups of healthy men (25.1 ± 3.1 years) were exposed to light for different durations in a parallel group design before a 40-min time-trial. In each group, subjects were exposed to either bright light (BL, 4420 lx) or moderate light (ML, 230 lx) in a randomized order in a crossover design. The durations of light exposure were 120 min prior to and during exercise (2HEX; n = 16), 60 min prior to and during exercise (1HEX; n = 10), or only for 60 min prior to exercise (1H; n = 15). Total work performed during the time-trial in kJ in the 2HEX group was significantly higher in the BL setting (527 kJ) than in ML (512 kJ) (P = 0.002), but not in 1HEX (BL: 485 kJ; ML: 498 kJ) or 1H (BL: 519 kJ; ML: 514 kJ) (P = 0.770; P = 0.485). There was a significant (P = 0.006) positive dose-response relationship between the duration of light exposure and the work performed over the three doses of light exposure. A long duration light exposure is an effective tool to increase total work in a medium length time-trial in subjects normalized for their individual chronotype. PMID:26271769

  8. Beetroot juice and exercise: pharmacodynamic and dose-response relationships.

    PubMed

    Wylie, Lee J; Kelly, James; Bailey, Stephen J; Blackwell, Jamie R; Skiba, Philip F; Winyard, Paul G; Jeukendrup, Asker E; Vanhatalo, Anni; Jones, Andrew M

    2013-08-01

    Dietary supplementation with beetroot juice (BR), containing approximately 5-8 mmol inorganic nitrate (NO3(-)), increases plasma nitrite concentration ([NO2(-)]), reduces blood pressure, and may positively influence the physiological responses to exercise. However, the dose-response relationship between the volume of BR ingested and the physiological effects invoked has not been investigated. In a balanced crossover design, 10 healthy men ingested 70, 140, or 280 ml concentrated BR (containing 4.2, 8.4, and 16.8 mmol NO3(-), respectively) or no supplement to establish the effects of BR on resting plasma [NO3(-)] and [NO2(-)] over 24 h. Subsequently, on six separate occasions, 10 subjects completed moderate-intensity and severe-intensity cycle exercise tests, 2.5 h postingestion of 70, 140, and 280 ml BR or NO3(-)-depleted BR as placebo (PL). Following acute BR ingestion, plasma [NO2(-)] increased in a dose-dependent manner, with the peak changes occurring at approximately 2-3 h. Compared with PL, 70 ml BR did not alter the physiological responses to exercise. However, 140 and 280 ml BR reduced the steady-state oxygen (O2) uptake during moderate-intensity exercise by 1.7% (P = 0.06) and 3.0% (P < 0.05), whereas time-to-task failure was extended by 14% and 12% (both P < 0.05), respectively, compared with PL. The results indicate that whereas plasma [NO2(-)] and the O2 cost of moderate-intensity exercise are altered dose dependently with NO3(-)-rich BR, there is no additional improvement in exercise tolerance after ingesting BR containing 16.8 compared with 8.4 mmol NO3(-). These findings have important implications for the use of BR to enhance cardiovascular health and exercise performance in young adults. PMID:23640589

  9. Shared Dosimetry Error in Epidemiological Dose-Response Analyses

    SciTech Connect

    Stram, Daniel; Preston, D. L.; Sokolnkov, Mikhail; Napier, Bruce A.; Kopecky, Kenneth; Boice, John; Beck, Harold L.; Till, John E.; Bouville, A.

    2015-03-23

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. Use of these methods for several studies, including the Mayak Worker Cohort and the U.S. Atomic Veterans Study, is discussed.

  10. Shared Dosimetry Error in Epidemiological Dose-Response Analyses

    PubMed Central

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J.; Boice, John; Beck, Harold; Till, John; Bouville, Andre

    2015-01-01

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed. PMID:25799311

  11. Dose-Response Relationship between Exercise and Respiratory Disease Mortality

    PubMed Central

    Williams, Paul T.

    2014-01-01

    Purpose To assess prospectively the dose-response relationship between respiratory disease (ICD10: J1-99), pneumonia (ICD10: J12.0-18.9), and asperation pneumonia mortality (ICD10: J69) vs. baseline walking and running energy expenditure (MET-hours/d, 1 MET = 3.5 ml O2/kg/min). Methods Cox proportional hazard analyses of 109,352 runners and 40,798 walkers adjusted for age, sex, smoking, diet, alcohol, and education. Results There were 236 deaths with respiratory disease listed as the underlying cause, and 833 deaths that were respiratory disease related (entity axis diagnosis). Included among these were 79 deaths with pneumonia listed as the underlying cause and 316 pneumonia-related deaths, and 77 deaths due to aspiration pneumonia. There was no significant difference in the effect of running compared to walking (per MET-hours/d) on mortality, thus runners and walkers were combined for analysis. Respiratory disease mortality decreased 7.9% per MET-hours/d as the underlying cause (95%CI: 1.6% to 14.0%, P=0.01) and 7.3% for all respiratory disease-related deaths (95%CI: 4.2% to 10.4%, P=10-5). Pneumonia mortality decreased 13.1% per MET-hours/d as the underlying cause (95%CI: 2.6% to 23.2%, P=0.01) and 10.5% per MET-hours/d for all pneumonia-related deaths (95%CI: 5.4% to 15.5%, P=0.0001). The risk for aspiration pneumonia mortality also did not differ between running and walking, and decreased 19.9% per MET-hours/d run or walked (95%CI: 8.9% to 30.2%, P=0.0004). These results remained significant when additionally adjusted for BMI. Conclusions Higher doses of running and walking were associated with lower risk of respiratory disease, pneumonia, and aspiration pneumonia mortality in a dose-dependent manner, and the effects of running and walking appear equivalent. These effects appear to be independent of the effects of exercise on cardiovascular disease. PMID:24002349

  12. Continuous Toxicological Dose-Response Relationships Are Pretty Homogeneous (Society for Risk Analysis Annual Meeting)

    EPA Science Inventory

    Dose-response relationships for a wide range of in vivo and in vitro continuous datasets are well-described by a four-parameter exponential or Hill model, based on a recent analysis of multiple historical dose-response datasets, mostly with more than five dose groups (Slob and Se...

  13. Shape and Steepness of Toxicological Dose-Response Relationships of Continuous Endpoints

    EPA Science Inventory

    A re-analysis of a large number of historical dose-response data for continuous endpoints indicates that an exponential or a Hill model with four parameters both adequately describe toxicological dose-responses. The four parameters relate to the background response, the potency o...

  14. ENDOCRINE ACTIVE SUBSTANCES AND DOSE-RESPONSE FOR INDIVIDUALS AND POPULATIONS

    EPA Science Inventory

    Endocrine Active Substances and Dose-Response for Individuals and Populations
    Hugh A. Barton

    Abstract for IUPAC-SCOPE article

    Dose-response characteristics for endocrine disruption have been major focuses in efforts to understand potential impacts on human and ec...

  15. The analysis of dose-response curve from bioassays with quantal response: Deterministic or statistical approaches?

    PubMed

    Mougabure-Cueto, G; Sfara, V

    2016-04-25

    Dose-response relations can be obtained from systems at any structural level of biological matter, from the molecular to the organismic level. There are two types of approaches for analyzing dose-response curves: a deterministic approach, based on the law of mass action, and a statistical approach, based on the assumed probabilities distribution of phenotypic characters. Models based on the law of mass action have been proposed to analyze dose-response relations across the entire range of biological systems. The purpose of this paper is to discuss the principles that determine the dose-response relations. Dose-response curves of simple systems are the result of chemical interactions between reacting molecules, and therefore are supported by the law of mass action. In consequence, the shape of these curves is perfectly sustained by physicochemical features. However, dose-response curves of bioassays with quantal response are not explained by the simple collision of molecules but by phenotypic variations among individuals and can be interpreted as individual tolerances. The expression of tolerance is the result of many genetic and environmental factors and thus can be considered a random variable. In consequence, the shape of its associated dose-response curve has no physicochemical bearings; instead, they are originated from random biological variations. Due to the randomness of tolerance there is no reason to use deterministic equations for its analysis; on the contrary, statistical models are the appropriate tools for analyzing these dose-response relations. PMID:26952004

  16. Estimation of dose-response models for discrete and continuous data in weed science

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dose-response analysis is widely used in biological sciences and has application to a variety of risk assessment, bioassay, and calibration problems. In weed science, dose-response methodologies have typically relied on least squares estimation under an assumption of normality. Advances in computati...

  17. NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

    EPA Science Inventory

    Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
    S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

    Dose-response estimation is a critical feature of risk assessment. It can be...

  18. BY HOW MUCH DO SHAPES OF TOXICOLOGICAL DOSE-RESPONSE RELATIONSHIPS VARY? (SOT)

    EPA Science Inventory

    A re-analysis of a large number of historical dose-response data for continuous endpoints showed that the shapes of the dose-response relationships were surprisingly homogenous. The datasets were selected on the sole criterion that they were expected to provide relatively good in...

  19. Nonmonotonic Dose-Response Curves and Endocrine-Disrupting Chemicals: Fact or Falderal?**

    EPA Science Inventory

    Nonmonotonic Dose-Response Curves and Endocrine-Disrupting Chemicals: Fact or Falderal? The shape of the dose response curve in the low dose region has been debated since the 1940s, originally focusing on linear no threshold (LNT) versus threshold responses for cancer and noncanc...

  20. An automated fitting procedure and software for dose-response curves with multiphasic features

    PubMed Central

    Veroli, Giovanni Y. Di; Fornari, Chiara; Goldlust, Ian; Mills, Graham; Koh, Siang Boon; Bramhall, Jo L; Richards, Frances M.; Jodrell, Duncan I.

    2015-01-01

    In cancer pharmacology (and many other areas), most dose-response curves are satisfactorily described by a classical Hill equation (i.e. 4 parameters logistical). Nevertheless, there are instances where the marked presence of more than one point of inflection, or the presence of combined agonist and antagonist effects, prevents straight-forward modelling of the data via a standard Hill equation. Here we propose a modified model and automated fitting procedure to describe dose-response curves with multiphasic features. The resulting general model enables interpreting each phase of the dose-response as an independent dose-dependent process. We developed an algorithm which automatically generates and ranks dose-response models with varying degrees of multiphasic features. The algorithm was implemented in new freely available Dr Fit software (sourceforge.net/projects/drfit/). We show how our approach is successful in describing dose-response curves with multiphasic features. Additionally, we analysed a large cancer cell viability screen involving 11650 dose-response curves. Based on our algorithm, we found that 28% of cases were better described by a multiphasic model than by the Hill model. We thus provide a robust approach to fit dose-response curves with various degrees of complexity, which, together with the provided software implementation, should enable a wide audience to easily process their own data. PMID:26424192

  1. The Maturing of Hormesis as a Credible Dose-Response Model

    PubMed Central

    Calabrese, Edward J.

    2003-01-01

    Hormesis is a dose-response phenomenon that has received little recognition, credibility and acceptance as evidenced by its absence from major toxicological/risk assessment texts, governmental regulatory dose-response modeling for risk assessment, and non-visibility in major professional toxicological society national meetings. This paper traces the historical evolution of the hormetic dose-response hypothesis, why this model is not only credible but also more common than the widely accepted threshold model in direct comparative evaluation, and how the toxicological community made a critical error in rejecting hormesis, a rejection sustained over 70 years. PMID:19330138

  2. Reproducibilty test of ferrous xylenol orange gel dose response with optical cone beam CT scanning

    NASA Astrophysics Data System (ADS)

    Jordan, K.; Battista, J.

    2004-01-01

    Our previous studies of ferrous xylenol orange gelatin gel have revealed a spatial dependence to the dose response of samples contained in 10 cm diameter cylinders. Dose response is defined as change in optical attenuation coefficient divided by the dose (units cm-1 Gy-1). This set of experiments was conducted to determine the reproducibility of our preparation, irradiation and full 3D optical cone beam CT scanning. The data provided an internal check of a larger storage time-dose response dependence study.

  3. The Use of Mode of Action Information in Risk Assessment: Quantitative Key Events/Dose-Response Framework for Modeling the Dose-Response for Key Events

    EPA Science Inventory

    The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Act...

  4. RASS SOT Webinar - Nonmonotonic Dose Response Curves (NMDRCs) Common after Estrogen or Androgen Signaling Pathway Disruption

    EPA Science Inventory

    The presentation provides the listening and viewing audience with Dr Gray's scientific information on the relevance of nonmonotonic dose response curves to the risk assessment of estrogenic and androgenic chemicals

  5. PCBS: CANCER DOSE-RESPONSE ASSESSMENT AND APPLICATION TO ENVIRONMENTAL MIXTURES (1996)

    EPA Science Inventory

    This report updates the cancer dose-response assessment for polychlorinated biphenyls (PCBs) and shows how information on toxicity, disposition, and environmental processes can be considered together to evaluate health risks from PCB mixtures in the environment. Processes that ch...

  6. Development of a Biologically Based Dose Response (BBDR) Model for Arsenic Induced Cancer (S)

    EPA Science Inventory

    Discuss the development of a biologically based dose response (BBDR) model for arsenic carcinogenicity in order to reduce uncertainty in estimates of low dose risk by maximizing the use of relevant data on the mode of action.

  7. Dose-response relationships and extrapolation in toxicology - Mechanistic and statistical considerations

    EPA Science Inventory

    Controversy on toxicological dose-response relationships and low-dose extrapolation of respective risks is often the consequence of misleading data presentation, lack of differentiation between types of response variables, and diverging mechanistic interpretation. In this chapter...

  8. The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview

    SciTech Connect

    Calabrese, Edward J. . E-mail: edwardc@schoolph.umass.edu; Blain, Robyn

    2005-02-01

    A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.

  9. The Key Events Dose-Response Framework: A Cross-Disciplinary Mode-of-Action Based Approach to Examining Dose-Response and Thresholds

    PubMed Central

    JULIEN, ELIZABETH; BOOBIS, ALAN R.; OLIN, STEPHEN S.

    2009-01-01

    The ILSI Research Foundation convened a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categories of bioactive agents—food allergens, nutrients, pathogenic microorganisms, and environmental chemicals. This effort generated a common analytical framework—the Key Events Dose-Response Framework (KEDRF)—for systematically examining key events that occur between the initial dose of a bioactive agent and the effect of concern. Individual key events are considered with regard to factors that influence the dose-response relationship and factors that underlie variability in that relationship. This approach illuminates the connection between the processes occurring at the level of fundamental biology and the outcomes observed at the individual and population levels. Thus, it promotes an evidence-based approach for using mechanistic data to reduce reliance on default assumptions, to quantify variability, and to better characterize biological thresholds. This paper provides an overview of the KEDRF and introduces a series of four companion papers that illustrate initial application of the approach to a range of bioactive agents. PMID:19690994

  10. A resource conservative procedure for comparison of dose-response relationships

    USGS Publications Warehouse

    Link, W.A.; Hill, E.F.; Hines, J.E.; Henry, P.F.P.

    1996-01-01

    The evaluation of effects of toxicants on a wildlife community can be complicated by varying responses among the community's constituent populations. Even within populations, considerable variability in dose-response relations may result from different avenues of exposure to the toxicant. Full scale investigations of the dose-response relations among a variety of species and avenues of exposure can therefore be prohibitively expensive, whether this expense is measured by the number of experimental animals needed, by the human resources committed to the study, or by laboratory expenses. We propose an abbreviated protocol for investigations of multiple dose-response relations that is designed to limit these expenses. The protocol begins with the judicious choice of a baseline dose-response relation to be estimated by a full scale study involving a minimum of 5 doses levels, with 10 subjects per dose level. This relation is then used as the basis for rapid screening of subsequent dose-response relations, which are compared to the baseline relation by testing for differences in the median effective dosages. These secondary studies can consist of as few as 14 animals exposed to the estimated LC50 from the baseline study. We describe MS-DOS compatible software available from the authors which can be used to analyze these data.

  11. Cellular Mechanism of the Nonmonotonic Dose Response of Bisphenol A in Rat Cardiac Myocytes

    PubMed Central

    Liang, Qian; Gao, Xiaoqian; Chen, Yamei; Hong, Kui

    2014-01-01

    Background: The need for mechanistic understanding of nonmonotonic dose responses has been identified as one of the major data gaps in the study of bisphenol A (BPA). Previously we reported that acute exposure to BPA promotes arrhythmogenesis in female hearts through alteration of myocyte Ca2+ handling, and that the dose response of BPA was inverted U-shaped. Objective: We sought to define the cellular mechanism underlying the nonmonotonic dose response of BPA in the heart. Methods: We examined rapid effects of BPA in female rat ventricular myocytes using video-edge detection, confocal and conventional fluorescence imaging, and patch clamp. Results: The rapid effects of BPA in cardiac myocytes, as measured by multiple end points, including development of arrhythmic activities, myocyte mechanics, and Ca2+ transient, were characterized by nonmonotonic dose responses. Interestingly, the effects of BPA on individual processes of myocyte Ca2+ handling were monotonic. Over the concentration range of 10–12 to 10–6 M, BPA progressively increased sarcoplasmic reticulum (SR) Ca2+ release and Ca2+ reuptake and inhibited the L-type Ca2+ current (ICaL). These effects on myocyte Ca2+ handling were mediated by estrogen receptor (ER) β signaling. The nonmonotonic dose responses of BPA can be accounted for by the combined effects of progressively increased SR Ca2+ reuptake/release and decreased Ca2+ influx through ICaL. Conclusion: The rapid effects of BPA on female rat cardiac myocytes are characterized by nonmonotonic dose responses as measured by multiple end points. The nonmonotonic dose response was produced by ERβ-mediated monotonic effects on multiple cellular Ca2+ handling processes. This represents a distinct mechanism underlying the nonmonotonicity of BPA’s actions. Citation: Liang Q, Gao X, Chen Y, Hong K, Wang HS. 2014. Cellular mechanism of the nonmonotonic dose response of bisphenol A in rat cardiac myocytes. Environ Health Perspect 122:601–608;

  12. BUMP: a FORTRAN program for identifying dose-response curves subject to downturns.

    PubMed

    Simpson, D G; Dallal, G E

    1989-02-01

    BUMP is a FORTRAN implementation of a modified Jonckheere-Terpstra test, proposed by Simpson and Margolin, to test nonparametrically for a dose-response curve when a downturn is possible at high doses. The Jonckheere-Terpstra statistic is commonly used to test for increasing or decreasing trends in dose-response relationships. In many experimental settings, however, a test agent has more than one effect, and a "bump"-shaped dose-response can occur. For instance, increasing the concentration of a certain nutrient on a petri dish may increase the growth rate at low doses yet decrease the growth rate at high doses because of toxicity. The modified test allows one to assess the significance of the initial increase in the dose-response curve and yet to minimize the effect on the conclusions of any downturn at higher doses. A complete system which operates directly on SYSTAT/MYSTAT files is available for the IBM-PC and compatibles; it includes a utility which converts ASCII data files to the SYSTAT/MYSTAT format. The FORTRAN 77 source code is available for those who would like to run BUMP on other machines. PMID:2914424

  13. PCBS: CANCER DOSE-RESPONSE ASSESSMENT AND APPLICATION TO ENVIRONMENTAL MIXTURES (EXTERNAL REVIEW DRAFT)

    EPA Science Inventory

    A cancer dose-response assessment is developed for PCBS, considering toxicity, disposition, and environmental processes to evaluate human cancer risk. ow-dose linear models are applied to animal cancer studies of commercial mixtures to develop a range of potency estimates, then i...

  14. Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dose-response curves with semiochemicals are reported in many articles in insect chemical ecology regarding neurophysiology and behavioral bioassays. Most such curves are shown in figures where the x-axis has order of magnitude increases in dosages versus responses on the y-axis represented by point...

  15. Toxicokinetics to identify nonlinearities in dose-response and implications for risk assessment

    EPA Science Inventory

    For presentation at the 45th Annual Symposium of the Society of Toxicology of Canada. The meeting will be held on 4-5 December 2013 at the Ottawa Convention Centre. Toxicokinetics to identify nonlinearities in dose-response and implications for risk assessment. Rory Conolly, Offi...

  16. Peer Review for EPA’s Biologically Based Dose-Response (BBDR) Model for Perchlorate

    EPA Science Inventory

    EPA is developing a regulation for perchlorate in drinking water. As part the regulatory process EPA must develop a Maximum Contaminant Level Goal (MCLG). FDA and EPA scientists developed a biologically based dose-response (BBDR) model to assist in deriving the MCLG. This mode...

  17. Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors

    EPA Science Inventory

    Dose response and time-course (DRTC) are, along with exposure, the major determinants of health risk. Adaptive changes within exposed organisms in response to environmental stress are common, and alter DRTC behaviors to minimize the effects caused by stressors. In this project, ...

  18. QUANTITATION OF MOLECULAR ENDPOINTS FOR THE DOSE-RESPONSE COMPONENT OF CANCER RISK ASSESSMENT

    EPA Science Inventory

    Cancer risk assessment involves the steps of hazard identification, dose-response assessment, exposure assessment and risk characterization. The rapid advances in the use of molecular biology approaches has had an impact on all four components, but the greatest overall current...

  19. Mode of Action (MOA) and Dose-Response Approaches for Nuclear Receptors

    EPA Science Inventory

    Abstract: The presence of sub-threshold doses for non-cancer and (in appropriate cases) cancer has been the dominant paradigm for the practice of risk assessment, but the application of dose-response modeling approaches that include a threshold have been questioned in a 2009 NRC ...

  20. Development of a biologically based dose response (BBDR) model for arsenic induced cancer

    EPA Science Inventory

    We are developing a biologically based dose response (BBDR) model for arsenic carcinogenicity in order to reduce uncertainty in estimates of low dose risk by maximizing the use of relevant data on the mode of action. Expert consultation and literature review are being conducted t...

  1. A Meta-Analysis To Determine the Dose Response for Strength Development.

    ERIC Educational Resources Information Center

    Rhea, Matthew R.; Alvar, Brent A.; Burkett, Lee N.; Ball, Stephen D.

    2003-01-01

    Examined the quantitative dose-response relationship for strength development by calculating the magnitude of gains elicited by various levels of training intensity, frequency, and volume; thus clarifying the effort to benefit ratio. A meta-analysis of 140 studies with 1,433 effect sizes (ES) was conducted. ES demonstrated different responses…

  2. Empirical evaluation of meta-analytic approaches for nutrient and health outcome dose-response data

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study is to empirically compare alternative meta-analytic methods for combining dose-response data from epidemiological studies. We identified meta-analyses of epidemiological studies that analyzed the association between a single nutrient and a dichotomous outcome. For each to...

  3. THYROID INSUFFICIENCY AND GENE EXPRESSION IN DEVELOPING RAT BRAIN: A DOSE RESPONSE STUDY.

    EPA Science Inventory

    Thyroid Insufficiency and Gene Expression in Developing Rat Brain: A Dose Response Study. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption is an area of major concern in environmental neurotoxicity. Deficits in thyroid hormone (TH) levels h...

  4. The Dose-Response Relationship of Adolescent Religious Activity and Substance Use: Variation across Demographic Groups

    ERIC Educational Resources Information Center

    Steinman, Kenneth J.; Ferketich, Amy K.; Sahr, Timothy

    2008-01-01

    This article addresses two inconsistent findings in the literature on adolescent religious activity (RA) and substance use: whether a dose-response relationship characterizes the association of these variables, and whether the association varies by grade, gender, ethnicity, family structure, school type, and type of substance. Multinomial logistic…

  5. Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults with ADHD: An Exploratory Study

    ERIC Educational Resources Information Center

    Faraone, Stephen V.; Spencer, Thomas J.; Kollins, Scott H.; Glatt, Stephen J.; Goodman, David

    2012-01-01

    Objective: To explore dose-response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD. Method: This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting "Diagnostic and Statistical Manual of Mental Disorders" (4th ed., text rev.)…

  6. Development of the dose-response relationship for human toxoplasma gondii infection associated with meat consumption

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States.A substantial portion of human T. gondii infections may be acquired through the consumption of meats. The dose-response relationship for human exposure...

  7. Dose-response measurement in gel dosimeter using various imaging modalities

    NASA Astrophysics Data System (ADS)

    Fujibuchi, T.; Kawamura, H.; Yamanashi, K.; Hiroki, A.; Yamashita, S.; Taguchi, M.; Sato, Y.; Mimura, K.; Ushiba, H.; Okihara, T.

    2013-06-01

    Measurement methods that accurately measure radiation dose distribution in a three dimensional manner in order to allow comparisons of treatment plans are needed for quality assurance. One such measurement method involves the use of a polymer gel dosimeter to measure the dose distribution in three dimensions. During irradiation, a polymerization reaction makes new chemical bonds and induces changes of the chemical structure of the gel of the gel dosimeter. In the present study, dose-response measurement of an environment-friendly material used in the gel dosimeter was performed by imaging with computed tomography (CT) and R1, R2, and fluid-attenuated inversion-recovery (FLAIR) magnetic resonance imaging (MRI) under various imaging conditions. Dose-response characteristics in the gel dosimeter used in the experiment were observed at doses of 5-20 Gy administered by X-ray CT and MRI. Although the FLAIR signal was a relative value, the dose-response values with FLAIR were excellent compared to those with R1, R2, and CT. Determination of more appropriate imaging conditions could help expand the dose-response parameters of each measurement method.

  8. Non-Targeted Effects and the Dose Response for Heavy Ion Tumorigenesis

    NASA Technical Reports Server (NTRS)

    Chappell, Lori J.; Cucinotta, Francis A.

    2010-01-01

    There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies.

  9. DEVELOPMENT AND EVALUATION OF NOVEL DOSE-RESPONSE MODELS FOR USE IN MICROBIAL RISK ASSESSMENT

    EPA Science Inventory

    This document contains a description of dose-response modeling methods designed to provide a robust approach under uncertainty for predicting human population risk from exposure to pathogens in drinking water.

    The purpose of this document is to describe a body of literatu...

  10. Concord grape juice polyphenols and cardiovascular risk factors: dose-response relationships

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship ...

  11. Dose-Response Issues Concerning the Relations between Regular Physical Activity and Health.

    ERIC Educational Resources Information Center

    Rankinen, Tuomo; Bouchard, Claude

    2002-01-01

    This paper categorizes the many benefits of physical activity, offering information concerning the type of dose necessary to get that benefit. In 2000, Health Canada and the United States Centers for Disease Control and Prevention, along with other agencies, sponsored a symposium to determine whether there was a dose-response relationship between…

  12. EXPERIMENTAL DESIGN STRATEGY FOR THE WEIBULL DOSE RESPONSE MODEL (JOURNAL VERSION)

    EPA Science Inventory

    The objective of the research was to determine optimum design point allocation for estimation of relative yield losses from ozone pollution when the true and fitted yield-ozone dose response relationship follows the Weibull. The optimum design is dependent on the values of the We...

  13. EVALUATION OF BIOLOGICALLY BASED DOSE-RESPONSE MODELING FOR DEVELOPMENTAL TOXICITY: A WORKSHOP REPORT

    EPA Science Inventory

    Evaluation of biologically based dose-response modeling for developmental toxicity: a workshop report.

    Lau C, Andersen ME, Crawford-Brown DJ, Kavlock RJ, Kimmel CA, Knudsen TB, Muneoka K, Rogers JM, Setzer RW, Smith G, Tyl R.

    Reproductive Toxicology Division, NHEERL...

  14. IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?

    EPA Science Inventory

    IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?
    Preston, RJ. Environmental Carcinogenesis Division, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

    For considerations of cancer risk assessment from exposure to environmenta...

  15. Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

    2011-01-01

    Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

  16. LARGE SCALE CARCINOGEN DOSE RESPONSE STUDIES WITH JAPANESE MEDAKA (ORYZIAS LATIPES)

    EPA Science Inventory

    To investigate the responses to low carcinogen doses in animal models, large sample sizes are needed and it is an advantage if the model has a low spontaneous tumor rate. Three large scale dose response studies were conducted using Japanese medaka and the carcinogen diethylnitros...

  17. Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

    SciTech Connect

    Appelt, Ane L.; Ploen, John; Vogelius, Ivan R.; Bentzen, Soren M.; Jakobsen, Anders

    2013-01-01

    Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D{sub 50,i}, and the normalized dose-response gradient, {gamma}{sub 50,i}. Results: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D{sub 50,TRG1} = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), {gamma}{sub 50,TRG1} = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D{sub 50,TRG1} and {sub 2} = 72.1 Gy (CI 65.3-94.0 Gy), {gamma}{sub 50,TRG1} and {sub 2} = 0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. Conclusions: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.

  18. Comparison of the modified relative dose response (MRDR) and the relative dose response (RDR) in the assessment of vitamin A status in malnourished children.

    PubMed

    Wahed, M A; Alvarez, J O; Khaled, M A; Mahalanabis, D; Rahman, M M; Habte, D

    1995-06-01

    The modified-relative-dose-response (MRDR) test and the relative-dose-response (RDR) test were compared in 49 mildly to moderately malnourished Bangladeshi children. The MRDR test had a significantly lower sensitivity, detecting only 71% of children with very low serum retinol (< or = 0.35 mumol/L) and 33% of children with low serum retinol (0.355-0.70 mumol/L) compared with 100% and 80% for the RDR test, respectively. The MRDR test showed a very strong dependency on retinol-binding protein (RBP) saturation (ie, percent saturation of RBP with retinol) compared with the RDR test. Only 3 (23%) of 13 children with RBP saturation > or = 55% but low vitamin A stores were diagnosed as abnormal by the MRDR test. This suggests that when apo-RBP concentration is limiting, as it is in malnourished children, didehydroretinol, the analog used in the MRDR test cannot effectively compete with retinol for binding to apo-RBP. Under these circumstances, the MRDR test is rendered ineffective. The possibility of increasing the sensitivity of the test by using a high dose of didehydroretinol needs to be investigated. PMID:7762526

  19. DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY

    EPA Science Inventory

    DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY. LE Gray Jr, C Wolf, J Furr, M Price, C Lambright, VS Wilson and J Ostby. USEPA, ORD, NHEERL, EB, RTD, RTP, NC, USA.
    Dose-response behavior of a...

  20. Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal?##

    EPA Science Inventory

    Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? Leon Earl Gray Jr, USEPA, ORD, NHEERL, TAD, RTB. RTP, NC, USA The shape of the dose response curve in the low dose region has been debated since th...

  1. Duration of exposure and the dose-response model of PTSD.

    PubMed

    Kaysen, Debra; Rosen, Gerald; Bowman, Marilyn; Resick, Patricia A

    2010-01-01

    A dose-response model underlies posttraumatic stress disorder (PTSD) and posits a relationship between event magnitude and clinical outcome. The present study examines whether one index of event magnitude--duration of exposure--contributes to risk of PTSD among female victims of sexual assault. Findings support a small but significant contribution of event duration to clinical status in the immediate aftermath of trauma but not at 3-month follow-up. The opposite pattern is obtained for subjective appraisals of threat. These findings add to a growing literature that suggests that a simple application of the dose-response model to objective event characteristics may be insufficient to explain the risk of PTSD. PMID:19252066

  2. Cancer risk assessment: Optimizing human health through linear dose-response models.

    PubMed

    Calabrese, Edward J; Shamoun, Dima Yazji; Hanekamp, Jaap C

    2015-07-01

    This paper proposes that generic cancer risk assessments be based on the integration of the Linear Non-Threshold (LNT) and hormetic dose-responses since optimal hormetic beneficial responses are estimated to occur at the dose associated with a 10(-4) risk level based on the use of a LNT model as applied to animal cancer studies. The adoption of the 10(-4) risk estimate provides a theoretical and practical integration of two competing risk assessment models whose predictions cannot be validated in human population studies or with standard chronic animal bioassay data. This model-integration reveals both substantial protection of the population from cancer effects (i.e. functional utility of the LNT model) while offering the possibility of significant reductions in cancer incidence should the hormetic dose-response model predictions be correct. The dose yielding the 10(-4) cancer risk therefore yields the optimized toxicologically based "regulatory sweet spot". PMID:25916915

  3. Dose-response analyses among atomic bomb survivors exposed to low-level radiation

    SciTech Connect

    Kato, H.; Schull, W.J.; Awa, A.; Akiyama, M.; Otake, M.

    1987-05-01

    An analysis of the dose response within the low-dose range (as here defined, doses of less than 50 cGy (50 rad) was conducted among A-bomb survivors in the ABCC-RERF cohort in an attempt to detect the phenomenon of radiation hormesis, if it is present. These studies include as endpoints cancer mortality, cancer incidence, the frequency of cells with chromosomal aberrations, the phytohemagglutinin response of peripheral lymphocytes and the frequency of mental retardation among survivors exposed in utero. In general, the dose response for these indices of radiation damage varied among comparison groups within the low-dose range, but failed to suggest the existence of radiation hormesis.

  4. Exploring the dose-response relationship between resistance exercise intensity and cognitive function.

    PubMed

    Chang, Yu-Kai; Etnier, Jennifer L

    2009-10-01

    The purpose of this study was to explore the dose-response relationship between resistance exercise intensity and cognitive performance. Sixty-eight participants were randomly assigned into control, 40%, 70%, or 100% of 10-repetition maximal resistance exercise groups. Participants were tested on Day 1 (baseline) and on Day 2 (measures were taken relative to performance of the treatment). Heart rate, ratings of perceived exertion, self-reported arousal, and affect were assessed on both days. Cognitive performance was assessed on Day 1 and before and following treatment on Day 2. Results from regression analyses indicated that there is a significant linear effect of exercise intensity on information processing speed, and a significant quadratic trend for exercise intensity on executive function. Thus, there is a dose-response relationship between the intensity of resistance exercise and cognitive performance such that high-intensity exercise benefits speed of processing, but moderate intensity exercise is most beneficial for executive function. PMID:20016113

  5. Diethylene glycol-induced toxicities show marked threshold dose response in rats

    SciTech Connect

    Landry, Greg M.; Dunning, Cody L.; Abreo, Fleurette; Latimer, Brian; Orchard, Elysse; McMartin, Kenneth E.

    2015-02-01

    Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

  6. Optimal experimental designs for dose-response studies with continuous endpoints.

    PubMed

    Holland-Letz, Tim; Kopp-Schneider, Annette

    2015-11-01

    In most areas of clinical and preclinical research, the required sample size determines the costs and effort for any project, and thus, optimizing sample size is of primary importance. An experimental design of dose-response studies is determined by the number and choice of dose levels as well as the allocation of sample size to each level. The experimental design of toxicological studies tends to be motivated by convention. Statistical optimal design theory, however, allows the setting of experimental conditions (dose levels, measurement times, etc.) in a way which minimizes the number of required measurements and subjects to obtain the desired precision of the results. While the general theory is well established, the mathematical complexity of the problem so far prevents widespread use of these techniques in practical studies. The paper explains the concepts of statistical optimal design theory with a minimum of mathematical terminology and uses these concepts to generate concrete usable D-optimal experimental designs for dose-response studies on the basis of three common dose-response functions in toxicology: log-logistic, log-normal and Weibull functions with four parameters each. The resulting designs usually require control plus only three dose levels and are quite intuitively plausible. The optimal designs are compared to traditional designs such as the typical setup of cytotoxicity studies for 96-well plates. As the optimal design depends on prior estimates of the dose-response function parameters, it is shown what loss of efficiency occurs if the parameters for design determination are misspecified, and how Bayes optimal designs can improve the situation. PMID:25155192

  7. Quantitative dose-response assessment of inhalation exposures to toxic air pollutants

    SciTech Connect

    Jarabek, A.M.; Foureman, G.L.; Gift, J.S.; Guth, D.J.

    1997-12-31

    Implementation of the 1990 Clean Air Act Amendments, including evaluation of residual risks. requires accurate human health risk estimates of both acute and chronic inhalation exposures to toxic air pollutants. The U.S. Environmental Protection Agency`s National Center for Environmental Assessment, Research Triangle Park, NC, has a research program that addresses several key issues for development of improved quantitative approaches for dose-response assessment. This paper describes three projects underway in the program. Project A describes a Bayesian approach that was developed to base dose-response estimates on combined data sets and that expresses these estimates as probability density functions. A categorical regression model has been developed that allows for the combination of all available acute data, with toxicity expressed as severity categories (e.g., mild, moderate, severe), and with both duration and concentration as governing factors. Project C encompasses two refinements to uncertainty factors (UFs) often applied to extrapolate dose-response estimates from laboratory animal data to human equivalent concentrations. Traditional UFs have been based on analyses of oral administration and may not be appropriate for extrapolation of inhalation exposures. Refinement of the UF applied to account for the use of subchronic rather than chronic data was based on an analysis of data from inhalation exposures (Project C-1). Mathematical modeling using the BMD approach was used to calculate the dose-response estimates for comparison between the subchronic and chronic data so that the estimates were not subject to dose-spacing or sample size variability. The second UF that was refined for extrapolation of inhalation data was the adjustment for the use of a LOAEL rather than a NOAEL (Project C-2).

  8. Analysis of Dose Response for Circulatory Disease After Radiotherapy for Benign Disease

    SciTech Connect

    Little, Mark P.; Kleinerman, Ruth A.; Stovall, Marilyn; Smith, Susan A.; Mabuchi, Kiyohiko

    2012-12-01

    Purpose: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. Methods and Materials: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). Results: There were significant excess risks for all circulatory disease, with an excess relative risk Gy{sup -1} of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy{sup -1} of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. There were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. Conclusions: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

  9. Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

    PubMed Central

    Blumberg, Jeffrey B.; Vita, Joseph A.; Chen, C. -Y. Oliver

    2015-01-01

    Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD), blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL) to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages. PMID:26633488

  10. Dopamine Transporter Genotype and Stimulant Dose-Response in Youth with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Waldman, Irwin; Newcorn, Jeffrey; Bishop, Jeffrey; Kittles, Rick; Cook, Edwin H.

    2014-01-01

    Abstract Objectives: This study seeks to determine if variation in the dopamine transporter gene (SLC6A3/DAT1) moderates the dose-response effects of long-acting dexmethylphenidate (D-MPH) and mixed amphetamine salts (MAS) in children with attention-deficit/hyperactivity disorder (ADHD). Methods: Fifty-six children and adolescents (mean age=11.7±2.2) participated in a double-blind, two period crossover, dose-response study with a randomized placebo week in each 4 week drug period. Each period consisted of sequential week-long exposures to three dose levels (10, 20, 25–30 mg, depending upon weight) of D-MPH or MAS. Results: Doses of 10–20 mg of either D-MPH or MAS had little to no effect on hyperactivity-impulsivity and total ADHD symptom scores in subjects with the 9/9 genotype; this was in contrast to the dose-response curves of subjects with either the 10/10 or 10/9 genotype. Conclusions: ADHD youth with the 9/9 genotype may require higher stimulant doses to achieve adequate symptom control. PMID:24813374

  11. Perception and annoyance due to wind turbine noise--a dose-response relationship.

    PubMed

    Pedersen, Eja; Waye, Kerstin Persson

    2004-12-01

    Installed global wind power increased by 26% during 2003, with U.S and Europe accounting for 90% of the cumulative capacity. Little is known about wind turbines' impact on people living in their vicinity. The aims of this study were to evaluate the prevalence of annoyance due to wind turbine noise and to study dose-response relationships. Interrelationships between noise annoyance and sound characteristics, as well as the influence of subjective variables such as attitude and noise sensitivity, were also assessed. A cross-sectional study was performed in Sweden in 2000. Responses were obtained through questionnaires (n = 351; response rate 68.4%), and doses were calculated as A-weighted sound pressure levels for each respondent. A statistically significant dose-response relationship was found, showing higher proportion of people reporting perception and annoyance than expected from the present dose-response relationships for transportation noise. The unexpected high proportion of annoyance could be due to visual interference, influencing noise annoyance, as well as the presence of intrusive sound characteristics. The respondents' attitude to the visual impact of wind turbines on the landscape scenery was found to influence noise annoyance. PMID:15658697

  12. The Key Events Dose-Response Framework: Its Potential for Application to Foodborne Pathogenic Microorganisms

    PubMed Central

    BUCHANAN, ROBERT L.; HAVELAAR, ARIE H.; SMITH, MARY ALICE; WHITING, RICHARD C.; JULIEN, ELIZABETH

    2009-01-01

    The Key Events Dose-Response Framework (KEDRF) is an analytical approach that facilitates the use of currently available data to gain insight regarding dose-response relationships. The use of the KEDRF also helps identify critical knowledge gaps that once filled, will reduce reliance on assumptions. The present study considers how the KEDRF might be applied to pathogenic microorganisms, using fetal listeriosis resulting from maternal ingestion of food contaminated with L. monocytogenes as an initial example. Major biological events along the pathway between food ingestion and the endpoint of concern are systematically considered with regard to dose (i.e., number of organisms), pathogen factors (e.g., virulence), and protective host mechanisms (e.g., immune response or other homeostatic mechanisms). It is concluded that the KEDRF provides a useful structure for systematically evaluating the complex array of host and pathogen factors that influence the dose-response relationship. In particular, the KEDRF supports efforts to specify and quantify the sources of variability, a prerequisite to strengthening the scientific basis for food safety decision making. PMID:19690997

  13. Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness

    NASA Technical Reports Server (NTRS)

    Cajochen, C.; Zeitzer, J. M.; Czeisler, C. A.; Dijk, D. J.

    2000-01-01

    Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to <3 lux for several hours. Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

  14. Dose response of selected solid state detectors in applied homogeneous transverse and longitudinal magnetic fields

    SciTech Connect

    Reynolds, M.; Fallone, B. G.; Rathee, S.

    2014-09-15

    Purpose: MR-Linac devices under development worldwide will require standard calibration, commissioning, and quality assurance. Solid state radiation detectors are often used for dose profiles and percent depth dose measurements. The dose response of selected solid state detectors is therefore evaluated in varying transverse and longitudinal magnetic fields for this purpose. Methods: The Monte Carlo code PENELOPE was used to model irradiation of a PTW 60003 diamond detector and IBA PFD diode detector in the presence of a magnetic field. The field itself was varied in strength, and oriented both transversely and longitudinally with respect to the incident photon beam. The long axis of the detectors was oriented either parallel or perpendicular to the photon beam. The dose to the active volume of each detector in air was scored, and its ratio to dose with zero magnetic field strength was determined as the “dose response” in magnetic field. Measurements at low fields for both detectors in transverse magnetic fields were taken to evaluate the accuracy of the simulations. Additional simulations were performed in a water phantom to obtain few representative points for beam profile and percent depth dose measurements. Results: Simulations show significant dose response as a function of magnetic field in transverse field geometries. This response can be near 20% at 1.5 T, and it is highly dependent on the detectors’ relative orientation to the magnetic field, the energy of the photon beam, and detector composition. Measurements at low transverse magnetic fields verify the simulations for both detectors in their relative orientations to radiation beam. Longitudinal magnetic fields, in contrast, show little dose response, rising slowly with magnetic field, and reaching 0.5%–1% at 1.5 T regardless of detector orientation. Water tank and in air simulation results were the same within simulation uncertainty where lateral electronic equilibrium is present and expectedly

  15. Dose response of ferrous-xylenol orange gels: the effects of gel substrate, gelation time and dose fractionation

    NASA Astrophysics Data System (ADS)

    Jordan, K.; Battista, J.

    2004-01-01

    Investigations of the dose dependent change in optical transmission, dose response, for radiochromic ferrous-xylenol orange-gelatin gels (FXG) 3D optical CT scanning has revealed that gelation time, temperature, and dose fractionation affect the dose response (Δμ/Δdose). Correction for these factors is important for developing a reproducible dosimeter that can be reliably calibrated and used clinically. The purpose of this report is to examine trends in dose response changes for the following parameters: gelation time-temperature, concentrations of ferrous ion and xylenol orange (XO), dose range and dose fractionation.

  16. Dose-response curve of a microfluidic magnetic bead-based surface coverage sandwich assay.

    PubMed

    Cornaglia, Matteo; Trouillon, Raphaël; Tekin, H Cumhur; Lehnert, Thomas; Gijs, Martin A M

    2015-09-25

    Magnetic micro- and nanoparticles ('magnetic beads') have been used to advantage in many microfluidic devices for sensitive antigen (Ag) detection. Today, assays that use as read-out of the signal the number count of immobilized beads on a surface for quantification of a sample's analyte concentration have been among the most sensitive and have allowed protein detection lower than the fgmL(-1) concentration range. Recently, we have proposed in this category a magnetic bead surface coverage assay (Tekin et al., 2013 [1]), in which 'large' (2.8μm) antibody (Ab)-functionalized magnetic beads captured their Ag from a serum and these Ag-carrying beads were subsequently exposed to a surface pattern of fixed 'small' (1.0μm) Ab-coated magnetic beads. When the system was exposed to a magnetic induction field, the magnet dipole attractive interactions between the two bead types were used as a handle to approach both bead surfaces and assist with Ag-Ab immunocomplex formation, while unspecific binding (in absence of an Ag) of a large bead was reduced by exploiting viscous drag flow. The dose-response curve of this type of assay had two remarkable features: (i) its ability to detect an output signal (i.e. bead number count) for very low Ag concentrations, and (ii) an output signal of the assay that was non-linear with respect to Ag concentration. We explain here the observed dose-response curves and show that the type of interactions and the concept of our assay are in favour of detecting the lowest analyte concentrations (where typically either zero or one Ag is carried per large bead), while higher concentrations are less efficiently detected. We propose a random walk process for the Ag-carrying bead over the magnetic landscape of small beads and this model description explains the enhanced overall capture probability of this assay and its particular non-linear dose response curves. PMID:25817550

  17. The OECD program to validate the rat uterotrophic bioassay. Phase 2: dose-response studies.

    PubMed Central

    Kanno, Jun; Onyon, Lesley; Peddada, Shyamal; Ashby, John; Jacob, Elard; Owens, William

    2003-01-01

    The Organisation for Economic Co-operation and Development has completed phase 2 of an international validation program for the rodent uterotrophic bioassay. The purpose of the validation program was to demonstrate the performance of two versions of the uterotrophic bioassay, the immature female rat and the adult ovariectomized rat, in four standardized protocols. This article reports the dose-response studies of the validation program; the coded single-dose studies are reported in an accompanying paper. The dose-response study design used five selected weak estrogen agonists, bisphenol A, genistein, methoxychlor, nonylphenol, and o,p -DDT. These weak agonists were administered in a prescribed series of doses to measure the performance and reproducibility of the protocols among the participating laboratories. All protocols successfully detected increases in uterine weights when the weak agonists were administered. Within each protocol, there was good agreement and reproducibility of the dose response among laboratories with each substance. Substance-specific variations were observed in the influence of the route of administration on the uterine response, the potency as related to the dose producing the first statistically significant increase in uterine weights, and the maximum increase in uterine weight. Substantive performance differences were not observed between the uterotrophic bioassay versions or among the standardized protocols, and these were judged to be qualitatively equivalent. It is noteworthy that these results were reproducible under a variety of different experimental conditions (e.g., animal strain, diet, housing, bedding, vehicle, animal age), indicating that the bioassay's performance as a screen is robust. In conclusion, both the intact, immature, and adult OVX versions, and all protocols appear to be reproducible and transferable across laboratories and are able to detect weak estrogen agonists. PMID:12948896

  18. Dose-Response of Aerobic Exercise on Cognition: A Community-Based, Pilot Randomized Controlled Trial

    PubMed Central

    Morris, Jill K.; Van Sciver, Angela; Greer, Colby S.; Billinger, Sandra A.; Donnelly, Joseph E.; Burns, Jeffrey M.

    2015-01-01

    Epidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition. Underactive or sedentary participants without cognitive impairment were randomized to one of four groups: no-change control, 75, 150, and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting. Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests: Verbal Memory, Visuospatial Processing, Simple Attention, Set Maintenance and Shifting, and Reasoning. Other outcome measures were cardiorespiratory fitness (peak oxygen consumption) and measures of function functional health. In intent-to-treat (ITT) analyses (n = 101), cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups. No other exercise-related effects were observed in ITT analyses. Analyses restricted to individuals who exercised per-protocol (n = 77) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing. A clear dose-response relationship exists between exercise and cardiorespiratory fitness. Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol. An individual’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose (i.e., duration) and thus maximizing an individual’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits. Trial Registration ClinicalTrials.gov NCT01129115 PMID:26158265

  19. Education and Risk of Dementia: Dose-Response Meta-Analysis of Prospective Cohort Studies.

    PubMed

    Xu, Wei; Tan, Lan; Wang, Hui-Fu; Tan, Meng-Shan; Tan, Lin; Li, Jie-Qiong; Zhao, Qing-Fei; Yu, Jin-Tai

    2016-07-01

    Educational level has been regarded as one of the most widely accepted risk factors in the epidemiological studies for dementia, despite with discordant qualitative results. However, the dose-response relation between education and incident dementia was still unknown. To quantitatively evaluate the association between exposure level to high and low education and risk of dementia, we searched PubMed, EMBASE, and the Cochrane Library up to November 2014 and references of retrieved literatures. Specific prospective cohort studies, in which educational attainment was categorized into at least three levels, were included. Newcastle-Ottawa scale was used to assess the quality of included studies. Fifteen prospective cohort studies with 55655 for low education and eight prospective cohort studies with 20172 for high education were included. In the qualitative analysis, both low and high education showed a dose-response trend with risk of dementia and Alzheimer's disease (AD). In the quantitative analysis, the dementia risk was reduced by 7 % for per year increase in education (RR, 0.93; 95 % CI, 0.92-0.94; p for overall trend = 0.000; p for nonlinearity = 0.0643). Nonetheless, we did not find statistically significant association between per year decrease in education and dementia (RR, 1.03; 95 % CI, 0.96-1.10; p for overall trend = 0.283; p for nonlinearity = 0.0041) or AD (RR, 1.03; 95 % CI, 0.97-1.10; p for overall trend = 0.357; p for nonlinearity = 0.0022). Both low and high education showed a trend of dose-response relation with risk of dementia and AD. The dementia risk was reduced by 7 % for per year increase in education. PMID:25983035

  20. A Randomized, Open-Label, Dose-Response Study of Losartan in Hypertensive Children

    PubMed Central

    Wells, Thomas G.; Shahinfar, Shahnaz; Massaad, Rachid; Dankner, Wayne M.; Lam, Chun; Santoro, Emanuela Palumbo; McCrary Sisk, Christine; Blaustein, Robert O.

    2014-01-01

    Background and objectives Once-daily losartan reduces BP in a dose-dependent manner and is well tolerated in hypertensive children aged 6–16 years. This study assessed the dose-response relationship, safety, and tolerability of losartan in hypertensive children aged 6 months to 6 years. Design, setting, participants, & measurements This was a 12-week, randomized, open-label, dose-ranging study, with a 2-year extension. Patients were randomized to losartan at the following dosages: 0.1 mg/kg per day (low), 0.3 mg/kg per day (medium), or 0.7 mg/kg per day (high). Losartan was titrated to the next dose level (to a 1.4 mg/kg per day maximum dosage, not exceeding 100 mg/d, which was not one of the three original doses offered at randomization) at weeks 3, 6, and 9 for patients who did not attain their goal BP and were not taking the highest dose. Dose response was evaluated by analyzing the slope of change in sitting systolic BP (SBP; primary end point) and diastolic BP (DBP; secondary end point) after 3 weeks compared with baseline. Adverse events (AEs) were recorded throughout. Results Of the 101 patients randomized, 99 were included in the analysis (low dose, n=32; medium dose, n=34; and high dose, n=33). Mean sitting BP decreased from baseline in the low-, medium-, and high-dose groups by 7.3, 7.6, and 6.7 mmHg, respectively, for SBP and 8.2, 5.1, and 6.7 mmHg, respectively, for DBP after 3 weeks. No dose-response relationship was established by the slope analysis on SBP (P=0.75) or DBP (P=0.64). The BP-lowering effect was observed throughout the 2-year extension. The incidence of AEs was low and comparable between groups. Conclusions Hypertensive children aged 6 months to 6 years treated with losartan 0.1–0.7 mg/kg per day had clinically significant decreases from baseline in SBP and DBP, yet no dose-response relationship was evident. Losartan, at a dosage up to 1.4 mg/kg per day, was well tolerated. PMID:24875194

  1. Dose-response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: Results of a workshop

    EPA Science Inventory

    A public workshop, organized by a Steering Committee of scientists from government, industry, universities, and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose-response implicat...

  2. Single-Grain Optical Dating Properties of JSC Mars-1: Preliminary Measurements of Radiation Dose Response and Sensitivity Change

    NASA Astrophysics Data System (ADS)

    Lepper, K.

    2003-03-01

    A preliminary evaluation of radiation dose response and measurement induced sensitivity change, two fundamental optical dating properties, of single sand-sized grains extracted from the JSC Mars-1 simulant.

  3. Dose-response relationships between mouse allergen exposure and asthma morbidity among urban children and adolescents.

    PubMed

    Torjusen, E N; Diette, G B; Breysse, P N; Curtin-Brosnan, J; Aloe, C; Matsui, E C

    2013-08-01

    Home mouse allergen exposure is associated with asthma morbidity, but little is known about the shape of the dose-response relationship or the relevance of location of exposure within the home. Asthma outcome and allergen exposure data were collected every 3 months for 1 year in 150 urban children with asthma. Participants were stratified by mouse sensitization, and relationships between continuous measures of mouse allergen exposure and outcomes of interest were analyzed. Every tenfold increase in the bed mouse allergen level was associated with an 87% increase in the odds of any asthma-related health care use among mouse-sensitized [Odds Ratio (95% CI): 1.87 (1.21-2.88)], but not non-mouse-sensitized participants. Similar relationships were observed for emergency department visit and unscheduled doctor visit among mouse-sensitized participants. Kitchen floor and bedroom air mouse allergen concentrations were also associated with greater odds of asthma-related healthcare utilization; however, the magnitude of the association was less than that observed for bed mouse allergen concentrations. In this population of urban children with asthma, there is a linear dose-response relationship between mouse allergen concentrations and asthma morbidity among mouse-sensitized asthmatics. Bed and bedroom air mouse allergen exposure compartments may have a greater impact on asthma morbidity than other compartments. PMID:23067271

  4. Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

    NASA Astrophysics Data System (ADS)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2004-01-01

    Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity.

  5. Analysis and comparison of sigmoidal curves: application to dose-response data.

    PubMed

    Meddings, J B; Scott, R B; Fick, G H

    1989-12-01

    A number of physiological or pharmacological studies generate sigmoidal dose-response curves. Ideally, data analysis should provide numerical solutions for curve parameters. In addition, for curves obtained under different experimental conditions, testing for significant differences should be easily performed. We have reviewed the literature over the past 3 years in six journals publishing papers in the field of gastrointestinal physiology and established the curve analysis technique used in each. Using simulated experimental data of known error structure, we have compared these techniques with nonlinear regression analysis. In terms of their ability to provide accurate estimates of ED50 and maximal response, none approached the accuracy and precision of nonlinear regression. This technique is as easily performed as the classic methods and additionally provides an opportunity for rigorous statistical analysis of data. We present a method of determining the significance of differences found in the ED50 and maximal response under different experimental conditions. The method is versatile and applicable to a variety of different physiological and pharmacological dose-response curves. PMID:2610264

  6. Hierarchical dose-response modeling for high-throughput toxicity screening of environmental chemicals.

    PubMed

    Wilson, Ander; Reif, David M; Reich, Brian J

    2014-03-01

    High-throughput screening (HTS) of environmental chemicals is used to identify chemicals with high potential for adverse human health and environmental effects from among the thousands of untested chemicals. Predicting physiologically relevant activity with HTS data requires estimating the response of a large number of chemicals across a battery of screening assays based on sparse dose-response data for each chemical-assay combination. Many standard dose-response methods are inadequate because they treat each curve separately and under-perform when there are as few as 6-10 observations per curve. We propose a semiparametric Bayesian model that borrows strength across chemicals and assays. Our method directly parametrizes the efficacy and potency of the chemicals as well as the probability of response. We use the ToxCast data from the U.S. Environmental Protection Agency (EPA) as motivation. We demonstrate that our hierarchical method provides more accurate estimates of the probability of response, efficacy, and potency than separate curve estimation in a simulation study. We use our semiparametric method to compare the efficacy of chemicals in the ToxCast data to well-characterized reference chemicals on estrogen receptor α (ERα) and peroxisome proliferator-activated receptor γ (PPARγ) assays, then estimate the probability that other chemicals are active at lower concentrations than the reference chemicals. PMID:24397816

  7. Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

    NASA Technical Reports Server (NTRS)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2004-01-01

    Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.

  8. Application of the International Life Sciences Institute Key Events Dose-Response Framework to food contaminants.

    PubMed

    Fenner-Crisp, Penelope A

    2012-12-01

    Contaminants are undesirable constituents in food. They may be formed during production of a processed food, present as a component in a source material, deliberately added to substitute for the proper substance, or the consequence of poor food-handling practices. Contaminants may be chemicals or pathogens. Chemicals generally degrade over time and become of less concern as a health threat. Pathogens have the ability to multiply, potentially resulting in an increased threat level. Formal structures have been lacking for systematically generating and evaluating hazard and exposure data for bioactive agents when problem situations arise. We need to know what the potential risk may be to determine whether intervention to reduce or eliminate contact with the contaminant is warranted. We need tools to aid us in assembling and assessing all available relevant information in an expeditious and scientifically sound manner. One such tool is the International Life Sciences Institute (ILSI) Key Events Dose-Response Framework (KEDRF). Developed as an extension of the WHO's International Program on Chemical Safety/ILSI mode of action/human relevance framework, it allows risk assessors to understand not only how a contaminant exerts its toxicity but also the dose response(s) for each key event and the ultimate outcome, including whether a threshold exists. This presentation will illustrate use of the KEDRF with case studies included in its development (chloroform and Listeriaonocytogenes) after its publication in the peer-reviewed scientific literature (chromium VI) and in a work in progress (3-monochloro-1, 2-propanediol). PMID:23077190

  9. Airway responsiveness to hypertonic saline: dose-response slope or PD15?

    PubMed

    de Meer, G; Marks, G B; de Jongste, J C; Brunekreef, B

    2005-01-01

    The result of airway challenge test with hypertonic saline (HS) is expressed as the dose causing a 15% fall in forced expiratory volume in one second (FEV1; PD15). A noncensored measure, such as the dose-response slope (DRS), allows the evaluation of the risk of asthma for subjects with a fall in FEV1 <15%. The aim of this study was to assess the relationship between airway responsiveness to HS by PD15 or DRS, asthma symptoms and markers of eosinophilic inflammation. Data on current wheeze and airway responsiveness were obtained for 1,107 children (aged 8-13 yrs). Blood eosinophils and serum eosinophil cationic protein (ECP) were assessed in subsets (n = 683 and 485). PD15 was assessed if FEV1 fell > or =15%, and the DRS was calculated for all tests. Graphs were constructed to visualise relationships with current wheeze, blood eosinophils and serum ECP. Odds ratios and Spearman's correlation coefficients were calculated to quantify these relationships. Children with features of asthma had lower PD15 and higher DRS, and separation was most pronounced for DRS. Prevalence of current wheeze increased continuously over the entire range of DRS values. Blood eosinophils were significantly higher only for the highest values of DRS. In conclusion, the continuous relationship between airway responsiveness and asthma symptoms is in favour of a noncensored measure of airway responsiveness, such as the dose-response slope. PMID:15640337

  10. Nut intake and stroke risk: A dose-response meta-analysis of prospective cohort studies

    PubMed Central

    Shao, Chuan; Tang, Hui; Zhao, Wei; He, Jianquan

    2016-01-01

    We aim to quantify the effects of nut intake on risk of stroke by a dose-response meta-analysis with a random-effects model. Two databases (PubMed and Emabse) were searched for prospective cohort studies regarding nut intake and stroke risk. Studies were included if they fulfilled the predefined criteria. Eleven articles encompassing fourteen cohort studies were included in final analysis. The pooled relative risk (RR) of stroke for the highest versus (vs.) lowest category of nut intake was 0.88 (95% confidence interval [CI] 0.80-0.97). The power to detect a RR of 0.88 for the highest versus vs. lowest category of nut intake was 86.2%. In multiple subset analyses by gender, location, and stroke subtype, the inverse association was only found in women (RR = 0.84, 95% CI 0.73–0.96) and Asia (RR = 0.79, 95% CI 0.67–0.93). In the dose-response meta-analysis, evidence for a nonlinear association between nut intake and stroke risk was observed and a RR of 0.86 was conferred for 12 g/day. Based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, the quality of evidence was moderate. In conclusions, finding from current meta-analysis of fourteen cohort studies indicates that nut intake may be related to decreased risk of stroke. PMID:27469072

  11. Application of the Key Events Dose-response Framework to Folate Metabolism.

    PubMed

    Hu, Jing; Wang, Bing; Sahyoun, Nadine R

    2016-06-10

    Folate is a vitamin that plays a role as a cofactor and coenzyme in many essential reactions. These reactions are interrelated and any change in folate homeostasis could affect other reactions. With food fortified with folic acid, and use of multivitamin, unmetabolized folic acid (UMFA) has been detected in blood circulation, particularly among older adults. This has raised concern about the potential harmful effect of high folic acid intake and UMFA on health conditions such as cognitive dysfunction and cancer. To examine what is known about folate metabolism and the release of circulating UMFA, the Key Events Dose-Response Framework (KEDRF) was used to review each of the major key events, dose-response characteristics and homeostatic mechanisms of folate metabolism. The intestine, liver and kidneys each play essential roles in regulating body folate homeostasis. But the determining event in folate metabolism leading to the release of UMFA in circulation appears to be the saturation of dihydrofolate reductase in the liver. However, at each of the key events in folate metabolism, limited information is available on threshold, homeostatic regulation and intracellular effects of folic acid. More studies are needed to fill in the knowledge gaps for quantitatively characterizing the dose-effect relationship especially in light of the call for extending folate fortification to other foods. PMID:25674817

  12. On use of the multistage dose-response model for assessing laboratory animal carcinogenicity

    PubMed Central

    Nitcheva, Daniella; Piegorsch, Walter W.; West, R. Webster

    2007-01-01

    We explore how well a statistical multistage model describes dose-response patterns in laboratory animal carcinogenicity experiments from a large database of quantal response data. The data are collected from the U.S. EPA’s publicly available IRIS data warehouse and examined statistically to determine how often higher-order values in the multistage predictor yield significant improvements in explanatory power over lower-order values. Our results suggest that the addition of a second-order parameter to the model only improves the fit about 20% of the time, while adding even higher-order terms apparently does not contribute to the fit at all, at least with the study designs we captured in the IRIS database. Also included is an examination of statistical tests for assessing significance of higher-order terms in a multistage dose-response model. It is noted that bootstrap testing methodology appears to offer greater stability for performing the hypothesis tests than a more-common, but possibly unstable, “Wald” test. PMID:17490794

  13. A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin

    PubMed Central

    2015-01-01

    This manuscript proposes a hypothesis to explain the U-shaped dose-response observed for angiostatin and other high-molecular-weight drugs in various anti-cancer bio-assays. The dose-response curves for angiostatin and endostatin (measured as suppression of tumor growth) go through an optimum (i.e., minimum tumor growth) and then becomes less effective at higher doses. The literature suggests that at lower doses the primary action of these high-molecular-weight drugs is to counteract the angiogenic effects of vascular endothelial growth factor (VEGF). To do this, the drugs must pass out of the blood vessel and enter the extra-cellular matrix (ECM) where VEGF induces the growth and fusion of tip cells. Ironically, VEGF actually facilitates access of the drugs to the ECM by making the vascular endothelium leaky. At higher doses, the high-molecular-weight drugs seem to reverse VEGF-induced permeability of the endothelium. Thus, at high dose rates, it is hypothesized that the drugs are not able to enter the ECM and block the angiogenic effects of VEGF there. As a result, high doses of the drugs do not suppress vascularization of the tumor or tumor growth. Moreover, if the permeability of the vessels is suppressed, the VEGF released by the stroma is concentrated in the ECM where it amplifies the angiogenic activity around the tumor. PMID:26675544

  14. Dose-Response Model for Chest Wall Tolerance of Stereotactic Body Radiation Therapy.

    PubMed

    Kimsey, Frank; McKay, Jesse; Gefter, Jeffrey; Milano, Michael T; Moiseenko, Vitali; Grimm, Jimm; Berg, Ronald

    2016-04-01

    Many recent studies have described rib fractures and chest wall pain following stereotactic body radiation therapy (SBRT). Although these toxicities generally are not life-threatening, the chest wall and ribs are considered dose-limiting tissues because of the potential effect on patients׳ quality of life. Few studies have reported dose-response models that can provide quantitative estimates of risk as a function of dose and volume. Notably, Memorial Sloan Kettering Cancer Center (Mutter et al(8)) analyzed grade 2 or higher chest wall toxicity in a cohort of 126 patients treated with linear accelerator-based SBRT; the authors provided detailed dose-volume histogram (DVH) data to allow for pooled analyses. We pooled these 126 patients with an additional 44 patients treated with CyberKnife at the Erlanger Medical Center to create an updated dose-response model for chest wall tolerance. In the aggregate analysis, the 10% risk level for grade 2 or higher complications for D70cc was 16.2Gy in 4 fractions, and the 50% risk level was D70cc = 65.1Gy in 4 fractions. For D2cc, the 10% and 50% risk levels in 4 fractions were 43.0Gy and 87.9Gy, respectively. These dose-tolerance limits may help quantify chest wall toxicity risks. Further research continues to determine more accurate estimates of grade 3 risk levels. PMID:27000509

  15. A dose-response analysis of skin cancer from inorganic arsenic in drinking water

    SciTech Connect

    Brown, K.G.; Boyle, K.E.; Chen, C.W.; Gibb, H.J. )

    1989-12-01

    A study of the prevalence of skin cancer among 40,421 persons consuming arsenic-contaminated drinking water in Taiwan was used for a cancer dose-response assessment of ingested arsenic. The numbers of persons at risk over three dose intervals and four exposure durations were estimated from the data in order to apply the method of maximum likelihood to a multistage-Weibull time/dose-response model. A constant exposure level since birth for each of the exposure categories was assumed. It was found that the cumulative hazard increases as a power of three in age, and is linear or quadratic (with a linear coefficient) in dose. Observations from a smaller epidemiologic survey in Mexico were similar to what would be predicted from the model of the Taiwan data. Assuming that the skin cancer risk from ingested arsenic in the American population would also be similar to the Taiwan population, an American male would have a lifetime risk of developing skin cancer of 1.3 x 10(-3) (3.0 x 10(-3)) if exposed to 1 microgram/kg/day for a 76-year lifespan (median lifespan in the U.S.).

  16. Dose-response involvement of constitutive androstane receptor in mouse liver hypertrophy induced by triazole fungicides.

    PubMed

    Tamura, Kei; Inoue, Kaoru; Takahashi, Miwa; Matsuo, Saori; Irie, Kaoru; Kodama, Yukio; Ozawa, Shogo; Nishikawa, Akiyoshi; Yoshida, Midori

    2013-07-31

    To clarify the dose-response relationship between constitutive androstane receptor (CAR) activity and induction of cytochrome P450 2B (CYP2B) expression and hypertrophy by triazole fungicides in mouse liver, three dose levels of cyproconazole (Cypro), tebuconazole (Teb), fluconazole (Flu), and phenobarbital (PB), a typical CYP2B inducer, were administrated in diet to male wild-type (WT) and CAR-knockout (CARKO) mice for one week. In WT mice, all compounds dose-dependently induced liver weight increases and hepatocellular hypertrophy accompanied by CYP2B expression. In CARKO mice, these effects were not induced by PB, while Cypro or Flu induced these effects only at the highest dose. Dose-dependent liver hypertrophy was detected in CARKO mice treated with Teb, but at the lowest dose the intensity was weakened compared to WT mice. The present results indicate that Cypro and Flu mainly induced CAR-mediated liver hypertrophy, while Teb slightly involved CAR. The involvement of CAR in triazole-induced liver hypertrophy was dose-responsive. In addition, all three triazoles have non-CAR-mediated liver hypertrophy pathways, indicating that the hypertrophy induced by these triazoles differs from that of PB. PMID:23721867

  17. Symptom overreporting obscures the dose-response relationship between trauma severity and symptoms.

    PubMed

    Merckelbach, Harald; Langeland, Willie; de Vries, Gerard; Draijer, Nel

    2014-07-30

    We investigated whether symptom overreporting affects the dose-response relationship between self-reported abuse severity and psychiatric symptoms in two samples. The first sample (N=599) consisted of adults who had previously reported to a public commission that they had been witnesses to or victims of childhood sexual abuse by Roman Catholic Church representatives. The second sample (N=1756) consisted of general population respondents who indicated that they had been victims of non-familial childhood sexual abuse. Using a web-based data collection procedure, both samples completed the Brief Symptom Inventory (BSI-18), items addressing abuse severity, and items flagging symptom overreporting. Adjusting for overreporting reduced the proportion of participants with clinically raised BSI-18 scores from 60% to 47% in sample 1 and from 26% to 22% in sample 2. Also, in both samples, normal range reporting participants exhibited the typical dose-response relationship between trauma severity and BSI-18 scores, whereas this pattern was largely non-significant in overreporting participants. Our findings show that symptom overreporting has a psychometric impact that may obscure relationships between clinically relevant variables and should therefore preferably be monitored in surveys. PMID:24704260

  18. A dose-responsive model of smoke inhalation injury. Severity-related alteration in cardiopulmonary function.

    PubMed Central

    Shimazu, T; Yukioka, T; Hubbard, G B; Langlinais, P C; Mason, A D; Pruitt, B A

    1987-01-01

    The dose responsiveness of selected physiologic indices was studied in a sheep model of smoke inhalation injury. In this model, graded severity of injury was achieved by changing the contact time with smoke (defined by "unit"), whereas other variables were kept constant. Blood gas and cardiopulmonary indices were measured in 70 sheep, including 12 controls, either 24 or 72 hours after exposure to 3, 6, 9, 12, 15, or 18 units of smoke. A 12-unit dose of smoke was fatal within 72 hours and an 18-unit dose was fatal within 24 hours. The best correlation between smoke dose and response was observed in arterial oxygen tension 24 hours after exposure. At 24 hours, most of the cardiopulmonary indices showed significant change only after a 12-unit exposure. Although the exact shape of the dose-response curve could not be defined, sigmoid or curved linear shape was suggested, reflecting the progressive deterioration. Images Fig. 3. Fig. 4A. Fig. 4B. PMID:3606236

  19. DOSE-RESPONSE RELATIONSHIP BETWEEN NOREPINEPHRINE AND ERYTHROPOIESIS: EVIDENCE FOR A CRITICAL THRESHOLD

    PubMed Central

    Penn, Angela; Mohr, Alicia M.; Shah, Salil G.; Sifri, Ziad C.; Kaiser, Vicki L.; Rameshwar, Pranela; Livingston, David H.

    2010-01-01

    Background Severe traumatic injury elicits a neuroendocrine response that activates the sympathetic nervous system. Our previous work suggests that norepinephrine (NE) influences the bone marrow (BM) erythropoietic response. However, the dose-response relationship between NE and erythropoiesis remains unclear. Materials and Methods Two days following chemical sympathectomy with 6-hydroxydopamine (6-OHDA) or injection with saline vehicle (SHAM), male Sprague-Dawley rats were infused continuously with either saline (NS) or increasing doses of NE for 5 days via osmotic pumps. Erythropoiesis was assessed by growth of erythroid progenitor colonies (BFU-E and CFU-E for early and late progenitors, respectively). Results Following chemical sympathectomy with 6-OHDA, both BFU-E and CFU-E growth is inhibited (42%* and 43%* vs. 100% SHAM, *P < 0.05). SHAM rats with continuous infusion of exogenous NE show a clear dose-response inhibition of both BFU-E and CFU-E colony growth. In the 6-OHDA rats, continuous infusion of NE restored BFU-E and CFU-E growth at 10−8g/hr and 10−9g/hr, respectively. Conclusions Erythroid precursor colony growth is inhibited in sympathectomized rats. In addition, supraphysiologic doses of exogenous NE inhibit normal erythropoiesis in a dose-dependent fashion. Following chemical sympathectomy with 6-OHDA, exogenous NE restores erythropoiesis in a narrow window. Therefore, NE has a complex interaction within the BM and the elevation of NE following traumatic injury impacts BM erythropoietic function. PMID:20605580

  20. Dose-Response Relationship Between Cigarette Smoking and Risk of Ischemic Stroke in Young Women

    PubMed Central

    Bhat, Viveca M.; Cole, John W.; Sorkin, John D.; Wozniak, Marcella A.; Malarcher, Ann M.; Giles, Wayne H.; Stern, Barney J.; Kittner, Steven J.

    2013-01-01

    Background and Purpose Although cigarette smoking is known to be a risk factor for ischemic stroke, there are few data on the dose-response relationship between smoking and stroke risk in a young ethnically diverse population. Methods We used data from the Stroke Prevention in Young Women Study, a population-based case-control study of risk factors for ischemic stroke in women aged 15 to 49 years to examine the relationship between cigarette smoking and ischemic stroke. Historical data, including smoking history, was obtained through standardized interviews. Odds ratios (OR) were estimated using logistic regression. Cases (n=466) were women with stroke in the greater Baltimore-Washington area, and controls (n=604) were women free of a stroke history identified by random digit dialing. Results After multivariable adjustment, the OR comparing current smokers to never smokers was 2.6 (P<0.0001); no difference in stroke risk was observed between former smokers and never smokers. Adjusted OR increased with increasing number of cigarettes smoked per day (OR=2.2 for 1 to 10 cigs/d; 2.5 for 11 to 20 cigs/d; 4.3 for 21 to 39 cigs/d; 9.1 for 40 or more cigs/d). Conclusion These results suggest a strong dose-response relationship between cigarette smoking and ischemic stroke risk in young women and reinforce the need for aggressive smoking cessation efforts in young adults. PMID:18703815

  1. Nut intake and stroke risk: A dose-response meta-analysis of prospective cohort studies.

    PubMed

    Shao, Chuan; Tang, Hui; Zhao, Wei; He, Jianquan

    2016-01-01

    We aim to quantify the effects of nut intake on risk of stroke by a dose-response meta-analysis with a random-effects model. Two databases (PubMed and Emabse) were searched for prospective cohort studies regarding nut intake and stroke risk. Studies were included if they fulfilled the predefined criteria. Eleven articles encompassing fourteen cohort studies were included in final analysis. The pooled relative risk (RR) of stroke for the highest versus (vs.) lowest category of nut intake was 0.88 (95% confidence interval [CI] 0.80-0.97). The power to detect a RR of 0.88 for the highest versus vs. lowest category of nut intake was 86.2%. In multiple subset analyses by gender, location, and stroke subtype, the inverse association was only found in women (RR = 0.84, 95% CI 0.73-0.96) and Asia (RR = 0.79, 95% CI 0.67-0.93). In the dose-response meta-analysis, evidence for a nonlinear association between nut intake and stroke risk was observed and a RR of 0.86 was conferred for 12 g/day. Based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, the quality of evidence was moderate. In conclusions, finding from current meta-analysis of fourteen cohort studies indicates that nut intake may be related to decreased risk of stroke. PMID:27469072

  2. Probabilistic dose-response modeling: case study using dichloromethane PBPK model results.

    PubMed

    Marino, Dale J; Starr, Thomas B

    2007-12-01

    A revised assessment of dichloromethane (DCM) has recently been reported that examines the influence of human genetic polymorphisms on cancer risks using deterministic PBPK and dose-response modeling in the mouse combined with probabilistic PBPK modeling in humans. This assessment utilized Bayesian techniques to optimize kinetic variables in mice and humans with mean values from posterior distributions used in the deterministic modeling in the mouse. To supplement this research, a case study was undertaken to examine the potential impact of probabilistic rather than deterministic PBPK and dose-response modeling in mice on subsequent unit risk factor (URF) determinations. Four separate PBPK cases were examined based on the exposure regimen of the NTP DCM bioassay. These were (a) Same Mouse (single draw of all PBPK inputs for both treatment groups); (b) Correlated BW-Same Inputs (single draw of all PBPK inputs for both treatment groups except for bodyweights (BWs), which were entered as correlated variables); (c) Correlated BW-Different Inputs (separate draws of all PBPK inputs for both treatment groups except that BWs were entered as correlated variables); and (d) Different Mouse (separate draws of all PBPK inputs for both treatment groups). Monte Carlo PBPK inputs reflect posterior distributions from Bayesian calibration in the mouse that had been previously reported. A minimum of 12,500 PBPK iterations were undertaken, in which dose metrics, i.e., mg DCM metabolized by the GST pathway/L tissue/day for lung and liver were determined. For dose-response modeling, these metrics were combined with NTP tumor incidence data that were randomly selected from binomial distributions. Resultant potency factors (0.1/ED(10)) were coupled with probabilistic PBPK modeling in humans that incorporated genetic polymorphisms to derive URFs. Results show that there was relatively little difference, i.e., <10% in central tendency and upper percentile URFs, regardless of the case

  3. No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

    SciTech Connect

    Sheehan, Daniel M. . E-mail: dansheeh@swbell.net

    2006-01-15

    We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.

  4. Dose-response fallacy in human reproductive studies of toxic exposures

    SciTech Connect

    Selevan, S.G.; Lemasters, G.K.

    1987-01-01

    The manner in which exposure is defined can affect the findings of reproductive studies of toxic exposures. The individual end points potentially examined, such as fetal loss, subfertility, and congenital malformations observed at birth, are on a continuum by severity of effect: the most extreme effects of the three being infertility because no pregnancy is possible, and the least extreme, congenital malformations recognized at birth. End points observed at birth are survivors of a long and complex process. The process yielding one of these adverse end points may result from a number of factors, including level of exposure could result in early fetal loss, whereas a lower one might result in a congenital malformation observed at birth. If the probability of a less-severe end point falls due to increasing probability of more-severe end points with increasing exposure, then a nontraditional dose-response relationship may be observed in the study of one type of outcome.

  5. Dose-response fallacy in human reproductive studies of toxic exposures

    SciTech Connect

    Selevan, S.G.; Lemasters, G.K.

    1987-05-01

    The manner in which exposure is defined can affect the findings of reproductive studies of toxic exposures. The individual end points potentially examined, such as fetal loss, subfertility, and congenital malformations observed at birth, are on a continuum by severity of effect: The most extreme effect of the three being infertility because no pregnancy is possible, and the least extreme, congenital malformations recognized at birth. End points observed at birth are survivors of a long and complex process. The process yielding one of these adverse end points may result from a number of factors, including level of exposure. For example, a very high exposure could result in early fetal loss, whereas a lower one might result in a congenital malformation observed at birth. If the probability of a less severe end point falls due to increasing probability of more severe end points with increasing exposure, then a nontraditional dose-response relationship may be observed in the study of one type of outcome.

  6. Dose response of surfactants to attenuate gas embolism related platelet aggregation

    NASA Astrophysics Data System (ADS)

    Eckmann, David M.; Eckmann, Yonaton Y.; Tomczyk, Nancy

    2014-03-01

    Intravascular gas embolism promotes blood clot formation, cellular activation, and adhesion events, particularly with platelets. Populating the interface with surfactants is a chemical-based intervention to reduce injury from gas embolism. We studied platelet activation and platelet aggregation, prominent adverse responses to blood contact with bubbles. We examined dose-response relationships for two chemically distinct surfactants to attenuate the rise in platelet function stimulated by exposure to microbubbles. Significant reduction in platelet aggregation and platelet activation occurred with increasing concentration of the surfactants, indicating presence of a saturable system. A population balance model for platelet aggregation in the presence of embolism bubbles and surfactants was developed. Monte Carlo simulations for platelet aggregation were performed. Results agree qualitatively with experimental findings. Surfactant dose-dependent reductions in platelet activation and aggregation indicate inhibition of the gas/liquid interface's ability to stimulate cellular activation mechanically.

  7. Quantitative aspects of informed consent: considering the dose response curve when estimating quantity of information.

    PubMed

    Lynöe, N; Hoeyer, K

    2005-12-01

    Information is usually supposed to be a prerequisite for people making decisions on whether or not to participate in a clinical trial. Previously conducted studies and research ethics scandals indicate that participants have sometimes lacked important pieces of information. Over the past few decades the quantity of information believed to be adequate has increased significantly, and in some instances a new maxim seems to be in place: the more information, the better the ethics in terms of respecting a participant's autonomy. The authors hypothesise that the dose-response curve from pharmacology or toxicology serves as a model to illustrate that a large amount of written information does not equal optimality. Using the curve as a pedagogical analogy when teaching ethics to students in clinical sciences, and also in engaging in dialogue with research institutions, may promote reflection on how to adjust information in relation to the preferences of individual participants, thereby transgressing the maxim that more information means better ethics. PMID:16319241

  8. SO/sub 2/ dose-response sensitivity classification data for crops and natural vegetation species

    SciTech Connect

    Irving, P.M.; Ballou, S.W.

    1980-09-01

    Over the past several years studies have been made on the interaction of sulfur dioxide (SO/sub 2/) and vegetation by performing field research and by developing analytical procedures for applying field observation data to energy impact assessments. As a result of this work, numerous reports have been prepared on crop-pollutant interactions, such as dose-response data; on the applications of such data to screening approaches for identifying crops at risk; and on models that predict crop yield reductions from point source emissions of SO/sub 2/. Data that were used for these studies, such as the crop-at-risk screening procedure, are presented in this report. Maps are also presented that show the national distribution of SO/sub 2/-sensitive crops and natural vegetation.

  9. Severity of killer whale behavioral responses to ship noise: a dose-response study.

    PubMed

    Williams, Rob; Erbe, Christine; Ashe, Erin; Beerman, Amber; Smith, Jodi

    2014-02-15

    Critical habitats of at-risk populations of northeast Pacific "resident" killer whales can be heavily trafficked by large ships, with transits occurring on average once every hour in busy shipping lanes. We modeled behavioral responses of killer whales to ship transits during 35 "natural experiments" as a dose-response function of estimated received noise levels in both broadband and audiogram-weighted terms. Interpreting effects is contingent on a subjective and seemingly arbitrary decision about severity threshold indicating a response. Subtle responses were observed around broadband received levels of 130 dB re 1 μPa (rms); more severe responses are hypothesized to occur at received levels beyond 150 dB re 1 μPa, where our study lacked data. Avoidance responses are expected to carry minor energetic costs in terms of increased energy expenditure, but future research must assess the potential for reduced prey acquisition, and potential population consequences, under these noise levels. PMID:24373666

  10. Clinical application of Chamomilla recutita in phlebitis: dose response curve study.

    PubMed

    Reis, Paula Elaine Diniz Dos; Carvalho, Emilia Campos de; Bueno, Paula Carolina Pires; Bastos, Jairo Kenupp

    2011-01-01

    This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98) and 5% concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs. PMID:21412623

  11. Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure

    PubMed Central

    Johnston, Sara C.; Lin, Kenny L.; Twenhafel, Nancy A.; Raymond, Jo Lynne W.; Shamblin, Joshua D.; Wollen, Suzanne E.; Wlazlowski, Carly B.; Wilkinson, Eric R.; Botto, Miriam A.; Goff, Arthur J.

    2015-01-01

    Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies. PMID:26413900

  12. The Dose Response Relationship between In Ear Occupational Noise Exposure and Hearing Loss

    PubMed Central

    Rabinowitz, Peter M.; Galusha, Deron; Dixon-Ernst, Christine; Clougherty, Jane E.; Neitzel, Richard L.

    2014-01-01

    Objectives Current understanding of the dose-response relationship between occupational noise and hearing loss is based on cross-sectional studies prior to the widespread use hearing protection and with limited data regarding noise exposures below 85dBA. We report on the hearing loss experience of a unique cohort of industrial workers with daily monitoring of noise inside of hearing protection devices. Methods At an industrial facility, workers exhibiting accelerated hearing loss were enrolled in a mandatory program to monitor daily noise exposures inside of hearing protection. We compared these noise measurements (as time-weighted LAVG) to interval rates of high frequency hearing loss over a six year period using a mixed effects model, adjusting for potential confounders. Results Workers’ high frequency hearing levels at study inception averaged more than 40 dB hearing threshold level (HTL). Most noise exposures were less than 85dBA (mean LAVG 76 dBA, interquartile range 74 to 80 dBA). We found no statistical relationship between LAvg and high frequency hearing loss (p = 0.53). Using a metric for monthly maximum noise exposure did not improve model fit. Conclusion At-ear noise exposures below 85dBA did not show an association with risk of high frequency hearing loss among workers with substantial past noise exposure and hearing loss at baseline. Therefore, effective noise control to below 85dBA may lead to significant reduction in occupational hearing loss risk in such individuals. Further research is needed on the dose response relationship of noise and hearing loss in individuals with normal hearing and little prior noise exposure. PMID:23825197

  13. An Experimental Toxoplasma gondii Dose Response Challenge Model to Study Therapeutic or Vaccine Efficacy in Cats

    PubMed Central

    Cornelissen, Jan B. W. J.; van der Giessen, Joke W. B.; Takumi, Katsuhisa; Teunis, Peter F. M.; Wisselink, Henk J.

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10), and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application. PMID:25184619

  14. Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study.

    PubMed

    Wali, Bushra; Ishrat, Tauheed; Won, Soonmi; Stein, Donald G; Sayeed, Iqbal

    2014-02-01

    Currently, the only approved treatment for ischaemic stroke is tissue plasminogen activator, a clot-buster. This treatment can have dangerous consequences if not given within the first 4 h after stroke. Our group and others have shown progesterone to be beneficial in preclinical studies of stroke, but a progesterone dose-response and time-window study is lacking. We tested male Sprague-Dawley rats (12 months old) with permanent middle cerebral artery occlusion or sham operations on multiple measures of sensory, motor and cognitive performance. For the dose-response study, animals received intraperitoneal injections of progesterone (8, 16 or 32 mg/kg) at 1 h post-occlusion, and subcutaneous injections at 6 h and then once every 24 h for 7 days. For the time-window study, the optimal dose of progesterone was given starting at 3, 6 or 24 h post-stroke. Behavioural recovery was evaluated at repeated intervals. Rats were killed at 22 days post-stroke and brains extracted for evaluation of infarct volume. Both 8 and 16 mg/kg doses of progesterone produced attenuation of infarct volume compared with the placebo, and improved functional outcomes up to 3 weeks after stroke on locomotor activity, grip strength, sensory neglect, gait impairment, motor coordination and spatial navigation tests. In the time-window study, the progesterone group exhibited substantial neuroprotection as late as 6 h after stroke onset. Compared with placebo, progesterone showed a significant reduction in infarct size with 3- and 6-h delays. Moderate doses (8 and 16 mg/kg) of progesterone reduced infarct size and improved functional deficits in our clinically relevant model of stroke. The 8 mg/kg dose was optimal in improving motor, sensory and memory function, and this effect was observed over a large therapeutic time window. Progesterone shows promise as a potential therapeutic agent and should be examined for safety and efficacy in a clinical trial for ischaemic stroke. PMID:24374329

  15. Application of Dempster-Shafer theory in dose response outcome analysis.

    PubMed

    Chen, Wenzhou; Cui, Yunfeng; He, Yanyan; Yu, Yan; Galvin, James; Hussaini, Yousuff M; Xiao, Ying

    2012-09-01

    The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reviews summarize the currently available three-dimensional dose/volume/outcome data from multi-institutions and numerous articles to update and refine the normal tissue dose/volume tolerance guidelines. As pointed out in the review, the data have limitations and even some inconsistency. However, with the help of new physical and statistical techniques, the information in the review could be updated so that patient care can be continually improved. The purpose of this work is to demonstrate the application of a mathematical theory, the Dempster-Shafer theory, in dose/volume/outcome data analysis. We applied this theory to the original data obtained from published clinical studies describing dose response for radiation pneumonitis. Belief and plausibility concepts were introduced for dose response evaluation. We were also able to consider the uncertainty and inconsistency of the data from these studies with Yager's combination rule, a special methodology of Dempster-Shafer theory, to fuse the data at several specific doses. The values of belief and plausibility functions were obtained at the corresponding doses. Then we applied the Lyman-Kutcher-Burman (LKB) model to fit these values and a belief-plausibility range was obtained. This range could be considered as a probability range to assist physicians and treatment planners in determining acceptable dose-volume constraints. Finally, the parameters obtained from the LKB model fitting were compared with those in Emami and Burman's papers and those from other frequentist statistics methods. We found that Emami and Burman's parameters are within the belief-plausibility range we calculated by the Dempster-Shafer theory. PMID:22892545

  16. Application of Dempster-Shafer theory in dose response outcome analysis

    NASA Astrophysics Data System (ADS)

    Chen, Wenzhou; Cui, Yunfeng; He, Yanyan; Yu, Yan; Galvin, James; Hussaini, Yousuff M.; Xiao, Ying

    2012-09-01

    The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reviews summarize the currently available three-dimensional dose/volume/outcome data from multi-institutions and numerous articles to update and refine the normal tissue dose/volume tolerance guidelines. As pointed out in the review, the data have limitations and even some inconsistency. However, with the help of new physical and statistical techniques, the information in the review could be updated so that patient care can be continually improved. The purpose of this work is to demonstrate the application of a mathematical theory, the Dempster-Shafer theory, in dose/volume/outcome data analysis. We applied this theory to the original data obtained from published clinical studies describing dose response for radiation pneumonitis. Belief and plausibility concepts were introduced for dose response evaluation. We were also able to consider the uncertainty and inconsistency of the data from these studies with Yager's combination rule, a special methodology of Dempster-Shafer theory, to fuse the data at several specific doses. The values of belief and plausibility functions were obtained at the corresponding doses. Then we applied the Lyman-Kutcher-Burman (LKB) model to fit these values and a belief-plausibility range was obtained. This range could be considered as a probability range to assist physicians and treatment planners in determining acceptable dose-volume constraints. Finally, the parameters obtained from the LKB model fitting were compared with those in Emami and Burman's papers and those from other frequentist statistics methods. We found that Emami and Burman's parameters are within the belief-plausibility range we calculated by the Dempster-Shafer theory.

  17. The Shape of the Dose-Response Relationship between Sugars and Caries in Adults.

    PubMed

    Bernabé, E; Vehkalahti, M M; Sheiham, A; Lundqvist, A; Suominen, A L

    2016-02-01

    Dental caries is considered a diet-mediated disease, as sugars are essential in the caries process. However, some gaps in knowledge about the sugars-caries relationship still need addressing. This longitudinal study aimed to explore 1) the shape of the dose-response association between sugars intake and caries in adults, 2) the relative contribution of frequency and amount of sugars intake to caries levels, and 3) whether the association between sugars intake and caries varies by exposure to fluoride toothpaste. We used data from 1,702 dentate adults who participated in at least 2 of 3 surveys in Finland (Health 2000, 2004/05 Follow-up Study of Adults' Oral Health, and Health 2011). Frequency and amount of sugars intake were measured with a validated food frequency questionnaire. The DMFT index was the repeated outcome measure. Data were analyzed with fractional polynomials and linear mixed effects models. None of the 43 fractional polynomials tested provided a better fit to the data than the simpler linear model. In a mutually adjusted linear mixed effects model, the amount of, but not the frequency of, sugars intake was significantly associated with DMFT throughout the follow-up period. Furthermore, the longitudinal association between amount of sugars intake and DMFT was weaker in adults who used fluoride toothpaste daily than in those using it less often than daily. The findings of this longitudinal study among Finnish adults suggest a linear dose-response relationship between sugars and caries, with amount of intake being more important than frequency of ingestion. Also, daily use of fluoride toothpaste reduced but did not eliminate the association between amount of sugars intake and dental caries. PMID:26553884

  18. Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception

    PubMed Central

    Oduwole, Olayiwola O.; Vydra, Natalia; Wood, Nicholas E. M.; Samanta, Luna; Owen, Laura; Keevil, Brian; Donaldson, Mandy; Naresh, Kikkeri; Huhtaniemi, Ilpo T.

    2014-01-01

    Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoospermia or severe oligozoospermia, commensurate with contraceptive efficacy. We tested here, using hypogonadal luteinizing hormone/choriongonadotropin receptor (LHCGR) knockout (LHR−/−) mice, the basic principle of the T-based male contraceptive method, that a specific T dose could maintain extragonadal androgen actions without simultaneously activating spermatogenesis. LHR−/− mice were treated with increasing T doses, and the responses of their spermatogenesis and extragonadal androgen actions (including gonadotropin suppression and sexual behavior) were assessed. Conspicuously, all dose responses to T were practically superimposable, and no dose of T could be defined that would maintain sexual function and suppress gonadotropins without simultaneously activating spermatogenesis. This finding, never addressed in clinical contraceptive trials, is not unexpected in light of the same androgen receptor mediating androgen actions in all organs. When extrapolated to humans, our findings may jeopardize the current approach to hormonal male contraception and call for more effective means of inhibiting intratesticular T production or action, to achieve consistent spermatogenic suppression.—Oduwole, O. O., Vydra, N., Wood, N. E. M., Samanta, L., Owen, L., Keevil, B., Donaldson, M., Naresh, K., Huhtaniemi, I. T. Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception. PMID:24599970

  19. Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

    PubMed Central

    Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

    2012-01-01

    For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

  20. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.

    PubMed

    Vandenberg, Laura N; Colborn, Theo; Hayes, Tyrone B; Heindel, Jerrold J; Jacobs, David R; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M; vom Saal, Frederick S; Welshons, Wade V; Zoeller, R Thomas; Myers, John Peterson

    2012-06-01

    For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of "the dose makes the poison," because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

  1. Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

    SciTech Connect

    Olson, J.J.; Friedman, R.; Orr, K.; Delaney, T.; Oldfield, E.H. )

    1990-05-01

    Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.

  2. Dose-response behavior of the bacterium Vibrio fischeri exposed to pharmaceuticals and personal care products.

    PubMed

    Ortiz de García, Sheyla; García-Encina, Pedro A; Irusta-Mata, Rubén

    2016-01-01

    The presence of pharmaceuticals and personal care products (PPCPs) in the environment has become a real and widespread concern in recent years. Therefore, the primary goal of this study was to investigate 20 common and widely used PPCPs to assess their individual and combined effect on an important species in one trophic level, i.e., bacteria. The ecotoxicological effects of PPCPs at two different concentration ranges were determined in the bacterium Vibrio fischeri using Microtox(®) and were statistically analyzed using three models in the GraphPad Prism 6 program for Windows, v.6.03. A four-parameter model best fit the majority of the compounds. The half maximal effective concentration (EC50) of each PPCP was estimated using the best-fitting model and was compared with the results from a recent study. Comparative analysis indicated that most compounds showed the same level of toxicity. Moreover, the stimulatory effects of PPCPs at environmental concentrations (low doses) were assessed. These results indicated that certain compounds have traditional inverted U- or J-shaped dose-response curves, and 55% of them presented a stimulatory effect below the zero effect-concentration point. Effective concentrations of 0 (EC0), 5 (EC5) and 50% (EC50) were calculated for each PPCP as the ecotoxicological points. All compounds that presented narcosis as a mode of toxic action at high doses also exhibited stimulation at low concentrations. The maximum stimulatory effect of a mixture was higher than the highest stimulatory effect of each individually tested compound. Moreover, when the exposure time was increased, the hormetic effect decreased. Hormesis is being increasingly included in dose-response studies because this may have a harmful, beneficial or indifferent effect in an environment. Despite the results obtained in this research, further investigations need to be conducted to elucidate the behavior of PPCPs in aquatic environments. PMID:26518677

  3. Curve fitting toxicity test data: Which comes first, the dose response or the model?

    SciTech Connect

    Gully, J.; Baird, R.; Bottomley, J.

    1995-12-31

    The probit model frequently does not fit the concentration-response curve of NPDES toxicity test data and non-parametric models must be used instead. The non-parametric models, trimmed Spearman-Karber, IC{sub p}, and linear interpolation, all require a monotonic concentration-response. Any deviation from a monotonic response is smoothed to obtain the desired concentration-response characteristics. Inaccurate point estimates may result from such procedures and can contribute to imprecision in replicate tests. The following study analyzed reference toxicant and effluent data from giant kelp (Macrocystis pyrifera), purple sea urchin (Strongylocentrotus purpuratus), red abalone (Haliotis rufescens), and fathead minnow (Pimephales promelas) bioassays using commercially available curve fitting software. The purpose was to search for alternative parametric models which would reduce the use of non-parametric models for point estimate analysis of toxicity data. Two non-linear models, power and logistic dose-response, were selected as possible alternatives to the probit model based upon their toxicological plausibility and ability to model most data sets examined. Unlike non-parametric procedures, these and all parametric models can be statistically evaluated for fit and significance. The use of the power or logistic dose response models increased the percentage of parametric model fits for each protocol and toxicant combination examined. The precision of the selected non-linear models was also compared with the EPA recommended point estimation models at several effect.levels. In general, precision of the alternative models was equal to or better than the traditional methods. Finally, use of the alternative models usually produced more plausible point estimates in data sets where the effects of smoothing and non-parametric modeling made the point estimate results suspect.

  4. Dose-Response Effects of the Text4baby Mobile Health Program: Randomized Controlled Trial

    PubMed Central

    Nielsen, Peter E; Szekely, Daniel R; Bihm, Jasmine W; Murray, Elizabeth A; Snider, Jeremy; Abroms, Lorien C

    2015-01-01

    Background Mobile health (mHealth) is growing rapidly, but more studies are needed on how to optimize programs, including optimal timing of messaging, dose of exposure, and value of interactive features. This study evaluates final outcomes of text4baby (a text message service for pregnant and postpartum women) from a randomized trial performed in a population of pregnant female soldiers and family members. Objective The study aims were to evaluate (1) treatment effects and (2) dose-response effects of text4baby on behavioral outcomes compared to control (no text4baby) condition. Methods The study was a randomized trial of text4baby at Madigan Army Medical Center. Female military health beneficiaries who met inclusion criteria were eligible for the study. Participants provided consent, completed a baseline questionnaire, and then were randomized to enroll in text4baby or not. They were followed up at 3 time points thereafter through delivery of their baby. Generalized estimating equation models were used to evaluate outcomes. We examined treatment effects and the effects of higher doses of text4baby messages on outcomes. Results We report descriptive statistics including dosage of text messages delivered. The main finding was a significant effect of high exposure to text4baby on self-reported alcohol consumption postpartum (OR 0.212, 95% CI 0.046-0.973, P=.046), as measured by the question “Since you found out about your pregnancy, have you consumed alcoholic beverages?” The text4baby participants also reported lower quantities of alcohol consumed postpartum. Conclusions Studies of text4baby have helped to build the mHealth evidence base. The effects of text4baby offer lessons for future scalable mHealth programs and suggest the need to study dose-response effects of these interventions. PMID:25630361

  5. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study.

    PubMed

    Ouwehand, Arthur C; DongLian, Cai; Weijian, Xu; Stewart, Morgan; Ni, Jiayi; Stewart, Tad; Miller, Larry E

    2014-01-16

    Probiotics are known to reduce antibiotic associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) risk in a strain-specific manner. The aim of this study was to determine the dose-response effect of a four strain probiotic combination (HOWARU(®) Restore) on the incidence of AAD and CDAD and severity of gastrointestinal symptoms in adult in-patients requiring antibiotic therapy. Patients (n=503) were randomized among three study groups: HOWARU(®) Restore probiotic 1.70×10(10) CFU (high-dose, n=168), HOWARU(®) Restore probiotic 4.17×10(9) CFU (low-dose, n=168), or placebo (n=167). Subjects were stratified by gender, age, and duration of antibiotic treatment. Study products were administered daily up to 7 days after the final antibiotic dose. The primary endpoint of the study was the incidence of AAD. Secondary endpoints included incidence of CDAD, diarrhea duration, stools per day, bloody stools, fever, abdominal cramping, and bloating. A significant dose-response effect on AAD was observed with incidences of 12.5, 19.6, and 24.6% with high-dose, low-dose, and placebo, respectively (p=0.02). CDAD was the same in both probiotic groups (1.8%) but different from the placebo group (4.8%; p=0.04). Incidences of fever, abdominal pain, and bloating were lower with increasing probiotic dose. The number of daily liquid stools and average duration of diarrhea decreased with higher probiotic dosage. The tested four strain probiotic combination appears to lower the risk of AAD, CDAD, and gastrointestinal symptoms in a dose-dependent manner in adult in-patients. PMID:24291194

  6. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats.

    PubMed

    Cornelissen, Jan B W J; van der Giessen, Joke W B; Takumi, Katsuhisa; Teunis, Peter F M; Wisselink, Henk J

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10), and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application. PMID:25184619

  7. Aspects of radiation beam quality and their effect on the dose response of polymer gels: Photons, electrons and fast neutrons

    NASA Astrophysics Data System (ADS)

    Berg, Andreas; Bayreder, Christian; Georg, Dietmar; Bankamp, Achim; Wolber, Gerd

    2009-05-01

    Polymer gels are generally assumed to exhibit no significant dependence of the dose response on the energy or type of irradiation for clinically used beam qualities. Based on reports on differences in dose response for low energy photons and particle beams with high linear energy transfer (LET) we here investigate the dose response and energy dependence for a normoxic methacrylic acid polymer gel (MAGAT) for X-rays (100 kV), high energy photon beams (E = 1.2 MeV (60Co), 6 MV and 15 MV) and for three different electron energies (4, 12 and 20 MeV). Due to the possible impact also the sensitivity of the dose response to the dose rate is reported. A reduction in polymer gel relaxation rate has been observed for proton and carbon beams due to the high Linear Energy Transfer (LET) of these types of radiations. We here report on the dose response of an acryl-amide polymer gel (PAG) in a fast neutron field along with collimation as proposed for Boron neutron capture therapy (BNCT).

  8. Generation of dose-response relationships to assess the effects of acidity in precipitation on growth and productivity of vegetation

    SciTech Connect

    Evans, L.S.

    1981-01-01

    Experiments were performed with several plant species in natural environments as well in a greenhouse and/or tissue culture facilities to establish dose-response functions of plant responses to simulated acidic rain in order to determine environmental risk assessments to ambient levels of acidic rain. Response functions of foliar injury, biomass of leaves and seed of soybean and pinto beans, root yields of radishes and garden beets, and reproduction of bracken fern are considered. The dose-response function of soybean seed yields with the hydrogen ion concentration of simulated acidic rainfalls was expressed by the equation y = 21.06-1.01 log x where y = seed yield in grams per plant and x = the hydrogen concentration if ..mu..eq l/sup -1/. The correlation coefficient of this relationship was -0.90. A similar dose-response function was generated for percent fertilization of ferns in a forest understory. When percent fertilization is plotted on logarithmic scale with hydrogen ion concentration of the simulated rain solution, the Y intercept is 51.18, slope -0.041 with a correlation coefficient of -0.98. Other dose-response functions were generated that assist in a general knowledge as to which plant species and which physiological processes are most impacted by acidic precipitation. Some responses did not produce convenient dose-response relationships. In such cases the responses may be altered by other environmental factors or there may be no differences among treatment means.

  9. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework

    SciTech Connect

    Calabrese, Edward J. . E-mail: edwardc@schoolph.umass.edu; Bachmann, Kenneth A.; Bailer, A. John; Bolger, P. Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M. George; Chiueh, Chuang C.; Clarkson, Thomas W.; Cook, Ralph R.; Diamond, David M.; Doolittle, David J.; Dorato, Michael A.; Duke, Stephen O.; Feinendegen, Ludwig; Gardner, Donald E.; Hart, Ronald W.; Hastings, Kenneth L.; Hayes, A. Wallace; Hoffmann, George R.; Ives, John A.; Jaworowski, Zbigniew; Johnson, Thomas E.; Jonas, Wayne B.; Kaminski, Norbert E.

    2007-07-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

  10. Complex, non-monotonic dose-response curves with multiple maxima: Do we (ever) sample densely enough?

    PubMed Central

    Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor

    2015-01-01

    We usually expect the dose-response curves of biological responses to quantifiable stimuli to be simple, either monotonic or exhibiting a single maximum or minimum. Deviations are often viewed as experimental noise. However, detailed measurements in plant primary tissue cultures (stem pith explants of kale and tobacco) exposed to varying doses of sucrose, cytokinins (BA or kinetin) or auxins (IAA or NAA) revealed that growth and several biochemical parameters exhibit multiple reproducible, statistically significant maxima over a wide range of exogenous substance concentrations. This results in complex, non-monotonic dose-response curves, reminiscent of previous reports of analogous observations in both metazoan and plant systems responding to diverse pharmacological treatments. These findings suggest the existence of a hitherto neglected class of biological phenomena resulting in dose-response curves exhibiting periodic patterns of maxima and minima, whose causes remain so far uncharacterized, partly due to insufficient sampling frequency used in many studies. PMID:26336980

  11. SU-E-J-51: Dose Response of Common Solid State Detectors in Homogeneous Transverse and Longitudinal Magnetic Fields

    SciTech Connect

    Reynolds, M; Fallone, B; Rathee, S

    2014-06-01

    Purpose: Solid state radiation detectors are often used for dose profiles and percent depth dose measurements. The dose response of selected solid state detectors is evaluated in varying transverse and longitudinal magnetic fields for eventual use in MR-Linac devices. Methods: A PTW 60003 and IBA PFD detector were modeled in the Monte Carlo code PENELOPE, incorporating a magnetic field which was varied in strength and oriented both transversely and longitudinally with respect to the incident photon beam. The detectors' long axis was in turn oriented either parallel or perpendicular to the photon beam. Dose to the active volume of each detector was scored, and its ratio to dose with zero magnetic field strength (dose response) was determined. Accuracy of the simulations was evaluated by measurements using both chambers taken at low field with a small electromagnet. Simulations were also performed in a water phantom to compare to the in air results. Results: Significant dose response was found in transverse field geometries, nearing 20% at 1.5T. The response is highly dependent on relative orientations to the magnetic field and photon beam, and on detector composition. Low field measurements confirm these results. In the presence of longitudinal magnetic fields, the detectors exhibit little dose response, reaching 0.5–1% at 1.5T regardless of detector orientation. Water tank simulations compared well to the in air simulations when not at the beam periphery, where in transverse magnetic fields only, the water tank simulations differed from the in air results. Conclusion: Transverse magnetic fields can cause large deviations in dose response, and are highly position orientation dependent. Comparatively, longitudinal magnetic fields exhibit little to no dose response in each detector as a function of magnetic field strength. Water tank simulations show longitudinal fields are generally easier to work with, but each detector must be evaluated separately.

  12. Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors.

    PubMed

    Schöllnberger, H; Kaiser, J C; Jacob, P; Walsh, L

    2012-05-01

    The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose-response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non-nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates. PMID:22437350

  13. Linearization of dose-response curve of the radiochromic film dosimetry system

    SciTech Connect

    Devic, Slobodan; Tomic, Nada; Aldelaijan, Saad; DeBlois, Francois; Seuntjens, Jan; Chan, Maria F.; Lewis, Dave

    2012-08-15

    Purpose: Despite numerous advantages of radiochromic film dosimeter (high spatial resolution, near tissue equivalence, low energy dependence) to measure a relative dose distribution with film, one needs to first measure an absolute dose (following previously established reference dosimetry protocol) and then convert measured absolute dose values into relative doses. In this work, we present result of our efforts to obtain a functional form that would linearize the inherently nonlinear dose-response curve of the radiochromic film dosimetry system. Methods: Functional form [{zeta}= (-1){center_dot}netOD{sup (2/3)}/ln(netOD)] was derived from calibration curves of various previously established radiochromic film dosimetry systems. In order to test the invariance of the proposed functional form with respect to the film model used we tested it with three different GAFCHROMIC Trade-Mark-Sign film models (EBT, EBT2, and EBT3) irradiated to various doses and scanned on a same scanner. For one of the film models (EBT2), we tested the invariance of the functional form to the scanner model used by scanning irradiated film pieces with three different flatbed scanner models (Epson V700, 1680, and 10000XL). To test our hypothesis that the proposed functional argument linearizes the response of the radiochromic film dosimetry system, verification tests have been performed in clinical applications: percent depth dose measurements, IMRT quality assurance (QA), and brachytherapy QA. Results: Obtained R{sup 2} values indicate that the choice of the functional form of the new argument appropriately linearizes the dose response of the radiochromic film dosimetry system we used. The linear behavior was insensitive to both film model and flatbed scanner model used. Measured PDD values using the green channel response of the GAFCHROMIC Trade-Mark-Sign EBT3 film model are well within {+-}2% window of the local relative dose value when compared to the tabulated Cobalt-60 data. It was also

  14. Influence of image slice thickness on rectal dose-response relationships following radiotherapy of prostate cancer

    PubMed Central

    Olsson, C.; Thor, M.; Liu, M.; Moissenko, V.; Petersen, S.E.; Høyer, M; Apte, A.; Deasy, J.O.

    2016-01-01

    When pooling retrospective data from different cohorts, slice thicknesses of acquired computed tomography (CT) images used for treatment planning may vary between cohorts. It is, however, not known if varying slice thickness influences derived dose-response relationships. We investigated this for rectal bleeding using dose-volume histograms (DVHs) of the rectum and rectal wall for dose distributions superimposed on images with varying CT slice thicknesses. We used dose and endpoint data from two prostate cancer cohorts treated with 3D-CRT to either 74 Gy (N=159) or 78 Gy (N=159) @ 2 Gy per fraction. The rectum was defined as the whole organ with content, and the morbidity cut-off was Grade ≥2 late rectal bleeding. Rectal walls were defined as 3-mm inner margins added to the rectum. DVHs for simulated slice thicknesses from 3 to 13 mm were compared to DVHs for the originally acquired slice thicknesses at 3 and 5 mm. Volumes, mean, and maximum doses were assessed from the DVHs, and gEUD values were calculated. For each organ and each of the simulated slice thicknesses, we performed predictive modeling of late rectal bleeding using the Lyman-Kutcher-Burman (LKB) model. For the most coarse slice thickness, rectal volumes increased (≤18%), whereas maximum and mean doses decreased (≤0.8 Gy and ≤4.2 Gy, respectively). For all a values, the gEUD for the simulated DVHs were ≤1.9 Gy different than the gEUD for the original DVHs. The best-fitting LKB model parameter values with 95% CIs were consistent between all DVHs. In conclusion, we found that the investigated slice thickness variations had minimal impact on rectal dose-response estimations. From the perspective of predictive modeling, our results suggest that variations within 10 mm in slice thickness between cohorts are unlikely to be a limiting factor when pooling multi-institutional rectal dose data that include slice thickness variations within this range. PMID:24936956

  15. Influence of image slice thickness on rectal dose-response relationships following radiotherapy of prostate cancer

    NASA Astrophysics Data System (ADS)

    Olsson, C.; Thor, M.; Liu, M.; Moissenko, V.; Petersen, S. E.; Høyer, M.; Apte, A.; Deasy, J. O.

    2014-07-01

    When pooling retrospective data from different cohorts, slice thicknesses of acquired computed tomography (CT) images used for treatment planning may vary between cohorts. It is, however, not known if varying slice thickness influences derived dose-response relationships. We investigated this for rectal bleeding using dose-volume histograms (DVHs) of the rectum and rectal wall for dose distributions superimposed on images with varying CT slice thicknesses. We used dose and endpoint data from two prostate cancer cohorts treated with three-dimensional conformal radiotherapy to either 74 Gy (N = 159) or 78 Gy (N = 159) at 2 Gy per fraction. The rectum was defined as the whole organ with content, and the morbidity cut-off was Grade ≥2 late rectal bleeding. Rectal walls were defined as 3 mm inner margins added to the rectum. DVHs for simulated slice thicknesses from 3 to 13 mm were compared to DVHs for the originally acquired slice thicknesses at 3 and 5 mm. Volumes, mean, and maximum doses were assessed from the DVHs, and generalized equivalent uniform dose (gEUD) values were calculated. For each organ and each of the simulated slice thicknesses, we performed predictive modeling of late rectal bleeding using the Lyman-Kutcher-Burman (LKB) model. For the most coarse slice thickness, rectal volumes increased (≤18%), whereas maximum and mean doses decreased (≤0.8 and ≤4.2 Gy, respectively). For all a values, the gEUD for the simulated DVHs were ≤1.9 Gy different than the gEUD for the original DVHs. The best-fitting LKB model parameter values with 95% CIs were consistent between all DVHs. In conclusion, we found that the investigated slice thickness variations had minimal impact on rectal dose-response estimations. From the perspective of predictive modeling, our results suggest that variations within 10 mm in slice thickness between cohorts are unlikely to be a limiting factor when pooling multi-institutional rectal dose data that include slice thickness

  16. Cigarette smoking and risk of rheumatoid arthritis: a dose-response meta-analysis

    PubMed Central

    2014-01-01

    Introduction Although previous studies found that cigarette smoking is associated with risk of rheumatoid arthritis (RA), the dose-response relationship remains unclear. This meta-analysis quantitatively summarizes accumulated evidence regarding the association of lifelong exposure to cigarette smoking assessed as pack-years with the risk of RA. Methods Relevant studies were identified by a search of MEDLINE and EMBASE from 1966 to October 2013, with no restrictions. Reference lists from retrieved articles were also reviewed. Studies that reported relative risks (RR) or odds ratio (OR) estimates with 95% confidence intervals (CIs) for the association between pack-years of cigarette smoking and rheumatoid arthritis were included in a dose-response random-effects meta-regression analysis. Results We included 3 prospective cohorts and 7 case-control studies in the meta-analysis. They included a total of 4,552 RA cases. There was no indication of heterogeneity (Pheterogeneity = 0.32) and publication bias did not affect the results. Compared to never smokers, the risk of developing RA increased by 26% (RR = 1.26, 95% CI 1.14 to 1.39) among those who smoked 1 to 10 pack-years and doubled among those with more than 20 pack-years (RR for 21 to 30 pack years = 1.94, 95% CI 1.65 to 2.27). The risk of RA was not increasing further for higher exposure levels (RR for >40 pack-years = 2.07, 95% CI 1.15 to 3.73). The risk of RA was statistically significantly higher among rheumatoid factor (RF)-positive RA cases (RR = 2.47, 95% CI 2.02 to 3.02) compared to RF-negative (RR = 1.58, 95% CI 1.15 to 2.18) when comparing the highest versus lowest category of pack-years for the individual studies. Conclusions Lifelong cigarette smoking was positively associated with the risk of RA even among smokers with a low lifelong exposure. The risk of RA did not further increase with an exposure higher than 20 pack-years. PMID:24594022

  17. Quantitative Models of the Dose-Response and Time Course of Inhalational Anthrax in Humans

    PubMed Central

    Schell, Wiley A.; Bulmahn, Kenneth; Walton, Thomas E.; Woods, Christopher W.; Coghill, Catherine; Gallegos, Frank; Samore, Matthew H.; Adler, Frederick R.

    2013-01-01

    Anthrax poses a community health risk due to accidental or intentional aerosol release. Reliable quantitative dose-response analyses are required to estimate the magnitude and timeline of potential consequences and the effect of public health intervention strategies under specific scenarios. Analyses of available data from exposures and infections of humans and non-human primates are often contradictory. We review existing quantitative inhalational anthrax dose-response models in light of criteria we propose for a model to be useful and defensible. To satisfy these criteria, we extend an existing mechanistic competing-risks model to create a novel Exposure–Infection–Symptomatic illness–Death (EISD) model and use experimental non-human primate data and human epidemiological data to optimize parameter values. The best fit to these data leads to estimates of a dose leading to infection in 50% of susceptible humans (ID50) of 11,000 spores (95% confidence interval 7,200–17,000), ID10 of 1,700 (1,100–2,600), and ID1 of 160 (100–250). These estimates suggest that use of a threshold to human infection of 600 spores (as suggested in the literature) underestimates the infectivity of low doses, while an existing estimate of a 1% infection rate for a single spore overestimates low dose infectivity. We estimate the median time from exposure to onset of symptoms (incubation period) among untreated cases to be 9.9 days (7.7–13.1) for exposure to ID50, 11.8 days (9.5–15.0) for ID10, and 12.1 days (9.9–15.3) for ID1. Our model is the first to provide incubation period estimates that are independently consistent with data from the largest known human outbreak. This model refines previous estimates of the distribution of early onset cases after a release and provides support for the recommended 60-day course of prophylactic antibiotic treatment for individuals exposed to low doses. PMID:24058320

  18. Dose response and factors related to interstitial pneumonitis after bone marrow transplant

    SciTech Connect

    Sampath, Sagus; Schultheiss, Timothy E. . E-mail: schultheiss@coh.org; Wong, Jeffrey

    2005-11-01

    Purpose: Total body irradiation (TBI) and chemotherapy are common components of conditioning regimens for bone marrow transplantation. Interstitial pneumonitis (IP) is a known regimen-related complication. Using published data of IP in a multivariate logistic regression, this study sought to identify the parameters in the bone marrow transplantation conditioning regimen that were significantly associated with IP and to establish a radiation dose-response function. Methods and Materials: A retrospective review was conducted of articles that reported IP incidence along with lung dose, fractionation, dose rate, and chemotherapy regimen. In the final analysis, 20 articles (n = 1090 patients), consisting of 26 distinct TBI/chemotherapy regimens, were included in the analysis. Multivariate logistic regression was performed to determine dosimetric and chemotherapeutic factors that influenced the incidence of IP. Results: A logistic model was generated from patients receiving daily fractions of radiation. In this model, lung dose, cyclophosphamide dose, and the addition of busulfan were significantly associated with IP. An incidence of 3%-4% with chemotherapy-only conditioning regimens is estimated from the models. The {alpha}/{beta} value of the linear-quadratic model was estimated to be 2.8 Gy. The dose eliciting a 50% incidence, D {sub 50}, for IP after 120 mg/kg of cyclophosphamide was 8.8 Gy; in the absence of chemotherapy, the estimated D {sub 50} is 10.6 Gy. No dose rate effect was observed. The use of busulfan as a substitute for radiation is equivalent to treating with 14.8 Gy in 4 fractions with 50% transmission blocks shielding the lung. The logistic regression failed to find a model that adequately fit the multiple-fraction-per-day data. Conclusions: Dose responses for both lung radiation dose and cyclophosphamide dose were identified. A conditioning regimen of 12 Gy TBI in 6 daily fractions induces an IP incidence of about 11% in the absence of lung shielding

  19. The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields

    SciTech Connect

    Schmitz, T.; Bassler, N.; Blaickner, M.; Ziegner, M.; Hsiao, M. C.; Liu, Y. H.; Koivunoro, H.; Auterinen, I.; Serén, T.; Kotiluoto, P.; Palmans, H.; Sharpe, P.; Langguth, P.; Hampel, G.

    2015-01-15

    Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The

  20. Dose-response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies.

    PubMed

    Webb, Nicholas E; Montefiori, David C; Lee, Benhur

    2015-01-01

    A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations. PMID:26416571

  1. A Dose-Response Study of Arsenic Exposure and Markers of Oxidative Damage in Bangladesh

    PubMed Central

    Harper, Kristin N.; Liu, Xinhua; Hall, Megan N.; Ilievski, Vesna; Oka, Julie; Calancie, Larissa; Slavkovich, Vesna; Levy, Diane; Siddique, Abu; Alam, Shafiul; Mey, Jacob L.; van Geen, Alexander; Graziano, Joseph H.; Gamble, Mary V.

    2014-01-01

    Objective To evaluate the dose-response relationship between arsenic exposure and markers of oxidative damage in Bangladeshi adults. Methods We recruited 378 participants drinking from wells assigned to five water arsenic exposure categories; the distribution of subjects was as follows: 1) <10 μg/L (n=76); 2) 10–100 μg/L (n=104); 3) 101–200 μg/L (n=86); 4) 201–300 μg/L (n=67); and 5) > 300 μg/L (n=45). Arsenic concentrations were measured in well water, as well as in urine and blood. Urinary 8-oxo-2’-deoxyguanosine (8-oxo-dG) and plasma protein carbonyls were measured to assess oxidative damage. Results None of our measures of arsenic exposure were significantly associated with protein carbonyl or 8-oxo-dG levels. Conclusions We found no evidence to support a significant relationship between chronic exposure to arsenic-contaminated drinking water and biomarkers of oxidative damage among Bangladeshi adults. PMID:24854259

  2. hνSABR: Photochemical Dose-Response Bead Screening in Droplets.

    PubMed

    Price, Alexander K; MacConnell, Andrew B; Paegel, Brian M

    2016-03-01

    With the potential for each droplet to act as a unique reaction vessel, droplet microfluidics is a powerful tool for high-throughput discovery. Any attempt at compound screening miniaturization must address the significant scaling inefficiencies associated with library handling and distribution. Eschewing microplate-based compound collections for one-bead-one-compound (OBOC) combinatorial libraries, we have developed hνSABR (Light-Induced and -Graduated High-Throughput Screening After Bead Release), a microfluidic architecture that integrates a suspension hopper for compound library bead introduction, droplet generation, microfabricated waveguides to deliver UV light to the droplet flow for photochemical compound dosing, incubation, and laser-induced fluorescence for assay readout. Avobenzone-doped PDMS (0.6% w/w) patterning confines UV exposure to the desired illumination region, generating intradroplet compound concentrations (>10 μM) that are reproducible between devices. Beads displaying photochemically cleavable pepstatin A were distributed into droplets and exposed with five different UV intensities to demonstrate dose-response screening in an HIV-1 protease activity assay. This microfluidic architecture introduces a new analytical approach for OBOC library screening, and represents a key component of a next-generation distributed small molecule discovery platform. PMID:26815064

  3. Estimation and uncertainty analysis of dose response in an inter-laboratory experiment

    NASA Astrophysics Data System (ADS)

    Toman, Blaza; Rösslein, Matthias; Elliott, John T.; Petersen, Elijah J.

    2016-02-01

    An inter-laboratory experiment for the evaluation of toxic effects of NH2-polystyrene nanoparticles on living human cancer cells was performed with five participating laboratories. Previously published results from nanocytoxicity assays are often contradictory, mostly due to challenges related to producing a reliable cytotoxicity assay protocol for use with nanomaterials. Specific challenges include reproducibility preparing nanoparticle dispersions, biological variability from testing living cell lines, and the potential for nano-related interference effects. In this experiment, such challenges were addressed by developing a detailed experimental protocol and using a specially designed 96-well plate layout which incorporated a range of control measurements to assess multiple factors such as nanomaterial interference, pipetting accuracy, cell seeding density, and instrument performance. Detailed data analysis of these control measurements showed that good control of the experiments was attained by all participants in most cases. The main measurement objective of the study was the estimation of a dose response relationship between concentration of the nanoparticles and metabolic activity of the living cells, under several experimental conditions. The dose curve estimation was achieved by imbedding a three parameter logistic curve in a three level Bayesian hierarchical model, accounting for uncertainty due to all known experimental conditions as well as between laboratory variability in a top-down manner. Computation was performed using Markov Chain Monte Carlo methods. The fit of the model was evaluated using Bayesian posterior predictive probabilities and found to be satisfactory.

  4. New flux based dose-response relationships for ozone for European forest tree species.

    PubMed

    Büker, P; Feng, Z; Uddling, J; Briolat, A; Alonso, R; Braun, S; Elvira, S; Gerosa, G; Karlsson, P E; Le Thiec, D; Marzuoli, R; Mills, G; Oksanen, E; Wieser, G; Wilkinson, M; Emberson, L D

    2015-11-01

    To derive O3 dose-response relationships (DRR) for five European forest trees species and broadleaf deciduous and needleleaf tree plant functional types (PFTs), phytotoxic O3 doses (PODy) were related to biomass reductions. PODy was calculated using a stomatal flux model with a range of cut-off thresholds (y) indicative of varying detoxification capacities. Linear regression analysis showed that DRR for PFT and individual tree species differed in their robustness. A simplified parameterisation of the flux model was tested and showed that for most non-Mediterranean tree species, this simplified model led to similarly robust DRR as compared to a species- and climate region-specific parameterisation. Experimentally induced soil water stress was not found to substantially reduce PODy, mainly due to the short duration of soil water stress periods. This study validates the stomatal O3 flux concept and represents a step forward in predicting O3 damage to forests in a spatially and temporally varying climate. PMID:26164201

  5. Increasing food deprivation relative to baseline influences D-amphetamine dose-response gradients.

    PubMed

    Lotfizadeh, Amin D; Zimmermann, Zachary J; Watkins, Erin E; Edwards, Timothy L; Poling, Alan

    2014-10-01

    Several studies using non-pharmacological discriminative stimuli have found that stimulus control, as evident in generalization gradients, changes when motivation for (i.e., deprivation of) the relevant reinforcer is altered. Drug-discrimination studies, however, have not consistently revealed such an effect. A procedural detail that may account for the lack of a reliable effect in drug-discrimination studies is that motivation was characteristically reduced relative to the training condition in these studies. The present experiment examined how substantially increasing motivation affects D-amphetamine discrimination. Rats initially were trained to discriminate D-amphetamine (1.0 mg/kg) from vehicle (0 mg/kg) injections under 22-h food deprivation conditions. Dose-response gradients were then obtained under 22-h and 46-h deprivation levels. The ED50 was significantly higher with greater deprivation. This finding suggests that increasing motivation relative to the training condition may reduce stimulus control by drugs, while decreasing it may sharpen stimulus control. PMID:25179163

  6. Inhalation of racemic epinephrine in children with asthma. Dose-response relation and comparison with salbutamol.

    PubMed

    Kjellman, B; Tollig, H; Wettrell, G

    1980-10-01

    In this study the effects of nebulized racemic epinephrine (Micronephrine) were investigated in children with asthma. The drug was inhaled by a compressor nebulizer with a plastic mask. In the first part of the study it is shown that nebulized Micronephrine has a dose-dependent bronchodilatory effect. In the second part the effect is compared with that of nebulized salbutamol in 10 children (7-16 years of age) with bronchial asthma. The highest dose used in the dose-response trials (=0.9 mg Micronephrine/kg body-weight) was compared with 0.15 mg salbutamol/kg body-weight, which is the dose commonly used in Sweden. There was no significant difference between the drugs as regards increase of forced expiratory volume in 1 sec or duration of the increase. There was a small but significant increase in systolic blood pressure, measured 5 min after the inhalation of Micronephrine but no significant change in diastolic pressure or heart rate. Four children complained of temporary sore throat after the inhalation. PMID:7468946

  7. Renal dysfunction from cadmium contamination of irrigation water: dose-response analysis in a Chinese population.

    PubMed Central

    Cai, S.; Yue, L.; Jin, T.; Nordberg, G.

    1998-01-01

    In a cadmium-contaminated area in China and a nearby non-contaminated area, 342 persons were selected for studies of a possible relationship between cadmium dose (i.e. total cadmium intake) and response in terms of renal dysfunction. An increase in urinary excretion of beta-2-microglobulin (UB2M), adjusted for age and sex, was used as an indicator of the response. A statistically significant relationship was found between measured cadmium concentrations in whole blood (range; < 3.5 to > 15 micrograms/l) and UB2M, and there was a statistically significant linear trend. Also, cadmium in urine (< 4 to > 16 micrograms/g creatinine) and UB2M displayed a statistically significant positive relationship when the total data set was analysed for males and females. The relationship between a dose index (obtained from calculated cumulative absorbed doses over a lifetime) and UB2M was statistically significant. The results of this first study on dose-response relationships in a Chinese population are similar to those observed in other populations. PMID:9648356

  8. Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms.

    PubMed

    Urbain, Paul; Jakobsen, Jette

    2015-09-23

    The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour of sunlight exposure, the vitamin D2 content of the mushrooms increased in a linear manner, with concentrations increasing from 0.1 μg/g up to 3.9 ± 0.8 μg/g dry weight (DW). At the subsequent two measurements one and 3 h later, respectively, a plateau was reached. Two hours of additional exposure triggered a significant decline in vitamin D2 content. After just 15 min of sun exposure and an UV-B dose of 0.13 J/cm(2), the vitamin D2 content increased significantly to 2.2 ± 0.5 μg/g DW (P < 0.0001), which is equivalent to 17.6 μg (704 IU) vitamin D2 per 100 g of fresh mushrooms and comparable to levels found in fatty fish like the Atlantic salmon. PMID:26314311

  9. Optical and NMR dose response of N-isopropylacrylamide normoxic polymer gel for radiation therapy dosimetry

    PubMed Central

    Mesbahi, Asghar; Jafarzadeh, Vahid; Gharehaghaji, Nahideh

    2012-01-01

    Background Application of less toxic normoxic polymer gel of N-isopropyl acrylamide (NIPAM) for radiation therapy has been studied in recent years. Aim In the current study the optical and NMR properties of NIPAM were studied for radiation therapy dosimetry application. Materials and methods NIPAM normoxic polymer gel was prepared and irradiated by 9 MV photon beam of a medical linac. The optical absorbance was measured using a conventional laboratory spectrophotometer in different wavelengths ranging from 390 to 860 nm. R2 measurements of NIPAM gels were performed using a 1.5 T scanner and R2–dose curve was obtained. Results Our results showed R2 dose sensitivity of 0.193 ± 0.01 s−1 Gy−1 for NIPAM gel. Both R2 and optical absorbance showed a linear relationship with dose from 1.5 to 11 Gy for NIPAM gel dosimeter. Moreover, absorbance–dose response varied considerably with light wavelength and highest sensitivity was seen for the blue part of the spectrum. Conclusion Our results showed that both optical and NMR approaches have acceptable sensitivity and accuracy for dose determination with NIPAM gel. However, for optical reading of the gel, utilization of an optimum optical wavelength is recommended. PMID:24377016

  10. Dose-Responsive Gene Expression Changes in Juvenile and Adult Mummichogs (Fundulus heteroclitus) After Arsenic Exposure

    PubMed Central

    Gonzalez, Horacio O.; Hu, Jianjun; Gaworecki, Kristen M.; Roling, Jonathan A.; Baldwin, William S.; Gardea-Torresdey, Jorge L.; Bain, Lisa J.

    2010-01-01

    The present study investigated arsenic's effects on mummichogs (Fundulus heteroclitus), while also examining what role that gender or exposure age might play. Adult male and female mummichogs were exposed to 172ppb, 575ppb, or 1,720ppb arsenic as sodium arsenite for 10 days immediately prior to spawning. No differences were noted in the number or viability of eggs between the groups, but there was a significant increase in deformities in 1,720ppb arsenic exposure group. Total RNA from adult livers or 6-week old juveniles was used to probe custom macroarrays for changes in gene expression. In females, 3% of the genes were commonly differentially expressed in the 172 and 575ppb exposure groups compared to controls. In the males, between 1.1-3% of the differentially expressed genes were in common between the exposure groups. Several genes, including apolipoprotein and serum amyloid precursor were commonly expressed in either a dose-responsive manner or were dose-specific, but consistent across genders. These patterns of regulation were confirmed by QPCR. These findings will provide us with a better understanding of the effects of dose, gender, and exposure age on the response to arsenic. PMID:20451245

  11. Low-level microwave irradiation and central cholinergic activity: a dose-response study

    SciTech Connect

    Lai, H.; Carino, M.A.; Horita, A.; Guy, A.W.

    1989-01-01

    Rats were irradiated with circularly polarized, 2,450-MHz pulsed microwaves (2-microseconds pulses, 500 pulses per second (pps)) for 45 min in the cylindrical waveguide system of Guy et al. Immediately after exposure, sodium-dependent high-affinity choline uptake, an indicator of cholinergic activity in neural tissue, was measured in the striatum, frontal cortex, hippocampus, and hypothalamus. The power density was set to give average whole-body specific absorption rates (SAR) of 0.3, 0.45, 0.6, 0.75, 0.9, or 1.2 W/kg to study the dose-response relationship between the rate of microwave energy absorption and cholinergic activity in the different areas of the brain. Decrease in choline uptake was observed in the striatum at a SAR of 0.75 W/kg and above, whereas for the frontal cortex and hippocampus, decreases in choline uptake were observed at a SAR of 0.45 W/kg and above. No significant effect was observed in the hypothalamus at the irradiation power densities studied. The probit analysis was used to determine the SAR50 in each brain area, i.e., the SAR at which 50% of maximum response was elicited. SAR50 values for the striatum, frontal cortex, and hippocampus were 0.65, 0.38, and 0.44 W/kg, respectively.

  12. Dose-response relationships for female radium dial workers: A new look

    SciTech Connect

    Rowland, R.E.

    1994-05-01

    The values of initial systemic intake and of skeletal dose for all of the U.S. radium cases have recently been revised. This revision was required following the demonstrations by Rundo and by Keane that humans who were exposed to radium as adults lost radium at a rate that depended on the quantity of radium originally deposited within their bodies. These new values have been used to define new dose-response relationships for both the bone sarcomas and the carcinomas arising in the paranasal sinuses and mastoid air cells induced by internally deposited radium. The population examined was employed in the U.S. dial painting industry prior to 1950 and consisted of 1530 female dial workers for whom radium body burden measurements were available. By the end of 1990, 46 cases of bone sarcomas and 19 cases of head carcinomas had been diagnosed in this cohort. The head carcinoma incidence can be adequately fitted by a simple linear function, as was found in previous analyses. The bone sarcoma cases were previously fitted by a dose-squared-exponential function. With the revised values of systemic intake, the sarcoma results could not be satisfactorily fitted with this expression. When the exponent on D was increased to larger values, excellent fits were obtained.

  13. Toluene diisocyanate (TDI) airway effects and dose-responses in different animal models

    PubMed Central

    Schupp, Thomas; Collins, Michael A.

    2012-01-01

    Many inhalation exposure studies have been performed with toluene diisocyanate (TDI) in different animal species. Many were targeted at respiratory irritation and/or sensitisation. As there is still no broadly accepted guideline for the performance of respiratory sensitisation tests, protocols used and endpoints investigated are numerous. In this review we collected data from those respiratory sensitisation and/or irritation studies that provided threshold or dose-response information. Against this aim, and as TDI is a model substance for a respiratory sensitiser, a great number of mechanistic studies are not cited in this paper, although they were checked for relevant information. The literature data available allow the conclusion that both respiratory irritation and sensitisation may be interdependent, and both irritation and sensitisation by TDI is a threshold phenomenon. Across species, the majority of NOAECs for respiratory sensitisation are in the range of 0.005 to 0.03 ppm, whereas the LOAEC is about 0.02 to 0.4 ppm. PMID:27298608

  14. Biologically based dose-response models for developmental toxicity risk assessment

    SciTech Connect

    Kavlock, R.J.

    1991-01-01

    Present risk assessment procedures for non-cancer endpoints generally rely on the determination of No Observed Adverse Effects levels (NOAELS) in animal models followed by the application of various Uncertainty Factors (UFs) to account for unknowns in extrapolating high dose toxicology studies to potentially sensitive human subpopulations. The Reference Dose (RfD) or Concentration (RfC) which results from the process is an estimate, with an uncertainty spanning an order of magnitude, of the exposure level to the human population that is likely to be without appreciable risk of deleterious effects during a lifetime. The US Environmental Protection Agency, through its Research to Improve Health Risk Assessment Program (RIHRA), has embarked on a concerted effort to introduce more pharmacokinetic and mechanistic information into the risk assessment process for non-cancer endpoints and to do this in a quantitative and predictive fashion. Such approaches are collectively termed biologically based dose-response (BBDR) models, and the presentation will focus on examples of such research in the area of developmental toxicity currently being conducted or supported by the EPA.

  15. Preconditioning is hormesis part I: Documentation, dose-response features and mechanistic foundations.

    PubMed

    Calabrese, Edward J

    2016-08-01

    This article provides the first extensive documentation of the dose response features of pre- and postconditioning. Pre- and postconditioning studies with rigorous study designs, using multiple doses/concentrations along with refined dose/concentration spacing strategies, often display hormetic dose/concentration response relationships with considerable generality across biological model, inducing (i.e., conditioning) agent, challenging dose treatment, endpoint, and mechanism. Pre- and postconditioning hormesis dose/concentration-response relationships are reported for 154 diverse conditioning agents, affecting more than 550 dose/concentration responses, across a broad range of biological models and endpoints. The quantitative features of the pre- and postconditioning-induced protective responses are modest, typically being 30-60% greater than control values at maximum, findings that are consistent with a large body (>10,000) of hormetic dose/concentration responses not related to pre- and postconditioning. Regardless of the biological model, inducing agent, endpoint or mechanism, the quantitative features of hormetic dose/concentration responses are similar, suggesting that the magnitude of response is a measure of biological plasticity. This paper also provides the first documentation that hormetic effects account for preconditioning induced early (1-3h) and delayed (12-72h) windows of protection. These findings indicate that pre- and postconditioning are specific types of hormesis. PMID:26757428

  16. Magnetization transfer proportion: a simplified measure of dose response for polymer gel dosimetry

    NASA Astrophysics Data System (ADS)

    Whitney, Heather M.; Gochberg, Daniel F.; Gore, John C.

    2008-12-01

    The response to radiation of polymer gel dosimeters has most often been described by measuring the nuclear magnetic resonance transverse relaxation rate as a function of dose. This approach is highly dependent upon the choice of experimental parameters, such as the echo spacing time for Carr-Purcell-Meiboom-Gill-type pulse sequences, and is difficult to optimize in imaging applications where a range of doses are applied to a single gel, as is typical for practical uses of polymer gel dosimetry. Moreover, errors in computing dose can arise when there are substantial variations in the radiofrequency (B1) field or resonant frequency, as may occur for large samples. Here we consider the advantages of using magnetization transfer imaging as an alternative approach and propose the use of a simplified quantity, the magnetization transfer proportion (MTP), to assess doses. This measure can be estimated through two simple acquisitions and is more robust in the presence of some sources of system imperfections. It also has a dependence upon experimental parameters that is independent of dose, allowing simultaneous optimization at all dose levels. The MTP is shown to be less susceptible to B1 errors than are CPMG measurements of R2. The dose response can be optimized through appropriate choices of the power and offset frequency of the pulses used in magnetization transfer imaging.

  17. Methylene chloride mortality study: dose-response characterization and animal model comparison.

    PubMed

    Hearne, F T; Grose, F; Pifer, J W; Friedlander, B R; Raleigh, R L

    1987-03-01

    To assess the potential chronic health effects of methylene chloride, the mortality experience of a maturing 1964 to 1970 cohort of 1,013 hourly men was evaluated through 1984. On average, employees were exposed at a rate of 26 ppm (eight-hour time-weighted average) for 22 years; median latency was 30 years. Compared with the general population, no statistically significant excesses were observed for such hypothesized causes as lung cancer (14 observed v 21.0 expected), liver cancer (0 v 0.8), and ischemic heart disease (69 v 98.1); dose-response relationships based on career methylene chloride exposure and latency were not demonstrated. Among nonhypothesized causes, a significant deficit was reported for total deaths (176 v 253.2). None of the industrial referent comparisons achieved statistical significance. Sufficient power was available to detect relative risks of 1.6 for lung malignancy and 1.3 for ischemic heart disease. In contrast, there was inadequate power to identify meaningful risk levels for hepatic cancer. With 14 combined lung and liver cancer deaths observed v 36.3 predicted (P less than .0001), the mortality estimate projected from a mathematical model derived from an animal bioassay substantially overestimated cancer mortality for these sites. This inconsistency emphasizes the need to incorporate epidemiologic evidence in assessing the human health risks associated with long-term exposure to this widely used solvent. PMID:3559766

  18. DOSE RESPONSE EFFECT OF Paracoccidioides brasiliensis IN AN EXPERIMENTAL MODEL OF ARTHRITIS

    PubMed Central

    Loth, Eduardo Alexandre; Biazim, Samia Khalil; dos Santos, José Henrique Fermino Ferreira; Puccia, Rosana; Brancalhão, Rosimeire Costa; Chasco, Lucinéia de Fátima; Gandra, Rinaldo Ferreira; Simão, Rita de Cássia Garcia; de Franco, Marcello Fabiano

    2014-01-01

    Paracoccidioidomycosis (PCM) is caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb) and corresponds to prevalent systemic mycosis in Latin America. The aim of the present work was to evaluate the dose response effect of the fungal yeast phase for the standardization of an experimental model of septic arthritis. The experiments were performed with groups of 14 rats that received doses of 103, 104 or 105 P. brasiliensis (Pb18) cells. The fungi were injected in 50 µL of phosphate-buffered saline (PBS) directly into the knee joints of the animals. The following parameters were analyzed in this work: the formation of swelling in knees infused with yeast cells and the radiological and anatomopathological alterations, besides antibody titer by ELISA. After 15 days of infection, signs of inflammation were evident. At 45 days, some features of damage and necrosis were observed in the articular cartilage. The systemic dissemination of the fungus was observed in 11% of the inoculated animals, and it was concluded that the experimental model is able to mimic articular PCM in humans and that the dose of 105 yeast cells can be used as standard in this model. PMID:24879005

  19. Pulmonary inflammation and crystalline silica in respirable coal mine dust: dose-response.

    PubMed

    Kuempel, E D; Attfield, M D; Vallyathan, V; Lapp, N L; Hale, J M; Smith, R J; Castranova, V

    2003-02-01

    This study describes the quantitative relationships between early pulmonary responses and the estimated lung-burden or cumulative exposure of respirable-quartz or coal mine dust. Data from a previous bronchoalveolar lavage (BAL) study in coal miners (n = 20) and nonminers (n = 16) were used including cell counts of alveolar macrophages (AMs) and polymorphonuclear leukocytes (PMNs), and the antioxidant superoxide dismutase (SOD) levels. Miners' individual working lifetime particulate exposures were estimated from work histories and mine air sampling data, and quartz lung-burdens were estimated using a lung dosimetry model. Results show that quartz, as either cumulative exposure or estimated lung-burden, was a highly statistically significant predictor of PMN response (P < 0.0001); however cumulative coal dust exposure did not significantly add to the prediction of PMNs (P = 0.2) above that predicted by cumulative quartz exposure (P < 0.0001). Despite the small study size, radiographic category was also significantly related to increasing levels of both PMNs and quartz lung burden (P-values < 0.04). SOD in BAL fluid rose linearly with quartz lung burden (P < 0.01), but AM count in BAL fluid did not (P > 0.4). This study demonstrates dose-response relationships between respirable crystalline silica in coal mine dust and pulmonary inflammation, antioxidant production, and radiographic small opacities. PMID:12682426

  20. Acute Effects of Classroom Exercise Breaks on Executive Function and Math Performance: A Dose-Response Study

    ERIC Educational Resources Information Center

    Howie, Erin K.; Schatz, Jeffrey; Pate, Russell R.

    2015-01-01

    Purpose: The purpose of this study was to determine the acute dose-response relationship of classroom exercise breaks with executive function and math performance in 9- to 12-year-old children by comparing 5-min, 10-min, or 20-min classroom exercise breaks to 10 min of sedentary classroom activity. Method: This study used a within-subjects…

  1. Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? ###SETAC

    EPA Science Inventory

    The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. Recently, claims have arisen tha...

  2. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model

    EPA Science Inventory

    A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (BPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the HPT axis. Model calibrations, carried out by adjusting key model p...

  3. Biological Stress Response Terminology: Integrating the Concepts of Adaptive Response and Preconditioning Stress Within a Hormetic Dose-Response Framework

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stres...

  4. Empirical evaluation of sufficient similarity in dose-response for environmental risk assessment of a mixture of 11 pyrethroids.

    EPA Science Inventory

    Chemical mixtures in the environment are often the result of a dynamic process. When dose-response data are available on random samples throughout the process, equivalence testing can be used to determine whether the mixtures are sufficiently similar based on a pre-specified biol...

  5. An empirical approach to sufficient similarity in dose-responsiveness: Utilization of statistical distance as a similarity measure.

    EPA Science Inventory

    Using statistical equivalence testing logic and mixed model theory an approach has been developed, that extends the work of Stork et al (JABES,2008), to define sufficient similarity in dose-response for chemical mixtures containing the same chemicals with different ratios ...

  6. Dose-Response Analysis of RNA-Seq Profiles in Archival Formalin-fixed paraffin-embedded (FFPE) Samples

    EPA Science Inventory

    Formalin-fixed paraffin-embedded (FFPE) samples provide a vast untapped resource for chemical safety and translational science. To date, genomic profiling of FFPE samples has been limited by poor RNA quality and inconsistent results with limited utility in dose-response assessmen...

  7. EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON THE SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY

    EPA Science Inventory

    Effects of Prenatal Testosterone Propionate on the Sexual Development of Male and Female Rats: A Dose-Response Study
    Cynthia J. Wolf1,2, Andrew Hotchkiss3, Joseph S. Ostby1, Gerald A. LeBlanc2 and
    L. Earl Gray1,4, Jr.

    ABSTRACT
    Testosterone plays a major role in ...

  8. EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY

    EPA Science Inventory

    Effects of Prenatal Testosterone Propionate on Sexual Development of Male and Female Rats: A Dose-Response Study
    Cynthia Wolf1,2, Joe Ostby1*, Andrew Hotchkiss3, Gerald LeBlanc2, and L. Earl Gray, Jr.1
    1USEPA, NHEERL, Reproductive Toxicology Division, RTP, NC; 2Dept. of To...

  9. X-ray dose response of calcite-A comprehensive analysis for optimal application in TL dosimetry

    NASA Astrophysics Data System (ADS)

    Kalita, J. M.; Wary, G.

    2016-09-01

    The effect of various annealing treatments on dosimetric characteristics of orange calcite (CaCO3) mineral has been studied in detail. Quantitative analysis on the dose response shows that the 573 K annealed sample showed sublinear dose response from 10 mGy to 1 Gy. The fading and reproducibility of this sample are also good enough for dosimetric application. However, a specific annealing treatment after irradiation shows some significant improvements in the dosimetric characteristics of the sample. The 773 K pre-annealed sample, after X-ray irradiation post-annealing at 340 K for 6 min provides linear dose response from 10 mGy to 3.60 Gy, very less fading and good reproducibility. Moreover, this sample after post-annealing at 380 K for 6 min shows linear dose response from 10 mGy to 5.40 Gy when analyzed from the ∼408 K thermoluminescence (TL) glow peak. Analysis of TL glow curves confirmed that the 1.30 eV trap center in calcite crystal is the most effective trapping site for dosimetric application.

  10. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose response (BBDR) Model***

    EPA Science Inventory

    A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (HPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the 1-IPT axis. Model calibrations, carried out by adjusting key model...

  11. Dose response on the 110 °C thermoluminescence peak of un-heated, synthetic Merck quartz

    NASA Astrophysics Data System (ADS)

    Kaya Keleş, Şule; Meriç, Niyazi; Polymeris, George S.

    2016-07-01

    Studies on 110 °C TL peak have been carried out using natural quartz from different origins and synthetic quartz produced by different suppliers. The interest in quartz is due to its usage in dating and retrospective dosimetry as a main material; both synthetic and natural types of quartz yield the 110 °C TL peak in their glow curve. In most studies to understand the physical mechanism behind the TL system, synthetic quartz samples are used and there are many investigations about dose response, in both low and high radiation dose region. In these studies generally synthetic quartz samples produced by Sawyer Research Products are used and the studies showed that both heated and un-heated synthetic quartz samples have intense supra-linear responses. Supra-linearity was enhanced by applying a pre-irradiation while several models have been developed towards an explanation to these supra-linearity effects. In this study commercially available synthetic Merck quartz was used. Different combinations of optical filters were used to obtain dose response curves upto 266 Gy and the effect of pre-dose to these dose response curves was studied. Un-pre-dosed Merck quartz samples dose supra-linearity index is below 1 independently on the optical filters; so Merck quartz showed linear or sub-linear dose response.

  12. RESEARCH TOWARD THE DEVELOPMENT OF A BIOLOGICALLY BASED DOSE RESPONSE ASSESSMENT FOR INORGANIC ARSENIC CARCINOGENICITY: A PROGRESS REPORT

    EPA Science Inventory

    Cancer risk assessments for inorganic arsenic have been based on human epidemiological data, assuming a linear dose-response below the range of observation of tumors. Part of the reason for the continued use of the linear approach in arsenic risk assessments is the lack of an ad...

  13. Body Mass Index and Risk of Breast Cancer: A Nonlinear Dose-Response Meta-Analysis of Prospective Studies

    PubMed Central

    Xia, Xiaoping; Chen, Wei; Li, Jiaoyuan; Chen, Xueqin; Rui, Rui; Liu, Cheng; Sun, Yu; Liu, Li; Gong, Jing; Yuan, Peng

    2014-01-01

    The role of Body Mass Index (BMI) for Breast Cancer (BC) remains to be great interest for a long time. However, the precise effect of nonlinear dose-response for BMI and BC risk is still unclear. We conducted a dose-response meta-analysis to quantitatively assess the effect of BMI on BC risk. Twelve prospective studies with 4,699 cases identified among 426,199 participants and 25 studies of 22,809 cases identified among 1,155,110 participants in premenopausal and postmenopausal groups, respectively, were included in this meta-analysis. Significant non-linear dose-response (P < 0.001) association was identified between BMI and BC risk in postmenopausal women. Individuals with BMI of 25, 30, and 35 kg/m2 yielded relative risks (RRs) of 1.02 [95% confidence interval (CI): 0.98–1.06], 1.12 (95% CI: 1.01–1.24), and 1.26 (95% CI: 1.07–1.50), respectively, when compared to the mean level of the normal BMI range. However, inverse result though not significant was observed in premenopausal women. In conclusion, the results of this meta-analysis highlighted that obesity contributed to increased BC risk in a nonlinear dose-response manner in postmenopausal women, and it is important to realize that body weight control may be a crucial process to reduce BC susceptibility. PMID:25504309

  14. Glyphosate resistant and susceptible soybean (Glycine max) and canola (Brassica napus) dose response and metabolism relationships with glyphosate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Experiments were conducted to determine 1) dose response of glyphosate-resistant (GR) and –susceptible (non-GR) soybean [Glycine max (L.) Merr.] and canola (Brassica napus L.) to glyphosate, 2) if differential metabolism of glyphosate to aminomethylphosphonic acid (AMPA) is the underlying mechanism ...

  15. NONMONOTONIC DOSE RESPONSE CURVES (NMDRCS) ARE COMMON AFTER ESTROGEN OR ANDROGEN SIGNALING PATHWAY DISRUPTION. FACT OR FALDERAL?

    EPA Science Inventory

    ABSTRACT BODY: The shape of the dose response curve in the low dose region has been debated since the 1940s, originally focusing on linear no threshold (LNT) versus threshold responses for cancer and noncancer effects. Recently, it has been claimed that endocrine disrupters (EDCs...

  16. Blood glucose concentration and risk of pancreatic cancer: systematic review and dose-response meta-analysis

    PubMed Central

    Liao, Wei-Chih; Wu, Ming-Shiang; Lin, Jaw-Town; Wang, Hsiu-Po

    2015-01-01

    Objective To evaluate potential linear and non-linear dose-response relations between blood glucose and risk of pancreatic cancer. Design Systematic review and dose-response meta-analysis of prospective observational studies. Data sources Search of PubMed, Scopus, and related reviews before 30 November 2013 without language restriction. Eligibility criteria Prospective studies evaluating the association between blood glucose concentration and pancreatic cancer. Retrospective and cross sectional studies excluded to avoid reverse causality. Data extraction and synthesis Two reviewers independently extracted relevant information and assessed study quality with the Newcastle-Ottawa scale. Random effects dose-response meta-analysis was conducted to assess potential linear and non-linear dose-response relations. Results Nine studies were included for analysis, with a total of 2408 patients with pancreatic cancer. There was a strong linear dose-response association between fasting blood glucose concentration and the rate of pancreatic cancer across the range of prediabetes and diabetes. No non-linear association was detected. The pooled rate ratio of pancreatic cancer per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose was 1.14 (95% confidence interval 1.06 to 1.22; P<0.001) without significant heterogeneity. Sensitivity analysis excluding blood glucose categories in the range of diabetes showed similar results (pooled rate ratio per 0.56 mmol/L increase in fasting blood glucose was 1.15, 95% confidence interval 1.05 to 1.27; P=0.003), strengthening the association between prediabetes and pancreatic cancer. Conclusions Every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in the rate of pancreatic cancer. As prediabetes can be improved or even reversed through lifestyle changes, early detection of prediabetes coupled with lifestyle changes could represent a viable strategy to curb the increasing incidence of pancreatic cancer. PMID

  17. Development of Dose-Response Models to Predict the Relationship for Human Toxoplasma gondii Infection Associated with Meat Consumption.

    PubMed

    Guo, Miao; Mishra, Abhinav; Buchanan, Robert L; Dubey, Jitender P; Hill, Dolores E; Gamble, H Ray; Jones, Jeffrey L; Du, Xianzhi; Pradhan, Abani K

    2016-05-01

    Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States. It is thought that a substantial portion of human T. gondii infections is acquired through the consumption of meats. The dose-response relationship for human exposures to T. gondii-infected meat is unknown because no human data are available. The goal of this study was to develop and validate dose-response models based on animal studies, and to compute scaling factors so that animal-derived models can predict T. gondii infection in humans. Relevant studies in literature were collected and appropriate studies were selected based on animal species, stage, genotype of T. gondii, and route of infection. Data were pooled and fitted to four sigmoidal-shaped mathematical models, and model parameters were estimated using maximum likelihood estimation. Data from a mouse study were selected to develop the dose-response relationship. Exponential and beta-Poisson models, which predicted similar responses, were selected as reasonable dose-response models based on their simplicity, biological plausibility, and goodness fit. A confidence interval of the parameter was determined by constructing 10,000 bootstrap samples. Scaling factors were computed by matching the predicted infection cases with the epidemiological data. Mouse-derived models were validated against data for the dose-infection relationship in rats. A human dose-response model was developed as P (d) = 1-exp (-0.0015 × 0.005 × d) or P (d) = 1-(1 + d × 0.003 / 582.414)(-1.479) . Both models predict the human response after consuming T. gondii-infected meats, and provide an enhanced risk characterization in a quantitative microbial risk assessment model for this pathogen. PMID:26477997

  18. Non-Targeted Effects and the Dose Response for Heavy Ion Tumorigenesis

    NASA Technical Reports Server (NTRS)

    Chappelli, Lori J.; Cucinotta, Francis A.

    2010-01-01

    BACKGROUND: There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies. DOSE RESPONSE MODELS: The Harderian Gland data of Alpen et al.[1-3] was re-analyzed [4] using non-linear least square regression. The data set measured the induction of Harderian gland tumors in mice by high-energy protons, helium, neon, iron, niobium and lanthanum with LET s ranging from 0.4 to 950 keV/micron. We were able to strengthen the individual ion models by combining data for all ions into a model that relates both radiation dose and LET for the ion to tumor prevalence. We compared models based on Targeted Effects (TE) to one motivated by Non-targeted Effects (NTE) that included a bystander term that increased tumor induction at low doses non-linearly. When comparing fitted models to the experimental data, we considered the adjusted R2, the Akaike Information Criteria (AIC), and the Bayesian Information Criteria (BIC) to test for Goodness of fit.In the adjusted R2test, the model with the highest R2values provides a better fit to the available data. In the AIC and BIC tests, the model with the smaller values of the summary value provides the better fit. The non-linear NTE models fit the combined data better than the TE models that are linear at low doses. We evaluated the differences in the relative biological effectiveness (RBE) and found the NTE model provides a higher RBE at low dose compared to the TE model. POWER ANALYSIS: The final NTE model estimates were used to simulate example data to consider the design of new experiments to detect NTE at low dose for validation. Power and sample sizes were calculated for a variety of radiation qualities including some not considered in the Harderian Gland data

  19. Dose-response-time modelling: Second-generation turnover model with integral feedback control.

    PubMed

    Andersson, Robert; Jirstrand, Mats; Peletier, Lambertus; Chappell, Michael J; Evans, Neil D; Gabrielsson, Johan

    2016-01-01

    This study presents a dose-response-time (DRT) analysis based on a large preclinical biomarker dataset on the interaction between nicotinic acid (NiAc) and free fatty acids (FFA). Data were collected from studies that examined different rates, routes, and modes of NiAc provocations on the FFA time course. All information regarding the exposure to NiAc was excluded in order to demonstrate the utility of a DRT model. Special emphasis was placed on the selection process of the biophase model. An inhibitory Imax-model, driven by the biophase amount, acted on the turnover rate of FFA. A second generation NiAc/FFA model, which encompasses integral (slow buildup of tolerance - an extension of the previously used NiAc/FFA turnover models) and moderator (rapid and oscillatory) feedback control, was simultaneously fitted to all time courses in normal rats. The integral feedback control managed to capture an observed 90% adaptation (i.e., almost a full return to baseline) when 10 days constant-rate infusion protocols of NiAc were used. The half-life of the adaptation process had a 90% prediction interval between 3.5-12 in the present population. The pharmacodynamic parameter estimates were highly consistent when compared to an exposure-driven analysis, partly validating the DRT modelling approach and suggesting the potential of DRT analysis in areas where exposure data are not attainable. Finally, new numerical algorithms, which rely on sensitivity equations to robustly and efficiently compute the gradients in the parameter optimization, were successfully used for the mixed-effects approach in the parameter estimation. PMID:26529383

  20. Lead-induced anemia: Dose-response relationships and evidence for a threshold

    SciTech Connect

    Schwartz, J.; Landrigan, P.J.; Baker, E.L. Jr.; Orenstein, W.A.; von Lindern, I.H. )

    1990-02-01

    We conducted a cross-sectional epidemiologic study to assess the association between blood lead level and hematocrit in 579 one to five year-old children living near a primary lead smelter in 1974. Blood lead levels ranged from 0.53 to 7.91 mumol/L (11 to 164 micrograms/dl). To predict hematocrit as a function of blood lead level and age, we derived non-linear regression models and fit percentile curves. We used logistic regression to predict the probability of hematocrit values less than 35 per cent. We found a strong non-linear, dose-response relationship between blood lead level and hematocrit. This relationship was influenced by age, but (in this age group) not by sex; the effect was strongest in youngest children. In one year-olds, the age group most severely affected, the risk of an hematocrit value below 35 percent was 2 percent above background at blood lead levels between 0.97 and 1.88 mumol/L (20 and 39 micrograms/dl), 18 percent above background at lead levels of 1.93 to 2.85 mumol/L (40 to 59 micrograms/dl), and 40 percent above background at lead levels of 2.9 mumol/L (60 micrograms/dl) and greater; background was defined as a blood lead level below 1.88 mumol/L (20 micrograms/dl). This effect appeared independent of iron deficiency. These findings suggest that blood lead levels close to the currently recommended limit value of 1.21 mumol/L (25 micrograms/dl) are associated with dose-related depression of hematocrit in young children.

  1. Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

    PubMed

    Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

    2016-07-01

    Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration. PMID:26717881

  2. Evaluation of the relative dose response test for vitamin A nutriture in cirrhotics.

    PubMed

    Mobarhan, S; Russell, R M; Underwood, B A; Wallingford, J; Mathieson, R D; Al-Midani, H

    1981-10-01

    The rise in serum vitamin A 5 h after a 450 microgram oral dose of the vitamin (retinyl palmitate) was used to assess vitamin A nutriture in patients with alcoholic cirrhosis. The test was carried out on 21 hospitalized male patients and 12 normal age and sex-matched control subjects. The relative dose response (RDR), expressed as percentage, was calculated as A5 - A0/A5 X 100 where A0 = the fasting serum retinol level and A5 = the serum retinol 5 h postdosing. Vitamin A-deficient patients (those with serum retinol levels less than 30 microgram/dl and an abnormal dark adaptation test or RDR greater than or equal to 14%) were treated with 4 wk of oral vitamin A (10,000 microgram/day), then repeat RDR and dark adaptation tests were carried out. Among eight cirrhotics with abnormal dark adaptation, the mean +/- SEM RDR was 21 +/- 9 versus 3 +/- 3% in patients with normal dark adaptation (p less than 0.01). RDR tests of patients with normal dark adaptation did not differ from those of 12 normal age and sex-matched control subjects (normal RDR response 0 to 14%). Among patients found to be vitamin A-deficient, treatment with vitamin A resulted in the mean +/- SEM RDR declining from 21 +/- 9 to 5 +/- 2%. However, this fall failed to reach statistical significance (p = 0.06). The RDR test appears to be useful as a predictor of vitamin A deficiency, even among patients with far advanced hepatic disease. PMID:7293954

  3. Dose-response relationships using brain-computer interface technology impact stroke rehabilitation.

    PubMed

    Young, Brittany M; Nigogosyan, Zack; Walton, Léo M; Remsik, Alexander; Song, Jie; Nair, Veena A; Tyler, Mitchell E; Edwards, Dorothy F; Caldera, Kristin; Sattin, Justin A; Williams, Justin C; Prabhakaran, Vivek

    2015-01-01

    Brain-computer interfaces (BCIs) are an emerging novel technology for stroke rehabilitation. Little is known about how dose-response relationships for BCI therapies affect brain and behavior changes. We report preliminary results on stroke patients (n = 16, 11 M) with persistent upper extremity motor impairment who received therapy using a BCI system with functional electrical stimulation of the hand and tongue stimulation. We collected MRI scans and behavioral data using the Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) before, during, and after the therapy period. Using anatomical and functional MRI, we computed Laterality Index (LI) for brain activity in the motor network during impaired hand finger tapping. Changes from baseline LI and behavioral scores were assessed for relationships with dose, intensity, and frequency of BCI therapy. We found that gains in SIS Strength were directly responsive to BCI therapy: therapy dose and intensity correlated positively with increased SIS Strength (p ≤ 0.05), although no direct relationships were identified with ARAT or 9-HPT scores. We found behavioral measures that were not directly sensitive to differences in BCI therapy administration but were associated with concurrent brain changes correlated with BCI therapy administration parameters: therapy dose and intensity showed significant (p ≤ 0.05) or trending (0.05 < p < 0.1) negative correlations with LI changes, while therapy frequency did not affect LI. Reductions in LI were then correlated (p ≤ 0.05) with increased SIS Activities of Daily Living scores and improved 9-HPT performance. Therefore, some behavioral changes may be reflected by brain changes sensitive to differences in BCI therapy administration, while others such as SIS Strength may be directly responsive to BCI therapy administration. Data preliminarily suggest that when using BCI in stroke rehabilitation, therapy frequency may be less important than dose and

  4. Dietary fat intake and endometrial cancer risk: dose-response meta-analysis of epidemiological studies

    PubMed Central

    Jiang, Luo; Hou, Rui; Gong, Ting-Ting; Wu, Qi-Jun

    2015-01-01

    Epidemiological studies have provided controversial evidence of the association between dietary fat intake and endometrial cancer (EC) risk. To address this inconsistency, we conducted this dose-response meta-analysis by total dietary fat intake, based on epidemiological studies published up to the end of June 2015 identified from PubMed, EMBASE and Web of Science. Two authors (RH and Q-JW) independently performed the eligibility evaluation and data extraction. All differences were resolved by discussion with the third investigator (LJ). Random-effects models were used to estimate summary relative risks (RRs) and 95% confidence intervals (CIs). Overall, the search yielded 16 studies (6 cohort and 10 case-control studies) that involved a total of 7556 EC cases and 563,781 non-cases. The summary RR for EC for each 30g/day increment intake was 0.98 (95%CI = 0.95–1.001; I2 = 0%; n = 11) for total dietary fat. Non-significant results were observed in plant-based fat (summary RR = 1.05, 95%CI = 0.94–1.18; I2 = 0%; n = 5) and animal-based fat (summary RR = 1.17, 95%CI = 0.92–1.36; I2 = 85.0%; n = 6). Additionally, the null associations were observed in almost all the subgroup and sensitivity analyses. In conclusion, findings of the present meta-analysis suggested a lack of association between total dietary fat intake and EC risk. Further studies, especially prospective designed studies are warranted to confirm our findings. PMID:26568366

  5. Buprenorphine alters ethanol self-administration in rats: dose-response and time-dependent effects.

    PubMed

    June, H L; Cason, C R; Chen, S H; Lewis, M J

    1998-11-01

    Buprenorphine is a partial opioid agonist derived from thebaine and has high affinity for mu and kappa opioid receptors. The present study investigated dose-response (0.03, 0.15, 0.3, 3 mg/kg) and time-dependent effects of buprenorphine (1.5 or 4 h post-treatment) on EtOH self-administration in outbred Sprague-Dawley rats. Freely feeding and drinking rats were trained to initiate EtOH self-administration for 1 h daily using the ascending concentration procedure, wherein they were provided with increasing concentrations of EtOH at 2, 5, 7, 9 and 11% (v/v), respectively. Water was concurrently available with each concentration. Animals were maintained on a given concentration of EtOH for 5 days. By day 21, animals began their stabilization on the 11% regimen and remained on this concentration throughout the remainder of the study. EtOH and water consumption were recorded daily at both 10- and 60-min intervals. At 1.5 h post-buprenorphine, all test doses greatly suppressed both EtOH and water intake at the 10-min interval. At the 60-min interval, all but the lowest dose (0.03 mg/kg) significantly suppressed EtOH intake, while only the highest dose (3 mg/kg) suppressed water intake. In contrast to the suppressant profile observed at 1.5 h post-buprenorphine, at 4 h post-buprenorphine the lower doses (0.03 and 0.15 mg/kg) significantly increased EtOH intake while the higher doses (0.3 and 3 mg/kg) continued to suppress intake. None of the doses of buprenorphine altered water intake 4 h post-buprenorphine. The results support previous research demonstrating the utility of low doses of buprenorphine in suppressing behavior rewarded by a non-opioid drug. PMID:9862399

  6. Dose-response relationship of autonomic nervous system responses to individualized training impulse in marathon runners.

    PubMed

    Manzi, Vincenzo; Castagna, Carlo; Padua, Elvira; Lombardo, Mauro; D'Ottavio, Stefano; Massaro, Michele; Volterrani, Maurizio; Iellamo, Ferdinando

    2009-06-01

    In athletes, exercise training induces autonomic nervous system (ANS) adaptations that could be used to monitor training status. However, the relationship between training and ANS in athletes has been investigated without regard for individual training loads. We tested the hypothesis that in long-distance athletes, changes in ANS parameters are dose-response related to individual volume/intensity training load and could predict athletic performance. A spectral analysis of heart rate (HR), systolic arterial pressure variability, and baroreflex sensitivity by the sequences technique was investigated in eight recreational athletes during a 6-mo training period culminating with a marathon. Individualized training load responses were monitored by a modified training impulse (TRIMP(i)) method, which was determined in each athlete using the individual HR and lactate profiling determined during a treadmill test. Monthly TRIMP(i) steadily increased during the training period. All the ANS parameters were significantly and very highly correlated to the dose of exercise with a second-order regression model (r(2) ranged from 0.90 to 0.99; P < 0.001). Variance, high-frequency oscillations of HR variability (HRV), and baroreflex sensitivity resembled a bell-shaped curve with a minimum at the highest TRIMP(i), whereas low-frequency oscillations of HR and systolic arterial pressure variability and the low frequency (LF)-to-high frequency ratio resembled an U-shaped curve with a maximum at the highest TRIMP(i). The LF component of HRV assessed at the last recording session was significantly and inversely correlated to the time needed to complete the nearing marathon. These results suggest that in recreational athletes, ANS adaptations to exercise training are dose related on an individual basis, showing a progressive shift toward a sympathetic predominance, and that LF oscillations in HRV at peak training load could predict athletic achievement in this athlete population. PMID

  7. Dose-response relationships using brain–computer interface technology impact stroke rehabilitation

    PubMed Central

    Young, Brittany M.; Nigogosyan, Zack; Walton, Léo M.; Remsik, Alexander; Song, Jie; Nair, Veena A.; Tyler, Mitchell E.; Edwards, Dorothy F.; Caldera, Kristin; Sattin, Justin A.; Williams, Justin C.; Prabhakaran, Vivek

    2015-01-01

    Brain–computer interfaces (BCIs) are an emerging novel technology for stroke rehabilitation. Little is known about how dose-response relationships for BCI therapies affect brain and behavior changes. We report preliminary results on stroke patients (n = 16, 11 M) with persistent upper extremity motor impairment who received therapy using a BCI system with functional electrical stimulation of the hand and tongue stimulation. We collected MRI scans and behavioral data using the Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) before, during, and after the therapy period. Using anatomical and functional MRI, we computed Laterality Index (LI) for brain activity in the motor network during impaired hand finger tapping. Changes from baseline LI and behavioral scores were assessed for relationships with dose, intensity, and frequency of BCI therapy. We found that gains in SIS Strength were directly responsive to BCI therapy: therapy dose and intensity correlated positively with increased SIS Strength (p ≤ 0.05), although no direct relationships were identified with ARAT or 9-HPT scores. We found behavioral measures that were not directly sensitive to differences in BCI therapy administration but were associated with concurrent brain changes correlated with BCI therapy administration parameters: therapy dose and intensity showed significant (p ≤ 0.05) or trending (0.05 < p < 0.1) negative correlations with LI changes, while therapy frequency did not affect LI. Reductions in LI were then correlated (p ≤ 0.05) with increased SIS Activities of Daily Living scores and improved 9-HPT performance. Therefore, some behavioral changes may be reflected by brain changes sensitive to differences in BCI therapy administration, while others such as SIS Strength may be directly responsive to BCI therapy administration. Data preliminarily suggest that when using BCI in stroke rehabilitation, therapy frequency may be less important than dose

  8. Dose-response relationship between sleep duration and human psychomotor vigilance and subjective alertness

    NASA Technical Reports Server (NTRS)

    Jewett, M. E.; Dijk, D. J.; Kronauer, R. E.; Dinges, D. F.

    1999-01-01

    Although it has been well documented that sleep is required for human performance and alertness to recover from low levels after prolonged periods of wakefulness, it remains unclear whether they increase in a linear or asymptotic manner during sleep. It has been postulated that there is a relation between the rate of improvement in neurobehavioral functioning and rate of decline of slow-wave sleep and/or slow-wave activity (SWS/SWA) during sleep, but this has not been verified. Thus, a cross-study comparison was conducted in which dose-response curves (DRCs) were constructed for Stanford Sleepiness Scale (SSS) and Psychomotor Vigilance Task (PVT) tests taken at 1000 hours by subjects who had been allowed to sleep 0 hours, 2 hours, 5 hours or 8 hours the previous night. We found that the DRCs to each PVT metric improved in a saturating exponential manner, with recovery rates that were similar [time constant (T) approximately 2.14 hours] for all the metrics. This recovery rate was slightly faster than, though not statistically significantly different from, the reported rate of SWS/SWA decline (T approximately 2.7 hours). The DRC to the SSS improved much more slowly than psychomotor vigilance, so that it could be fit equally well by a linear function (slope = -0.26) or a saturating exponential function (T = 9.09 hours). We conclude that although SWS/SWA, subjective alertness, and a wide variety of psychomotor vigilance metrics may all change asymptotically during sleep, it remains to be determined whether the underlying physiologic processes governing their expression are different.

  9. Energy crop (Sida hermaphrodita) fertilization using digestate under marginal soil conditions: A dose-response experiment

    NASA Astrophysics Data System (ADS)

    Nabel, Moritz; Bueno Piaz Barbosa, Daniela; Horsch, David; Jablonowski, Nicolai David

    2014-05-01

    The global demand for energy security and the mitigation of climate change are the main drivers pushing energy-plant production in Germany. However, the cultivation of these plants can cause land use conflicts since agricultural soil is mostly used for plant production. A sustainable alternative to the conventional cultivation of food-based energy-crops is the cultivation of special adopted energy-plants on marginal lands. To further increase the sustainability of energy-plant cultivation systems the dependency on synthetic fertilizers needs to be reduced via closed nutrient loops. In the presented study the energy-plant Sida hermaphrodita (Malvaceae) will be used to evaluate the potential to grow this high potential energy-crop on a marginal sandy soil in combination with fertilization via digestate from biogas production. With this dose-response experiment we will further identify an optimum dose, which will be compared to equivalent doses of NPK-fertilizer. Further, lethal doses and deficiency doses will be observed. Two weeks old Sida seedlings were transplanted to 1L pots and fertilized with six doses of digestate (equivalent to a field application of 5, 10, 20, 40, 80, 160t/ha) and three equivalent doses of NPK-fertilizer. Control plants were left untreated. Sida plants will grow for 45 days under greenhouse conditions. We hypothesize that the nutrient status of the marginal soil can be increased and maintained by defined digestate applications, compared to control plants suffering of nutrient deficiency due to the low nutrient status in the marginal substrate. The dose of 40t/ha is expected to give a maximum biomass yield without causing toxicity symptoms. Results shall be used as basis for further experiments on the field scale in a field trial that was set up to investigate sustainable production systems for energy crop production under marginal soil conditions.

  10. Reanalysis of dose-response data from the Iraqi methylmercury poisoning episode

    SciTech Connect

    Crump, K.; Clewell, H.; Gearhart, J.

    1995-08-01

    Applying a hockey stick parametric dose-response model to data on late or retarded development in Iraqi children exposed in utero to methylmercury, with mercury (Hg) exposure characterized by the peak Hg concentration in mothers` hair during pregnancy, Cox et al. calculated the {open_quotes}best statistical estimate{close_quotes} of the threshold for health effects as 10 ppm Hg in hair with a 95% range of uncertainty of between 0 and 13.6 ppm. A new application of the hockey stick model to the Iraqi data shows, however, that the statistical upper limit of the threshold based on the hockey stick model could be as high as 255 ppm. Futhermore, the maximum likelihood estimate of the threshold using a different parametric model is virtually zero. These and other analyses demonstrate that threshold estimates based on parametric models exhibit high statistical variability and model dependency, and are highly sensitive to the precise definition of an abnormal response. Consequently, they are not a reliable basis for setting a reference dose (RfD) for methylmercury. Benchmark analyses and statistical analyses useful for deriving NOAELs are also presented. We believe these latter analyses-particularly the benchmark analyses-generally form a sounder basis for determining RfDs than the type of hockey stick analysis presented by Cox et al. However, the acute nature of the exposures, as well as other limitations in the Iraqi data suggest that other data may be more appropriate for determining acceptable human exposures to methylmercury. 24 refs., 5 figs., 2 tabs.

  11. Arsenic-induced enhancement of ultraviolet radiation carcinogenesis in mouse skin: a dose-response study.

    PubMed Central

    Burns, Fredric J; Uddin, Ahmed N; Wu, Feng; Nádas, Arthur; Rossman, Toby G

    2004-01-01

    The present study was designed to establish the form of the dose-response relationship for dietary sodium arsenite as a co-carcinogen with ultraviolet radiation (UVR) in a mouse skin model. Hairless mice (strain Skh1) were fed sodium arsenite continuously in drinking water starting at 21 days of age at concentrations of 0.0, 1.25, 2.5, 5.0, and 10 mg/L. At 42 days of age, solar spectrum UVR exposures were applied three times weekly to the dorsal skin at 1.0 kJ/m2 per exposure until the experiment ended at 182 days. Untreated mice and mice fed only arsenite developed no tumors. In the remaining groups a total of 322 locally invasive squamous carcinomas occurred. The carcinoma yield in mice exposed only to UVR was 2.4 +/- 0.5 cancers/mouse at 182 days. Dietary arsenite markedly enhanced the UVR-induced cancer yield in a pattern consistent with linearity up to a peak of 11.1 +/- 1.0 cancers/mouse at 5.0 mg/L arsenite, representing a peak enhancement ratio of 4.63 +/- 1.05. A decline occurred to 6.8 +/- 0.8 cancers/mouse at 10.0 mg/L arsenite. New cancer rates exhibited a consistent-with-linear dependence on time beginning after initial cancer-free intervals ranging between 88 and 95 days. Epidermal hyperplasia was elevated by arsenite alone and UVR alone and was greater than additive for the combined exposures as were growth rates of the cancers. These results demonstrate the usefulness of a new animal model for studying the carcinogenic action of dietary arsenite on skin exposed to UVR and should contribute to understanding how to make use of animal data for assessment of human cancer risks in tissues exposed to mixtures of carcinogens and cancer-enhancing agents. PMID:15064167

  12. Dose-response study of vigabatrin in children with refractory epilepsy.

    PubMed

    Herranz, J L; Arteaga, R; Farr, I N; Valdizan, E; Beaumont, D; Armijo, J A

    1991-01-01

    Twenty children aged 2 months to 18 years were included in a dose-response study of vigabatrin as add-on therapy to preexisting antiepileptic drugs (up to two per patient). All children had severe refractory epilepsy: partial seizures with or without secondary generalization in 19, and myoclonic seizures in one. After a 2-month observation period and a 1-month add-on placebo period, a fixed dose of add-on vigabatrin was given for 2 months: 1, 1.5, or 2 g/day, according to body weight (mean dose, 60 mg/kg/day). Three patients (15%) became seizure free, and nine (45%) showed a 50% to 99% reduction in seizure frequency. In the 17 patients whose seizures were not totally suppressed, vigabatrin dose was increased for a further 2 months, and in 7 patients who still showed less than 50% reduction in seizure frequency, vigabatrin dose was increased again. Efficacy appeared unchanged by these higher doses. During a 9-month follow-up phase, no tolerance to the effects of vigabatrin was observed, with three children seizure free and 13 (65%) reporting a 50% to 99% reduction in seizure frequency. During the study, adverse effects were recorded in three children (15%), namely drowsiness, constipation, fatigue, and apathy. These effects were generally transient, being observed during the dose-modification phase and disappearing either spontaneously or on reduction of vigabatrin dose. Clinical and laboratory tolerability to vigabatrin appeared to be very good, with no patients having withdrawn from the study because of side effects. A slight reduction in red blood cell count and hemoglobin levels was noted but was of doubtful clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1940124

  13. Dose-response relationship between sports activity and musculoskeletal pain in adolescents.

    PubMed

    Kamada, Masamitsu; Abe, Takafumi; Kitayuguchi, Jun; Imamura, Fumiaki; Lee, I-Min; Kadowaki, Masaru; Sawada, Susumu S; Miyachi, Motohiko; Matsui, Yuzuru; Uchio, Yuji

    2016-06-01

    Physical activity has multiple health benefits but may also increase the risk of developing musculoskeletal pain (MSP). However, the relationship between physical activity and MSP has not been well characterized. This study examined the dose-response relationship between sports activity and MSP among adolescents. Two school-based serial surveys were conducted 1 year apart in adolescents aged 12 to 18 years in Unnan, Japan. Self-administered questionnaires were completed by 2403 students. Associations between time spent in organized sports activity and MSP were analyzed cross-sectionally (n = 2403) and longitudinally (n = 374, students free of pain and in seventh or 10th grade at baseline) with repeated-measures Poisson regression and restricted cubic splines, with adjustment for potential confounders. The prevalence of overall pain, defined as having pain recently at least several times a week in at least one part of the body, was 27.4%. In the cross-sectional analysis, sports activity was significantly associated with pain prevalence. Each additional 1 h/wk of sports activity was associated with a 3% higher probability of having pain (prevalence ratio = 1.03, 95% confidence interval = 1.02-1.04). Similar trends were found across causes (traumatic and nontraumatic pain) and anatomic locations (upper limbs, lower back, and lower limbs). In longitudinal analysis, the risk ratio for developing pain at 1-year follow-up per 1 h/wk increase in baseline sports activity was 1.03 (95% confidence interval = 1.02-1.05). Spline models indicated a linear association (P < 0.001) but not a nonlinear association (P ≥ 0.45). The more the adolescents played sports, the more likely they were to have and develop pain. PMID:26894915

  14. Ondansetron: A newer aspect of dose response relationship on ileal smooth muscles of rabbit.

    PubMed

    Afzal, Ayesha; Khan, Bushra Tayyaba; Bakhtiar, Salman

    2016-01-01

    There are several life threatening deadly diseases in our world but ‘Cancer’ out powers them all in recent years. Chemotherapy may be used on its own or an adjunct to other forms of therapy. Despite the advancement in cytotoxic drug therapy and supportive treatment almost 70% of patient suffer from chemotherapy induced nausea and vomiting (CINV). Ondansetron, a 5-HT(3) receptor antagonist has now become a gold standard in the treatment of chemotherapy induced nausea and vomiting. The central actions of ondansetron are well established but its peripheral actions are not well recognized. The aim of our study was to explore the peripheral actions of ondansetron. Experiments were performed in five groups (n=6) and ileal smooth muscles activity was recorded on power lab (USA). The effects of increasing concentrations of acetylcholine, serotonin & ondansetron alone was observed in first three groups. In the next two groups effects of acetylcholine and serotonin pretreated with fixed concentration (1ml) of ondansetron (10¯ϖ M)were studied. The maximum response obtained by acetylcholine served as a control for our study. Maximum response with acetylcholine was taken as 100% and with serotonin was 177 percent of control. Cumulative dose response curve with ondansetron was triphasic. At 10¯ψM it was 28.8%, whereas with 10¯ξM the amplitude decreased to 16.87%, it reached to plateau at 10¯ϖ M. Response of acetylcholine & serotonin was decreased to 57% and 78% respectively in the presence of fixed concentration of ondansetron (10¯ϖ M). Ondansetron reduces the acetylcholine and serotonin induced gastrointestinal motility. Our study has indicated that ondansetron apart from having central action also has marked peripheral actions that play an important role in CINV and may act as a partial agonist. PMID:26826825

  15. The effects of progressive dehydration on strength and power: is there a dose response?

    PubMed

    Hayes, Lawrence D; Morse, Christopher I

    2010-03-01

    This study examined the effect of exercise- and heat-induced dehydration on strength, jump capacity and neuromuscular function. Twelve recreationally active males completed six resistance exercise bouts (baseline and after each 5 exposure sessions) in an increasing state of hypohydration obtained by repeated heat exposure and exercise sessions (5 periods of 20 min jogging at up to approximately 80% age predicted heart rate maximum at 48.5 +/- 0.48 degrees C, relative humidity 50 +/- 4%). Relative to starting values, body mass decreased 1.0 +/- 0.5, 1.9 +/- 0.7, 2.6 +/- 0.8, 3.3 +/- 0.9 and 3.9 +/- 1.0% after exposure 1, 2, 3, 4 and 5, respectively. However, plasma volume remained constant. No significant differences existed amongst trials in vertical jump height, electromyography data or isokinetic leg extension at a rate of 120 degrees s(-1). Isometric leg extensions were significantly reduced (P < 0.05) after the first (1% body mass loss) and subsequent exposures in comparison to baseline. Isokinetic leg extensions at a rate of 30 degrees s(-1) were significantly reduced after the third (2.6% body mass loss) and subsequent exposures compared with baseline. No dose response was identified in any of the tested variables yet a threshold was observed in isometric and isokinetic strength at 30 degrees s(-1). In conclusion, dehydration caused by jogging in the heat had no effect on vertical jumping or isokinetic leg extensions at a rate of 120 degrees s(-1). Alternatively, exercise-induced dehydration was detrimental to isometric and isokinetic leg extensions at a rate of 30 degrees s(-1), suggesting the force-velocity relationship in hypohydration merits further research. PMID:19908058

  16. Qualitative and quantitative approaches in the dose-response assessment of genotoxic carcinogens.

    PubMed

    Fukushima, Shoji; Gi, Min; Kakehashi, Anna; Wanibuchi, Hideki; Matsumoto, Michiharu

    2016-05-01

    Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2'-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment. PMID:26152227

  17. Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT)

    PubMed Central

    Churilov, Leonid; Ellery, Fiona; Collier, Janice; Chamberlain, Jan; Langhorne, Peter; Lindley, Richard I.; Moodie, Marj; Dewey, Helen; Thrift, Amanda G.; Donnan, Geoff

    2016-01-01

    Objective: Our prespecified dose-response analyses of A Very Early Rehabilitation Trial (AVERT) aim to provide practical guidance for clinicians on the timing, frequency, and amount of mobilization following acute stroke. Methods: Eligible patients were aged ≥18 years, had confirmed first (or recurrent) stroke, and were admitted to a stroke unit within 24 hours of stroke onset. Patients were randomized to receive very early and frequent mobilization, commencing within 24 hours, or usual care. We used regression analyses and Classification and Regression Trees (CART) to investigate the effect of timing and dose of mobilization on efficacy and safety outcomes, irrespective of assigned treatment group. Results: A total of 2,104 patients were enrolled, of whom 2,083 (99.0%) were followed up at 3 months. We found a consistent pattern of improved odds of favorable outcome in efficacy and safety outcomes with increased daily frequency of out-of-bed sessions (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.18, p < 0.001), keeping time to first mobilization and mobilization amount constant. Increased amount (minutes per day) of mobilization reduced the odds of a good outcome (OR 0.94, 95% CI 0.91 to 0.97, p < 0.001). Session frequency was the most important variable in the CART analysis, after prognostic variables age and baseline stroke severity. Conclusion: These data suggest that shorter, more frequent mobilization early after acute stroke is associated with greater odds of favorable outcome at 3 months when controlling for age and stroke severity. Classification of evidence: This study provides Class III evidence that shorter, more frequent early mobilization improves the chance of regaining independence after stroke. PMID:26888985

  18. Inhaled nitric oxide: Dose response and the effects of blood in the isolated rat lung

    SciTech Connect

    Rich, G.F.; Roos, C.M.; Anderson, S.M.; Urich, D.C.; Daugherty, M.O.; Johns, R.A. )

    1993-09-01

    Inhaled nitric oxide (NO) is a vasodilator selective to the pulmonary circulation. Using isolated rat lungs, the authors determined the dose-response relationship of NO and the role of blood in mediating pulmonary vasodilation and selectivity. Inhaled 20, 50, 100, and 1,000 ppm NO attenuated (P < 0.001) hypoxic pulmonary vasoconstriction by 16.1 [+-] 4.9, 22.6 [+-] 6.8, 28.4 [+-] 3.5, and 69.3 [+-] 4.2%, respectively. Inhaled 13, 34, 67, and 670 ppm NO attenuated the increase in pulmonary arterial pressure secondary to angiotensin II more (P < 0.001) in Greenberg-Bohr buffer- (GB) than in blood-perfused lungs (51.7 [+-] 0.0, 71.9 [+-] 8.9, 78.2 [+-] 5.3, and 91.9 [+-] 2.1% vs. 14.3 [+-] 4.2, 23.8 [+-] 4.6, 28.4 [+-] 3.8, and 55.5 [+-] 5.9%, respectively). Samples from GB- but not blood-perfused lungs contained NO (93.0 [+-] 26.3 nM). Intravascular NO attenuated the response to angiotensin II more (P < 0.001) in GB- (with and without plasma) than in blood- (hematocrit = 41 and 5%) perfused lungs (75.6 [+-] 6.4 and 70.9 [+-] 4.8% vs. 22.2 [+-] 2.4 and 39.4 [+-] 7.6%). In conclusion, inhaled NO produces reversible dose-dependent pulmonary vasodilation over a large range of concentrations. Inhaled NO enters the circulation, but red blood cells prevent systematic vasodilation and also a significant amount of pulmonary vasodilation. 24 refs., 7 figs., 2 tabs.

  19. Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs

    SciTech Connect

    Koplovitz, I.; Menton, R.; Matthews, C.; Shutz, M.; Nalls, C.

    1995-12-31

    H1-6 (1-2-hydrnxyiminomethyl-1 pyridino-3-(4-carbameyl- 1--pyddino)-2- oxaprnpane dichioride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine and HI-6 against soman was also investigated. Animals of either sex were challenged s.c. with OP and treated i.m. 1 min later with ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI-6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanced the efficacy of HI-6 and atropine against soman.

  20. Toolkit for determination of dose-response relations, validation of radiobiological parameters and treatment plan optimization based on radiobiological measures.

    PubMed

    Mavroidis, Panayiotis; Tzikas, Athanasios; Papanikolaou, Nikos; Lind, Bengt K

    2010-10-01

    Accurately determined dose-response relations of the different tumors and normal tissues should be estimated and used in the clinic. The aim of this study is to demonstrate developed tools that are necessary for determining the dose-response parameters of tumors and normal tissues, for clinically verifying already published parameter sets using local patient materials and for making use of all this information in the optimization and comparison of different treatment plans and radiation techniques. One of the software modules (the Parameter Determination Module) is designed to determine the dose-response parameters of tumors and normal tissues. This is accomplished by performing a maximum likelihood fitting to calculate the best estimates and confidence intervals of the parameters used by different radiobiological models. Another module of this software (the Parameter Validation Module) concerns the validation and compatibility of external or reported dose-response parameters describing tumor control and normal tissue complications. This is accomplished by associating the expected response rates, which are calculated using different models and published parameter sets, with the clinical follow-up records of the local patient population. Finally, the last module of the software (the Radiobiological Plan Evaluation Module) is used for estimating and optimizing the effectiveness a treatment plan in terms of complication-free tumor control, P(+). The use of the Parameter Determination Module is demonstrated by deriving the dose-response relation of proximal esophagus from head and neck cancer radiotherapy. The application of the Parameter Validation Module is illustrated by verifying the clinical compatibility of those dose-response parameters with the examined treatment methodologies. The Radiobiological Plan Evaluation Module is demonstrated by evaluating and optimizing the effectiveness of head and neck cancer treatment plans. The results of the radiobiological

  1. The dose-response curve of the gravitropic reaction: a re-analysis.

    PubMed

    Perbal, Gérald; Jeune, Bernard; Lefranc, Agnès; Carnero-Diaz, Eugénie; Driss-Ecole, Dominique

    2002-03-01

    The dose-response curve of the gravitropic reaction is often used to evaluate the gravisensing of plant organs. It has been proposed (Larsen 1957) that the response (curvature) varies linearly as a function of the logarithm of the dose of gravistimulus. As this model fitted correctly most of the data obtained in the literature, the presentation time (tp, minimal duration of stimulation in the gravitational field to induce a response) or the presentation dose (dp, minimal quantity in g.s of stimulation to induce a response) were estimated by extrapolating down to zero curvature the straight line representing the response as a function of the logarithm of the stimulus. This method was preferred to a direct measurement of dp or tp with minute stimulations, since very slight gravitropic response cannot be distinguished from the background oscillations of the extremity of the organs. In the present review, it is shown that generally the logarithmic model (L) does not fit the experimental data published in the literature as well as the hyperbolic model (H). The H model in its simplest form is related to a response in which a ligand-receptor system is the limiting phase in the cascade of events leading to the response (Weyers et al. 1987). However, it is demonstrated that the differential growth, responsible for the curvature (and the angle of curvature), would vary as a hyperbolic function of the dose of stimulation, even if several steps involving ligand-receptor systems are responsible for the gravitropic curvature. In the H model, there is theoretically no presentation time (or presentation dose) since the curve passes through the origin. The value of the derivative of the H function equals a/b and represents the slope of the cune at the origin. It could be therefore used to estimate gravisensitivity. This provides a measurement of graviresponsiveness for threshold doses of stimulation. These results imply that the presentation time (or presentation dose) derived from

  2. Liposomal Bupivacaine as a Single-Injection Peripheral Nerve Block: A Dose-Response Study

    PubMed Central

    Ilfeld, Brian M.; Malhotra, Nisha; Furnish, Timothy J.; Donohue, Michael C.; Madison, Sarah J.

    2013-01-01

    Background Currently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration less than 24 hours. A liposomal bupivacaine formulation (EXPAREL®, Pacira Pharmaceuticals, Inc., San Diego, California), releasing bupivacaine over 96 hours, recently gained Food and Drug Administration approval exclusively for wound infiltration, but not peripheral nerve blocks. Methods Bilateral single-injection femoral nerve blocks were administered in healthy volunteers (n=14). For each block, liposomal bupivacaine (0–80 mg) was mixed with normal saline to produce 30 mL of study fluid. Each subject received two different doses, one on each side, applied randomly in a double-masked fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally. Results There were statistically significant dose responses in MVIC (0.09% / mg, SE = 0.03, 95% CI 0.04 to 0.14, p = 0.002) and tolerance to cutaneous current (−0.03 mA / mg, SE = 0.01, 95% CI −0.04 to 0.02, p < 0.001), however, in the opposite direction than expected (the higher the dose, the lower the observed effect). This inverse relationship is biologically implausible, and most likely due to the limited sample size and the subjective nature of the measurement instruments. While peak effects occurred within 24 hours after block administration in 75% of cases (95% CI 43 to 93%), block duration usually lasted much longer: for bupivacaine doses above 40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 h in 100% of subjects (95% CI 56 to 100). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI 54 to 100%). Motor block duration was not correlated with

  3. Lipid metabolic dose response to dietary alpha-linolenic acid in monk parrot (Myiopsitta monachus).

    PubMed

    Petzinger, Christina; Heatley, J J; Bailey, Christopher A; Bauer, John E

    2014-03-01

    Monk parrots (Myiopsitta monachus) are susceptible to atherosclerosis, a progressive disease characterized by the formation of plaques in the arteries accompanied by underlying chronic inflammation. The family of n-3 fatty acids, especially eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA), have consistently been shown to reduce atherosclerotic risk factors in humans and other mammals. Some avian species have been observed to convert α-linolenic acid (18:3n-3, ALA) to EPA and DHA (Htin et al. in Arch Geflugelk 71:258-266, 2007; Petzinger et al. in J Anim Physiol Anim Nutr, 2013). Therefore, the metabolic effects of including flaxseed oil, as a source of ALA, in the diet at three different levels (low, medium, and high) on the lipid metabolism of Monk parrots was evaluated through measuring plasma total cholesterol (TC), free cholesterol (FC), triacylglycerols (TAG), and phospholipid fatty acids. Feed intake, body weight, and body condition score were also assessed. Thus the dose and possible saturation response of increasing dietary ALA at constant linoleic acid (18:2n-6, LNA) concentration on lipid metabolism in Monk parrots (M. monachus) was evaluated. Calculated esterified cholesterol in addition to plasma TC, FC, and TAG were unaltered by increasing dietary ALA. The high ALA group had elevated levels of plasma phospholipid ALA, EPA, and docosapentaenoic acid (DPAn-3, 22:5n-3). The medium and high ALA groups had suppressed plasma phospholipid 20:2n-6 and adrenic acid (22:4n-6, ADA) compared to the low ALA group. When the present data were combined with data from a previous study (Petzinger et al. in J Anim Physiol Anim Nutr, 2013) a dose response to dietary ALA was observed when LNA was constant. Plasma phospholipid ALA, EPA, DPAn-3, DHA, and total n-3 were positively correlated while 20:2n-6, di-homo-gamma-linoleic acid (20:3n-6Δ7), arachidonic acid (20:4n-6), ADA, and total n-6 were inversely correlated with dietary en% ALA. PMID

  4. The impact of different dose response parameters on biologically optimized IMRT in breast cancer

    NASA Astrophysics Data System (ADS)

    Costa Ferreira, Brigida; Mavroidis, Panayiotis; Adamus-Górka, Magdalena; Svensson, Roger; Lind, Bengt K.

    2008-05-01

    The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P+), the biologically effective uniform dose (\\bar{\\bar{D}} ), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P+ between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven-beam plan, the differences in P+ are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients

  5. Dose-response effect of elevated plasma free fatty acid on insulin signaling.

    PubMed

    Belfort, Renata; Mandarino, Lawrence; Kashyap, Sangeeta; Wirfel, Kelly; Pratipanawatr, Thongchai; Berria, Rachele; Defronzo, Ralph A; Cusi, Kenneth

    2005-06-01

    The dose-response relationship between elevated plasma free fatty acid (FFA) levels and impaired insulin-mediated glucose disposal and insulin signaling was examined in 21 lean, healthy, normal glucose-tolerant subjects. Following a 4-h saline or Liposyn infusion at 30 (n = 9), 60 (n = 6), and 90 (n = 6) ml/h, subjects received a 2-h euglycemic insulin (40 mU . m(-2) . min(-1)) clamp. Basal plasma FFA concentration ( approximately 440 micromol/l) was increased to 695, 1,251, and 1,688 micromol/l after 4 h of Liposyn infusion and resulted in a dose-dependent reduction in insulin-stimulated glucose disposal (R(d)) by 22, 30, and 34%, respectively (all P < 0.05 vs. saline control). At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05-0.01). The highest lipid infusion rate (90 ml/h) caused a further significant reduction in all insulin signaling events compared with the low-dose lipid infusion (P < 0.05-0.01) whereas the 60-ml/h lipid infusion caused an intermediate reduction in insulin signaling. However, about two-thirds of the maximal inhibition of insulin-stimulated glucose disposal already occurred at the rather modest increase in plasma FFA induced by the low-dose (30-ml/h) lipid infusion. Insulin-stimulated glucose disposal was inversely correlated with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.50, P = 0.001) and the plasma FFA level during the last 30 min of the insulin clamp (r = -0.54, P < 0.001). PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = -0.43, P < 0.01). In summary, in skeletal muscle of lean

  6. A study of the shape of dose-response curves for acute lethality at low response: a megadaphnia study'

    SciTech Connect

    Sebaugh, J.L.; Wilson, J.D.; Tucker, M.W.; Adams, W.J. )

    1991-12-01

    Dose-response curves were developed for the immobilization response in Daphnia magna to four toxicants. The purpose of this work was to study the effect of the form of the model and the number of concentration levels used on the estimates of typical low-dose effective concentrations (1%, 5%, 10%). The generalized four-parameter logistic model was used as the reference. When using 12 concentration levels, one of the logistic family two- or three-parameter models was shown reliably to represent each of these various sets of dose-response data, and to provide adequate estimates of EC01 and EC05, as well as EC10 and EC50. For two of the toxicants, an asymmetric model was required. When reducing the number of concentrations to five, the EC10 and EC50 were well estimated by the probit model, with acceptable results at the EC05 level.

  7. Dose response of commercially available optically stimulated luminescent detector, Al2O3:C for megavoltage photons and electrons.

    PubMed

    Kim, Dong Wook; Chung, Weon Kuu; Shin, Dong Oh; Yoon, Myonggeun; Hwang, Ui-Jung; Rah, Jeong-Eun; Jeong, Hojin; Lee, Sang Yeob; Shin, Dongho; Lee, Se Byeong; Park, Sung Yong

    2012-04-01

    This study examined the dose response of an optically stimulated luminescence dosemeter (OSLD) to megavoltage photon and electron beams. A nanoDot™ dosemeter was used to measure the dose response of the OSLD. Photons of 6-15 MV and electrons of 9-20 MeV were delivered by a Varian 21iX machine (Varian Medical System, Inc. Milpitas, CA, USA). The energy dependency was <1 %. For the 6-MV photons, the dose was linear until 200 cGy. The superficial dose measurements revealed photon irradiation to have an angular dependency. The nanoDot™ dosemeter has potential use as an in vivo dosimetric tool that is independent of the energy, has dose linearity and a rapid response compared with normal in vivo dosimetric tools, such as thermoluminescence detectors. However, the OSLD must be treated very carefully due to the high angular dependency of the photon beam. PMID:21636557

  8. Isometric exercise and cognitive function: an investigation of acute dose-response effects during submaximal fatiguing contractions.

    PubMed

    Brown, Denver M Y; Bray, Steven R

    2015-01-01

    The purpose of this study was to explore the dose-response relationship between exercise and cognitive performance using an acute bout of isometric exercise. University students (N = 55) were randomly assigned to control, 30%, 50% and 70% of maximum voluntary handgrip contraction groups. Participants performed a modified Stroop task before and after completion of an isometric handgrip endurance trial at their assigned exercise intensity. Ratings of perceived exertion (RPE) and forearm muscle activation (EMG) showed linear trends of progressively greater RPE and muscle activation at greater exercise intensity levels. Regression analysis showed significant (P < .05) linear degradations in frequency of errors on the Stroop task with increasing exercise intensity. We conclude that performing isometric exercise until exhaustion is associated with reduced cognitive performance and that higher intensity isometric exercise leads to greater performance impairments in a linear dose-response manner. PMID:25260112

  9. Gamma-glutamyltransferase and risk of hypertension: a systematic review and dose-response meta-analysis of prospective evidence.

    PubMed

    Kunutsor, Setor K; Apekey, Tanefa A; Cheung, Bernard M Y

    2015-12-01

    The objective of this review was to obtain a reliable estimate of the magnitude of the prospective association between gamma-glutamyltransferase (GGT) and risk of hypertension, and to characterize the nature of the dose-response relationship. We conducted a systematic review and dose-response meta-analysis of published prospective studies. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science databases up to May 2015. Study-specific relative risks (RRs) were meta-analyzed using random effects models. We examined a potential nonlinear relationship using restricted cubic splines. Of the 612 titles reviewed, we included 14 cohort studies with data on 44 582 participants and 5 270 hypertension cases. In a comparison of extreme thirds of baseline levels of GGT, RR for hypertension in pooled analysis of all 14 studies was 1.32 (95% confidence interval: 1.23-1.43). There was heterogeneity among the studies (P < 0.001), which was to a large part explained by average age of participants at baseline, average duration of follow-up, and the degree of confounder adjustment. In a pooled dose-response analysis of 10 studies with relevant data, there was evidence of a linear association between GGT and hypertension risk (P for nonlinearity = 0.37). The pooled RR of hypertension per 5 U/l increment in GGT levels was 1.08 (95% confidence interval: 1.04-1.13). Baseline circulating GGT level is associated with an increased risk of hypertension in the general population, consistent with a linear dose-response relationship. Further investigation of any potential relevance of GGT in hypertension prevention is warranted. PMID:26485462

  10. Laboratory measurement error in external dose estimates and its effects on dose-response analyses of Hanford worker mortality data

    SciTech Connect

    Gilbert, E.S.; Fix, J.J.

    1996-08-01

    This report addresses laboratory measurement error in estimates of external doses obtained from personnel dosimeters, and investigates the effects of these errors on linear dose-response analyses of data from epidemiologic studies of nuclear workers. These errors have the distinguishing feature that they are independent across time and across workers. Although the calculations made for this report were based on Hanford data, the overall conclusions are likely to be relevant for other epidemiologic studies of workers exposed to external radiation.

  11. Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat

    EPA Science Inventory

    Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat M.F. Hughes1, D.G. Ross1, J.M. Starr1, E.J. Scollon1,2, M.J. Wolansky1,3, K.M. Crofton1, M.J. DeVito1,4 1U.S. EPA, ORD, Research Triangle Park, NC, 2U.S. EPA,...

  12. Dose-response studies on the spermatogonial stem cells of the rhesus monkey (Macaca mulatta) after X irradiation

    SciTech Connect

    van Alphen, M.M.; van de Kant, H.J.; Davids, J.A.; Warmer, C.J.; Bootsma, A.L.; de Rooij, D.G. )

    1989-09-01

    Studies of the dose response of the spermatogonial stem cells in the rhesus monkey were performed at intervals of 130 and 160 days after graded doses of X irradiation. The D0 of the spermatogonial stem cells was established using the total numbers of the type A spermatogonia that were present at 130 and 160 days after irradiation and was found to be 1.07 Gy; the 95% confidence interval was 0.90-1.34 Gy.

  13. QMRA for Drinking Water: 2. The Effect of Pathogen Clustering in Single-Hit Dose-Response Models.

    PubMed

    Nilsen, Vegard; Wyller, John

    2016-01-01

    Spatial and/or temporal clustering of pathogens will invalidate the commonly used assumption of Poisson-distributed pathogen counts (doses) in quantitative microbial risk assessment. In this work, the theoretically predicted effect of spatial clustering in conventional "single-hit" dose-response models is investigated by employing the stuttering Poisson distribution, a very general family of count distributions that naturally models pathogen clustering and contains the Poisson and negative binomial distributions as special cases. The analysis is facilitated by formulating the dose-response models in terms of probability generating functions. It is shown formally that the theoretical single-hit risk obtained with a stuttering Poisson distribution is lower than that obtained with a Poisson distribution, assuming identical mean doses. A similar result holds for mixed Poisson distributions. Numerical examples indicate that the theoretical single-hit risk is fairly insensitive to moderate clustering, though the effect tends to be more pronounced for low mean doses. Furthermore, using Jensen's inequality, an upper bound on risk is derived that tends to better approximate the exact theoretical single-hit risk for highly overdispersed dose distributions. The bound holds with any dose distribution (characterized by its mean and zero inflation index) and any conditional dose-response model that is concave in the dose variable. Its application is exemplified with published data from Norovirus feeding trials, for which some of the administered doses were prepared from an inoculum of aggregated viruses. The potential implications of clustering for dose-response assessment as well as practical risk characterization are discussed. PMID:26812258

  14. A New Method for Synthesizing Radiation Dose-Response Data From Multiple Trials Applied to Prostate Cancer

    SciTech Connect

    Diez, Patricia; Vogelius, Ivan S.; Bentzen, Soren M.

    2010-07-15

    Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, {gamma}{sub 50}, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies. Results: Nonrandomized studies produced a statistically significantly higher {gamma}{sub 50} than randomized studies for intermediate- to high-risk patients ({gamma}{sub 50} = 1.63 vs. {gamma}{sub 50} = 0.93, p = 0.03) and a borderline significantly higher ({gamma}{sub 50} = 1.78 vs. {gamma}{sub 50} = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in {gamma}{sub 50} was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of {gamma}{sub 50} = 0.84 with 95% confidence interval 0.54-1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients.

  15. Influence of the Culture Medium in Dose-Response Effect of the Chlorhexidine on Streptococcus mutans Biofilms

    PubMed Central

    de Queiroz, Vanessa Salvadego; Ccahuana-Vásquez, Renzo Alberto; Tedesco, Alcides Fabiano; Lyra, Luzia; Cury, Jaime Aparecido; Schreiber, Angélica Zaninelli

    2016-01-01

    The aim of this study was to evaluate the influence of culture medium on dose-response effect of chlorhexidine (CHX) on Streptococcus mutans UA159 biofilm and validate the use of the cation-adjusted-Müller-Hinton broth (MH) for the evaluation of antibacterial activity. Ultrafiltered Tryptone-Yeast Extract Broth (UTYEB) was compared against MH and MH with blood supplementation (MHS). For each medium, six groups (n = 4) were assessed: two negative control groups (baseline 48 and 120 h) and four experimental groups (0.0001, 0.001, 0.012, and 0.12% CHX). S. mutans biofilm grew on glass slides of each media containing 1% sucrose. After 48 h of growth, biofilms of baseline 48 h were collected and the other groups were treated for 1 min, twice a day, for 3 days, with their respective treatments. The media were changed daily and pH was measured. After 120 h, biofilms were collected and dry weight and viable microorganisms were determined. Results showed CHX dose-response effect being observed in all media for all the variables. However, MH and MHS showed higher sensitivity than UTYEB (p < 0.05). We can conclude that the culture medium does influence dose-response effect of CHX on Streptococcus mutans biofilm and that MH can be used for antibacterial activity. PMID:27293967

  16. In situ protocol for the determination of dose-response effect of low-fluoride dentifrices on enamel remineralization

    PubMed Central

    AFONSO, Rebeca Lima; PESSAN, Juliano Pelim; IGREJA, Bruna Babler; CANTAGALLO, Camila Fernandes; DANELON, Marcelle; DELBEM, Alberto Carlos Botazzo

    2013-01-01

    No in situ protocol has assessed the dose-response effects of fluoride dentifrices involving low-fluoride formulations. Objective To assess the ability of an in situ remineralization model in determining dose-response effects of dentifrices containing low fluoride concentrations ([F]) on bovine enamel. Material and Methods Volunteers wore palatal appliances containing demineralized enamel blocks and brushed their teeth and devices with the dentifrices supplied (double-blind, crossover protocol) separately for 3 and 7 days. Surface hardness (SH), integrated subsurface hardness (ΔKHN) and [F] in enamel were determined. Data were analyzed by ANOVA, Tukey's test and Pearson's correlation (p<0.05). Results Dose-response relationships were verified between [F] in dentifrices and SH, ΔKHN and enamel [F]. Higher correlation coefficients between enamel [F] and SH and ΔKHN were obtained for the 3-day period. Significant differences in SH and ΔKHN were observed among all groups for the 3-day period, but not between 0-275, 275-550, and 550-1,100 µg F/g dentifrices for the 7-day period, nor between 3- and 7-day periods for the 1,100 µg F/g groups. Conclusions Considering that the peak remineralization capacity of the conventional dentifrice (1,100 µg F/g) was achieved in 3 days, this experimental period could be used in future studies assessing new dentifrice formulations, especially at low-fluoride concentrations. PMID:24473718

  17. Dose-response of x-ray-induced anaphase aberrations in the mitotic root tip chromosomes of allium

    SciTech Connect

    Ma, T.H.; Lee, K.H.; Kong, M.S.

    1995-11-01

    A simplified Allium root mitotic chromosome aberration assay by using only the aberrant anaphases (fragments, laggards and bridges) as the end-points were developed by Rank and Nielsen (1993) for screening water soluble chemicals and complex mixtures. A dose-response curve was established by Meir et al., (1994) using a known clastogen, 4-nitroquinolene-N-oxide between the dose range of 0.1-0.5 ug/ml. In order to further validate this assay for clastogen detection, a series of X-ray dose response experiments was carried out. Allium roots were germinated in tapwater for 48 h and treated with a series of 10, 20, 30, 40, 50, 60 R (80 Kvp, 5 ma, dose rate 60 R/min) dosages. After an 18 hr recovery time, the root tips were hydrolyzed in 45% acetic and 1 N HC1 acid (9:1 ratio) solution under 50{degrees} C for 5 min and stained with aceto-carmine. Each of the data points were derived from scoring 7-10 slides (15-50 anaphases/slide). The corrrelation coefficient, slope and intercept values of the dose-response curve are: 0.954, 0.515 and 1.155 respectively.

  18. Diverse dose-response effects of yolk androgens on embryo development and nestling growth in a wild passerine.

    PubMed

    Muriel, Jaime; Pérez-Rodríguez, Lorenzo; Puerta, Marisa; Gil, Diego

    2015-07-01

    Avian egg yolks contain various amounts of maternally derived androgens that can modify offspring phenotype and adjust their development to the post-hatching environment. Seemingly adaptive variation in yolk androgen levels with respect to breeding density conditions or male attractiveness has been found in numerous studies. One important consideration that has been overlooked in previous research is the likely non-linear nature of hormone effects. To examine possible complex dose-response effects of maternal androgens on chick development, we experimentally administered three different androgen doses of the naturally occurring mixture of yolk testosterone and androstenedione to spotless starling eggs (Sturnus unicolor). We found that yolk androgens induce a non-linear dose-response pattern in several traits. Androgens had a stimulatory effect on hatchling body mass and nestling skeletal growth, but maximum values were found at intermediate doses, whereas our highest dose resulted in a decrease. However, the opposite U-shaped effect was found on nestling body mass. We also detected linear negative and positive effects on embryonic development period and nestling gape width, respectively. Our results suggest differential tissue responsiveness to yolk androgens, which may result in compromises in maternal allocation to produce adapted phenotypes. Because of the non-linear dose-response pattern, future investigations should carefully consider a wide range of concentrations, as the balance of costs and benefits may strongly differ depending on concentration. PMID:25987739

  19. Influence of the Culture Medium in Dose-Response Effect of the Chlorhexidine on Streptococcus mutans Biofilms.

    PubMed

    de Queiroz, Vanessa Salvadego; Ccahuana-Vásquez, Renzo Alberto; Tedesco, Alcides Fabiano; Lyra, Luzia; Cury, Jaime Aparecido; Schreiber, Angélica Zaninelli

    2016-01-01

    The aim of this study was to evaluate the influence of culture medium on dose-response effect of chlorhexidine (CHX) on Streptococcus mutans UA159 biofilm and validate the use of the cation-adjusted-Müller-Hinton broth (MH) for the evaluation of antibacterial activity. Ultrafiltered Tryptone-Yeast Extract Broth (UTYEB) was compared against MH and MH with blood supplementation (MHS). For each medium, six groups (n = 4) were assessed: two negative control groups (baseline 48 and 120 h) and four experimental groups (0.0001, 0.001, 0.012, and 0.12% CHX). S. mutans biofilm grew on glass slides of each media containing 1% sucrose. After 48 h of growth, biofilms of baseline 48 h were collected and the other groups were treated for 1 min, twice a day, for 3 days, with their respective treatments. The media were changed daily and pH was measured. After 120 h, biofilms were collected and dry weight and viable microorganisms were determined. Results showed CHX dose-response effect being observed in all media for all the variables. However, MH and MHS showed higher sensitivity than UTYEB (p < 0.05). We can conclude that the culture medium does influence dose-response effect of CHX on Streptococcus mutans biofilm and that MH can be used for antibacterial activity. PMID:27293967

  20. Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.

    PubMed

    Ji, Zhiying; LeBaron, Matthew J; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Gollapudi, B Bhaskar; Pottenger, Lynn H

    2016-05-01

    The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose-response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose-response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA-reactive agents. PMID:26040483

  1. A Linear Dose-Response Relationship between Fasting Plasma Glucose and Colorectal Cancer Risk: Systematic Review and Meta-analysis

    PubMed Central

    Shi, Jianguo; Xiong, Lijuan; Li, Jiaoyuan; Cao, Heng; Jiang, Wen; Liu, Bo; Chen, Xueqin; Liu, Cheng; Liu, Ke; Wang, Guobin; Cai, Kailin

    2015-01-01

    For many years, the question of whether hyperglycaemia, a manifestation of prediabetes, diabetes mellitus and metabolic syndrome, is a risk factor for colorectal cancer has been intensely studied. In fact, even after the conclusion of several prospective studies, the topic is still controversial. We conducted a systematic review and meta-analysis to investigate the dose-response relationship between blood glucose concentration and the incidence of colorectal cancer. A linear (P = 0.303 for non-linearity) dose-response relationship was observed between fasting plasma glucose (FPG) and colorectal cancer risk without significant heterogeneity. The relative risk (RR) for colorectal cancer per 20 mg/dL increase in FPG was 1.015 (95% CI: 1.012–1.019, P = 0.000). In subgroup analyses, the pooled RRs for colon cancer (CC) and rectal cancer (RC) studies were 1.035 (95% CI 1.008–1.062, P = 0.011) and 1.031 (95% CI: 0.189–5.628, P = 0.972), respectively; in the analysis comparing men and women, the pooled RRs were 1.016 (95% CI: 1.012–1.020, P = 0.000) and 1.011 (95% CI: 0.995–1.027, P = 0.164), respectively. Sensitivity analyses using two methods showed similar results. In conclusion, there is a significant linear dose-response relationship between FPG and the incidence risk of colorectal cancer. For people with diabetes or prediabetes, controlling blood glucose might be useful to prevent colorectal cancer. PMID:26620869

  2. Body mass index and risk of lung cancer: Systematic review and dose-response meta-analysis

    PubMed Central

    Duan, Peng; Hu, Chunhui; Quan, Chao; Yi, Xianfu; Zhou, Wei; Yuan, Meng; Yu, Tingting; Kourouma, Ansoumane; Yang, Kedi

    2015-01-01

    Questions remain about the significance of the dose-response relationship between body mass index (BMI) and lung cancer (LC) risk. Pertinent studies were identified through a search in EMBASE and PUBMED from July 2014 until March 2015. The summary relative risk (SRR) and confidence interval (CI) were estimated. The dose-response relationship was assessed using a restricted cubic spline. The overall meta-analysis showed evidence of a nonlinear association between BMI and LC risk (Pnonlinearity < 0.001). The SRR were 0.98 (95%CI: 0.95–1.01) for 25 kg/m2, 0.91 (95%CI: 0.85–0.98) for 30 kg/m2 and 0.81 (95% CI: 0.72–0.91) for 35 kg/m2, with mild between-study heterogeneity (I2 = 5%). The results of the stratified analysis by gender were comparable to those of the overall meta-analysis. When stratified by smoking status, linear dose-response associations were observed for current smokers, ex-smokers and non-smokers (Pnonlinearity > 0.05), whereas the effects were attenuated when restricting analysis to non-smokers, and at the point of 30 kg/m2, the SRR was 0.96 (95%CI: 0.86–1.07) for males and 0.95 (95%CI: 0.89–1.02) for females. This meta-analysis provides quantitative evidence that increasing BMI is a protective factor against LC. Keeping normal-to-moderate BMI should be prescribed as an evidence-based lifestyle tip for LC prevention in smokers. PMID:26582414

  3. Cholesterol consumption and risk of endometrial cancer: a systematic review and dose-response meta-analysis of observational studies

    PubMed Central

    Gong, Ting-Ting; Li, Da; Wu, Qi-Jun; Wang, Ya-Zhu

    2016-01-01

    In vivo and in vitro studies have indicated the link of cholesterol consumption and endometrial cancer risk, however, previous observational studies have yielded inconsistent results. Additionally, a previous meta-analysis published in 2007 found limited evidence of aforementioned association. Therefore, we performed the dose-response meta-analysis to address this concern. Studies were identified using the PubMed, EMBASE and Web of Science databases from the database inception to the end of June 2015 as well as by examining the references of retrieved articles. Two authors independently performed the eligibility evaluation and data extraction. The summary risk estimates and 95% confidence intervals (CIs) were summarized by the random-effects models. One cohort and nine case-control studies were included in the dose-response analyses. Risk of endometrial cancer increased by 6% for 100 mg/day increment in the dietary consumption of cholesterol (Odds ratio (OR) = 1.06; 95% CI = 1.00–1.12), with significant heterogeneity (I2 = 64.2, P = 0.003). When stratified by study design, the result was significant in case-control studies (OR = 1.07; 95% CI = 1.01–1.13). Additionally, although the direction of the associations were consistent in the subgroup analyses stratified by study characteristics and adjustment for potential confounders, not all of them showed statistical significance. In summary, findings of the present dose-response meta-analysis partly support the positive association between dietary cholesterol consumption and risk of endometrial cancer. Since only one cohort study was included, more prospective studies and pooled analysis of observational studies are warranted to confirm our findings in the future. PMID:26959738

  4. Second Solid Cancers After Radiation Therapy: A Systematic Review of the Epidemiologic Studies of the Radiation Dose-Response Relationship

    SciTech Connect

    Berrington de Gonzalez, Amy; Gilbert, Ethel; Curtis, Rochelle; Inskip, Peter; Kleinerman, Ruth; Morton, Lindsay; Rajaraman, Preetha; Little, Mark P.

    2013-06-01

    Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.

  5. Dose-Response Analysis of Chemotactic Signaling Response in Salmonella typhimurium LT2 upon Exposure to Cysteine / Cystine Redox Pair

    PubMed Central

    2016-01-01

    The chemotaxis system enables motile bacteria to search for an optimum level of environmental factors. Salmonella typhimurium senses the amino acid cysteine as an attractant and its oxidized dimeric form, cystine, as a repellent. We investigated the dose-response dependence of changes in chemotactic signaling activity upon exposure to cysteine and cystine of S. typhimurium LT2 using in vivo fluorescence resonance energy transfer (FRET) measurements. The dose-response curve of the attractant response to cysteine had a sigmoidal shape, typical for receptor-ligand interactions. However, in a knockout strain of the chemoreceptor genes tsr and tar, we detected a repellent response to cysteine solutions, scaling linearly with the logarithm of the cysteine concentration. Interestingly, the magnitude of the repellent response to cystine also showed linear dependence to the logarithm of the cystine concentration. This linear dependence was observed over more than four orders of magnitude, where detection started at nanomolar concentrations. Notably, low concentrations of another oxidized compound, benzoquinone, triggered similar responses. In contrast to S. typhimurium 14028, where no response to cystine was observed in a knockout strain of chemoreceptor genes mcpB and mcpC, here we showed that McpB / McpC-independent responses to cystine existed in the strain S. typhimurium LT2 even at nanomolar concentrations. Additionally, knocking out mcpB and mcpC did not affect the linear dose-response dependence, whereas enhanced responses were only observed to solutions that where not pH neutral (>100 μM cystine) in the case of McpC overexpression. We discuss that the linear dependence of the response on the logarithm of cystine concentrations could be a result of a McpB / C-independent redox-sensing pathway that exists in S. typhimurium LT2. We supported this hypothesis with experiments with defined cysteine / cystine mixed solutions, where a transition from repellent to

  6. An apparent threshold dose response in ferrous xylenol-orange gel dosimeters when scanned with a yellow light source

    NASA Astrophysics Data System (ADS)

    Babic, Steven; Battista, Jerry; Jordan, Kevin

    2008-03-01

    Freshly prepared radiochromic ferrous xylenol-orange (FX) gels optically scanned with a light source exhibit a threshold dose response that is thermally and wavelength dependent. Correction for this threshold dose leads to accurate dose calibration and better reproducibility in multiple fraction radiation exposures. The objective of this study was to determine the cause of the threshold dose effect and to control it through improved dose calibration procedures. The results of a systematic investigation into the chemical cause revealed that impurities within the various FX gel constituents (i.e. xylenol-orange, gelatin, sulfuric acid and ferrous ammonium sulfate) were not directly responsible for the threshold dose. Rather, it was determined that the threshold dose response stems from a spectral sensitivity to different chemical complexes that are formed at different dose levels in FX gels between ferric (Fe(III)) ions and xylenol-orange (XO), i.e. Fe(III)i:XOj. A double Fe(III)2:XO1 complex preferentially absorbs at longer wavelengths (i.e. yellow), while at shorter wavelengths (i.e. green) the sensitivity is biased toward the single Fe(III)1:XO1 complex. As a result, when scanning with yellow light, freshly prepared FX gels require a minimum concentration of Fe(III) ions to shift the equilibrium concentration to favor the predominant production of the double Fe(III)2:XO1 complex at low doses. This can be accomplished via pre-irradiation of freshly prepared gels to a priming dose of ~0.5 Gy or allowing auto-oxidation to generate the startup concentration of Fe(III) ions required to negate the apparent threshold dose response.

  7. Synchrotron radiation in the study of the variation of dose response in thermoluminescence dosimeters with radiation energy.

    PubMed

    Kron, T; Smith, A; Hyodo, K

    1996-12-01

    Thermoluminescence dosimetry (TLD) is a versatile technique with many applications for dosimetry of ionising radiation. However, in the range of kilovoltage x-rays which is widely used for diagnostic and therapeutic medical applications, problems arise from the differing dose response of most TL dosimeters with the radiation energy. The dose response of various TL detector types was investigated in mono-energetic x-ray beams of 26.8, 33.2, 40, 80.4 and 99.6keV from a synchrotron radiation source at the National Laboratory for High Energy Physics in Japan. This response was studied as a function of TL material (LiF:Mg,Ti, LiF:Mg,Cu,P and Al2O3), the detector geometry and size, and their thermal history. Due to the asymmetric diffraction from a Si crystal employed to produce monoenergetic photons there was more than 50% dose inhomogeneity in some of radiation fields used. Therefore, the different TL dosimeter types were rotated around and the results related to the reading of a set of "standard" LiF:Mg,Ti ribbons which were included in all experiments as reference detectors. No significant influence of the detector shape (physical size, thickness) on the dose response with energy could be found. However, the pre-irradiation thermal history influences the dose response with radiation energy: a fast cool down of LiF:Mg,Ti after a high temperature anneal will increase the sensitivity by more than a factor of two. The relatively new TLD material LiF:Mg,Cu,P (GR-200, obtained from Solid Dosimeter & Detector Laboratories, Beijing) was found to be approximately 100 times more sensitive than the standard LiF:Mg,Ti. In addition it proved to be more tissue equivalent for photon radiation between 27keV and 40keV. The performance of LiF:Mg,Cu,P makes it a very interesting TL material deserving further evaluation for applications in diagnostic and therapeutic x-rays. PMID:9060209

  8. Occupational Exposure to Diesel Motor Exhaust and Lung Cancer: A Dose-Response Relationship Hidden by Asbestos Exposure Adjustment? The ICARE Study.

    PubMed

    Matrat, Mireille; Guida, Florence; Cénée, Sylvie; Févotte, Joelle; Carton, Matthieu; Cyr, Diane; Menvielle, Gwenn; Paget-Bailly, Sophie; Radoï, Loredana; Schmaus, Annie; Bara, Simona; Velten, Michel; Luce, Danièle; Stücker, Isabelle; The Icare Study Group

    2015-01-01

    Background. In a French large population-based case-control study we investigated the dose-response relationship between lung cancer and occupational exposure to diesel motor exhaust (DME), taking into account asbestos exposure. Methods. Exposure to DME was assessed by questionnaire. Asbestos was taken into account through a global indicator of exposure to occupational carcinogens or by a specific JEM. Results. We found a crude dose response relationship with most of the indicators of DME exposure, including with the cumulative exposure index. All results were affected by adjustment for asbestos exposure. The dose response relationships between DME and lung cancer were observed among subjects never exposed to asbestos. Conclusions. Exposure to DME and to asbestos is frequently found among the same subjects, which may explain why dose-response relationships in previous studies that adjusted for asbestos exposure were inconsistent. PMID:26425123

  9. Occupational Exposure to Diesel Motor Exhaust and Lung Cancer: A Dose-Response Relationship Hidden by Asbestos Exposure Adjustment? The ICARE Study

    PubMed Central

    Matrat, Mireille; Guida, Florence; Cénée, Sylvie; Févotte, Joelle; Carton, Matthieu; Cyr, Diane; Menvielle, Gwenn; Paget-Bailly, Sophie; Radoï, Loredana; Schmaus, Annie; Bara, Simona; Velten, Michel; Luce, Danièle; Stücker, Isabelle; The Icare Study Group

    2015-01-01

    Background. In a French large population-based case-control study we investigated the dose-response relationship between lung cancer and occupational exposure to diesel motor exhaust (DME), taking into account asbestos exposure. Methods. Exposure to DME was assessed by questionnaire. Asbestos was taken into account through a global indicator of exposure to occupational carcinogens or by a specific JEM. Results. We found a crude dose response relationship with most of the indicators of DME exposure, including with the cumulative exposure index. All results were affected by adjustment for asbestos exposure. The dose response relationships between DME and lung cancer were observed among subjects never exposed to asbestos. Conclusions. Exposure to DME and to asbestos is frequently found among the same subjects, which may explain why dose-response relationships in previous studies that adjusted for asbestos exposure were inconsistent. PMID:26425123

  10. The Key Events Dose-Response Framework: A cross-Disciplinary Mode-of-Action Based Approach to Examining Does-Response and Thresholds

    EPA Science Inventory

    the ILSI Research Foundation conveded a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categoreis of bioactive agents: food allergens, nutrients, pathogenic microorganisms, and ...

  11. BIOLOGICALLY-BASED DOSE-RESPONSE MODELING IN DEVELOPMENTAL TOXICOLOGY: BIOCHEMICAL AND CELLULAR SEQUELAE OF 5-FLUOROURACIL EXPOSURE IN THE DEVELOPING RAT

    EPA Science Inventory

    Mechanistically-based dose-response models for developmental toxicity require elucidation of biological events that intervene between maternal exposure and adverse developmental outcome. We examined some of the major events in the rat embryo following subcutaneous injection of 5-...

  12. Biphasic and triphasic dose responses in zebrafish embryos to low-dose 150 kV X-rays with different levels of hardness

    PubMed Central

    Kong, Eva Yi; Cheng, Shuk Han; Yu, Kwan Ngok

    2016-01-01

    The in vivo low-dose responses of zebrafish (Danio rerio) embryos to 150 kV X-rays with different levels of hardness were examined through the number of apoptotic events revealed at 24 h post fertilization by vital dye acridine orange staining. Our results suggested that a triphasic dose response was likely a common phenomenon in living organisms irradiated by X-rays, which comprised an ultra-low-dose inhibition, low-dose stimulation and high-dose inhibition. Our results also suggested that the hormetic zone (or the stimulation zone) was shifted towards lower doses with application of filters. The non-detection of a triphasic dose response in previous experiments could likely be attributed to the use of hard X-rays, which shifted the hormetic zone into an unmonitored ultra-low-dose region. In such cases where the subhormetic zone was missed, a biphasic dose response would be reported instead. PMID:26951078

  13. Dose-response relations between second-hand smoke exposure and depressive symptoms among middle-aged women.

    PubMed

    Ye, Xiaohua; Li, LiXia; Gao, Yanhui; Zhou, Shudong; Yang, Yi; Chen, Sidong

    2015-09-30

    A growing body of evidence indicates a strong association between smoking and depression. However, little is known about the possible effects of second-hand smoke (SHS) exposure on depression. This study aimed to examine the potential dose-response relation between SHS exposure and depressive symptoms among non-smoking middle-aged women. A cross-sectional survey was conducted using a stratified three-stage sampling method. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale with a cut-off point of 16. Self-reported SHS exposure was defined as non-smokers׳ inhalation of the smoke exhaled from smokers on at least one day a week. The multivariable logistic regression analysis was completed with adjustment for potential confounders. Among 1280 middle-aged women, 19.4% were classified as having depressive symptoms. There was a 104% increased odds of depressive symptoms corresponding to SHS exposure in general (OR=2.04, 95% CI 1.48-2.79) using no exposure as reference. There were significant positive relations between SHS exposure in general and depressive symptoms in a dose-response manner. These significant trends were observed consistently whether SHS exposure occurred in homes or workplaces. Our findings suggest that long-term and regular SHS exposure is associated with a significant, dose-dependent increase in risk of depressive symptoms. PMID:26231582

  14. Origins and application of the European Union Position paper on dose response relationships between transportation noise and annoyance

    NASA Astrophysics Data System (ADS)

    Berry, Bernard F.

    2003-10-01

    Dose-response relationships of the sort pioneered by Schultz figure prominently in the current European noise regulation policy. A position paper developed by the Working Group on Dose-effects (part of the EU Expert Network) reviewed a range of potential health effects, but decided that annoyance and sleep disturbance remain the most prevalent and sensitive effects of transportation noise exposure, and those for which the best data were available. A Position paper providing guidance on the dose-effect relations to be used for the assessment of numbers of people annoyed by noise from transportation sources (rail, road and air) may be found at http://europa.eu.int/comm/environment/noise/home.htm This presentation explains the context in which the Paper was developed, outlines the process by which the dose-response relationships were derived and summarizes the key recommendations. Finally some observations are made as the Position Paper is being applied, and related future developments are discussed. The author acknowledges with deep gratitude the assistance of Dr. Henk Miedema of TNO in preparing this paper.

  15. Limitations in dose-response and surrogate species methodologies for risk assessment of Cry toxins on arthropod natural enemies.

    PubMed

    Paula, Débora P; Andow, David A; Bellinati, André; Timbó, Renata Velozo; Souza, Lucas M; Pires, Carmen S S; Sujii, Edison R

    2016-04-01

    Dose-response assays and surrogate species are standard methods for risk analysis for environmental chemicals. These assume that individuals within a species have unimodal responses and that a surrogate species can predict responses of other related taxa. We exposed immature individuals of closely related aphidophagous coccinellid predators, Cycloneda sanguinea and Harmonia axyridis, to Cry1Ac and Cry1F toxins through uniform and constant artificial tritrophic exposure through Myzus persicae aphids. Both toxins were detected in coccinellid pupae, with individual and interspecific variation. Uptake was significantly higher in H. axyridis than in C. sanguinea, both in the proportion of individuals and the concentrations per individual. We also observed bimodal uptake of the Cry toxins by H. axyridis, which indicated that some individuals had low bioaccumulation and some had high bioaccumulation. This suggests that standard dose-response assays need to be interpreted with caution and future assays should examine the modality of the responses. In addition, the similarity in the biological effects of the Cry toxins in the two predators was due to different biological exposure mechanisms. The majority of H. axyridis were exposed both internally and in the gut, while C. sanguinea was exposed primarily in the gut. Thus, despite their close phylogenetic relatedness, these species would not be good surrogates for each other and the surrogate species methodology should be tested more rigorously. PMID:26846212

  16. Untargeted Metabolomics Reveals Dose-Response Characteristics for Effect of Rhubarb in a Rat Model of Cholestasis

    PubMed Central

    Zhang, Cong-En; Niu, Ming; Li, Rui-Yu; Feng, Wu-Wen; Ma, Xiao; Dong, Qin; Ma, Zhi-Jie; Li, Guang-Quan; Meng, Ya-Kun; Wang, Ya; Yin, Ping; He, Lan-Zhi; Li, Yu-Meng; Tan, Peng; Zhao, Yan-Ling; Wang, Jia-Bo; Dong, Xiao-Ping; Xiao, Xiao-He

    2016-01-01

    Cholestasis is a serious manifestation of liver diseases with limited therapies. Rhubarb, a widely used herbal medicine, has been frequently used at a relatively large dose for treating cholestasis. However, whether large doses are optimal and the therapeutic mechanism remain unclear. To explore these questions, the anti-cholestatic effect of five doses of rhubarb (0.21, 0.66, 2.10, 6.60, and 21.0 g/kg) in an alpha-naphthylisothiocyanate (ANIT)-induced rat model of cholestasis was examined by histopathology and serum biochemistry. A dose-dependent anti-cholestatic effect of rhubarb (0.21–6.6 g/kg) was observed, and an overdose of 21.0 g/kg showed a poor effect. LC-MS-based untargeted metabolomics together with pathway analysis were further applied to characterize the metabolic alterations induced by the different rhubarb doses. Altogether, 13 biomarkers were identified. The dose-response curve based on nine important biomarkers indicated that doses in the 0.42–6.61 g/kg range (EC20–EC80 range, corresponding to 4.00–62.95 g in the clinic) were effective for cholestasis treatment. The pathway analysis showed that bile acid metabolism and excretion, inflammation and amino acid metabolism were altered by rhubarb in a dose-dependent manner and might be involved in the dose-response relationship and therapeutic mechanism of rhubarb for cholestasis treatment. PMID:27065293

  17. Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment

    NASA Astrophysics Data System (ADS)

    Al-Mayah, Adil; Moseley, Joanne; Hunter, Shannon; Brock, Kristy

    2015-11-01

    Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose-induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D).

  18. Benchmarking B-Cell Epitope Prediction with Quantitative Dose-Response Data on Antipeptide Antibodies: Towards Novel Pharmaceutical Product Development

    PubMed Central

    Caoili, Salvador Eugenio C.

    2014-01-01

    B-cell epitope prediction can enable novel pharmaceutical product development. However, a mechanistically framed consensus has yet to emerge on benchmarking such prediction, thus presenting an opportunity to establish standards of practice that circumvent epistemic inconsistencies of casting the epitope prediction task as a binary-classification problem. As an alternative to conventional dichotomous qualitative benchmark data, quantitative dose-response data on antibody-mediated biological effects are more meaningful from an information-theoretic perspective in the sense that such effects may be expressed as probabilities (e.g., of functional inhibition by antibody) for which the Shannon information entropy (SIE) can be evaluated as a measure of informativeness. Accordingly, half-maximal biological effects (e.g., at median inhibitory concentrations of antibody) correspond to maximally informative data while undetectable and maximal biological effects correspond to minimally informative data. This applies to benchmarking B-cell epitope prediction for the design of peptide-based immunogens that elicit antipeptide antibodies with functionally relevant cross-reactivity. Presently, the Immune Epitope Database (IEDB) contains relatively few quantitative dose-response data on such cross-reactivity. Only a small fraction of these IEDB data is maximally informative, and many more of them are minimally informative (i.e., with zero SIE). Nevertheless, the numerous qualitative data in IEDB suggest how to overcome the paucity of informative benchmark data. PMID:24949474

  19. Dose-response effect of black maca (Lepidium meyenii) in mice with memory impairment induced by ethanol.

    PubMed

    Rubio, Julio; Yucra, Sandra; Gasco, Manuel; Gonzales, Gustavo F

    2011-10-01

    Previous studies have shown that black variety of maca has beneficial effects on learning and memory in experimental animal models. The present study aimed to determine whether the hydroalcoholic extract of black maca (BM) showed a dose-response effect in mice treated with ethanol 20% (EtOH) as a model of memory impairment. Mice were divided in the following groups: control, EtOH, ascorbic acid (AA) and 0.125, 0.25, 0.50 and 1.00 g/kg of BM plus EtOH. All treatments were orally administered for 28 days. Open field test was performed to determine locomotor activity and water Morris maze was done to determine spatial memory. Also, total polyphenol content in the hydroalcoholic extract of BM was determined (0.65 g pyrogallol/100 g). Mice treated with EtOH took more time to find the hidden platform than control during escape acquisition trials; meanwhile, AA and BM reversed the effect of EtOH. In addition, AA and BM ameliorated the deleterious effect of EtOH during the probe trial. Correlation analyses showed that the effect of BM a dose-dependent behavior. Finally, BM improved experimental memory impairment induced by ethanol in a dose-response manner due, in part, to its content of polyphenolic compounds. PMID:21780878

  20. Dose-response relationships for the onset of avoidance of sonar by free-ranging killer whales.

    PubMed

    Miller, Patrick J O; Antunes, Ricardo N; Wensveen, Paul J; Samarra, Filipa I P; Alves, Ana Catarina; Tyack, Peter L; Kvadsheim, Petter H; Kleivane, Lars; Lam, Frans-Peter A; Ainslie, Michael A; Thomas, Len

    2014-02-01

    Eight experimentally controlled exposures to 1-2 kHz or 6-7 kHz sonar signals were conducted with four killer whale groups. The source level and proximity of the source were increased during each exposure in order to reveal response thresholds. Detailed inspection of movements during each exposure session revealed sustained changes in speed and travel direction judged to be avoidance responses during six of eight sessions. Following methods developed for Phase-I clinical trials in human medicine, response thresholds ranging from 94 to 164 dB re 1 μPa received sound pressure level (SPL) were fitted to Bayesian dose-response functions. Thresholds did not consistently differ by sonar frequency or whether a group had previously been exposed, with a mean SPL response threshold of 142 ± 15 dB (mean ± s.d.). High levels of between- and within-individual variability were identified, indicating that thresholds depended upon other undefined contextual variables. The dose-response functions indicate that some killer whales started to avoid sonar at received SPL below thresholds assumed by the U.S. Navy. The predicted extent of habitat over which avoidance reactions occur depends upon whether whales responded to proximity or received SPL of the sonar or both, but was large enough to raise concerns about biological consequences to the whales. PMID:25234905

  1. Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice.

    PubMed

    Cai, Hong; Scott, Edwina; Kholghi, Abeer; Andreadi, Catherine; Rufini, Alessandro; Karmokar, Ankur; Britton, Robert G; Horner-Glister, Emma; Greaves, Peter; Jawad, Dhafer; James, Mark; Howells, Lynne; Ognibene, Ted; Malfatti, Michael; Goldring, Christopher; Kitteringham, Neil; Walsh, Joanne; Viskaduraki, Maria; West, Kevin; Miller, Andrew; Hemingway, David; Steward, William P; Gescher, Andreas J; Brown, Karen

    2015-07-29

    Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times higher. The dose-response relationship for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels. In Apc(Min) mice (a model of colorectal carcinogenesis) that received a high-fat diet, the low resveratrol dose suppressed intestinal adenoma development more potently than did the higher dose. Efficacy correlated with activation of adenosine monophosphate-activated protein kinase (AMPK) and increased expression of the senescence marker p21. Nonlinear dose responses were observed for AMPK and mechanistic target of rapamycin (mTOR) signaling in mouse adenoma cells, culminating in autophagy and senescence. In human colorectal tissues exposed to low dietary concentrations of resveratrol ex vivo, we measured enhanced AMPK phosphorylation and autophagy. The expression of the cytoprotective NAD(P)H dehydrogenase, quinone 1 (NQO1) enzyme was also increased in tissues from cancer patients participating in our [(14)C]-resveratrol trial. These findings warrant a revision of developmental strategies for diet-derived agents designed to achieve cancer chemoprevention. PMID:26223300

  2. Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment.

    PubMed

    Al-Mayah, Adil; Moseley, Joanne; Hunter, Shannon; Brock, Kristy

    2015-11-01

    Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose-induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D). PMID:26485227

  3. The Key Events Dose-Response Framework: A Foundation for Examining Variability in Elicitation Thresholds for Food Allergens

    PubMed Central

    TAYLOR, STEVE L.; GENDEL, STEVEN M.; HOUBEN, GEERT F.; JULIEN, ELIZABETH

    2009-01-01

    Food allergies are caused by immunological reactions in individuals sensitized to normal protein components of foods. For any given sensitized individual, the severity of a reaction is generally assumed to be proportional to the dose of allergenic protein. There is substantial clinical evidence that “threshold” doses exist for the elicitation of an allergic reaction; however, the threshold (i.e., lowest dose that elicits a reaction) varies substantially across the sensitized population. Current approaches to protecting sensitized individuals from exposure to food allergens are highly qualitative (i.e., they rely on food avoidance). The Key Events Dose-Response Framework is an analytical approach for refining understanding of the biological basis of the dose-response. Application of this approach to food allergy provides a foundation for a more rigorous quantitative understanding of variability in allergic response. This study reviews the allergic disease process and the current approaches to identifying thresholds for food allergens. The pathway of key biological events occurring between food intake and allergic response is considered, along with factors that may determine the nature and severity of response to food allergens. Data needs, as well as implications for identifying thresholds, and for characterizing variability in thresholds, are also discussed. PMID:19690998

  4. Post-radioembolization yttrium-90 PET/CT - part 2: dose-response and tumor predictive dosimetry for resin microspheres

    PubMed Central

    2013-01-01

    Background Coincidence imaging of low-abundance yttrium-90 (90Y) internal pair production by positron emission tomography with integrated computed tomography (PET/CT) achieves high-resolution imaging of post-radioembolization microsphere biodistribution. Part 2 analyzes tumor and non-target tissue dose-response by 90Y PET quantification and evaluates the accuracy of tumor 99mTc macroaggregated albumin (MAA) single-photon emission computed tomography with integrated CT (SPECT/CT) predictive dosimetry. Methods Retrospective dose quantification of 90Y resin microspheres was performed on the same 23-patient data set in part 1. Phantom studies were performed to assure quantitative accuracy of our time-of-flight lutetium-yttrium-oxyorthosilicate system. Dose-responses were analyzed using 90Y dose-volume histograms (DVHs) by PET voxel dosimetry or mean absorbed doses by Medical Internal Radiation Dose macrodosimetry, correlated to follow-up imaging or clinical findings. Intended tumor mean doses by predictive dosimetry were compared to doses by 90Y PET. Results Phantom studies demonstrated near-perfect detector linearity and high tumor quantitative accuracy. For hepatocellular carcinomas, complete responses were generally achieved at D70 > 100 Gy (D70, minimum dose to 70% tumor volume), whereas incomplete responses were generally at D70 < 100 Gy; smaller tumors (<80 cm3) achieved D70 > 100 Gy more easily than larger tumors. There was complete response in a cholangiocarcinoma at D70 90 Gy and partial response in an adrenal gastrointestinal stromal tumor metastasis at D70 53 Gy. In two patients, a mean dose of 18 Gy to the stomach was asymptomatic, 49 Gy caused gastritis, 65 Gy caused ulceration, and 53 Gy caused duodenitis. In one patient, a bilateral kidney mean dose of 9 Gy (V20 8%) did not cause clinically relevant nephrotoxicity. Under near-ideal dosimetric conditions, there was excellent correlation between intended tumor mean doses by predictive dosimetry and those

  5. Parity and All-cause Mortality in Women and Men: A Dose-Response Meta-Analysis of Cohort Studies

    PubMed Central

    Zeng, Yun; Ni, Ze-min; Liu, Shu-yun; Gu, Xue; Huang, Qin; Liu, Jun-an; Wang, Qi

    2016-01-01

    To quantitatively assess the association between parity and all-cause mortality, we conducted a meta-analysis of cohort studies. Relevant reports were identified from PubMed and Embase databases. Cohort studies with relative risks (RRs) and 95% confidence intervals (CIs) of all-cause mortality in three or more categories of parity were eligible. Eighteen articles with 2,813,418 participants were included. Results showed that participants with no live birth had higher risk of all-cause mortality (RR= 1.19, 95% CI = 1.03–1.38; I2 = 96.7%, P < 0.001) compared with participants with one or more live births. Nonlinear dose-response association was found between parity and all-cause mortality (P for non-linearity < 0.0001). Our findings suggest that moderate-level parity is inversely associated with all-cause mortality. PMID:26758416

  6. Mutations induced in Tradescantia by small doses of X-rays and neutrons - Analysis of dose-response curves.

    NASA Technical Reports Server (NTRS)

    Sparrow, A. H.; Underbrink, A. G.; Rossi, H. H.

    1972-01-01

    Dose-response curves for pink somatic mutations in Tradescantia stamen hairs were analyzed after neutron and X-ray irradiation with doses ranging from a fraction of a rad to the region of saturation. The dose-effect relation for neutrons indicates a linear dependence from 0.01 to 8 rads; between 0.25 and 5 rads, a linear dependence is indicated for X-rays also. As a consequence the relative biological effectiveness reaches a constant value (about 50) at low doses. The observations are in good agreement with the predictions of the theory of dual radiation action and support its interpretation of the effects of radiation on higher organisms. The doubling dose of X-rays was found to be nearly 1 rad.

  7. CurveP Method for Rendering High-Throughput Screening Dose-Response Data into Digital Fingerprints.

    PubMed

    Sedykh, Alexander

    2016-01-01

    The nature of high-throughput screening (HTS) puts certain limits on optimal test conditions for each particular sample, therefore, on top of usual data normalization, additional parsing is often needed to account for incomplete read outs or various artifacts that arise from signal interferences.CurveP is a heuristic, user-tunable, curve-cleaning algorithm that attempts to find a minimum set of corrections, which would give a monotonic dose-response curve. After applying the corrections, the algorithm proceeds to calculate a set of numeric features, which can be used as a fingerprint characterizing the sample, or as a vector of independent variables (e.g., molecular descriptors in case of chemical substances testing). The resulting output can be a part of HTS data analysis or can be used as input for a broad spectrum of computational applications, such as Quantitative Structure-Activity Relationship (QSAR) modeling, computational toxicology, bio- and cheminformatics. PMID:27518631

  8. Dose--response of initial G2-chromatid breaks induced in normal human fibroblasts by heavy ions

    NASA Technical Reports Server (NTRS)

    Kawata, T.; Durante, M.; Furusawa, Y.; George, K.; Takai, N.; Wu, H.; Cucinotta, F. A.; Dicello, J. F. (Principal Investigator)

    2001-01-01

    PURPOSE: To investigate initial chromatid breaks in prematurely condensed G2 chromosomes following exposure to heavy ions of different LET. MATERIAL AND METHODS: Exponentially growing human fibroblast cells AG1522 were irradiated with gamma-rays, energetic carbon (13 keV/ microm, 80 keV/microm), silicon (55 keV/microm) and iron (140 keV/microm, 185keV/microm, 440keV/microm) ions. Chromosomes were prematurely condensed using calyculin-A. Initial chromatid-type and isochromatid breaks in G2 cells were scored. RESULTS: The dose response curves for total chromatid breaks were linear regardless of radiation type. The relative biological effectiveness (RBE) showed a LET-dependent increase, peaking around 2.7 at 55-80keV/microm and decreasing at higher LET. The dose response curves for isochromatid-type breaks were linear for high-LET radiations, but linear-quadratic for gamma-rays and 13 keV/microm carbon ions. The RBE for the induction of isochromatid breaks obtained from linear components increased rapidly between 13keV/microm (about 7) and 80keV/microm carbon (about 71), and decreased gradually until 440 keV/microm iron ions (about 66). CONCLUSIONS: High-LET radiations are more effective at inducing isochromatid breaks, while low-LET radiations are more effective at inducing chromatid-type breaks. The densely ionizing track structures of heavy ions and the proximity of sister chromatids in G2 cells result in an increase in isochromatid breaks.

  9. The influences of nitric oxide, epinephrine, and dopamine on vascular tone: dose-response modeling and simulations

    PubMed Central

    Eugene, Andy R.

    2016-01-01

    Introduction Sodium Nitroprusside has successfully been an excellent choice when considering a decrease in systemic vascular resistance in the critical care setting. However, reflex tachycardia and ventilation-perfusion mismatch are possible side effects of this agent. To maintaining cardiac output, cerebral perfusion pressure, and concurrently drop SVR, low-dose epinephrine or dopamine are viable options. The aim of this paper is to conduct dose-response simulations to identify the equivalent dopamine, epinephrine, and nitroprusside infusion doses to decrease the systemic vascular resistance by 20% and by 40% from baseline resting values. Methods Three studies were identified in the literature with reported epinephrine, dopamine, and sodium nitroprusside infusion doses with corresponding systemic vascular resistance responses. Infusion doses were normalized to mcg/kg/min and SVR values were normalized and scaled to the percent decrease (%SVR) in SVR from baseline resting values. The original published studies were mathematically modeled and the Hill equation parameters used for further dose-response simulations of a virtual population. One-hundred patients were simulated various doses resulting in corresponding %SVR responses for each of the three drugs. Results Equivalent infusion doses achieving in an approximate 20-25% decrease in SVR, from baseline, were identified for epinephrine, dopamine, and sodium nitroprusside. Moreover, equivalent infusion doses were identified for epinephrine and nitroprusside to decrease the SVR by 40% from baseline. Conclusion Even though sodium nitroprusside is traditionally used in decreasing SVR, low doses of dopamine or epinephrine are viable alternatives to patients with contraindications to nitroprusside infusions or who will require prolonged infusions to avoid toxicity. The multiple comparisons procedure-modeling approach is an excellent methodology for dose-finding exercises and has enabled identification of equivalent

  10. CHILDHOOD MALTREATMENT AND THE COURSE OF BIPOLAR DISORDERS AMONG ADULTS: EPIDEMIOLOGIC EVIDENCE OF DOSE-RESPONSE EFFECTS

    PubMed Central

    Sala, Regina; Goldstein, Benjamin I.; Wang, Shuai; Blanco, Carlos

    2014-01-01

    BACKGROUND Childhood maltreatment (CM) is highly prevalent among individuals with bipolar disorders (BP); however few studies have examined its potential role in the course and outcome of individuals with BP. We aim to examine the dose response relationship between the number of types of CM and the course of individuals with BP. METHODS As part of the National Epidemiologic Survey on Alcohol and Related Conditions, 1600 adults who met lifetime DSM-IV criteria for BP-I (n=1172) and BP-II (n=428) were included. Individuals were evaluated using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DMS-IV Version and data was analyzed lifetime and from Waves 1 and 2, approximately 3 years apart. RESULTS Around half of individuals with BP had a history of at least one type of CM. Overall, there was a clear dose-response relationship between number of CM and severity of BP across several domains, including clinical characteristics, probability of treatment, lifetime prevalence of psychiatric comorbidity, incidence of anxiety disorders, substance use disorder, and nicotine dependence, and level of psychosocial functioning. LIMITATIONS The interviews were conducted by lay professional interviewers rather than clinicians, use of retrospective report to determine CM in individuals with BP, and not all respondents from Wave 1 were able to be interviewed in Wave 2. CONCLUSIONS The number of types of CM confers developmental differences in the course of BP with a worse course and outcome of BP. Early identification and treatment of CM are warranted to improve the course and outcome of individuals with BP. PMID:24882181

  11. Nonlinear dose-response relationship in the immune system following exposure to ionizing radiation: mechanisms and implications.

    PubMed

    Liu, Shu-Zheng

    2003-01-01

    The health effects of low-dose radiation (LDR) have been the concern of the academic spheres, regulatory bodies, governments, and the public. Among these effects, the most important is carcinogenesis. In view of the importance of immune surveillance in cancer control, the dose-response relationship of the changes in different cell types of the immune system after whole-body irradiation is analyzed on the basis of systemic data from the author's laboratory in combination with recent reports in the literature. For T lymphocytes J- or inverted J-shaped curves are usually demonstrated after irradiation, while for macrophages dose-response curves of chiefly stimulation with irregular patterns are often observed. The intercellular reactions between the antigen presenting cell (APC) and T lymphocyte (TLC) in the immunologic synapse via expression of surface molecules and secretion of cytokines by the two cell types after different doses of radiation are illustrated. The different pathways of signal transduction thus facilitated in the T lymphocyte by different doses of radiation are analyzed to explain the mechanism of the phenomenon of low-dose stimulation and high-dose suppression of immunity. Experimental and clinical data are cited to show that LDR retards tumor growth, reduces metastasis, increases the efficacy of conventional radiotherapy and chemotherapy as well as alleviates the suppression of immunity due to tumor burden. The incidence of thymic lymphoma after high-dose radiation is lowered by preexposure to low-dose radiation, and its mechanism is supposed to be related to the stimulation of anticancer immunity induced by low-dose radiation. Recent reports on lowering of standardized cancer mortality rate and all cause death rate of cohorts occupationally exposed to low-dose radiation from the US, UK, and Canada are cited. PMID:19330113

  12. Egg consumption and risk of incident type 2 diabetes: a dose-response meta-analysis of prospective cohort studies.

    PubMed

    Tamez, Martha; Virtanen, Jyrki K; Lajous, Martin

    2016-06-01

    Experimental data suggest that egg intake could have a beneficial impact on several risk factors for type 2 diabetes. In contrast, some recent epidemiological studies have concluded that egg consumption may increase diabetes risk. We performed a dose-response meta-analysis of prospective cohorts on the relation of egg consumption with incident type 2 diabetes. We searched for cohort studies that assessed egg consumption and diabetes risk up to June 2015. We identified 416 articles and extracted data independently and in duplicate from ten eligible studies. We used random-effects generalised least squares models for pooled dose-response estimation based on thirteen estimates. Our study included 251 213 individuals and 12 156 incident type 2 diabetes cases. Egg intake was associated with incident type 2 diabetes (risk ratio (RR)/egg per d 1·13; 95 % CI 1·04, 1·22). We identified study location as a major source of heterogeneity. For studies conducted in the USA, we observed a stronger association (RR 1·47; 95 % CI 1·32, 1·64), whereas results were null for studies conducted elsewhere. Studies considered to be of high quality yielded null findings (RR 0·94; 95 % CI 0·74, 1·19). The association of egg intake with increased risk of incident type 2 diabetes may be restricted to US cohort studies. There are limited data to support a biological mechanism that could underlie this association; thus, the possibility that these results may be due to residual confounding by dietary behaviours restricted to certain populations cannot be excluded. PMID:27108219

  13. Genotoxicity testing: moving beyond qualitative "screen and bin" approach towards characterization of dose-response and thresholds.

    PubMed

    Pottenger, Lynn H; Gollapudi, B Bhaskar

    2010-01-01

    For more than 40+ years, genotoxicity data have been interpreted in a qualitative, binary mode; a chemical is considered either positive or negative for a response in the test system. Although dose-response information is sometimes used in this decision, it is not routine to obtain the amount of information needed to inform risk assessment, for example to determine no-observed-genotoxic-effect-levels, primarily due to the historical view of genotoxic responses as "linear, no-threshold." Only recently have researchers begun to address this issue through robust experimental designs and application of statistical models. A growing body-of-evidence supports the existence of response thresholds for a number of mutagenic agents, in vitro and in vivo. Clearly, simple observation of a "hockey-stick" dose-response curve is not sufficient to establish a threshold. Collection of robust empirical data must be supported with an analysis of biological plausibility for the observed threshold. In this context, a chemical-specific mode-of-action (MOA) approach, which identifies key events responsible for the observed mutagenic effect, is extremely valuable. Biomarkers of key events, providing qualitative and quantitative information, can be integrated in a weight-of-evidence-based assessment of genotoxicity data from multiple test systems and used to identify data gaps to resolve/reduce uncertainties during the risk assessment process. To this end, specific recommendations on study design and data analysis are proposed. As the Environmental Mutagen Society celebrates its 40th anniversary, the field of genetic toxicology is marking a milestone on the path to a new paradigm, using a MOA, data-driven approach to answer questions about thresholds for genotoxic agents. PMID:20806283

  14. Functional MRI determination of a dose-response relationship to lower extremity neuromuscular electrical stimulation in healthy subjects.

    PubMed

    Smith, Gerald V; Alon, Gad; Roys, Steven R; Gullapalli, Rao P

    2003-05-01

    Although empirical evidence supports the use of neuromuscular electrical stimulation (NMES) to treat physical impairments associated with stroke, the mechanisms underlying the efficacy of this modality are poorly understood. Recent studies have employed functional imaging to investigations of brain responses to median nerve stimulation. These studies suggest a dose-response relationship may exist between selected stimulation parameters and hemodynamic responses in sensorimotor regions. However, substantial gaps exist in this literature. The present study was designed to address these deficiencies. Ten healthy subjects participated. In phase one, four stimulus intensity levels were established: (1). sensory threshold [Th], (2). (MM-Th)x0.333+Th [low-intermediate level, LI], (3). (MM-Th)x0.666+Th [high-intermediate level, HI], and (4). maximal motor (MM). In phase two, subjects were scanned using a spiral-echoplanar imaging technique at each stimulus level. Image sets were analyzed to determine hemodynamic responses at the highest Pearson correlation level ( r) ascertained for each of five areas of interest (AOI): (1). primary sensory, (2). primary motor, (3). cingulate gyrus, (4). thalamus, and (5). cerebellum. ANOVA demonstrated significant main effects for BOLD signal amplitude ( p<0.05) changes in all AOI. Similarly, ANOVA showed significant differences in the volume of activation ( p<0.05) with increasing stimulus intensity in four AOI. Secondary analyses of pooled data showed increasing probabilities of activation at higher stimulus intensities within each AOI. Collectively, these data indicate a dose-response relationship exists between lower extremity NMES and brain activation in specific neural regions. The current results, while limited in their generalizability, are foundational for future studies of interventions using NMES. PMID:12698214

  15. Quantitative global sensitivity analysis of a biologically based dose-response pregnancy model for the thyroid endocrine system

    PubMed Central

    Lumen, Annie; McNally, Kevin; George, Nysia; Fisher, Jeffrey W.; Loizou, George D.

    2015-01-01

    A deterministic biologically based dose-response model for the thyroidal system in a near-term pregnant woman and the fetus was recently developed to evaluate quantitatively thyroid hormone perturbations. The current work focuses on conducting a quantitative global sensitivity analysis on this complex model to identify and characterize the sources and contributions of uncertainties in the predicted model output. The workflow and methodologies suitable for computationally expensive models, such as the Morris screening method and Gaussian Emulation processes, were used for the implementation of the global sensitivity analysis. Sensitivity indices, such as main, total and interaction effects, were computed for a screened set of the total thyroidal system descriptive model input parameters. Furthermore, a narrower sub-set of the most influential parameters affecting the model output of maternal thyroid hormone levels were identified in addition to the characterization of their overall and pair-wise parameter interaction quotients. The characteristic trends of influence in model output for each of these individual model input parameters over their plausible ranges were elucidated using Gaussian Emulation processes. Through global sensitivity analysis we have gained a better understanding of the model behavior and performance beyond the domains of observation by the simultaneous variation in model inputs over their range of plausible uncertainties. The sensitivity analysis helped identify parameters that determine the driving mechanisms of the maternal and fetal iodide kinetics, thyroid function and their interactions, and contributed to an improved understanding of the system modeled. We have thus demonstrated the use and application of global sensitivity analysis for a biologically based dose-response model for sensitive life-stages such as pregnancy that provides richer information on the model and the thyroidal system modeled compared to local sensitivity analysis

  16. Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis.

    PubMed

    Conrado, Daniela J; Krishnaswami, Sriram; Shoji, Satoshi; Kolluri, Sheela; Hey-Hadavi, Judith; McCabe, Dorothy; Rojo, Ricardo; Tammara, Brinda K

    2016-06-01

    PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose-response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose-response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be -1.2 points (95 % CI -1.7, -0.84), and the evaluated dose range provided 31-87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were -0.27 (95 % CI -0.55, 0.006) and -0.94 point (95 % CI -1.3, -0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials. PMID:27178257

  17. Radiation dose response estimation with emphasis on low dose range using restricted cubic splines: application to all solid cancer mortality data, 1950-2003, in atomic bomb survivors.

    PubMed

    Nakashima, Eiji

    2015-07-01

    Using the all solid cancer mortality data set of the Life Span Study (LSS) cohort from 1950 to 2003 (LSS Report 14) data among atomic bomb survivors, excess relative risk (ERR) statistical analyses were performed using the second degree polynomial and the threshold and restricted cubic spline (RCS) dose response models. For the RCS models with 3 to 7 knots of equally spaced percentiles with margins in the dose range greater than 50 mGy, the dose response was assumed to be linear at less than 70 to 90 mGy. Due to the skewed dose distribution of atomic bomb survivors, the current knot system for the RCS analysis results in a detailed depiction of the dose response as less than approximately 0.5 Gy. The 6 knot RCS models for the all-solid cancer mortality dose response of the whole dose or less than 2 Gy were selected with the AIC model selection criterion and fit significantly better (p < 0.05) than the linear (L) model. The usual RCS includes the L-global model but not the quadratic (Q) nor linear-quadratic (LQ) global models. The authors extended the RCS to include L or LQ global models by putting L or LQ constraints on the cubic spline in the lower and upper tails, and the best RCS model selected with AIC criterion was the usual RCS with L-constraints in both the lower and upper tails. The selected RCS had a linear dose-response model in the lower dose range (i.e., < 0.2-0.3 Gy) and was compatible with the linear no-threshold (LNT) model in this dose range. The proposed method is also useful in describing the dose response of a specific cancer or non-cancer disease incidence/mortality. PMID:26011495

  18. Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery.

    PubMed

    Hiniker, Susan M; Modlin, Leslie A; Choi, Clara Y; Atalar, Banu; Seiger, Kira; Binkley, Michael S; Harris, Jeremy P; Liao, Yaping Joyce; Fischbein, Nancy; Wang, Lei; Ho, Anthony; Lo, Anthony; Chang, Steven D; Harsh, Griffith R; Gibbs, Iris C; Hancock, Steven L; Li, Gordon; Adler, John R; Soltys, Scott G

    2016-04-01

    Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures

  19. The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

    PubMed

    MacVittie, Thomas J; Farese, Ann M; Jackson, William

    2015-11-01

    Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total

  20. An electromyographic method of objectively assessing cough intensity and use of the method to assess effects of codeine on the dose-response curve to citric acid.

    PubMed Central

    Cox, I D; Wallis, P J; Apps, M C; Hughes, D T; Empey, D W; Osman, R C; Burke, C A

    1984-01-01

    The integrated surface abdominal electromyogram (EMG) has been used as a simple measurement of cough intensity which correlates well with the volume, air flow and noise produced in different coughs. Using the integrated abdominal EMG as a measure of cough intensity, dose response curves to inhaled citric acid can be drawn which are highly reproducible. We have studied the effects of codeine (60 mg) on these curves, and have demonstrated a reduction in cough intensity. It is suggested that this method of testing the effects of an antitussive on such a dose-response curve may be a useful one. PMID:6487476

  1. The dose response relation for rat spinal cord paralysis analyzed in terms of the effective size of the functional subunit

    NASA Astrophysics Data System (ADS)

    Adamus-Górka, Magdalena; Mavroidis, Panayiotis; Brahme, Anders; Lind, Bengt K.

    2008-11-01

    Radiobiological models for estimating normal tissue complication probability (NTCP) are increasingly used in order to quantify or optimize the clinical outcome of radiation therapy. A good NTCP model should fulfill at least the following two requirements: (a) it should predict the sigmoid shape of the corresponding dose-response curve and (b) it should accurately describe the probability of a specified response for arbitrary non-uniform dose delivery for a given endpoint as accurately as possible, i.e. predict the volume dependence. In recent studies of the volume effect of a rat spinal cord after irradiation with narrow and broad proton beams the authors claim that none of the existing NTCP models is able to describe their results. Published experimental data have been used here to try to quantify the change in the effective dose (D50) causing 50% response for different field sizes. The present study was initiated to describe the induction of white matter necrosis in a rat spinal cord after irradiation with narrow proton beams in terms of the mean dose to the effective volume of the functional subunit (FSU). The physically delivered dose distribution was convolved with a function describing the effective size or, more accurately, the sensitivity distribution of the FSU to obtain the effective mean dose deposited in it. This procedure allows the determination of the mean D50 value of the FSUs of a certain size which is of interest for example if the cell nucleus of the oligodendrocyte is the sensitive target. Using the least-squares method to compare the effective doses for different sizes of the functional subunits with the experimental data the best fit was obtained with a length of about 9 mm. For the non-uniform dose distributions an effective FSU length of 8 mm gave the optimal fit with the probit dose-response model. The method could also be used to interpret the so-called bath and shower experiments where the heterogeneous dose delivery was used in the

  2. Airborne trichloramine (NCl(3)) levels and self-reported health symptoms in indoor swimming pool workers: dose-response relationships.

    PubMed

    Fantuzzi, Guglielmina; Righi, Elena; Predieri, Guerrino; Giacobazzi, Pierluigi; Petra, Berchotd; Aggazzotti, Gabriella

    2013-01-01

    The hypothesis that attendance at indoor chlorinated swimming pool is a risk factor for irritative ocular and respiratory symptoms and bronchial asthma is well known in literature, although epidemiological evidence is still inconclusive. The aim of this study was to evaluate the association between airborne trichloramine (NCl(3)) levels and irritative symptoms in swimming pool employees in order to obtain detailed data regarding dose-response relationships and to identify the airborne NCl(3) exposure level, if any, without health effects. A total of 20 indoor swimming pools in the Emilia Romagna region of Italy were included in the study. Information about the health status of 128 employees was collected using a self-administered questionnaire. Exposure to airborne NCl(3) was evaluated in indoor swimming pools by a modified DPD/KI method. The results of the study evidenced a mean value of airborne NCl(3) of 0.65±0.20 mg/m(3) (ranging from 0.20 to 1.02 mg/m(3)). Both ocular and upper respiratory symptoms, in particular red eyes, runny nose, voice loss and cold symptoms, were declared more frequently by lifeguards and trainers when compared with employees working in other areas of the facility (office, cafe, and so on). Pool attendants exposed to airborne NCl(3) levels of >0.5 mg/m(3) experienced higher risks for runny nose (OR: 2.91; 95% CI: 1.22-6.93) red eyes (OR: 3.16; 95% CI: 1.46-6.82), voice loss (OR: 3.56; 95% CI: 1.60-7.95) and itchy eyes (OR: 2.23; 95% CI: 1.04-4.78) than other employees. Moreover, red eyes, itchy eyes, runny nose and voice loss are related to airborne NCl(3) levels, with strong dose-response relationships. In conclusion, this study shows that lifeguards and trainers experience ocular and respiratory irritative symptoms more frequently than employees not exposed. Irritative symptoms become significant starting from airborne NCl(3) levels of >0.5 mg/m(3), confirming that the WHO-recommended value can be considered protective in

  3. Phototherapy in Gunn rats. A study to assess the photobiologically most effective radiant energy and dose/response relationships.

    PubMed

    Ballowitz, L; Geutler, G; Krochmann, J; Pannitschka, R; Roemer, G; Roemer, I

    1977-01-01

    In order to get a more realistic spectral efficiency curve and to evaluate dose/response relationships in phototherapy, homozygous weanling Gunn rats -- nondepilated, with fur -- were illuminated under standardized conditions with 8 different fluorescent tubes. Some of the tubes were operated with different electric power. Clear spectal differences in the extent and the rapidity of the bilirubin decay could be ascertained. Furthermore, the sharpness of the bilirubin decrease depended on the baseline concentration. For the calculations the animals were therefore divided into 3 groups with starting levels of larger than or equal to 8 mg%, 6.5--7.9 mg% and less than 6.5 mg%. Correlating the spectral power distribution of the lamps with the bilirubin decomposition found in the experiment, the spectral response function s(lambda)bili, rel was calculated by an integral method. A comparison of our results with data from the literature shows that so far near UV radiation was evaluated too high. A new radiometer for digital measuring the effective irradiance Ebili was developed. On a logarithmic scale a comparatively sharp dose/response relationship could be demonstrated in dependence on the measured effective radiant exposure. Serum bilirubin decrease is directly proportional to log Ebili. A dose of about 2.5 mW - h/cm2 is necessary to achieve a constant serum bilirubin decrease at all. Good results were obtained at doses of about 35 mW - h/cm2 with the most efficient being at 160 mW - h/cm2. Highly effective doses can be applied with different types of lamps. However, there are great differences in the time of illumination required. 24 h are necessary with daylight tubes (Osram L 20 W/19) to apply 20 mW - h/cm2, whereas the same dose is already attained after 4 h with BAM blue tubes (Philips). The accuracy of the radiometer was finally controlled by screening Westinghouse special blue and Osram standard blue tubes with black tapes, so that the effective irradiance (Ebili

  4. ESTIMATING A DOSE-RESPONSE RELATIONSHIP BETWEEN LENGTH OF STAY AND FUTURE RECIDIVISM IN SERIOUS JUVENILE OFFENDERS.

    PubMed

    Loughran, Thomas A; Mulvey, Edward P; Schubert, Carol A; Fagan, Jeffrey; Piquero, Alex R; Losoya, Sandra H

    2009-01-01

    The effect of sanctions on subsequent criminal activity is of central theoretical importance in criminology. A key question for juvenile justice policy is the degree to which serious juvenile offenders respond to sanctions and/or treatment administered by the juvenile court. The policy question germane to this debate is finding the level of confinement within the juvenile justice system that maximizes the public safety and therapeutic benefits of institutional confinement. Unfortunately, research on this issue has been limited with regard to serious juvenile offenders. We use longitudinal data from a large sample of serious juvenile offenders from two large cities to 1) estimate a causal treatment effect of institutional placement, as opposed to probation, on future rate of rearrest and 2) investigate the existence of a marginal effect (i.e., benefit) for longer length of stay once the institutional placement decision had been made. We accomplish the latter by determining a dose-response relationship between the length of stay and future rates of rearrest and self-reported offending. The results suggest that an overall null effect of placement exists on future rates of rearrest or self-reported offending for serious juvenile offenders. We also find that, for the group placed out of the community, it is apparent that little or no marginal benefit exists for longer lengths of stay. Theoretical, empirical, and policy issues are outlined. PMID:20052309

  5. Dose-response analysis of heavy metal toxicants in man. Direct in vivo assessment of body burden

    SciTech Connect

    Ellis, K.J.

    1985-06-01

    Differences in uptake, metabolism, and excretion of heavy metals makes selection of a suitable biological media as a monitor of body burden very difficult. Exposure assessments based on body fluid levels can provide, at best, only general population estimates. The most frequently monitored media are blood, urine, nail or hair clippings, sweat, and saliva. Unfortunately each of these tissues can be influenced by recent exposure conditions and are not accurate indices of the total dose or body burden. However, direct in vivo measurements of body burden in humans, have recently been performed. This nuclear technique has focused on the measurements of kidney and liver cadmium (Cd) by neutron activation analysis and bone lead (Pb) determinations using x-ray fluorescence. The dose-response relationship for renal dysfunction based on the direct in vivo body burden for Cd is presented. The most probable Cd value for the kidney associated with renal impairment is approximately 35 mg. Approximately 10% of the subjects with 20 mg Cd in the kidney will have moderately elevated ..beta../sub 2/-microglobulin, an early indicator of potential renal functional changes. 11 refs., 5 figs., 2 tabs.

  6. Dose-effect and dose-response relationships of blood lead to erythrocytic protoporphyrin in young children

    SciTech Connect

    Hammond, P.B.; Bornschein, R.L.; Succop, P.

    1985-10-01

    Dose-effect and dose-response relationships were analyzed for blood lead concentration (PbB) vs blood protoporphyrin concentration using multiple data points from 165 children, ages 3-36 months. Protoporphyrin concentrations were measured using a front-face flurometer designed to measure zinc protoporphyrin (ZPP) and an extraction method designed to measure total protoporphyrin as the free base (FEP). Estimations were made of the thresholds for PbB effects on FEP and ZPP, as well as the slopes of the PbB-FEP and PbB-ZPP interactions. There was essentially no difference in thresholds estimated using ZPP vs FEP as the effect parameter. There was no apparent effect of age on threshold. However, the slope for PbB vs ZPP was less steep than the slope for PbB vs FEP. Moreover, the average ratio FEP:ZPP was markedly elevated at 3 months (1.84:1) and decreased slowly, attaining unity at 33 months. The possible reasons for this discrepancy are discussed, as well as the implications for interpretation of lead screening program data.

  7. A Novel Method of Estimating Dose Responses for Polymer Gels Using Texture Analysis of Scanning Electron Microscopy Images

    PubMed Central

    Shih, Cheng-Ting; Hsu, Jui-Ting; Han, Rou-Ping; Hsieh, Bor-Tsung; Chang, Shu-Jun; Wu, Jay

    2013-01-01

    Polymer gels are regarded as a potential dosimeter for independent validation of absorbed doses in clinical radiotherapy. Several imaging modalities have been used to convert radiation-induced polymerization to absorbed doses from a macro-scale viewpoint. This study developed a novel dose conversion mechanism by texture analysis of scanning electron microscopy (SEM) images. The modified N-isopropyl-acrylamide (NIPAM) gels were prepared under normoxic conditions, and were administered radiation doses from 5 to 20 Gy. After freeze drying, the gel samples were sliced for SEM scanning with 50×, 500×, and 3500× magnifications. Four texture indices were calculated based on the gray level co-occurrence matrix (GLCM). The results showed that entropy and homogeneity were more suitable than contrast and energy as dose indices for higher linearity and sensitivity of the dose response curves. After parameter optimization, an R2 value of 0.993 can be achieved for homogeneity using 500× magnified SEM images with 27 pixel offsets and no outlier exclusion. For dose verification, the percentage errors between the prescribed dose and the measured dose for 5, 10, 15, and 20 Gy were −7.60%, 5.80%, 2.53%, and −0.95%, respectively. We conclude that texture analysis can be applied to the SEM images of gel dosimeters to accurately convert micro-scale structural features to absorbed doses. The proposed method may extend the feasibility of applying gel dosimeters in the fields of diagnostic radiology and radiation protection. PMID:23843998

  8. Dose response and time course of manganese-enhanced magnetic resonance imaging for visual pathway tracing in vivo

    PubMed Central

    Wang, Wei-ling; Xu, Hui; Li, Ying; Ma, Zhi-zhong; Sun, Xiao-dong; Hu, Yun-tao

    2016-01-01

    Axonal tracing is useful for detecting optic nerve injury and regeneration, but many commonly used methods cannot be used to observe axoplasmic flow and synaptic transmission in vivo. Manganese (Mn2+)-enhanced magnetic resonance imaging (MEMRI) can be used for in vivo longitudinal tracing of the visual pathway. Here, we explored the dose response and time course of an intravitreal injection of MnCl2 for tracing the visual pathway in rabbits in vivo using MEMRI. We found that 2 mM MnCl2 enhanced images of the optic nerve but not the lateral geniculate body or superior colliculus, whereas at all other doses tested (5–40 mM), images of the visual pathway from the retina to the contralateral superior colliculus were significantly enhanced. The images were brightest at 24 hours, and then decreased in brightness until the end of the experiment (7 days). No signal enhancement was observed in the visual cortex at any concentration of MnCl2. These results suggest that MEMRI is a viable method for temporospatial tracing of the visual pathway in vivo. Signal enhancement in MEMRI depends on the dose of MnCl2, and the strongest signals appear 24 hours after intravitreal injection.

  9. Dietary flavonoid intake and the risk of stroke: a dose-response meta-analysis of prospective cohort studies

    PubMed Central

    Tang, Zhenyu; Li, Min; Zhang, Xiaowei; Hou, Wenshang

    2016-01-01

    Objective To clarify and quantify the potential association between intake of flavonoids and risk of stroke. Design Meta-analysis of prospective cohort studies. Data source Studies published before January 2016 identified through electronic searches using PubMed, Embase and the Cochrane Library. Eligibility criteria for selecting studies Prospective cohort studies with relative risks and 95% CIs for stroke according to intake of flavonoids (assessed as dietary intake). Results The meta-analysis yielded 11 prospective cohort studies involving 356 627 participants and more than 5154 stroke cases. The pooled estimate of the multivariate relative risk of stroke for the highest compared with the lowest dietary flavonoid intake was 0.89 (95% CI 0.82 to 0.97; p=0.006). Dose-response analysis indicated that the summary relative risk of stroke for an increase of 100 mg flavonoids consumed per day was 0.91 (95% CI 0.77 to 1.08) without heterogeneity among studies (I2=0%). Stratifying by follow-up duration, the relative risk of stroke for flavonoid intake was 0.89 (95% CI 0.81 to 0.99) in studies with more than 10 years of follow-up. Conclusions Results from this meta-analysis suggest that higher dietary flavonoid intake may moderately lower the risk of stroke. PMID:27279473

  10. Meta-Analysis for Linear and Nonlinear Dose-Response Relations: Examples, an Evaluation of Approximations, and Software

    PubMed Central

    Orsini, Nicola; Li, Ruifeng; Wolk, Alicja; Khudyakov, Polyna; Spiegelman, Donna

    2012-01-01

    Two methods for point and interval estimation of relative risk for log-linear exposure-response relations in meta-analyses of published ordinal categorical exposure-response data have been proposed. The authors compared the results of a meta-analysis of published data using each of the 2 methods with the results that would be obtained if the primary data were available and investigated the circumstances under which the approximations required for valid use of each meta-analytic method break down. They then extended the methods to handle nonlinear exposure-response relations. In the present article, methods are illustrated using studies of the relation between alcohol consumption and colorectal and lung cancer risks from the ongoing Pooling Project of Prospective Studies of Diet and Cancer. In these examples, the differences between the results of a meta-analysis of summarized published data and the pooled analysis of the individual original data were small. However, incorrectly assuming no correlation between relative risk estimates for exposure categories from the same study gave biased confidence intervals for the trend and biased P values for the tests for nonlinearity and between-study heterogeneity when there was strong confounding by other model covariates. The authors illustrate the use of 2 publicly available user-friendly programs (Stata and SAS) to implement meta-analysis for dose-response data. PMID:22135359

  11. Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software.

    PubMed

    Orsini, Nicola; Li, Ruifeng; Wolk, Alicja; Khudyakov, Polyna; Spiegelman, Donna

    2012-01-01

    Two methods for point and interval estimation of relative risk for log-linear exposure-response relations in meta-analyses of published ordinal categorical exposure-response data have been proposed. The authors compared the results of a meta-analysis of published data using each of the 2 methods with the results that would be obtained if the primary data were available and investigated the circumstances under which the approximations required for valid use of each meta-analytic method break down. They then extended the methods to handle nonlinear exposure-response relations. In the present article, methods are illustrated using studies of the relation between alcohol consumption and colorectal and lung cancer risks from the ongoing Pooling Project of Prospective Studies of Diet and Cancer. In these examples, the differences between the results of a meta-analysis of summarized published data and the pooled analysis of the individual original data were small. However, incorrectly assuming no correlation between relative risk estimates for exposure categories from the same study gave biased confidence intervals for the trend and biased P values for the tests for nonlinearity and between-study heterogeneity when there was strong confounding by other model covariates. The authors illustrate the use of 2 publicly available user-friendly programs (Stata and SAS) to implement meta-analysis for dose-response data. PMID:22135359

  12. Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

    NASA Astrophysics Data System (ADS)

    El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

    2006-11-01

    Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

  13. Coffee consumption and risk of endometrial cancer: a dose-response meta-analysis of prospective cohort studies.

    PubMed

    Zhou, Quan; Luo, Mei-Ling; Li, Hui; Li, Min; Zhou, Jian-Guo

    2015-01-01

    This is a dose-response (DR) meta-analysis to evaluate the association of coffee consumption on endometrial cancer (EC) risk. A total 1,534,039 participants from 13 published articles were added in this meta-analysis. The RR of total coffee consumption and EC were 0.80 (95% CI: 0.74-0.86). A stronger association between coffee intake and EC incidence was found in patients who were never treated with hormones, 0.60 (95% CI: 0.50-0.72), and subjects with a BMI ≥25 kg/m(2), 0.57 (95% CI: 0.46-0.71). The overall RRs for caffeinated and decaffeinated coffee were 0.66 (95% CI: 0.52-0.84) and 0.77 (95% CI: 0.63-0.94), respectively. A linear DR relationship was seen in coffee, caffeinated coffee, decaffeinated coffee and caffeine intake. The EC risk decreased by 5% for every 1 cup per day of coffee intake, 7% for every 1 cup per day of caffeinated coffee intake, 4% for every 1 cup per day of decaffeinated intake of coffee, and 4% for every 100 mg of caffeine intake per day. In conclusion, coffee and intake of caffeine might significantly reduce the incidence of EC, and these effects may be modified by BMI and history of hormone therapy. PMID:26302813

  14. Coffee consumption and risk of endometrial cancer: a dose-response meta-analysis of prospective cohort studies

    PubMed Central

    Zhou, Quan; Luo, Mei-Ling; Li, Hui; Li, Min; Zhou, Jian-Guo

    2015-01-01

    This is a dose-response (DR) meta-analysis to evaluate the association of coffee consumption on endometrial cancer (EC) risk. A total 1,534,039 participants from 13 published articles were added in this meta-analysis. The RR of total coffee consumption and EC were 0.80 (95% CI: 0.74–0.86). A stronger association between coffee intake and EC incidence was found in patients who were never treated with hormones, 0.60 (95% CI: 0.50–0.72), and subjects with a BMI ≥25 kg/m2, 0.57 (95% CI: 0.46–0.71). The overall RRs for caffeinated and decaffeinated coffee were 0.66 (95% CI: 0.52–0.84) and 0.77 (95% CI: 0.63–0.94), respectively. A linear DR relationship was seen in coffee, caffeinated coffee, decaffeinated coffee and caffeine intake. The EC risk decreased by 5% for every 1 cup per day of coffee intake, 7% for every 1 cup per day of caffeinated coffee intake, 4% for every 1 cup per day of decaffeinated intake of coffee, and 4% for every 100 mg of caffeine intake per day. In conclusion, coffee and intake of caffeine might significantly reduce the incidence of EC, and these effects may be modified by BMI and history of hormone therapy. PMID:26302813

  15. Statistical issues in radiation dose-response analysis of employees of the nuclear industry in Oak Ridge, Tennessee

    SciTech Connect

    Frome, E.L.; Watkins, J.P.

    1997-11-01

    Poisson regression methods are used to describe dose-response relations for cancer mortality for a subcohort of 28,347 white male radiation workers. Age specific baseline rates are described using both internal and external (US white male) rates. Regression analyses are based on an analytic data structure (ADS) that consists of a table of observed deaths, expected deaths, and person-years at risk for each combination of levels of seven risk factors. The factors are socioeconomic status, length of employment, birth cohort, age at risk, facility, internal exposure, and external exposure. Each observation in the ADS consists of the index value of each of the stratifying factors, the observed deaths, the expected deaths, the person-years, and the ten year lagged average cumulative dose. Regression diagnostics show that a linear exponential relative risk model is not appropriate for these data. Results are presented using a main effects model for factors other than external radiation, and an excess relative risk term for cumulative external radiation dose.

  16. ESTIMATING A DOSE-RESPONSE RELATIONSHIP BETWEEN LENGTH OF STAY AND FUTURE RECIDIVISM IN SERIOUS JUVENILE OFFENDERS*

    PubMed Central

    Loughran, Thomas A.; Mulvey, Edward P.; Schubert, Carol A.; Fagan, Jeffrey; Piquero, Alex R.; Losoya, Sandra H.

    2009-01-01

    The effect of sanctions on subsequent criminal activity is of central theoretical importance in criminology. A key question for juvenile justice policy is the degree to which serious juvenile offenders respond to sanctions and/or treatment administered by the juvenile court. The policy question germane to this debate is finding the level of confinement within the juvenile justice system that maximizes the public safety and therapeutic benefits of institutional confinement. Unfortunately, research on this issue has been limited with regard to serious juvenile offenders. We use longitudinal data from a large sample of serious juvenile offenders from two large cities to 1) estimate a causal treatment effect of institutional placement, as opposed to probation, on future rate of rearrest and 2) investigate the existence of a marginal effect (i.e., benefit) for longer length of stay once the institutional placement decision had been made. We accomplish the latter by determining a dose-response relationship between the length of stay and future rates of rearrest and self-reported offending. The results suggest that an overall null effect of placement exists on future rates of rearrest or self-reported offending for serious juvenile offenders. We also find that, for the group placed out of the community, it is apparent that little or no marginal benefit exists for longer lengths of stay. Theoretical, empirical, and policy issues are outlined. PMID:20052309

  17. Vigabatrin pediatric dosing information for refractory complex partial seizures: results from a population dose-response analysis.

    PubMed

    Nielsen, Jace C; Tolbert, Dwain; Patel, Mahlaqa; Kowalski, Kenneth G; Wesche, David L

    2014-12-01

    We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose-response model related seizure-count data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure-count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10-15 and >15-20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10-15 and >15-20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/day for weight ranges 25-60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25-60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10 kg. PMID:25311090

  18. Identification of low-dose responsive metabolites in X-irradiated human B lymphoblastoid cells and fibroblasts

    PubMed Central

    Tsuyama, Naohiro; Mizuno, Hajime; Katafuchi, Atsushi; Abe, Yu; Kurosu, Yumiko; Yoshida, Mitsuaki; Kamiya, Kenji; Sakai, Akira

    2015-01-01

    Ionizing radiation (IR) induces cellular stress responses, such as signal transduction, gene expression, protein modification, and metabolite change that affect cellular behavior. We analyzed X-irradiated human Epstein-Barr virus-transformed B lymphoblastoid cells and normal fibroblasts to search for metabolites that would be suitable IR-responsive markers by Liquid Chromotography–Mass spectrometry (LC–MS). Mass spectra, as analyzed with principal component analysis, showed that the proportion of peaks with IR-induced change was relatively small compared with the influence of culture time. Dozens of peaks that had either been upregulated or downregulated by IR were extracted as candidate IR markers. The IR-changed peaks were identified by comparing mock-treated groups to 100 mGy-irradiated groups that had recovered after 10 h, and the results indicated that the metabolites involved in nucleoside synthesis increased and that some acylcarnitine levels decreased in B lymphoblastoids. Some peaks changed by as much as 20 mGy, indicating the presence of an IR-sensitive signal transduction/metabolism control mechanism in these cells. On the other hand, we could not find common IR-changed peaks in fibroblasts of different origin. These data suggest that cell phenotype-specific pathways exist, even in low-dose responses, and could determine cell behavior. PMID:25227127

  19. Normal Liver Tissue Density Dose Response in Patients Treated With Stereotactic Body Radiation Therapy for Liver Metastases

    SciTech Connect

    Howells, Christopher C.; Stinauer, Michelle A.; Diot, Quentin; Westerly, David C.; Schefter, Tracey E.; Kavanagh, Brian D.; Miften, Moyed

    2012-11-01

    Purpose: To evaluate the temporal dose response of normal liver tissue for patients with liver metastases treated with stereotactic body radiation therapy (SBRT). Methods and Materials: Ninety-nine noncontrast follow-up computed tomography (CT) scans of 34 patients who received SBRT between 2004 and 2011 were retrospectively analyzed at a median of 8 months post-SBRT (range, 0.7-36 months). SBRT-induced normal liver tissue density changes in follow-up CT scans were evaluated at 2, 6, 10, 15, and 27 months. The dose distributions from planning CTs were mapped to follow-up CTs to relate the mean Hounsfield unit change ({Delta}HU) to dose received over the range 0-55 Gy in 3-5 fractions. An absolute density change of 7 HU was considered a significant radiographic change in normal liver tissue. Results: Increasing radiation dose was linearly correlated with lower post-SBRT liver tissue density (slope, -0.65 {Delta}HU/5 Gy). The threshold for significant change (-7 {Delta}HU) was observed in the range of 30-35 Gy. This effect did not vary significantly over the time intervals evaluated. Conclusions: SBRT induces a dose-dependent and relatively time-independent hypodense radiation reaction within normal liver tissue that is characterized by a decrease of >7 HU in liver density for doses >30-35 Gy.

  20. Red Meat and Processed Meat Consumption and Nasopharyngeal Carcinoma Risk: A Dose-response Meta-analysis of Observational Studies.

    PubMed

    Li, Fuqin; Duan, Fujiao; Zhao, Xia; Song, Chunhua; Cui, Shuli; Dai, Liping

    2016-01-01

    The purpose of this study is to clarify and quantify the potential dose-response association between the intake of total red and total processed meat and risk of nasopharyngeal carcinoma (NPC). Relevant studies were identified by searching PubMed, EMBASE, and Chinese databases (CNKI and Wanfang). The summary relative risk (RR) with 95% confidence interval (95%CI) was calculated. A total of 15 independent studies with 12,735 subjects were identified. Compared with the low-rank intake, the summary RR of NPC was 1.35 (95%CI, 1.21-1.51) for total red meat and 1.46 (95%CI, 1.34-1.64) for total processed meat. For the moderate-rank intake, the summary RR of NPC was 1.54 (95%CI, 1.36-1.79) for total red meat and 1.59 (95%CI, 1.3-1.90) for total processed meat. The summary RR for high-rank intake was 1.71 (95%CI, 1.14-2.55) for total red meat and 2.11 (95%CI, 1.31-3.42) for total processed meat. The combined estimates showed obvious evidence of statistically significant association between total red and total processed meat consumption dose and risk of NPC (Ptrend< 0.01). In conclusion, our data suggest that a high intake of total red or total processed meat is associated with a significantly increased risk of NPC. PMID:27367552

  1. Home dampness, childhood asthma, hay fever, and airway symptoms in Shanghai, China: associations, dose-response relationships, and lifestyle's influences.

    PubMed

    Hu, Y; Liu, W; Huang, C; Zou, Z J; Zhao, Z H; Shen, L; Sundell, J

    2014-10-01

    Numerous studies of associations between dampness and respiratory diseases have been conducted, but their implications remain inconclusive. In this study of 13,335 parent-reported questionnaires (response rate: 85.3%), we analyzed associations between home dampness and asthma and related symptoms in 4- to 6-year-old children in a cross-sectional study of Shanghai. Indicators of home dampness were strongly and significantly associated with dry cough, wheeze, and rhinitis symptoms. In the current residence, children with visible mold spots (VMS) exposure had 32% higher risk of asthma (adjusted OR, 95% CI: 1.32, 1.07-1.64); damp clothing and/or bedding (frequently) was strongly associated with dry cough (1.78, 1.37-2.30); condensation on windows was strongly associated with hay fever (1.60, 1.27-2.01). In the early-life residence, VMS or damp stains (frequently) were strongly associated with dry cough (2.20, 1.55-3.11) and rhinitis ever (1.57, 1.11-2.21). Associations between dampness and diseases among children with or without family history of atopy were similar. The total number of dampness indicators had strong dose-response relationships with investigated health outcomes. Actions, including opening windows of the child's room at night and cleaning the child's room frequently, could potentially mitigate 25% of home VMS, thereby preventing more than 1.5% of attributable risk of the studied symptoms. PMID:24571077

  2. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts after Exposure to Very Low Doses of High LET Radiation

    NASA Technical Reports Server (NTRS)

    Hada, M.; George, Kerry; Cucinotta, Francis A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivors with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (1-20 cGy) of 170 MeV/u Si-28- ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving greater than 2 breaks in 2 or more chromosomes). The curves for doses above 10 cGy were fitted with linear or linear-quadratic functions. For Si-28- ions no dose response was observed in the 2-10 cGy dose range, suggesting a non-target effect in this range.

  3. Study of the dose response of the system ferrous ammonium sulfate-sucrose-xylenol orange in acid aqueous solution

    NASA Astrophysics Data System (ADS)

    Juarez-Calderon, J. M.; Negron-Mendoza, A.; Ramos-Bernal, S.

    2014-11-01

    An aqueous solution of ammonium ferrous sulfate-sucrose-xylenol orange in sulfuric acid (FSX) is proposed as a dosimetric system for the processes of gamma irradiation in a range between 0.3 and 6 Gy. This system is based on the indirect oxidation of ferrous ion by an organic compound (sucrose) to ferric ion and on the formation of a color complex of Fe3+ in an acidic medium with xylenol orange (a dye). After gamma radiation, an observable change occurs in the color of the system. Irradiation was executed at three different temperatures (13 °C, 22 °C, and 40 °C). A spectrometric readout method at 585 nm was employed to evaluate the system's dose response. In all of the cases analyzed, the responses had a linear behavior, and a slight effect of irradiation temperature was observed. Post-irradiation response was also evaluated and showed the stability of the solutions 24 h after the irradiation. The results obtained suggest that FSX might be used as a dosimeter for low doses of gamma irradiation because it provides a stable signal, good reproducibility, and an accessible technique for analysis.

  4. Understanding the lateral dose response functions of high-resolution photon detectors by reverse Monte Carlo and deconvolution analysis.

    PubMed

    Looe, Hui Khee; Harder, Dietrich; Poppe, Björn

    2015-08-21

    The purpose of the present study is to understand the mechanism underlying the perturbation of the field of the secondary electrons, which occurs in the presence of a detector in water as the surrounding medium. By means of 'reverse' Monte Carlo simulation, the points of origin of the secondary electrons contributing to the detector's signal are identified and associated with the detector's mass density, electron density and atomic composition. The spatial pattern of the origin of these secondary electrons, in addition to the formation of the detector signal by components from all parts of its sensitive volume, determines the shape of the lateral dose response function, i.e. of the convolution kernel K(x,y) linking the lateral profile of the absorbed dose in the undisturbed surrounding medium with the associated profile of the detector's signal. The shape of the convolution kernel is shown to vary essentially with the electron density of the detector's material, and to be attributable to the relative contribution by the signal-generating secondary electrons originating within the detector's volume to the total detector signal. Finally, the representation of the over- or underresponse of a photon detector by this density-dependent convolution kernel will be applied to provide a new analytical expression for the associated volume effect correction factor. PMID:26267311

  5. Dose-Response Analysis of Factors Involved in Germination and Secondary Dormancy of Seeds of Sisymbrium officinale

    PubMed Central

    Hilhorst, Henk W. M.

    1990-01-01

    The germination of seeds of Sisymbrium officinale is light- and nitrate dependent. A close interaction between the effects of light and nitrate on germination has been reported previously (HWM Hilhorst, CM Karssen [1988] Plant Physiol 86: 591-597). In this study, a detailed dose-response analysis of the light-induced germination during induction of secondary dormancy is presented. Germination in water dropped from 90 to 0% after a dark incubation of 15°C of approximately 160 hours. In the presence of 25 millimolar KNO3, the decrease in germination level was delayed. At 24-hour intervals fluence-response curves were obtained in the presence of 25 millimolar KNO3. With increasing length of the preincubation period, fluence-response curves shifted along the abscissa to the right. After 120 hours the maximal germination level started to decline. The fluence-response curves were simulated by using formulations from receptor occupancy theory for a simple bimolecular reaction in which the reaction partners were Pfr and its tentative receptor X. A good simulation was obtained when cooperativity of the binding of Pfr to X was assumed. The experimental curve parameters could then be interpreted as binding parameters. PMID:16667801

  6. DEVELOPING AN EXPOSURE-DOSE-RESPONSE MODEL FOR THE ACUTE NEUROTOXICITY OF ORGANIC SOLVENTS: OVERVIEW AND PROGRESS ON IN VITRO MODELS AND DOSIMETRY.

    EPA Science Inventory

    This article provides an overview of the current status of an exposure-dose-response (EDR) model for the volatile organic compound toluene. This model is being developed as a vehicle for understanding the neurotoxicity of organic solvents and will be used to support risk assessme...

  7. 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (Tcdd) Dose-Response Studies: Preliminary Literature Search Results and Request for Additional Studies

    EPA Science Inventory

    EPA invited the public to comment on the preliminary list of in vivo mammalian dose-response citations for 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). This list was compiled as a first step in the development of EPA’s response to the National Academy of Sciences comments (NAS, 2...

  8. The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells

    DOE PAGESBeta

    Lemon, Jennifer A.; Taylor, Kristina; Verdecchia, Kyle; Phan, Nghi; Boreham, Douglas R.

    2014-01-01

    Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01-2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/-) mice. The dose response for Trp53+/+ mice showed higher initial levelsmore » of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.« less

  9. NITRO MUSK ADDUCTS OF RAINBOW TROUT HEMOGLOBIN: DOSE-RESPONSE AND TOXICOKINETICS DETERMINATION BY GC-NICI-MS FOR A SENTINEL SPECIES

    EPA Science Inventory

    Rainbow trout and other fish species can serve as 'sentinel' species for the assessment of ecological status and the presence of certain environmental contaminants. As such they act as bioindicators of exposure. Here we present seminal data regarding dose-response and toxicokinet...

  10. Dose-response and time-course of neurotoxicity and tissue concentrations of carbaryl in Brown Norway rats from preweaning to senescence.

    EPA Science Inventory

    Factors impacting sensitivity to chemicals across life stages include toxicokinetic and toxicodynamic changes. We systematically compared the dose-response (3, 7.5, 15,22.5 mg/kg) and time-course (3 or 15 mg/kg at 30, 60, 120, 240 min) of acute effects of carbaryl (oral gavage) i...

  11. A dose-response of consuming high fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    National Health and Nutrition Examination Survey data show increased risk of cardiovascular disease (CVD) mortality with increased intake of added sugar across quintiles. Objective: To determine the dose response effects of consuming beverages sweetened with high fructose corn syrup (HFCS) at zero, ...

  12. DOSE-RESPONSE FOR UV-INDUCED IMMUNE SUPPRESSION IN PEOPLE OF COLOR: DIFFERENCES BASED ON ERYTHEMAL REACTIVITY RATHER THAN SKIN PIGMENTATION

    EPA Science Inventory

    Ultraviolet radiation (UVR) is known to suppress immune responses in human subjects. The purpose of this study was to develop dose responses across a broad range of skin pigmentation in order to facilitate risk assessment. UVR was administered using FS 20 bulbs. Skin pigmentation...

  13. TIME COURSE AND DOSE RESPONSE ASSESSMENT OF CHOLINESTERASE (CHE) INHIBITION IN ADULT RATS TREATED ACUTELY WITH CARBARYL, METHOMYL, METHIOCARB, OXAMYL, OR PROPOXUR.

    EPA Science Inventory

    To compare the toxicity of 5 N-methyl carbamates, the time course and dose response profiles for ChE inhibition were established for each. For the time course comparison, adult male Long Evans rats (n=5 dose group) were dosed orally with either carbaryl (CB; 30 mg/kg in corn oi...

  14. Henry S. Kaplan Distinguished Scientist Award 2003. The crooked shall be made straight; dose-response relationships for carcinogenesis.

    PubMed

    Hall, E J

    2004-05-01

    Estimates of radiation-induced malignancies come principally from the atomic (A)-bomb survivors and show an excess incidence of carcinomas that is linearly related to dose from about 5 cGy to 2.5 Gy. Above and below this dose range there is considerable uncertainty about the shape of the dose-response relationship. Both the International Commission of Radiation Protected (ICRP) and the National Council of Radiation Protection (NCRP) suggest that cancer risks at doses lower than those at which direct epidemiological observations are possible should be obtained by a linear extrapolation from higher doses. The demonstrated bystander effect for irradiation exaggerates the consequences of small doses of radiation and implies that a linear extrapolation from high doses would underestimate low dose risks. It is possible to make estimates of the cancer risk of diagnostic radiological procedures. Helical computed tomography in children is of particular interest since it is rapidly increasing in use and the doses involved are close to the lower limit of significance in the A-bomb survivors. For example, an abdominal computed tomographic scan in a 1-year-old child can be estimated to result in a lifetime cancer risk of about 1:1000. In the context of radiotherapy, some normal tissues receive 70 Gy, while a larger volume receives a lower dose, but still far higher than the range for which data are available from the A-bomb survivors. Data are available for the risk of radiation-induced malignancies for patients who received radiotherapy, e.g. for prostate or cervical cancer. New technologies such as intensity modulated radiation therapy could result in a doubling of radiation-induced second cancers since the technique involves a larger total-body dose due to leakage radiation and the dose distribution obtained involves a larger volume of normal tissue exposed to lower radiation doses. PMID:15223765

  15. Dose-Response Relationship for Image-Guided Stereotactic Body Radiotherapy of Pulmonary Tumors: Relevance of 4D Dose Calculation

    SciTech Connect

    Guckenberger, Matthias Wulf, Joern; Mueller, Gerd; Krieger, Thomas; Baier, Kurt; Gabor, Manuela; Richter, Anne; Wilbert, Juergen; Flentje, Michael

    2009-05-01

    Purpose: To evaluate outcome after image-guided stereotactic body radiotherapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) and pulmonary metastases. Methods and Materials: A total of 124 patients with 159 pulmonary lesions (metastases n = 118; NSCLC, n = 41; Stage IA, n = 13; Stage IB, n = 19; T3N0, n = 9) were treated with SBRT. Patients were treated with hypofractionated schemata (one to eight fractions of 6-26 Gy); biologic effective doses (BED) to the clinical target volume (CTV) were calculated based on four-dimensional (4D) dose calculation. The position of the pulmonary target was verified using volume imaging before all treatments. Results: With mean/median follow-up of 18/14 months, actuarial local control was 83% at 36 months with no difference between NSCLC and metastases. The dose to the CTV based on 4D dose calculation was closely correlated with local control: local control rates were 89% and 62% at 36 months for >100 Gy and <100 Gy BED (p = 0.0001), respectively. Actuarial freedom from regional and systemic progression was 34% at 36 months for primary NSCLC group; crude rate of regional failure was 15%. Three-year overall survival was 37% for primary NSCLC and 16% for metastases; no dose-response relationship for survival was observed. Exacerbation of comorbidities was the most frequent cause of death for primary NSCLC. Conclusions: Doses of >100 Gy BED to the CTV based on 4D dose calculation resulted in excellent local control rates. This cutoff dose is not specific to the treatment technique and protocol of our study and may serve as a general recommendation.

  16. Odor detection by humans of lineal aliphatic aldehydes and helional as gauged by dose-response functions.

    PubMed

    Cometto-Muñiz, J Enrique; Abraham, Michael H

    2010-05-01

    We have measured concentration detection (i.e., psychometric) functions to determine the odor detectability of homologous aliphatic aldehydes (propanal, butanal, hexanal, octanal, and nonanal) and helional. Subjects (16 < or = n < or = 18) used a 3-alternative forced-choice procedure against carbon-filtered air (blanks), under an ascending concentration approach. Generation, delivery, and control of each vapor were achieved via an 8-station vapor delivery device. Gas chromatography served to quantify the concentrations presented. Group and individual functions were modeled by a sigmoid (logistic) equation. Odor detection thresholds (ODTs) were defined as the concentration producing a detectability (P) halfway (P = 0.5) between chance (P = 0.0) and perfect detection (P = 1.0). ODTs decreased with carbon chain length: 2.0, 0.46, 0.33, and 0.17 ppb, respectively, from propanal to octanal, but the threshold increased for nonanal (0.53 ppb), revealing maximum sensitivity for the 8-carbon member. The strong olfactory receptor (OR) ligands octanal and helional (0.14 ppb) showed the lowest thresholds. ODTs fell at the lower end of previously reported values. Interindividual variability (ODT ratios) amounted to a factor ranging from 10 to 50, lower than typically reported, and was highest for octanal and hexanal. The behavioral dose-response functions emerge at concentrations 2-5 orders of magnitude lower than those required for functions tracing the activation of specific human ORs by the same aldehydes in cell/molecular studies, after all functions were expressed as vapor concentrations. PMID:20190010

  17. Dose-response relationship of the cardiovascular adaptation to endurance training in healthy adults: how much training for what benefit?

    PubMed

    Iwasaki, Ken-Ichi; Zhang, Rong; Zuckerman, Julie H; Levine, Benjamin D

    2003-10-01

    Occupational or recreational exercise reduces mortality from cardiovascular disease. The potential mechanisms for this reduction may include changes in blood pressure (BP) and autonomic control of the circulation. Therefore, we conducted the present long-term longitudinal study to quantify the dose-response relationship between the volume and intensity of exercise training, and regulation of heart rate (HR) and BP. We measured steady-state hemodynamics and analyzed dynamic cardiovascular regulation by spectral and transfer function analysis of cardiovascular variability in 11 initially sedentary subjects during 1 yr of progressive endurance training sufficient to allow them to complete a marathon. From this, we found that 1) moderate exercise training for 3 mo decreased BP, HR, and total peripheral resistance, and increased cardiovascular variability and arterial baroreflex sensitivity; 2) more prolonged and intense training did not augment these changes further; and 3) most of these changes returned to control values at 12 mo despite markedly increased training duration and intensity equivalent to that routinely observed in competitive athletes. In conclusion, increases in R-wave-R-wave interval and cardiovascular variability indexes are consistent with an augmentation of vagal modulation of HR after exercise training. It appears that moderate doses of training for 3 mo are sufficient to achieve this response as well as a modest hypotensive effect from decreasing vascular resistance. However, more prolonged and intense training does not necessarily lead to greater enhancement of circulatory control and, therefore, may not provide an added protective benefit via autonomic mechanisms against death by cardiovascular disease. PMID:12832429

  18. Test-retest reproducibility of the relative dose response for vitamin A status in Guatemalan adults: issues of diagnostic specificity.

    PubMed

    Morrow, F D; Guerrero, A M; Russell, R M; Dallal, G; Solomons, N W

    1990-07-01

    The relative dose response (RDR) test was examined with regard to specificity and reproducibility in subjects with adequate dietary intake and normal liver reserves of vitamin A. Twelve subjects were administered an RDR test four times over 22 d, including one placebo test in which the oral dose of vitamin A was omitted. Additionally, static measures of retinol, tocopherol, retinol binding protein (RBP) and prealbumin (PAL) were taken to determine the intra- and inter-individual coefficient of variation for these blood constituents. Intra-individual coefficients of variation were as follows: retinol, 8.8%; RBP, 11.5%; PAL, 7.6%; and alpha-tocopherol, 8.8%. The mean RDR in vitamin A-replete subjects was 1.2% and ranged from approximately -25% to 11%. No differences were observed between placebo and true RDR (i.e., with vitamin A) test responses, and there was no difference among the three true RDRs over a period of 22 d. Consistent with the hypothesis upon which the RDR test is based, nascently absorbed vitamin A evidently entered a storage pool in the liver of vitamin A-replete subjects without immediate release to peripheral sites of utilization. Because the RDR test results were normal in all subjects, the procedure appears to offer high test specificity and does not falsely diagnose hypovitaminosis A. Nevertheless, the magnitude and direction of the RDR within an individual over 22 d were highly variable, and this variability may preclude the use of a single measure of the RDR to grade the relative vitamin A nutriture of an individual subject. PMID:2366108

  19. Chronic exposure to odorous chemicals in residential areas and effects on human psychosocial health: dose-response relationships.

    PubMed

    Blanes-Vidal, Victoria; Bælum, Jesper; Nadimi, Esmaeil S; Løfstrøm, Per; Christensen, Lars P

    2014-08-15

    Perceived air pollution, including environmental odor pollution, is known to be an environmental stressor that affects individuals' psychosocial health and well-being. However, very few studies have been able to quantify exposure-response associations based on individual-specific residential exposures to a proxy gas and to examine the mechanisms underlying these associations. In this study, individual-specific exposures in non-urban residential environments during 2005-2010 on a gas released from animal biodegradable wastes (ammonia, NH3) were calculated by the Danish Eulerian long-range transport model and the local-scale transport deposition model. We used binomial and multinomial logistic regression and mediation analyses to examine the associations between average exposures and questionnaire-based data on psychosocial responses, after controlling for person-specific covariates. About 45% of the respondents were annoyed by residential odor pollution. Exposures were associated with annoyance (adjusted odds ratio [ORadj]=3.54, 95% confidence interval [CI]=2.33-5.39), health risk perception (ORadj=4.94; 95% CI=1.95-12.5) and behavioral interference (ORadj=3.28; 95% CI=1.77-6.11), for each unit increase in loge(NH3 exposure). Annoyance was a strong mediator in exposure-behavior interference and exposure-health risk perception relationships (81% and 44% mediation, respectively). Health risk perception did not play a mediating role in exposure-annoyance or exposure-behavioral interference relationships. This is the first study to provide a quantitative estimation of the dose-response associations between ambient NH3 exposures and psychosocial effects caused by odor pollution in non-urban residential outdoor environments. It further shows that these effects are both direct and mediated by other psychosocial responses. The results support the use of NH3 as a proxy gas of air pollution from animal biodegradable wastes in epidemiologic studies. PMID:24880544

  20. A dose-response relationship between maternal smoking during late pregnancy and adult intelligence in male offspring.

    PubMed

    Mortensen, Erik Lykke; Michaelsen, Kim Fleischer; Sanders, Stephanie A; Reinisch, June Machover

    2005-01-01

    An association between maternal smoking during pregnancy and cognitive and behavioural development has been observed in several studies, but potential effects of maternal smoking on offspring adult intelligence have not been investigated. The objective of the present study was to investigate a potential association between maternal smoking during pregnancy and offspring intelligence in young adulthood. Adult intelligence was assessed at the mean age of 18.7 years by a military draft board intelligence test (Borge Priens Prove) for 3044 singleton males from the Copenhagen Perinatal Cohort with information regarding maternal smoking during the third trimester coded into five categories (about 50% of the mothers were smokers). The following potential confounders were included as covariates in multivariable analyses: parental social status and education, single mother status, mother's height and age, number of pregnancies, and gestational age. In separate analyses, birthweight and length were also included as covariates. Maternal cigarette smoking during the third trimester, adjusted for the seven covariates, showed a negative association with offspring adult intelligence (P=0.0001). The mean difference between the no-smoking and the heaviest smoking category amounted to 0.41 standard deviation, corresponding to an IQ difference of 6.2 points [95% confidence interval 0.14, 0.68]. The association remained significant when further adjusted for birthweight and length (P=0.007). Both unadjusted and adjusted means suggested a dose-response relationship between maternal smoking during pregnancy and offspring adult intelligence. When subjects with missing data were excluded, essentially the same results were obtained in the reduced sample (n=1829). These results suggest that smoking during pregnancy may have long-term negative consequences on offspring adult intelligence. PMID:15670102

  1. Dose-response effect of tomato paste on 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.

    PubMed

    Bhuvaneswari, V; Velmurugan, B; Nagini, S

    2004-06-01

    We evaluated the dose-response effect of tomato paste on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis using lipid peroxidation, reduced glutathione (GSH) and the GSH-dependent enzymes; glutathione peroxidase (GPx), glutathione-S-transferase (GST) and gamma-glutamyltranspeptidase (GGT) as biomarkers of chemoprevention. Hamsters were divided into eight groups of six animals each. The right buccal pouches of animals in group 1 were painted with a 0.5 per cent DMBA in liquid paraffin three times per week. Animals in groups 2 to 4 painted with DMBA as in group 1, received in addition, intragastric administration of tomato paste containing lycopene at concentrations of 2.5, 5 and 10 mgkg(-1)bw, respectively three times per week on days alternate to DMBA application. Groups 5 through 7 were given tomato paste alone. Animals in group 8 served as controls. All animals were killed after an experimental period of 14 weeks. Lipid peroxidation and GSH-dependent antioxidants were measured in the buccal pouch, liver and erythrocytes. Diminished lipid peroxidation in the HBP tumours was associated with enhanced levels of GSH and GSH-dependent enzymes. In contrast to the buccal pouch, the liver and erythrocytes of tumour-bearing hamsters exhibited elevated lipid peroxidation accompanied by compromised antioxidant status. Administration of tomato paste significantly reduced the incidence of HBP tumours, modulated lipid peroxidation and enhanced GSH and GSH-dependent enzymes in the pouch, liver and erythrocytes. Among the three doses used, tomato paste containing 5 mgkg(-1)bw lycopene showed the optimum effect. It is suggested that tomato paste exerts its chemopreventive effects by modulating lipid peroxidation and enhancing antioxidants in the target organ as well as in the liver and erythrocytes. PMID:15354408

  2. Salvage Radiotherapy for Rising Prostate-Specific Antigen Levels After Radical Prostatectomy for Prostate Cancer: Dose-Response Analysis

    SciTech Connect

    Bernard, Johnny Ray; Buskirk, Steven J.; Heckman, Michael G.; Diehl, Nancy N.; Ko, Stephen J.; Macdonald, Orlan K.; Schild, Steven E.; Pisansky, Thomas M.

    2010-03-01

    Purpose: To investigate the association between external beam radiotherapy (EBRT) dose and biochemical failure (BcF) of prostate cancer in patients who received salvage prostate bed EBRT for a rising prostate-specific antigen (PSA) level after radical prostatectomy. Methods and Materials: We evaluated patients with a rising PSA level after prostatectomy who received salvage EBRT between July 1987 and October 2007. Patients receiving pre-EBRT androgen suppression were excluded. Cox proportional hazards models were used to investigate the association between EBRT dose and BcF. Dose was considered as a numeric variable and as a categoric variable (low, <64.8 Gy; moderate, 64.8-66.6 Gy; high, >66.6 Gy). Results: A total of 364 men met study selection criteria and were followed up for a median of 6.0 years (range, 0.1-19.3 years). Median pre-EBRT PSA level was 0.6 ng/mL. The estimated cumulative rate of BcF at 5 years after EBRT was 50% overall and 57%, 46%, and 39% for the low-, moderate-, and high-dose groups, respectively. In multivariable analysis adjusting for potentially confounding variables, there was evidence of a linear trend between dose and BcF, with risk of BcF decreasing as dose increased (relative risk [RR], 0.77 [5.0-Gy increase]; p = 0.05). Compared with the low-dose group, there was evidence of a decreased risk of BcF for the high-dose group (RR, 0.60; p = 0.04), but no difference for the moderate-dose group (RR, 0.85; p = 0.41). Conclusions: Our results suggest a dose response for salvage EBRT. Doses higher than 66.6 Gy result in decreased risk of BcF.

  3. Dose Response of Listeria monocytogenes Invasion, Fetal Morbidity, and Fetal Mortality after Oral Challenge in Pregnant and Nonpregnant Mongolian Gerbils

    PubMed Central

    Roulo, Rebecca M.; Fishburn, Jillian D.; Amosu, Mayowa; Etchison, Ashley R.

    2014-01-01

    Listeria monocytogenes is a food-borne pathogen that can result in adverse pregnancy outcomes, such as stillbirth or premature delivery. The Mongolian gerbil was recently proposed as the most appropriate small-animal model of listeriosis due to its susceptibility to the same invasion pathways as humans. The objectives of this study were to investigate invasion and adverse pregnancy outcomes in gerbils orally exposed to L. monocytogenes, to compare the dose-response data to those of other animal models, and to investigate differences in the responses of pregnant versus nonpregnant gerbils. Gerbils were orally exposed to 0 (control), 103, 105, 107, or 109 CFU L. monocytogenes in whipping cream. L. monocytogenes was recovered in a dose-dependent manner from fecal samples, adult organs, and pregnancy-associated tissues. Dams exposed to 109 CFU had more invaded organs and higher concentrations of L. monocytogenes in almost all organs than nonpregnant animals, though no differences in fecal shedding were seen between the two groups. Adverse pregnancy outcomes occurred only in the dams treated with 109 CFU. A 50% infectivity dose (ID50) of 2.60 × 106 CFU for fetuses was calculated by fitting the data to a logistic model. Our results suggest that the 50% lethal dose (LD50) falls within the range of 5 × 106 to 5 × 108 CFU. This range includes the guinea pig and nonhuman primate LD50s, but the observation that L. monocytogenes-induced stillbirths can be seen in guinea pigs and primates exposed to lower doses than those at which stillbirths were seen in gerbils indicates that gerbils are not more sensitive to L. monocytogenes invasion. PMID:25156729

  4. SU-E-T-116: Dose Response in the Treatment of Unresectable Cholangiocarcinoma with Yttrium-90 Microspheres

    SciTech Connect

    Yu, S; Green, G; Sehgal, V; Samford, G; Kuo, J; Imagawa, D; Fernando, D; Al-Ghazi, M

    2014-06-01

    Purpose: The purpose of this study is to assess the dose response of radioembolization using yttrium-90 (Y-90) microspheres in patients treated for unresectable cholangiocarcinoma. This study utilized partition dosimetry model for the dose calculation. The results show survival benefit with dose escalation. Methods: Between February 2009 and March 2013, ten patients with pathology proven unresectable cholangiocarcinoma were radioembolized with Y-90 microspheres. Patients underwent initial pre-treatment angiographic assessment for blood flow and 99mTc- MAA for lung shunt evaluation. Activity of Y-90 administration was calculated using the Body Surface Area (BSA) and target volumes which were determined by contouring the pre-treatment MRI/CT images using a radiation therapy treatment planning system. Medical Internal Radiation Dose (MIRD) method was used to assess the dosimetric results of Y90. Partition model based on the tumor to-liver activity uptake estimated from pretreatment 99mTc- MAA study was used to calculate the dose delivered to the target. The variables assessed included: administered dose, toxicity based on clinical changes, imaging based tumor response, and survival. Results: Ten patients were radioembolized with Y-90 microspheres to either one hepatic lobe or both left and right lobes. Patients were stratified by dose. Four patients who received dose greater than 140Gy (p < 0.05) all survived. The corresponding activity they received was greater than 35 mCi. Six out of ten patients died of disease with median survival of 18 weeks (range 12–81wks). Conclusion: Given the growing body of data for Y-90 microspheres in the context of cholangiocarcinoma, radioembolization may become an important treatment modality for an appropriately selected group of patients. Our study further substantiates past studies and shows additional evidence of a survival benefit with dose escalation.

  5. Isoflavone consumption and risk of breast cancer: a dose-response meta-analysis of observational studies.

    PubMed

    Xie, Qi; Chen, Ming-Liang; Qin, Yu; Zhang, Qian-Yong; Xu, Hong-Xia; Zhou, Yong; Mi, Man-Tian; Zhu, Jun-Dong

    2013-01-01

    Epidemiologic studies that examine whether isoflavone consumption protects against breast cancer have yielded inconsistent results. The controversy focuses on the effects of the menopausal status and exposure dose of isoflavone. We aim to conduct a meta-analysis on the association between isoflavone intake and breast cancer risk by comprehensively assessing isoflavone exposure in the targeted populations. We searched PUBMED and EMBASE databases for case-control and cohort studies that assess the association between isoflavone intake and breast cancer risk. We extracted relative risks (RR) and odds ratios (OR) of different reported categories of isoflavone intake from each study. Fixed- or random-effects models were used to summarize dose-response data. Twenty-two studies were selected for the meta-analysis. Overall, the results showed that isoflavone reduced the breast cancer risk (a combined RR/OR of 0.68, 95% CI: 0.52-0.89) in Asian populations rather than Western populations (a combined RR/OR of 0.98, 95% CI: 0.87, 1.11) for the high-dose category. Further analysis showed that the intake of isoflavone in postmenopausal Asian women 0.46 (95% CI: 0.28-0.78) was better than premenopausal 0.63 (95% CI: 0.50-0.80) but similar in postmenopausal Western women 1.00 (95% CI: 0.98-1.02) and premenopausal 0.99 (95% CI: 0.87-1.12). Exposure to high isoflavone may be associated with a reduced breast cancer risk in Asian populations, especially in postmenopausal women. However, no significant difference in the studies of Western populations may be due to the low intake of isoflavone levels. PMID:23353619

  6. Dose Response Effects of Dermally applied Diethanolamine on Neurogenesis in Fetal Mouse Hippocampus and Potential Exposure of Humans

    PubMed Central

    Craciunescu, Corneliu N.; Niculescu, Mihai D.; Guo, Zhong; Johnson, Amy R.; Fischer, Leslie; Zeisel, Steven H.

    2009-01-01

    Diethanolamine (DEA) is a common ingredient of personal care products. Dermal administration of DEA diminishes hepatic stores of the essential nutrient choline and alters brain development. We previously reported that 80 mg/kg/day of DEA during pregnancy in mice reduced neurogenesis and increased apoptosis in the fetal hippocampus. This study was designed to establish the dose-response relationships for this effect of DEA. Timed-pregnant C57BL/6 mouse dams were dosed dermally from gestation day 7–17 with DEA at 0 (controls), 5, 40, 60, and 80 mg/kg body/day. Fetuses (embryonic day 17 [E17]) from dams treated dermally with 80 mg/kg body/day DEA had decreased neural progenitor cell mitosis at the ventricular surface of the ventricular zone (hippocampus, 54.1 ± 5.5%; cortex, 58.9 ± 6.8%; compared to controls; p < 0.01). Also, this dose of DEA to dams increased rates of apoptosis in E17 fetal hippocampus (to 177.2 ± 21.5% of control; measured using activated caspase-3; p < 0.01). This dose of DEA resulted in accumulation of DEA and its metabolites in liver and in plasma. At doses of DEA less than 80 mg/kg body/day to dams, there were no differences between treated and control groups. In a small group of human subjects, dermal treatment for 1 month with a commercially available skin lotion containing 1.8 mg DEA per gram resulted in detectable plasma concentrations of DEA and dimethyldiethanolamine, but these were far below those concentrations associated with perturbed brain development in the mouse. PMID:18948303

  7. Adult weight gain and risk of prostate cancer: A dose-response meta-analysis of observational studies.

    PubMed

    Chen, Qi; Chen, Tao; Shi, Wentao; Zhang, Tianyi; Zhang, Wei; Jin, Zhichao; Wei, Xin; Liu, Yuzhou; He, Jia

    2016-02-15

    The association between adult weight gain and risk of prostate cancer has not been widely studied and the findings are inconsistent. Therefore, our study aimed to investigate the association between adult weight gain and risk of prostate cancer. PubMed, Embase and Web of Science databases were searched for relevant studies published before September 2014 using terms related to weight gain and prostate cancer. Summary estimates were obtained using the random-effects model. Dose-response meta-analysis, sensitivity analysis and publication bias tests were performed. Nine studies involving 497,634 participants and 22,338 cancer cases were included. For total prostate cancer, a positive relationship with adult weight gain was observed until weight gain increased to >30 kg. For low-intermediate-risk prostate cancer, a positive relationship with adult weight gain was observed until weight gain increased to >15 kg. For high-risk prostate cancer, we observed a positive linear relationship with adult weight gain with a relative risk (RR) of 1.02 [95% confidence interval (CI) 1.00-1.04] for every 5-kg increase. For fatal prostate cancer, we observed a positive linear relationship with adult weight gain with an RR of 1.12 (95% CI: 1.05-1.19) for every 5-kg increase. There is evidence that adult weight gain is associated with an increased risk of high-risk and fatal prostate cancer, but only low weight gain is positively associated with low-intermediate-risk prostate cancer. PMID:26356247

  8. Test-retest reproducibility of the relative dose response for vitamin A status in Guatemalan adults: issues of diagnostic sensitivity.

    PubMed

    Solomons, N W; Morrow, F D; Vasquez, A; Bulux, J; Guerrero, A M; Russell, R M

    1990-07-01

    The relative dose response (RDR) test has been used as a functional measure of whole-body stores of vitamin A in humans. We have examined the reproducibility of the RDR procedure in a population of Guatemalan adult subjects who would be expected to show a moderate prevalence of hypovitaminosis A. Fifty-one subjects were administered a standard RDR test, and the plasma samples were analyzed for retinol, tocopherol, retinol binding protein (RBP) and prealbumin (PAL). Thirty-four of the subjects underwent repeat RDR tests 7 d later. Plasma levels in fasted subjects were as follows: retinol, 1.35 +/- 0.30 mumol/L; RBP, 37.8 +/- 7.7 mg/L; PAL, 187.0 +/- 39.0 mg/L; and tocopherol, 16.6 +/- 6.2 mumol/L. RDRs ranged from -35.2% to +63.1%, with a mean of 2.6 +/- 10.4%. Overall, we observed poor within-subject reproducibility of the RDR procedure whether expressed numerically or by diagnostic classification. Moreover, in contrast to previous studies in children, we observed fewer positive RDR tests than would be expected for the population studied. Nevertheless, the mean RDR was inversely proportional to fasting retinol levels, thus confirming the validity of the biological basis of the RDR procedure in humans. Because of high intra-individual variability with this test, investigators should be cautious when using the RDR procedure in serial studies to monitor the efficacy of therapeutic interventions or subject compliance to dietary regimens. PMID:2366107

  9. Has the sensitivity of soybean cultivars to ozone pollution increased with time? An analysis of published dose-response data.

    PubMed

    Osborne, Stephanie A; Mills, Gina; Hayes, Felicity; Ainsworth, Elizabeth A; Büker, Patrick; Emberson, Lisa

    2016-09-01

    The rising trend in concentrations of ground-level ozone (O3 ) - a common air pollutant and phytotoxin - currently being experienced in some world regions represents a threat to agricultural yield. Soybean (Glycine max (L.) Merr.) is an O3 -sensitive crop species and is experiencing increasing global demand as a dietary protein source and constituent of livestock feed. In this study, we collate O3 exposure-yield data for 49 soybean cultivars, from 28 experimental studies published between 1982 and 2014, to produce an updated dose-response function for soybean. Different cultivars were seen to vary considerably in their sensitivity to O3 , with estimated yield loss due to O3 ranging from 13.3% for the least sensitive cultivar to 37.9% for the most sensitive, at a 7-h mean O3 concentration (M7) of 55 ppb - a level frequently observed in regions of the USA, India and China in recent years. The year of cultivar release, country of data collection and type of O3 exposure used were all important explanatory variables in a multivariate regression model describing soybean yield response to O3 . The data show that the O3 sensitivity of soybean cultivars increased by an average of 32.5% between 1960 and 2000, suggesting that selective breeding strategies targeting high yield and high stomatal conductance may have inadvertently selected for greater O3 sensitivity over time. Higher sensitivity was observed in data from India and China compared to the USA, although it is difficult to determine whether this effect is the result of differential cultivar physiology, or related to local environmental factors such as co-occurring pollutants. Gaining further understanding of the underlying mechanisms that govern the sensitivity of soybean cultivars to O3 will be important in shaping future strategies for breeding O3 -tolerant cultivars. PMID:27082950

  10. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Dose of High Let Radiation

    NASA Technical Reports Server (NTRS)

    Hada, M.; George, K.; Chappell, L.; Cucinotta, F. A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (0.01 - 0.20 Gy) of 170 MeV/u Si-28 ions or 600 MeV/u Fe-56 ions, including doses where on average less than one direct ion traversal per cell nucleus occurs. Chromosomes were analyzed using the whole-chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The responses for doses above 0.1 Gy (more than one ion traverses a cell) showed linear dose responses. However, for doses less than 0.1 Gy, both Si-28 ions and Fe-56 ions showed a dose independent response above background chromosome aberrations frequencies. Possible explanations for our results are non-targeted effects due to aberrant cell signaling [1], or delta-ray dose fluctuations [2] where a fraction of cells receive significant delta-ray doses due to the contributions of multiple ion tracks that do not directly traverse cell nuclei where chromosome aberrations are scored.

  11. Dose-response relationships of polycyclic aromatic hydrocarbons exposure and oxidative damage to DNA and lipid in coke oven workers.

    PubMed

    Kuang, Dan; Zhang, Wangzhen; Deng, Qifei; Zhang, Xiao; Huang, Kun; Guan, Lei; Hu, Die; Wu, Tangchun; Guo, Huan

    2013-07-01

    Polycyclic aromatic hydrocarbons (PAHs) are known to induce reactive oxygen species and oxidative stress, but the dose-response relationships between exposure to PAHs and oxidative stress levels have not been established. In this study, we recruited 1333 male coke oven workers, monitored the levels of environmental PAHs, and measured internal PAH exposure biomarkers including 12 urinary PAH metabolites and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, as well as the two oxidative biomarkers urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α). We found that the total concentration of urinary PAH metabolites and plasma BPDE-Alb adducts were both significantly associated with increased 8-OHdG and 8-iso-PGF2α in both smokers and nonsmokers (all p < 0.05). This exposure-response effect was also observed for most PAH metabolites (all p(trend) < 0.01), except for 4-hydroxyphenanthrene and 8-OHdG (p(trend) = 0.108). Furthermore, it was shown that only urinary 1-hydroxypyrene has a significant positive association with both 8-OHdG and 8-iso-PGF2α after a Bonferroni correction (p < 0.005). Our results indicated that urinary ΣOH-PAHs and plasma BPDE-Alb adducts can result in significant dose-related increases in oxidative damage to DNA and lipids. Furthermore, when a multianalyte method is unavailable, our findings demonstrate that urinary 1-hydroxypyrene is a useful biomarker for evaluating total PAHs exposure and assessing oxidative damage in coke oven workers. PMID:23745771

  12. Prospective Evaluation to Establish a Dose Response for Clinical Oral Mucositis in Patients Undergoing Head-and-Neck Conformal Radiotherapy

    SciTech Connect

    Narayan, Samir Lehmann, Joerg; Coleman, Matthew A.; Vaughan, Andrew; Yang, Claus Chunli; Enepekides, Danny; Farwell, Gregory; Purdy, James A.; Laredo, Grace; Nolan, Kerry A.S.; Pearson, Francesca S.; Vijayakumar, Srinivasan

    2008-11-01

    Purpose: We conducted a clinical study to correlate oral cavity dose with clinical mucositis, perform in vivo dosimetry, and determine the feasibility of obtaining buccal mucosal cell samples in patients undergoing head-and-neck radiation therapy. The main objective is to establish a quantitative dose response for clinical oral mucositis. Methods and Materials: Twelve patients undergoing radiation therapy for head-and-neck cancer were prospectively studied. Four points were chosen in separate quadrants of the oral cavity. Calculated dose distributions were generated by using AcQPlan and Eclipse treatment planning systems. MOSFET dosimeters were used to measure dose at each sampled point. Each patient underwent buccal sampling for future RNA analysis before and after the first radiation treatment at the four selected points. Clinical and functional mucositis were assessed weekly according to National Cancer Institute Common Toxicity Criteria, Version 3. Results: Maximum and average doses for sampled sites ranged from 7.4-62.3 and 3.0-54.3 Gy, respectively. A cumulative point dose of 39.1 Gy resulted in mucositis for 3 weeks or longer. Mild severity (Grade {<=} 1) and short duration ({<=}1 week) of mucositis were found at cumulative point doses less than 32 Gy. Polymerase chain reaction consistently was able to detect basal levels of two known radiation responsive genes. Conclusions: In our sample, cumulative doses to the oral cavity of less than 32 Gy were associated with minimal acute mucositis. A dose greater than 39 Gy was associated with longer duration of mucositis. Our technique for sampling buccal mucosa yielded sufficient cells for RNA analysis using polymerase chain reaction.

  13. Biological regulation of receptor-hormone complex concentrations in relation to dose-response assessments for endocrine-active compounds.

    PubMed

    Andersen, M E; Barton, H A

    1999-03-01

    Some endocrine-active compounds (EACs) act as agonists or antagonists of specific hormones and may interfere with cellular control processes that regulate gene transcription. Many mechanisms controlling gene expression are universal to organisms ranging from unicellular bacteria to more complex plants and animals. One mechanism, coordinated control of batteries of gene products, is critical in adaptation of bacteria to new environments and for development and tissue differentiation in multi-cellular organisms. To coordinately activate sets of genes, all living organisms have devised molecular modules to permit transitions, or switching, between different functional states over a small range of hormone concentration, and other modules to stabilize the new state through homeostatic interactions. Both switching and homeostasis are regulated by controlling concentrations of hormone-receptor complexes. Molecular control processes for switching and homeostasis are inherently nonlinear and often utilize autoregulatory feedback loops. Among the biological processes contributing to switching phenomena are receptor autoinduction, induction of enzymes for ligand synthesis, mRNA stabilization/activation, and receptor polymerization. This paper discusses a variety of molecular switches found in animal species, devises simple quantitative models illustrating roles of specific molecular interactions in creating switching modules, and outlines the impact of these switching processes and other feedback loops for risk assessments with EACs. Quantitative simulation modeling of these switching mechanisms made it apparent that highly nonlinear dose-response curves for hormones and EACs readily arise from interactions of several linear processes acting in concert on a common control point. These nonlinear mechanisms involve amplification of response, rather than multimeric molecular interactions as in conventional Hill relationships. PMID:10330682

  14. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    SciTech Connect

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y

    2014-06-15

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  15. A Reanalysis of Curvature in the Dose Response for Cancer and Modifications by Age at Exposure Following Radiation Therapy for Benign Disease

    SciTech Connect

    Little, Mark P.; Stovall, Marilyn; Smith, Susan A.; Kleinerman, Ruth A.

    2013-02-01

    Purpose: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. Methods and Materials: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). Results: There are statistically significant (P<.05) excess risks for all cancer and for lung cancer and borderline statistically significant risks for stomach cancer (P=.07), and leukemia (P=.06), with excess relative risks Gy{sup -1} of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI -0.002, 0.119), and 1.087 (95% CI -0.018, 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. Conclusions: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

  16. A Review: Development of a Microdose Model for Analysis of Adaptive Response and Bystander Dose Response Behavior

    PubMed Central

    Leonard, Bobby E.

    2008-01-01

    Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type 125I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite

  17. Dose-response association between hepatitis B surface antigen levels and liver cancer risk in Chinese men and women

    PubMed Central

    Yang, Yang; Gao, Jing; Li, Hong-Lan; Zheng, Wei; Yang, Gong; Zhang, Wei; Ma, Xiao; Tan, Yu-Ting; Rothman, Nat; Gao, Yu-Tang; Chow, Wong-Ho; Shu, Xiao-Ou; Xiang, Yong-Bing

    2016-01-01

    We aimed at evaluating the risk of liver cancer in different levels of HBsAg among Chinese men and women. We carried out a nested case-control study including 363 cases and 3,511 controls in two population-based cohorts in Shanghai. Plasma samples collected at enrollment were quantified for HBsAg levels using the Architect QT assay. Conditional logistic regression was performed to estimate the odds ratios (ORs) and 95% confidence intervals (95%CIs) for liver cancer, with adjustment for potential confounders. HBsAg was detected in 6.29% of control subjects overall (7.02% in men and 4.98% in women). HBsAg levels were positively associated with liver cancer risk in a dose-response manner (Ptrend<0.001). Such association showed a significant gender disparity. With increasing levels of HBsAg, liver cancer risks rose more steeply in men than in women. In men, the adjusted ORs increased from 7.27 (95%CI: 3.49–15.15) at the lowest detectable level of HBsAg (5–9 IU/ml) to 7.16 (95%CI: 3.21–15.96), 34.30 (95%CI: 16.94–69.44), and 47.33 (95%CI: 23.50–95.34) at the highest level of HBsAg (≥1,000 IU/ml) compared to those negative for HBsAg. The corresponding ORs were much lower for women, from 1.37 (95%CI: 0.25–7.47) to 3.81 (95%CI: 1.09–13.28), 7.36 (95%CI: 2.41–22.46), and 16.86 (95%CI: 7.24–39.27), respectively. HBsAg quantification has potential to distinguish individuals at different risks of liver cancer. Men with the lowest detectable level of HBsAg should still pay attention to their liver cancer risks, but those with a higher level may be given a higher priority in future liver cancer surveillance program. PMID:26990915

  18. Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial1234

    PubMed Central

    Ng, Kimmie; Scott, Jamil B; Drake, Bettina F; Chan, Andrew T; Hollis, Bruce W; Chandler, Paulette D; Bennett, Gary G; Giovannucci, Edward L; Gonzalez-Suarez, Elizabeth; Meyerhardt, Jeffrey A; Emmons, Karen M; Fuchs, Charles S

    2014-01-01

    Background: Association studies have suggested that lower circulating 25-hydroxyvitamin D [25(OH)D] in African Americans may partially underlie higher rates of cardiovascular disease and cancer in this population. Nonetheless, the relation between vitamin D supplementation and 25(OH)D concentrations in African Americans remains undefined. Objective: Our primary objective was to determine the dose-response relation between vitamin D and plasma 25(OH)D. Design: A total of 328 African Americans in Boston, MA, were enrolled over 3 winters from 2007 to 2010 and randomly assigned to receive a placebo or 1000, 2000, or 4000 IU vitamin D3/d for 3 mo. Subjects completed sociodemographic and dietary questionnaires, and plasma samples were drawn at baseline and 3 and 6 mo. Results: Median plasma 25(OH)D concentrations at baseline were 15.1, 16.2, 13.9, and 15.7 ng/mL for subjects randomly assigned to receive the placebo or 1000, 2000, or 4000 IU/d, respectively (P = 0.63). The median plasma 25(OH)D concentration at 3 mo differed significantly between supplementation arms at 13.7, 29.7, 34.8, and 45.9 ng/mL, respectively (P < 0.001). An estimated 1640 IU vitamin D3/d was needed to raise the plasma 25(OH)D concentration to ≥20 ng/mL in ≥97.5% of participants, whereas a dose of 4000 IU/d was needed to achieve concentrations ≥33 ng/mL in ≥80% of subjects. No significant hypercalcemia was seen in a subset of participants. Conclusions: Within African Americans, an estimated 1640 IU vitamin D3/d was required to achieve concentrations of plasma 25(OH)D recommended by the Institute of Medicine, whereas 4000 IU/d was needed to reach concentrations predicted to reduce cancer and cardiovascular disease risk in prospective observational studies. These results may be helpful for informing future trials of disease prevention. This trial was registered at clinicaltrials.gov as NCT00585637. PMID:24368437

  19. Dose-response association between hepatitis B surface antigen levels and liver cancer risk in Chinese men and women.

    PubMed

    Yang, Yang; Gao, Jing; Li, Hong-Lan; Zheng, Wei; Yang, Gong; Zhang, Wei; Ma, Xiao; Tan, Yu-Ting; Rothman, Nathaniel; Gao, Yu-Tang; Chow, Wong-Ho; Shu, Xiao-Ou; Xiang, Yong-Bing

    2016-07-15

    We aimed at evaluating the risk of liver cancer in different levels of HBsAg among Chinese men and women. We carried out a nested case-control study including 363 cases and 3,511 controls in two population-based cohorts in Shanghai. Plasma samples collected at enrollment were quantified for HBsAg levels using the Architect QT assay. Conditional logistic regression was performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for liver cancer, with adjustment for potential confounders. HBsAg was detected in 6.29% of control subjects overall (7.02% in men and 4.98% in women). HBsAg levels were positively associated with liver cancer risk in a dose-response manner (ptrend  < 0.001). Such association showed a significant gender disparity. With increasing levels of HBsAg, liver cancer risks rose more steeply in men than in women. In men, the adjusted ORs increased from 7.27 (95% CI: 3.49-15.15) at the lowest detectable level of HBsAg (5-9 IU/ml) to 7.16 (95% CI: 3.21-15.96), 34.30 (95% CI: 16.94-69.44), and 47.33 (95% CI: 23.50-95.34) at the highest level of HBsAg (≥1,000 IU/ml) compared to those negative for HBsAg. The corresponding ORs were much lower for women, from 1.37 (95% CI: 0.25-7.47), 3.81 (95% CI: 1.09-13.28), 7.36 (95% CI: 2.41-22.46) and 16.86 (95% CI: 7.24-39.27), respectively. HBsAg quantification has potential to distinguish individuals at different risks of liver cancer. Men with the lowest detectable level of HBsAg should still pay attention to their liver cancer risks, but those with a higher level may be given a higher priority in future liver cancer surveillance program. PMID:26990915

  20. Permeability control by cholinergic receptors in Torpedo postsynaptic membranes: agonist dose-response relations measured at second and millisecond times.

    PubMed

    Neubig, R R; Cohen, J B

    1980-06-10

    A quantitative analysis of nicotine acetylcholine receptor function in Torpedo postsynaptic membranes is presented. 22Na+ efflux induced by carbamylcholine (Carb) and the partial agonist phenyltrimethylammonium (PTA) is assessed by determining dose-response relations using three approaches: (1) a filtration assay measuring responses on the 10-s time scale, (2) the same filtration assay after blocking different fractions of the receptor sites with alpha-bungarotoxin (alpha-BgTx), and (3) a rapid-mix quenched-flow technique which permits measurement of the initial rate of 22Na+ efflux on the millisecond time scale. The concentrations of agonist producing half-maximal responses in these three assays at 4 degrees C are 13, 150, and 600 microM, respectively, for Carb and 50, 50, and 200 microM, respectively, for PTA. The rate constants for 22Na+ efflux are 1.3 x 10(-4) s-1 in the absence of agonst and 65 s-1 and 0.8 s-1 in the presence of maximal concentrations of Carb and PTA, respectively, representing a stimulation of 5 x 10(5) by Carb. The Hill coefficient for the Carb response, expressed as rate constants for 22N+ efflux, is 1.97 +/- 0.06 for Carb concentrations between 3 microM and 1 mM. The inhibition of the agonist-stimulated 22Na+ efflux by alpha-BgTx is compatible with two alpha-BgTx (and acetylcholine) sites per functional unit. Inhibition of Carb responses (slow assay) by d-tubocurarine appears competitive with a KI approximately 0.5 microM, while responses to PTA are inhibited noncompetitively with KI = 0.3 microM. This paradox is due to the presence of spare receptors and to complexities in the binding of dTC to the nicotinic acetylcholine receptor. Determination of responses without the complication of spare receptors allows a meaningful comparison to direct measurements of agonist and antagonist binding in the same system. A model is proposed to account for both binding and response. PMID:7397104

  1. Repetitive TASER X26 discharge resulted in adverse physiologic events with a dose-response relationship related to the duration of discharge in anesthetized swine model.

    PubMed

    Park, Eun-Jung; Choi, Sang-Cheon; Ahn, Jung-Hwan; Min, Young-Gi

    2013-01-01

    The objectives of our study were to investigate the dose-response relationship of the TASER X26 discharge duration in an anesthetized swine model. Fourteen swines were anesthetized and then exposed to TASER X26 discharge for 5 sec (n = 5) or for 10 sec (n = 6). The sham control group (n = 3) was anesthetized and studied using the same protocol except TASER X26 discharges during the experiments. Hemodynamic parameters were obtained. Blood pressure and total peripheral resistance decreased significantly after TASER discharge and returned to baseline value at 15 min after 5 sec of TASER discharge but did not return to baseline values during the 30-min observation period after 10 sec of TASER discharge. Repetitive TASER X26 discharge resulted in adverse physiologic events with a dose-response relationship related to the duration of TASER X26 discharge in an anesthetized swine model. PMID:23066880

  2. Establishment of in vitro 192Ir γ-ray dose-response relationship for dose assessment by the lymphocyte dicentric assay

    NASA Astrophysics Data System (ADS)

    Kowalska, Maria; Meronka, Katarzyna; Szewczak, Kamil

    2012-03-01

    In vitro dose-response relationships are used to describe the relation between dicentric chromosomes and radiation dose for human peripheral blood lymphocytes. The dicentric yield depends on both the dose and the radiation quality. Thus, for reliable dose estimation in vitro dose responses must be determined for different radiation qualities. This paper reports the work for setting up the relationship for the dicentric production in the lymphocytes exposed in vitro to 192Ir g-rays at Central Laboratory for Radiological Protection (CLOR). In a case of a radiation accident in industrial radiography using 192Ir sealed sources, this will be the basis for the indirect evaluation of the g-ray dose to which an accidental victim was exposed.

  3. A 3-year oral health dose-response study of sodium monofluorophosphate dentifrices with and without zinc citrate: anti-caries results.

    PubMed

    Stephen, K W; Creanor, S L; Russell, J I; Burchell, C K; Huntington, E; Downie, C F

    1988-12-01

    A 3-yr clinical trial has been conducted on 3000 12-yr-old children in Lanarkshire, Scotland, with the aim of investigating the effects on oral health of toothpastes containing both sodium monofluorophosphate and zinc citrate, the former being present at fluoride levels of 1000, 1500, and 2500 ppm F. No significant difference in caries increments was found between the group of children using toothpastes incorporating zinc citrate and their counterparts using zinc-free pastes. However, a significant anti-caries dose-response was demonstrated over the SMFP range used. This dose-response was evident for boys and girls and also for the various types of teeth and tooth surfaces. PMID:3060308

  4. The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells

    SciTech Connect

    Lemon, Jennifer A.; Taylor, Kristina; Verdecchia, Kyle; Phan, Nghi; Boreham, Douglas R.

    2014-01-01

    Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01-2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/-) mice. The dose response for Trp53+/+ mice showed higher initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.

  5. Are Bigger Datasets Better for Machine Learning? Fusing Single-Point and Dual-event Dose Response Data For Mycobacterium tuberculosis

    PubMed Central

    Ekins, Sean; Freundlich, Joel S.; Reynolds, Robert C.

    2016-01-01

    Tuberculosis is a major neglected disease for which the quest to find new treatments continues. There is an abundance of data from large phenotypic screens in the public domain against Mycobacterium tuberculosis (Mtb). Since machine learning methods can learn from past data, we were interested in addressing whether more data builds better models. We now describe using Bayesian machine learning to assess whether we can improve our models by combining the large quantities of single-point data with the much smaller (higher quality) dual-event datasets, which use both dose-response data for both whole-cell antitubercular activity and Vero cell cytotoxicity. We have evaluated 12 models ranging from different single-point, dual-event dose response, single-point and dual-event dose response as well as combined datasets for three distinct datasets from the same laboratory. We used a fourth dataset of active and inactive compounds from the same group as well as a smaller set of 177 active compounds from GlaxoSmithKline as test sets. Our data suggest combining single-point with dual-event dose response data does not diminish the internal or external predictive ability of the models based on the receiver operator curve (ROC) for these models (internal ROC range 0.83-0.91, external ROC range 0.62-0.83) compared to the orders of magnitude smaller dual event models (internal ROC range 0.6-0.83 and external ROC 0.54-0.83). In conclusion, models developed with 1200-5000 compounds appear to be as predictive as those generated with 25,000 to 350,000 molecules. Our results have implications for justifying further HTS versus focused testing based on model predictions. PMID:24968215

  6. Waterborne microbial risk assessment : a population-based dose-response function for Giardia spp. (E.MI.R.A study)

    PubMed Central

    Zmirou-Navier, D; Gofti-Laroche, L; Hartemann, Ph

    2006-01-01

    Background Dose-response parameters based on clinical challenges are frequently used to assess the health impact of protozoa in drinking water. We compare the risk estimates associated with Giardia in drinking water derived from the dose-response parameter published in the literature and the incidence of acute digestive conditions (ADC) measured in the framework of an epidemiological study in a general population. Methods The study combined a daily follow-up of digestive morbidity among a panel of 544 volunteers and a microbiological surveillance of tap water. The relationship between incidence of ADC and concentrations of Giardia cysts was modeled with Generalized Estimating Equations, adjusting on community, age, tap water intake, presence of bacterial indicators, and genetic markers of viruses. The quantitative estimate of Giardia dose was the product of the declared amount of drinking water intake (in L) by the logarithm of cysts concentrations. Results The Odds Ratio for one unit of dose [OR = 1.76 (95% CI: 1.21, 2.55)] showed a very good consistency with the risk assessment estimate computed after the literature dose-response, provided application of a 20 % abatement factor to the cysts counts that were measured in the epidemiological study. Doing so, a daily water intake of 2 L and a Giardia concentration of 10 cysts/100 L, would yield an estimated relative excess risk of 12 % according to the Rendtorff model, against 11 % when multiplying the baseline rate of ADC by the corresponding OR. This abatement parameter encompasses uncertainties associated with germ viability, infectivity and virulence in natural settings. Conclusion The dose-response function for waterborne Giardia risk derived from clinical experiments is consistent with epidemiological data. However, much remains to be learned about key characteristics that may heavily influence quantitative risk assessment results. PMID:16672062

  7. A Comparison of Dose-Response Models for the Parotid Gland in a Large Group of Head-and-Neck Cancer Patients

    SciTech Connect

    Houweling, Antonetta C.; Philippens, Marielle E.P.; Dijkema, Tim; Roesink, Judith M.; Terhaard, Chris H.J.; Schilstra, Cornelis; Ten Haken, Randall K.; Eisbruch, Avraham; Raaijmakers, Cornelis P.J.

    2010-03-15

    Purpose: The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. Methods and Materials: A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulated salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC). Results: None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD{sub 50} in these models was approximately 39 Gy. Conclusions: The mean dose model was preferred for describing the dose-response relationship of the parotid gland.

  8. Dose-response relationship between serum 2,3,7,8-tetrachlorodibenzo-p-dioxin and diabetes mellitus: a meta-analysis.

    PubMed

    Goodman, Michael; Narayan, K M Venkat; Flanders, Dana; Chang, Ellen T; Adami, Hans-Olov; Boffetta, Paolo; Mandel, Jack S

    2015-03-15

    We systematically evaluated studies published through May 2014 in which investigators assessed the dose-response relationship between serum levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the occurrence of diabetes mellitus (DM), and we investigated the extent and sources of interstudy heterogeneity. The dose-response relationship between serum TCDD and DM across studies was examined using 2 dependent variables: an exposure level-specific proportion of persons with DM and a corresponding natural log-transformed ratio measure of the association between TCDD and DM. Regression slopes for each dependent variable were obtained for each study and included in a random-effects meta-analysis. Sensitivity analyses were used to assess the influence of inclusion and exclusion decisions, and sources of heterogeneity were explored using meta-regression models and a series of subanalyses. None of the summary estimates in the main models or in the sensitivity analyses indicated a statistically significant association. We found a pronounced dichotomy: a positive dose-response in cross-sectional studies of populations with low-level TCDD exposures (serum concentrations <10 pg/g lipid) and heterogeneous, but on balance null, results for prospective studies of persons with high prediagnosis TCDD body burdens. Considering the discrepancy of results for low current versus high past TCDD levels, the available data do not indicate that increasing TCDD exposure is associated with an increased risk of DM. PMID:25731889

  9. Does beer, wine or liquor consumption correlate with the risk of renal cell carcinoma? A dose-response meta-analysis of prospective cohort studies

    PubMed Central

    Xu, Xin; Zhu, Yi; Zheng, Xiangyi; Xie, Liping

    2015-01-01

    Despite plenty of evidence supports an inverse association between alcohol drinking and risk of renal cell carcinoma (RCC), sex-specific and beverage-specific dose-response relationships have not been well established. We examined this association by performing a systematic review and meta-analysis of prospective studies. Studies were identified by comprehensively searching PubMed and EMBASE databases through February 21, 2015. Categorical and dose-response meta-analyses were conducted to identify the effects of alcohol on RCC. A total of eight publications (including seven cohort studies and one pooled analysis of 12 cohort studies) were eligible for this meta-analysis. Dose-response analysis showed that each 5 g/day increment of alcohol intake corresponded to a 5% decrease in risk of RCC for males and 9% for females. Alcohol intakes from wine, beer, and liquor were each associated with a reduced risk of RCC. When these associations were examined separately by gender, statistically significant inverse associations were restricted to alcohol from wine among females (RR = 0.82, 95% CI 0.73–0.91) and to alcohol from beer and from liquor among males (RR = 0.87, 95% CI 0.83–0.91 and RR = 0.95, 95% CI 0.92–0.99, respectively). In conclusion, there exist gender-specific and beverage-specific differences in the association between alcohol intake and RCC risk. PMID:25965820

  10. Dose-Response Relationship Between Serum 2,3,7,8-Tetrachlorodibenzo-p-Dioxin and Diabetes Mellitus: A Meta-Analysis

    PubMed Central

    Goodman, Michael; Narayan, K. M. Venkat; Flanders, Dana; Chang, Ellen T.; Adami, Hans-Olov; Boffetta, Paolo; Mandel, Jack S.

    2015-01-01

    We systematically evaluated studies published through May 2014 in which investigators assessed the dose-response relationship between serum levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the occurrence of diabetes mellitus (DM), and we investigated the extent and sources of interstudy heterogeneity. The dose-response relationship between serum TCDD and DM across studies was examined using 2 dependent variables: an exposure level–specific proportion of persons with DM and a corresponding natural log-transformed ratio measure of the association between TCDD and DM. Regression slopes for each dependent variable were obtained for each study and included in a random-effects meta-analysis. Sensitivity analyses were used to assess the influence of inclusion and exclusion decisions, and sources of heterogeneity were explored using meta-regression models and a series of subanalyses. None of the summary estimates in the main models or in the sensitivity analyses indicated a statistically significant association. We found a pronounced dichotomy: a positive dose-response in cross-sectional studies of populations with low-level TCDD exposures (serum concentrations <10 pg/g lipid) and heterogeneous, but on balance null, results for prospective studies of persons with high prediagnosis TCDD body burdens. Considering the discrepancy of results for low current versus high past TCDD levels, the available data do not indicate that increasing TCDD exposure is associated with an increased risk of DM. PMID:25731889

  11. A graphic user interface toolkit for specification, report and comparison of dose-response relations and treatment plans using the biologically effective uniform dose.

    PubMed

    Su, Fan-Chi; Mavroidis, Panayiotis; Shi, Chengyu; Ferreira, Brigida Costa; Papanikolaou, Niko

    2010-10-01

    A toolkit (BEUDcal) has been developed for evaluating the effectiveness and for predicting the outcome of treatment plans by calculating the biologically effective uniform dose (BEUD) and complication-free tumor control probability. The input for the BEUDcal is the differential dose-volume histograms of organs exported from the treatment planning system. A clinical database is built for the dose-response parameters of different tumors and normal tissues. Dose-response probabilities of all the examined organs are illustrated together with the corresponding BEUDs and the P(+) values. Furthermore, BEUDcal is able to generate a report that simultaneously presents the radiobiological evaluation together with the physical dose indices, showing the complementary relation between the physical and radiobiological treatment plan analysis performed by BEUDcal. Comparisons between treatment plans for helical tomotherapy and multileaf collimator-based intensity modulated radiotherapy of a lung patient were demonstrated to show the versatility of BEUDcal in the assessment and report of dose-response relations. PMID:20338661

  12. Site-specific dose-response relationships for cancer induction from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy

    PubMed Central

    2011-01-01

    Background and Purpose Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. Materials and methods For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship. Results The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy. Conclusions In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three

  13. Dose-Response Relationship of Physical Activity to Premature and Total All-Cause and Cardiovascular Disease Mortality in Walkers

    PubMed Central

    Williams, Paul T.

    2013-01-01

    Purpose To assess the dose-response relationships between cause-specific mortality and exercise energy expenditure in a prospective epidemiological cohort of walkers. Methods The sample consisted of the 8,436 male and 33,586 female participants of the National Walkers' Health Study. Walking energy expenditure was calculated in metabolic equivalents (METs, 1 MET = 3.5 ml O2/kg/min), which were used to divide the cohort into four exercise categories: category 1 (≤1.07 MET-hours/d), category 2 (1.07 to 1.8 MET-hours/d), category 3 (1.8 to 3.6 MET-hours/d), and category 4 (≥3.6 MET-hours/d). Competing risk regression analyses were use to calculate the risk of mortality for categories 2, 3 and 4 relative to category 1. Results 22.9% of the subjects were in category 1, 16.1% in category 2, 33.3% in category 3, and 27.7% in category 4. There were 2,448 deaths during the 9.6 average years of follow-up. Total mortality was 11.2% lower in category 2 (P = 0.04), 32.4% lower in category 3 (P<10−12) and 32.9% lower in category 4 (P = 10−11) than in category 1. For underlying causes of death, the respective risk reductions for categories 2, 3 and 4 were 23.6% (P = 0.008), 35.2% (P<10−5), and 34.9% (P = 0.0001) for cardiovascular disease mortality; 27.8% (P = 0.18), 20.6% (P = 0.07), and 31.4% (P = 0.009) for ischemic heart disease mortality; and 39.4% (P = 0.18), 63.8% (P = 0.005), and 90.6% (P = 0.002) for diabetes mortality when compared to category 1. For all related mortality (i.e., underlying and contributing causes of death combined), the respective risk reductions for categories 2, 3 and 4 were 18.7% (P = 0.22), 42.5% (P = 0.001), and 57.5% (P = 0.0001) for heart failure; 9.4% (P = 0.56), 44.3% (P = 0.0004), and 33.5% (P = 0.02) for hypertensive diseases; 11.5% (P = 0.38), 41.0% (P<10−4), and 35.5% (P = 0.001) for dysrhythmias: and 23.2% (P = 0.13), 45.8% (P = 0.0002), and 41

  14. Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset.

    PubMed

    Conolly, Rory B; Kimbell, Julia S; Janszen, Derek; Schlosser, Paul M; Kalisak, Darin; Preston, Julian; Miller, Frederick J

    2004-11-01

    Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The quantitative implications of the rat tumors for human cancer risk are of interest, since epidemiological studies have provided only equivocal evidence that formaldehyde is a human carcinogen. Conolly et al. (Toxicol. Sci. 75, 432-447, 2003) analyzed the rat tumor dose-response assuming that both DNA-reactive and cytotoxic effects of formaldehyde contribute to SCC development. The key elements of their approach were: (1) use of a three-dimensional computer reconstruction of the rat nasal passages and computational fluid dynamics (CFD) modeling to predict regional dosimetry of formaldehyde; (2) association of the flux of formaldehyde into the nasal mucosa, as predicted by the CFD model, with formation of DNA-protein cross-links (DPX) and with cytolethality/regenerative cellular proliferation (CRCP); and (3) use of a two-stage clonal growth model to link DPX and CRCP with tumor formation. With this structure, the prediction of the tumor dose response was extremely sensitive to cell kinetics. The raw dose-response data for CRCP are J-shaped, and use of these data led to a predicted J-shaped dose response for tumors, notwithstanding a concurrent low-dose-linear, directly mutagenic effect of formaldehyde mediated by DPX. In the present work the modeling approach used by Conolly et al. (ibid.) was extended to humans. Regional dosimetry predictions for the entire respiratory tract were obtained by merging a three-dimensional CFD model for the human nose with a one-dimensional typical path model for the lower respiratory tract. In other respects, the human model was structurally identical to the rat model. The predicted human dose response for DPX was obtained by scale-up of a computational model for DPX calibrated against rat and rhesus monkey data. The rat dose response for CRCP was used "as is" for the human model, since no preferable alternative was identified. Three

  15. Immune response to a new hepatitis B vaccine in healthcare workers who had not responded to standard vaccine: randomised double blind dose-response study.

    PubMed Central

    Zuckerman, J. N.; Sabin, C.; Craig, F. M.; Williams, A.; Zuckerman, A. J.

    1997-01-01

    OBJECTIVE: To evaluate the immunogenicity and reactogenicity of a new triple S recombinant hepatitis B vaccine in a cohort of healthy people in whom currently licensed hepatitis B vaccines had persistently not induced an immune response. DESIGN: Single centre, randomised, double blind, dose-response study. SETTING: Research vaccine evaluation centre at a teaching hospital. SUBJECTS: 100 healthcare workers aged 18-70 years with a history of failure to seroconvert after at least four doses of a licensed hepatitis B vaccine containing the S component. INTERVENTION: Each subject was randomly allocated two doses of 5, 10, 20, or 40 micrograms of a new hepatitis B vaccine two months apart. MAIN OUTCOME MEASURES: Immunogenicity of the four doses. Seroconversion and seroprotection were defined as an antibody tire > 10 IU/l and > 100 IU/l respectively against an international antibody standard. RESULTS: 69 subjects seroconverted after a single dose of the vaccine. After the booster vaccination one other subject seroconverted, bringing the overall seroconversion rate to 70%. Fifteen subjects given 5 micrograms of vaccine, 19 given 10 micrograms, 16 given 20 micrograms, and 20 given 40 micrograms seroconverted. Seroconversion rates in the four antigen dose groups were 60% (15/25), 76% (19/25), 64% (16/25), and 80% (20/25). After the booster dose there was no significant dose-response effect on the overall seroconversion rate, although the small sample size meant that a clinically important dose-response could not be ruled out. CONCLUSION: A single dose of 20 micrograms of the vaccine was as effective as two doses of either 40 micrograms or 20 micrograms of this vaccine formulation in terms of seroconversion, seroprotection, and geometric mean titres. PMID:9040320

  16. SU-D-16A-03: A Radiation Pneumonitis Dose-Response Model Incorporating Non- Local Radiation-Induced Bystander Effect

    SciTech Connect

    Gordon, J; Snyder, K; Zhong, H; Chetty, I

    2014-06-01

    Purpose: Dose-response models that can reliably predict radiation pneumonitis (RP) to guide radiation therapy (RT) for lung cancer presently do not exist. A model is proposed that incorporates non-local radiationinduced bystander effect (RIBE). Methods: A single sigmoid response function, derived from published data for whole lung irradiation, relates RP probability to cumulative lung damage, regardless of fractionation scheme. Lung damage is assumed to be caused by direct local radiation damage, quantified via the linear-quadratic (LQ) model, and RIBE. Based on published data, RIBE is assumed to be activated when per-fraction dose rises above ∼0.6 Gy, but is constant with dose above that threshold. Integral RIBE damage is assumed proportional to lung volume irradiated above ∼0.6 Gy per fraction. Key model parameters include LQ α and β, and two RIBE parameters: the single-fraction probability δ of damage, and a proportionality parameter κ that relates the potential for RIBE damage to irradiated lung volume. All parameters are tentatively fitted from published data, the RIBE parameters from published RP rates for conventionally fractionated RT (CFRT) and stereotactic body RT (SBRT). Results: The model predicts dose-response curves that are consistent with clinical experience. It provides a tentative explanation for why V20 (33 fractions), V13 (20 fractions) and V5 (<10 fractions) are observed to be correlated with RP. It also provides a plausible explanation for the success of SBRT — RIBE damage increases with the number of fractions, so penalizes CFRT relative to SBRT. Conclusion: The proposed model is relatively simple, extrapolates from published data, plausibly explains several clinical observations, and produces dose-response curves that are consistent with clinical experience. While capable of elaboration, its ability to explain doseresponse experience with different fractionation schemes using a small number of assumptions and parameters is an

  17. Dose-response analysis indicating time-dependent neurotoxicity caused by organic and inorganic mercury-Implications for toxic effects in the developing brain.

    PubMed

    Pletz, Julia; Sánchez-Bayo, Francisco; Tennekes, Henk A

    2016-03-10

    A latency period preceding neurotoxicity is a common characteristic in the dose-response relationship induced by organic mercury. Latency periods have typically been observed with genotoxicants in carcinogenesis, with cancer being manifested a long time after the initiating event. These observations indicate that even a very small dose may cause extensive adverse effects later in life, so the toxicity of the genotoxic compound is dose and time-dependent. In children, methylmercury exposure during pregnancy (in utero) has been associated with delays in reaching developmental milestones (e.g., age at first walking) and decreases in intelligence, increasing in severity with increasing exposure. Ethylmercury exposure from thimerosal in some vaccines has been associated, in some studies, with autism and other neurological disorders in children. In this paper, we have examined whether dose-response data from in vitro and in vivo organic mercury toxicity studies fit the Druckrey-Küpfmüller equation c·t(n)=constant (c=exposure concentration, t=latency period), first established for genotoxic carcinogens, and whether or not irreversible effects are enhanced by time of exposure (n≥1), or else toxic effects are dose-dependent while time has only minor influence on the adverse outcome (n<1). The mode of action underlying time-dependent toxicity is irreversible binding to critical receptors causing adverse and cumulative effects. The results indicate that the Druckrey-Küpfmüller equation describes well the dose-response characteristics of organic mercury induced neurotoxic effects. This amounts to a paradigm shift in chemical risk assessment of mercurial compounds and highlights that it is vital to perform toxicity testing geared to investigate time-dependent effects. PMID:26945727

  18. mFISH analysis of chromosome aberrations induced in vitro by α-particle radiation: examination of dose-response relationships.

    PubMed

    Curwen, Gillian B; Tawn, E Janet; Cadwell, Kevin K; Guyatt, Laura; Thompson, James; Hill, Mark A

    2012-11-01

    A multicolored FISH (mFISH) technique was used to characterize the cytogenetic damage associated with exposure to α-particle radiation with particular emphasis on the quality and quantity that is likely to be transmitted through cell division to descendant cells. Peripheral blood lymphocytes were irradiated in vitro with (238)Pu α particles with a range of mean doses up to 936 mGy and were cultured for 47 h. The dose responses for total aberrant cells, stable and unstable cells, and cells with one simple chromosome aberration and multiple chromosome aberrations were predominantly linear for doses that resulted in cell nuclei receiving a single α-particle traversal. However, there was a decrease per unit dose in aberrant cells of all types at higher doses because of cells increasingly receiving multiple traversals. The proportion of radiation-induced aberrant cells containing multiple aberrations ranged from 48 to 74% with little evidence of dose dependency. Ninety-one percent of all cells with multiple aberrations were classified as unstable. Resolving the chromosome rearrangements into simple categories resulted in a linear dose response for dicentrics of 24.9 ± 3.3 × 10(-2) per Gy. The predominant aberration in stable transmissible cells was a single translocation with a dose response for predominantly single hit cell nuclei of 4.1 ± 1.3 × 10(-2) per Gy. Thus, translocations are the most likely aberration to be observed in peripheral blood lymphocytes from individuals with incorporated α-emitting radionuclides resulting in long-term chronic exposure. PMID:23083107

  19. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

    PubMed

    Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

    2009-06-01

    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P < 0.05) the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05) after exposing the animals to the open field test. PMID:19448906

  20. Uncertainty analysis in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cancer dose-response for three occupational cohorts.

    PubMed

    Dong, Zhaomin; Yuan, Guanxiang; Hu, Jianying

    2016-03-01

    While the U.S. EPA has issued a draft report with a 1% TCDD effective dose (ED01) of 87.9pg/kg/day based on continuous integration of key scientific evidence, a detailed and comprehensive uncertainty analysis has not been well documented. In this study, a new estimate for ED01 was derived based on uncertainty analysis by quantitatively assessing the potential bias arising from the selection of kinetic models, dose-response models and cohorts. The cumulative serum lipid concentration (CSLC) and cumulative body burden (CBB) were reconstructed as dose metrics using a concentration- and age-dependent pharmacokinetic model (CADM), physiologically based pharmacokinetic model (PBPK), and age-dependent half-life model (FV), and the reconstructed dose metrics based on CADM and PBPK were generally higher than those based on the FV model. Three dose-response curves (linear, multiplicative and power) were used to link dose metrics and cancer risk to estimate ED01, and the linear model resulted in the lowest ED01, followed by the power model and multiplicative model, for the same cohort. Meanwhile, ED01 based on the CADM model was the highest, followed by those based on the PBPK model and first-order model. Finally, the ED01 was estimated to be 17.03±7.83pg/kg/day by statistically analyzing the distribution of ED01 values based on various kinetic models, cohorts and dose-response models. The study presented here strengthens the scientific basis for understanding the potential health implications of TCDD exposure. PMID:26708281

  1. Monte Carlo simulation of the dose response of a novel 2D silicon diode array for use in hybrid MRI–LINAC systems

    SciTech Connect

    Gargett, Maegan Rosenfeld, Anatoly; Oborn, Brad; Metcalfe, Peter

    2015-02-15

    Purpose: MRI-guided radiation therapy systems (MRIgRT) are being developed to improve online imaging during treatment delivery. At present, the operation of single point dosimeters and an ionization chamber array have been characterized in such systems. This work investigates a novel 2D diode array, named “magic plate,” for both single point calibration and 2D positional performance, the latter being a key element of modern radiotherapy techniques that will be delivered by these systems. Methods: GEANT4 Monte Carlo methods have been employed to study the dose response of a silicon diode array to 6 MV photon beams, in the presence of in-line and perpendicularly aligned uniform magnetic fields. The array consists of 121 silicon diodes (dimensions 1.5 × 1.5 × 0.38 mm{sup 3}) embedded in kapton substrate with 1 cm pitch, spanning a 10 × 10 cm{sup 2} area in total. A geometrically identical, water equivalent volume was simulated concurrently for comparison. The dose response of the silicon diode array was assessed for various photon beam field shapes and sizes, including an IMRT field, at 1 T. The dose response was further investigated at larger magnetic field strengths (1.5 and 3 T) for a 4 × 4 cm{sup 2} photon field size. Results: The magic plate diode array shows excellent correspondence (< ± 1%) to water dose in the in-line orientation, for all beam arrangements and magnetic field strengths investigated. The perpendicular orientation, however, exhibits a dose shift with respect to water at the high-dose-gradient beam edge of jaw-defined fields [maximum (4.3 ± 0.8)% over-response, maximum (1.8 ± 0.8)% under-response on opposing side for 1 T, uncertainty 1σ]. The trend is not evident in areas with in-field dose gradients typical of IMRT dose maps. Conclusions: A novel 121 pixel silicon diode array detector has been characterized by Monte Carlo simulation for its performance inside magnetic fields representative of current prototype and proposed MRI

  2. Dose-response relationship between arsenic exposure and the serum enzymes for liver function tests in the individuals exposed to arsenic: a cross sectional study in Bangladesh

    PubMed Central

    2011-01-01

    Background Chronic arsenic exposure has been shown to cause liver damage. However, serum hepatic enzyme activity as recognized on liver function tests (LFTs) showing a dose-response relationship with arsenic exposure has not yet been clearly documented. The aim of our study was to investigate the dose-response relationship between arsenic exposure and major serum enzyme marker activity associated with LFTs in the population living in arsenic-endemic areas in Bangladesh. Methods A total of 200 residents living in arsenic-endemic areas in Bangladesh were selected as study subjects. Arsenic concentrations in the drinking water, hair and nails were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The study subjects were stratified into quartile groups as follows, based on concentrations of arsenic in the drinking water, as well as in subjects' hair and nails: lowest, low, medium and high. The serum hepatic enzyme activities of alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) were then assayed. Results Arsenic concentrations in the subjects' hair and nails were positively correlated with arsenic levels in the drinking water. As regards the exposure-response relationship with arsenic in the drinking water, the respective activities of ALP, AST and ALT were found to be significantly increased in the high-exposure groups compared to the lowest-exposure groups before and after adjustments were made for different covariates. With internal exposure markers (arsenic in hair and nails), the ALP, AST and ALT activity profiles assumed a similar shape of dose-response relationship, with very few differences seen in the higher groups compared to the lowest group, most likely due to the temporalities of exposure metrics. Conclusions The present study demonstrated that arsenic concentrations in the drinking water were strongly correlated with arsenic concentrations in the subjects' hair and nails. Further, this study revealed a

  3. Egg intake and cancers of the breast, ovary and prostate: a dose-response meta-analysis of prospective observational studies.

    PubMed

    Keum, N; Lee, D H; Marchand, N; Oh, H; Liu, H; Aune, D; Greenwood, D C; Giovannucci, E L

    2015-10-14

    Evidence suggests that egg intake may be implicated in the aetiology of sex hormone-related cancers. However, dose-response relationships between egg intake and such cancers are unclear. Thus, we conducted a dose-response meta-analysis to summarise the dose-response relationships between egg consumption and the risk of breast, prostate and gynaecological cancers. A literature search was performed using PubMed and Embase up to April 2015 to identify relevant prospective observational studies. Summary relative risk (RR) and 95% CI were estimated using a random-effects model. For breast cancer, the linear dose-response meta-analysis found a non-significantly increased risk (RR for an increase of 5 eggs consumed/week: 1·05, 95% CI 0·99, 1·11, n 16,023 cases). Evidence for non-linearity was not statistically significant (P non-linearity= 0·50, n 15,415 cases) but consuming ≥ 5 eggs/week was significantly associated with an increased risk of breast cancer compared with no egg consumption, with the summary RR being 1·04 (95% CI 1·01, 1·07) for consuming 5 eggs/week and 1·09 (95% CI 1·03, 1·15) for consuming about 9 eggs/week. For other cancers investigated, the summary RR for an increase of 5 eggs consumed/week was 1·09 (95% CI 0·96, 1·24, n 2636 cases) for ovarian cancer; 1·47 (95% CI 1·01, 2·14, n 609 cases) for fatal prostate cancer, with evidence of small-study effects (P Egger= 0·04). No evidence was found for an association with the risk of total prostate cancer. While our conclusion was tempered by the potential for publication bias and confounding, high egg intake may be associated with a modestly elevated risk of breast cancer, and a positive association between egg intake and ovarian and fatal prostate cancers cannot be ruled out. PMID:26293984

  4. No evident dose-response relationship between cellular ROS level and its cytotoxicity--a paradoxical issue in ROS-based cancer therapy.

    PubMed

    Zhu, Chunpeng; Hu, Wei; Wu, Hao; Hu, Xun

    2014-01-01

    Targeting cancer via ROS-based mechanism has been proposed as a radical therapeutic approach. Cancer cells exhibit higher endogenous oxidative stress than normal cells and pharmacological ROS insults via either enhancing ROS production or inhibiting ROS-scavenging activity can selectively kill cancer cells. In this study, we randomly chose 4 cancer cell lines and primary colon or rectal cancer cells from 4 patients to test the hypothesis and obtained following paradoxical results: while piperlongumin (PL) and β-phenylethyl isothiocyanate (PEITC), 2 well-defined ROS-based anticancer agents, induced an increase of cellular ROS and killed effectively the tested cells, lactic acidosis (LA), a common tumor environmental factor that plays multifaceted roles in promoting cancer progression, induced a much higher ROS level in the tested cancer cells than PL and PEITC, but spared them; L-buthionine sulfoximine (L-BSO, 20 μM) depleted cellular GSH more effectively and increased higher ROS level than PL or PEITC but permitted progressive growth of the tested cancer cells. No evident dose-response relationship between cellular ROS level and cytotoxicity was observed. If ROS is the effecter, it should obey the fundamental therapeutic principle - the dose-response relationship. This is a major concern. PMID:24848642

  5. Less is more for cancer chemoprevention: evidence of a non-linear dose response for the protective effects of resveratrol in humans and mice

    PubMed Central

    Scott, Edwina; Cai, Hong; Kholghi, Abeer; Andreadi, Catherine; Rufini, Alessandro; Karmokar, Ankur; Britton, Robert G.; Horner-Glister, Emma; Greaves, Peter; Jawad, Dhafer; James, Mark; Howells, Lynne; Ognibene, Ted; Malfatti, Mike; Goldring, Christopher; Kitteringham, Neil; Walsh, Joanne; Viskaduraki, Maria; West, Kevin; Miller, Andrew; Hemingway, David; Steward, William P.; Gescher, Andreas J.

    2016-01-01

    Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials assessing efficacy. To challenge the assumption that ‘more is better’ we compared the pharmacokinetics and activity of a dietary dose with an intake 200-times higher. The dose response relationship and metabolite profile of [14C]-resveratrol in colorectal tissue of patients helped define clinically achievable concentrations. In ApcMin mice receiving a high-fat diet the low dose supressed intestinal adenoma development more potently than the higher dose. Efficacy correlated with increased AMP-activated protein kinase (AMPK) activation and the senescence marker p21. Non-linear dose responses were observed for AMPK and mTOR signalling in adenoma cells, culminating in autophagy and senescence. In human tissues low dietary exposures caused enhanced AMPK phosphorylation, autophagy and expression of the cytoprotective enzyme NQO1. These findings warrant revision of developmental strategies for diet-derived agents for cancer chemoprevention. PMID:26223300

  6. Behavioral and electrophysiological dose-response relationships in adult western corn rootworm (Diabrotica virgifera virgifera LeConte) for host pollen amino acids.

    PubMed

    Hollister, Benedict; Mullin, Christopher A.

    1998-05-01

    A strong correlation is shown between taste cell inputs and phagostimulatory outputs with predominant dietary pollen amino acids for western corn rootworm, Diabrotica virgifera virgifera. Behavioral and electrophysiological dose-response profiles in adult beetles are presented for five major free amino acids in host pollens. Differential responses were found with strongest phagostimulation and sensory response elicited by L-alanine and L-serine, followed in order by L-proline and beta-alanine. gamma-Aminobutyric acid gave the weakest and most sporadic response. ED(50) values for phagostimulation and chemosensory input were 28.3nmol/disk and 13mM, respectively, for L-alanine and 17nmol/disk and 11mM, respectively, for serine. Threshold values for the responses were approximately 1-2mM. These behavioral and chemosensory dose-response ranges correspond closely to levels of free amino acids present in host plant pollens. Use of these response values in development of a pollen chemosensory code for western corn rootworm feeding is discussed. PMID:12770166

  7. Dose-response relationships between plasma adrenocorticotropin (ACTH), cortisol, aldosterone, and 18-hydroxycorticosterone after injection of ACTH-(1-39) or human corticotropin-releasing hormone in man.

    PubMed

    Oelkers, W; Boelke, T; Bähr, V

    1988-01-01

    The effects of sc injections (at 1500 h) of increasing amounts of synthetic human ACTH-(1-39) (1.25-30 micrograms) on plasma ACTH, cortisol, aldosterone, and 18-hydroxycorticosterone were compared with those of iv injections of 30 and 100 micrograms synthetic human CRH in nine normal men. Five micrograms of ACTH, sc, was the lowest dose that significantly increased plasma levels of the three steroids. CRH (30 micrograms, iv) increased plasma cortisol and 18-hydroxycorticosterone, but not aldosterone, while 100 micrograms CRH also raised aldosterone secretion. The dose-response curve (peak plasma ACTH level vs. maximum increment of plasma cortisol within the first hour) was initially very steep. Plasma ACTH levels between 50 and 60 ng/L (11-13 pmol/L) stimulated cortisol to almost 80% of the maximal increment obtained with plasma ACTH levels above 300 ng/L (greater than 66 pmol/L). This dose-response relationship is similar to that found in clinical tests of the pituitary-adrenal axis (insulin test, metyrapone test). The effects of plasma ACTH released by CRH on cortisol secretion were not significantly different from those of injected ACTH. Our results argue against the hypothesis that the effect of CRH on steroid secretion is mediated or modulated by POMC-derived peptides other than ACTH. PMID:2826525

  8. Maternal Caffeine Consumption during Pregnancy and Risk of Low Birth Weight: A Dose-Response Meta-Analysis of Observational Studies

    PubMed Central

    Rhee, Jongeun; Kim, Rockli; Kim, Yongjoo; Tam, Melanie; Lai, Yizhen; Keum, NaNa; Oldenburg, Catherine Elizabeth

    2015-01-01

    Epidemiologic studies have shown inconsistent conclusions about the effect of caffeine intake during pregnancy on the risk of low birth weight (LBW). We performed a meta-analysis and linear-dose response analysis examining the association between caffeine consumption during pregnancy and risk of LBW. PubMed and EMBASE were searched for relevant articles published up to March 2014. Eight cohort and four case-control studies met all inclusion criteria. Using a random-effects model of the twelve studies, the pooled odds ratio (OR) for the risk of LBW comparing the highest versus lowest level of caffeine intake during pregnancy was 1.38 (95% CI: 1.10, 1.73). Linear dose-response analysis showed that every additional 100 mg of caffeine intake (1 cup of coffee or 2 cups of tea) per day during pregnancy was associated with a 3.0% increase in OR for LBW. There was a moderate level of overall heterogeneity with an I-squared value of 55% (95% CI: 13, 76%), and no evidence of publication bias based on Egger’s test (P = 0.20) and the funnel plot. Thus, high caffeine intake during pregnancy is associated with a significant increase in the risk of LBW, and this risk appears to increase linearly as caffeine intake increases. PMID:26193706

  9. Accounting for shared and unshared dosimetric uncertainties in the dose response for ultrasound-detected thyroid nodules after exposure to radioactive fallout.

    PubMed

    Land, Charles E; Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M; Simon, Steven L

    2015-02-01

    Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population

  10. Accounting for Shared and Unshared Dosimetric Uncertainties in the Dose Response for Ultrasound-Detected Thyroid Nodules after Exposure to Radioactive Fallout

    PubMed Central

    Hoffman, F. Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M.; Simon, Steven L.

    2015-01-01

    Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semi-palatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point “best estimates”. In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5

  11. Nonlinear dose-response relationship between radon exposure and the risk of lung cancer: evidence from a meta-analysis of published observational studies.

    PubMed

    Duan, Peng; Quan, Chao; Hu, Chunhui; Zhang, Jicai; Xie, Fei; Hu, Xiuxue; Yu, Zongtao; Gao, Bo; Liu, Zhixiang; Zheng, Hong; Liu, Changjiang; Wang, Chengmin; Yu, Tingting; Qi, Suqin; Fu, Wenjuan; Kourouma, Ansoumane; Yang, Kedi

    2015-07-01

    Although radon exposure (RE) has been confirmed to increase the risk of lung cancer (LC), questions remain about the shape of the dose-response relationship between RE and the risk of LC. We carried out a dose-response meta-analysis to investigate and quantify the potential dose-response association between residential and occupational exposure to radon and the risk of LC. All cohort and case-control studies published in English and Chinese on Embase, PubMed, and China National Knowledge Infrastructure (CNKI) digital databases through November 2013 were identified systematically. We extracted effect measures (relative risk, odds ratio, standardized mortality ratio, standardized incidence ratio, or standardized rate ratio) from individual studies to generate pooled results using meta-analysis approaches. We derived meta-analytic estimates using random-effects models taking into account the correlation between estimates. Restricted cubic splines and generalized least-squares regression methods were used to model a potential curvilinear relationship and to carry out a dose-response meta-analysis. Stratified analysis, sensitivity analysis, and assessment of bias were performed in our meta-analysis. Sixty publications fulfilling the inclusion criteria for this meta-analysis were finally included. Occupational RE was associated with LC [risk ratio 1.86, 95% confidence interval (CI)=1.67-2.09; I²=92.2%; 27 prospective studies], for pooled risk estimate of the: standardized mortality ratio [2.00 (95% CI=1.82-2.32)]; standardized incidence ratio [1.45 (95% CI=1.20-1.74)]; relative risk [2.10 (95% CI=1.64-2.69)]. In a subgroup analysis of uranium miners and residents exposed to occupational uranium, the summary risk was 2.23 (95% CI=1.86-2.68) and 1.23 (95% CI=1.05-1.44). The overall meta-analysis showed evidence of a nonlinear association between RE and the risk of LC (P(nonlinearity)<0.014); in addition, the point value of residential radon also improved the results

  12. Daytime Napping and the Risk of Cardiovascular Disease and All-Cause Mortality: A Prospective Study and Dose-Response Meta-Analysis

    PubMed Central

    Yamada, Tomohide; Hara, Kazuo; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi

    2015-01-01

    Study Objectives: To summarize evidence about the association between daytime napping and the risk of cardiovascular disease and all-cause mortality, and to quantify the potential dose-response relation. Design: Meta-analysis of prospective cohort studies. Methods and Results: Electronic databases were searched for articles published up to December 2014 using the terms nap, cardiovascular disease, and all-cause mortality. We selected well-adjusted prospective cohort studies reporting risk estimates for cardiovascular disease and all-cause mortality related to napping. Eleven prospective cohort studies were identified with 151,588 participants (1,625,012 person-years) and a mean follow-up period of 11 years (60% women, 5,276 cardiovascular events, and 18,966 all-cause deaths). Pooled analysis showed that a long daytime nap (≥ 60 min/day) was associated with a higher risk of cardiovascular disease (rate ratio [RR]: 1.82 [1.22–2.71], P = 0.003, I2 = 37%) compared with not napping. All-cause mortality was associated with napping for ≥ 60 min/day (RR: 1.27 [1.11–1.45], P < 0.001, I2 = 0%) compared with not napping. In contrast, napping for < 60 min/day was not associated with cardiovascular disease (P = 0.98) or all-cause mortality (P = 0.08). Meta-analysis demonstrated a significant J-curve dose-response relation between nap time and cardiovascular disease (P for nonlinearity = 0.01). The RR initially decreased from 0 to 30 min/day. Then it increased slightly until about 45 min/day, followed by a sharp increase at longer nap times. There was also a positive linear relation between nap time and all-cause mortality (P for non-linearity = 0.97). Conclusions: Nap time and cardiovascular disease may be associated via a J-curve relation. Further studies are needed to confirm the efficacy of a short nap. Citation: Yamada T, Hara K, Shojima N, Yamauchi T, Kadowaki T. Daytime napping and the risk of cardiovascular disease and all-cause mortality: a prospective study and

  13. Experimental determination of the lateral dose response functions of detectors to be applied in the measurement of narrow photon-beam dose profiles

    NASA Astrophysics Data System (ADS)

    Poppinga, D.; Meyners, J.; Delfs, B.; Muru, A.; Harder, D.; Poppe, B.; Looe, HK

    2015-12-01

    This study aims at the experimental determination of the detector-specific 1D lateral dose response function K(x) and of its associated rotational symmetric counterpart K(r) for a set of high-resolution detectors presently used in narrow-beam photon dosimetry. A combination of slit-beam, radiochromic film, and deconvolution techniques served to accomplish this task for four detectors with diameters of their sensitive volumes ranging from 1 to 2.2 mm. The particular aim of the experiment was to examine the existence of significant negative portions of some of these response functions predicted by a recent Monte-Carlo-simulation (Looe et al 2015 Phys. Med. Biol. 60 6585-607). In a 6 MV photon slit beam formed by the Siemens Artiste collimation system and a 0.5 mm wide slit between 10 cm thick lead blocks serving as the tertiary collimator, the true cross-beam dose profile D(x) at 3 cm depth in a large water phantom was measured with radiochromic film EBT3, and the detector-affected cross-beam signal profiles M(x) were recorded with a silicon diode, a synthetic diamond detector, a miniaturized scintillation detector, and a small ionization chamber. For each detector, the deconvolution of the convolution integral M(x)  =  K(x)  ∗  D(x) served to obtain its specific 1D lateral dose response function K(x), and K(r) was calculated from it. Fourier transformations and back transformations were performed using function approximations by weighted sums of Gaussian functions and their analytical transformation. The 1D lateral dose response functions K(x) of the four types of detectors and their associated rotational symmetric counterparts K(r) were obtained. Significant negative curve portions of K(x) and K(r) were observed in the case of the silicon diode and the diamond detector, confirming the Monte-Carlo-based prediction (Looe et al 2015 Phys. Med. Biol. 60 6585-607). They are typical for the perturbation of the secondary electron field by a detector with

  14. Experimental determination of the lateral dose response functions of detectors to be applied in the measurement of narrow photon-beam dose profiles.

    PubMed

    Poppinga, D; Meyners, J; Delfs, B; Muru, A; Harder, D; Poppe, B; Looe, H K

    2015-12-21

    This study aims at the experimental determination of the detector-specific 1D lateral dose response function K(x) and of its associated rotational symmetric counterpart K(r) for a set of high-resolution detectors presently used in narrow-beam photon dosimetry. A combination of slit-beam, radiochromic film, and deconvolution techniques served to accomplish this task for four detectors with diameters of their sensitive volumes ranging from 1 to 2.2 mm. The particular aim of the experiment was to examine the existence of significant negative portions of some of these response functions predicted by a recent Monte-Carlo-simulation (Looe et al 2015 Phys. Med. Biol. 60 6585-607). In a 6 MV photon slit beam formed by the Siemens Artiste collimation system and a 0.5 mm wide slit between 10 cm thick lead blocks serving as the tertiary collimator, the true cross-beam dose profile D(x) at 3 cm depth in a large water phantom was measured with radiochromic film EBT3, and the detector-affected cross-beam signal profiles M(x) were recorded with a silicon diode, a synthetic diamond detector, a miniaturized scintillation detector, and a small ionization chamber. For each detector, the deconvolution of the convolution integral M(x)  =  K(x)  ∗  D(x) served to obtain its specific 1D lateral dose response function K(x), and K(r) was calculated from it. Fourier transformations and back transformations were performed using function approximations by weighted sums of Gaussian functions and their analytical transformation. The 1D lateral dose response functions K(x) of the four types of detectors and their associated rotational symmetric counterparts K(r) were obtained. Significant negative curve portions of K(x) and K(r) were observed in the case of the silicon diode and the diamond detector, confirming the Monte-Carlo-based prediction (Looe et al 2015 Phys. Med. Biol. 60 6585-607). They are typical for the perturbation of the secondary electron field by a detector with

  15. Total-dose response of silicon-on-insulator (soi) metal-oxide- semiconductor field-effect transistor's (mosfet's). Master's thesis

    SciTech Connect

    Biwer, M.C.

    1988-06-01

    Total-dose response of both NMOS and PMOS FET's fabricated on SIMOX and ZMR substrates was studied. Two types of back-channel leakage currents were identified for the SIMOX devices. A back channel leakage due to MOSFET action uses the substrate bias as the gate bias. The other component is due to soft reverse characteristics of the body-drain junction. The back-channel leakage due to MOSFET action varies with the substrate bias and thus varies with irradiation due to threshold-voltage shift. The soft reverse current is a function of drain-body voltage and hence varies with substrate bias and irradiation. The threshold-voltage, I-V characteristics, and subthreshold currents of both front and back channels as a function of total dose were obtained.

  16. Statistical Estimation of Dose-response Functions of Respiratory Diseases and Societal Costs of Haze-related Air Pollution in Brunei Darussalam

    NASA Astrophysics Data System (ADS)

    Anaman, K. A.; Ibrahim, N.

    - The effects on human health resulting from the January to April 1998 haze-related air pollution episode in Brunei Darussalam were analysed for five groups of diseases of the respiratory system. The analysis concentrated on the statistical estimation of dose-response functions which related the number of cases of respiratory diseases to the level of quality of ambient environment as measured by the pollutants standards index (PSI) and other environmental variables. The total number of cases of the five groups of diseases was shown to be significantly related to PSI and temperature. Societal costs were also estimated. The results showed that societal costs were significantly related to PSI, temperature and relative humidity. Societal costs increased with higher PSI and relative humidity but decreased with increasing temperature.

  17. Dose-response and intrinsic efficiency of thermoluminescent dosimeters in a 15 MV clinical photon beam in a liquid water phantom.

    PubMed

    Bravim, A; Sakuraba, R K; Cruz, J C; Campos, L L

    2012-07-01

    This paper compares the performance of CaSO4:Dy and LiF dosimeters irradiated with a 15 MV photon beam of a clinical linear accelerator to 0.1-10 Gy in a liquid water. The dose-response curves are linear up to 5 Gy. The average TL sensitivity of CaSO4:Dy is 26 and 287 times higher than the sensitivities of LiF:Mg,Ti and microLiF:Mg,Ti, respectively. CaSO4:Dy has an intrinsic efficiency 71% and 94% higher than the intrinsic efficiencies of LiF:Mg,Ti and microLiF:Mg,Ti, respectively. PMID:22342311

  18. Dose-Response Relationship between Cumulative Occupational Lead Exposure and the Associated Health Damages: A 20-Year Cohort Study of a Smelter in China

    PubMed Central

    Wu, Yue; Gu, Jun-Ming; Huang, Yun; Duan, Yan-Ying; Huang, Rui-Xue; Hu, Jian-An

    2016-01-01

    Long-term airborne lead exposure, even below official occupational limits, has been found to cause lead poisoning at higher frequencies than expected, which suggests that China’s existing occupational exposure limits should be reexamined. A retrospective cohort study was conducted on 1832 smelting workers from 1988 to 2008 in China. These were individuals who entered the plant and came into continuous contact with lead at work for longer than 3 months. The dose-response relationship between occupational cumulative lead exposure and lead poisoning, abnormal blood lead, urinary lead and erythrocyte zinc protoporphyrin (ZPP) were analyzed and the benchmark dose lower bound confidence limits (BMDLs) were calculated. Statistically significant positive correlations were found between cumulative lead dust and lead fumes exposures and workplace seniority, blood lead, urinary lead and ZPP values. A dose-response relationship was observed between cumulative lead dust or lead fumes exposure and lead poisoning (p < 0.01). The BMDLs of the cumulative occupational lead dust and fumes doses were 0.68 mg-year/m3 and 0.30 mg-year/m3 for lead poisoning, respectively. The BMDLs of workplace airborne lead concentrations associated with lead poisoning were 0.02 mg/m3 and 0.01 mg/m3 for occupational exposure lead dust and lead fume, respectively. In conclusion, BMDLs for airborne lead were lower than occupational exposure limits, suggesting that the occupational lead exposure limits need re-examination and adjustment. Occupational cumulative exposure limits (OCELs) should be established to better prevent occupational lead poisoning. PMID:26999177

  19. Dose-Response Relationship between Cumulative Occupational Lead Exposure and the Associated Health Damages: A 20-Year Cohort Study of a Smelter in China.

    PubMed

    Wu, Yue; Gu, Jun-Ming; Huang, Yun; Duan, Yan-Ying; Huang, Rui-Xue; Hu, Jian-An

    2016-03-01

    Long-term airborne lead exposure, even below official occupational limits, has been found to cause lead poisoning at higher frequencies than expected, which suggests that China's existing occupational exposure limits should be reexamined. A retrospective cohort study was conducted on 1832 smelting workers from 1988 to 2008 in China. These were individuals who entered the plant and came into continuous contact with lead at work for longer than 3 months. The dose-response relationship between occupational cumulative lead exposure and lead poisoning, abnormal blood lead, urinary lead and erythrocyte zinc protoporphyrin (ZPP) were analyzed and the benchmark dose lower bound confidence limits (BMDLs) were calculated. Statistically significant positive correlations were found between cumulative lead dust and lead fumes exposures and workplace seniority, blood lead, urinary lead and ZPP values. A dose-response relationship was observed between cumulative lead dust or lead fumes exposure and lead poisoning (p < 0.01). The BMDLs of the cumulative occupational lead dust and fumes doses were 0.68 mg-year/m³ and 0.30 mg-year/m³ for lead poisoning, respectively. The BMDLs of workplace airborne lead concentrations associated with lead poisoning were 0.02 mg/m³ and 0.01 mg/m³ for occupational exposure lead dust and lead fume, respectively. In conclusion, BMDLs for airborne lead were lower than occupational exposure limits, suggesting that the occupational lead exposure limits need re-examination and adjustment. Occupational cumulative exposure limits (OCELs) should be established to better prevent occupational lead poisoning. PMID:26999177

  20. Prevalence of hyperthyroidism after exposure during childhood or adolescence to radioiodines from the chornobyl nuclear accident: dose-response results from the Ukrainian-American Cohort Study.

    PubMed

    Hatch, M; Furukawa, K; Brenner, A; Olinjyk, V; Ron, E; Zablotska, L; Terekhova, G; McConnell, R; Markov, V; Shpak, V; Ostroumova, E; Bouville, A; Tronko, M

    2010-12-01

    Relatively few data are available on the prevalence of hyperthyroidism (TSH concentrations of <0.3 mIU/liter, with normal or elevated concentrations of free T4) in individuals exposed to radioiodines at low levels. The accident at the Chornobyl (Chernobyl) nuclear plant in Ukraine on April 26, 1986 exposed large numbers of residents to radioactive fallout, principally to iodine-131 ((131)I) (mean and median doses  =  0.6 Gy and 0.2 Gy). We investigated the relationship between (131)I and prevalent hyperthyroidism among 11,853 individuals exposed as children or adolescents in Ukraine who underwent an in-depth, standardized thyroid gland screening examination 12-14 years later. Radioactivity measurements taken shortly after the accident were available for all subjects and were used to estimate individual thyroid doses. We identified 76 cases of hyperthyroidism (11 overt, 65 subclinical). Using logistic regression, we tested a variety of continuous risk models and conducted categorical analyses for all subjects combined and for females (53 cases, n  =  5,767) and males (23 cases, n  =  6,086) separately but found no convincing evidence of a dose-response relationship between (131)I and hyperthyroidism. There was some suggestion of elevated risk among females in an analysis based on a dichotomous dose model with a threshold of 0.5 Gy chosen empirically (OR  =  1.86, P  =  0.06), but the statistical significance level was reduced (P  =  0.13) in a formal analysis with an estimated threshold. In summary, after a thorough exploration of the data, we found no statistically significant dose-response relationship between individual (131)I thyroid doses and prevalent hyperthyroidism. PMID:21128800

  1. Effect of Carotene and Lycopene on the Risk of Prostate Cancer: A Systematic Review and Dose-Response Meta-Analysis of Observational Studies

    PubMed Central

    Xiao, Yuanyuan; Fang, Juemin; Xu, Qing

    2015-01-01

    Background Many epidemiologic studies have investigated the association between carotenoids intake and risk of Prostate cancer (PCa). However, results have been inconclusive. Methods We conducted a systematic review and dose-response meta-analysis of dietary intake or blood concentrations of carotenoids in relation to PCa risk. We summarized the data from 34 eligible studies (10 cohort, 11 nested case-control and 13 case-control studies) and estimated summary Risk Ratios (RRs) and 95% confidence intervals (CIs) using random-effects models. Results Neither dietary β-carotene intake nor its blood levels was associated with reduced PCa risk. Dietary α-carotene intake and lycopene consumption (both dietary intake and its blood levels) were all associated with reduced risk of PCa (RR for dietary α-carotene intake: 0.87, 95%CI: 0.76–0.99; RR for dietary lycopene intake: 0.86, 95%CI: 0.75–0.98; RR for blood lycopene levels: 0.81, 95%CI: 0.69–0.96). However, neither blood α-carotene levels nor blood lycopene levels could reduce the risk of advanced PCa. Dose-response analysis indicated that risk of PCa was reduced by 2% per 0.2mg/day (95%CI: 0.96–0.99) increment of dietary α-carotene intake or 3% per 1mg/day (95%CI: 0.94–0.99) increment of dietary lycopene intake. Conclusions α-carotene and lycopene, but not β-carotene, were inversely associated with the risk of PCa. However, both α-carotene and lycopene could not lower the risk of advanced PCa. PMID:26372549

  2. Probabilistic hazard assessment for skin sensitization potency by dose-response modeling using feature elimination instead of quantitative structure-activity relationships.

    PubMed

    Luechtefeld, Thomas; Maertens, Alexandra; McKim, James M; Hartung, Thomas; Kleensang, Andre; Sá-Rocha, Vanessa

    2015-11-01

    Supervised learning methods promise to improve integrated testing strategies (ITS), but must be adjusted to handle high dimensionality and dose-response data. ITS approaches are currently fueled by the increasing mechanistic understanding of adverse outcome pathways (AOP) and the development of tests reflecting these mechanisms. Simple approaches to combine skin sensitization data sets, such as weight of evidence, fail due to problems in information redundancy and high dimensionality. The problem is further amplified when potency information (dose/response) of hazards would be estimated. Skin sensitization currently serves as the foster child for AOP and ITS development, as legislative pressures combined with a very good mechanistic understanding of contact dermatitis have led to test development and relatively large high-quality data sets. We curated such a data set and combined a recursive variable selection algorithm to evaluate the information available through in silico, in chemico and in vitro assays. Chemical similarity alone could not cluster chemicals' potency, and in vitro models consistently ranked high in recursive feature elimination. This allows reducing the number of tests included in an ITS. Next, we analyzed with a hidden Markov model that takes advantage of an intrinsic inter-relationship among the local lymph node assay classes, i.e. the monotonous connection between local lymph node assay and dose. The dose-informed random forest/hidden Markov model was superior to the dose-naive random forest model on all data sets. Although balanced accuracy improvement may seem small, this obscures the actual improvement in misclassifications as the dose-informed hidden Markov model strongly reduced " false-negatives" (i.e. extreme sensitizers as non-sensitizer) on all data sets. PMID:26046447

  3. Hyperuricemia and the risk for coronary heart disease morbidity and mortality a systematic review and dose-response meta-analysis

    PubMed Central

    Li, Min; Hu, Xiaolan; Fan, Yingli; Li, Kun; Zhang, Xiaowei; Hou, Wenshang; Tang, Zhenyu

    2016-01-01

    Considerable controversy exists regarding the association between hyperuricemia and coronary heart disease (CHD). Therefore, we performed a systematic review and dose-response meta-analysis of prospective studies to examine the controversy. Prospective cohort studies with relative risks (RRs) and 95% confidence intervals (CIs) for CHD according to serum uric acid levels in adults were eligible. A random-effects model was used to compute the pooled risk estimate. The search yielded 29 prospective cohort studies (n = 958410 participants). Hyperuricemia was associated with increased risk of CHD morbidity (adjusted RR 1.13; 95% CI 1.05 to 1.21) and mortality (adjusted RR 1.27; 95% CI 1.16 to 1.39). For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR of CHD mortality was 1.13 (95% CI 1.06 to 1.20). Dose-response analysis indicated that the combined RR of CHD mortality for an increase of 1 mg uric acid level per dl was 1.02 (95% CI 0.84 to 1.24) without heterogeneity among males (P = 0.879, I2 = 0%) and 2.44 (95% CI 1.69 to 3.54) without heterogeneity among females (P = 0.526, I2 = 0%). The increased risk of CHD associated with hyperuricemia was consistent across most subgroups. Hyperuricemia may increase the risk of CHD events, particularly CHD mortality in females. PMID:26814153

  4. Annual report on long-term dose-response studies of inhaled or injected radionuclides, October 1, 1989--September 30, 1990

    SciTech Connect

    Boecker, B.B.; Muggenburg, B.A.; Miller, S.C.; Bradley, P.L. . Inhalation Toxicology Research Inst.)

    1991-03-01

    This report, is divided into two main sections dealing with the Inhalation Toxicology Research Institute (ITRI) and Utah studies. These sections are organized along similar lines, addressing basic research approaches, study designs, recent accomplishments and the current status of study-completion activities. Study-specific features are presented for the 19 major studies being conducted with either inhaled beta- or alpha-emitting radionuclides. A broad range of dose- and effect-modifying factors are being examined including the effects of total dose, dose rate, LET, solubility, nonuniformity of dose, species, age, sex, health status, and exposure mode. The ITRI section of this report concludes with a group of brief reports of recent accomplishments. These accomplishments fall into five general categories: dosimetry, dose-response results for beta-emitting radionuclides, dose-response results for alpha-emitting radionuclides, molecular mechanism of carcinogenesis, and immunologic studies of exposed and aging dogs. The other major section this annual report describes the current status and recent progress of the life-span studies from the University of Utah. The main difference between the Utah studies and the ITRI studies is the exposure route. All of the Utah studies involved exposure by intravenous injection whereas all the ITRI exposures, except for {sup 137}CsCl, were given by single or repeated inhalation exposures. The research efforts currently devoted to the Utah studies fall into three main areas: continuation of the care and study of dogs still alive in these studies, detailed dosimetric studies, at the organ and local levels, of injected radionuclides and the factors that influence dose patterns, and completion of final reviews of biological materials and data, compilations and analyses of data, and preparation of final study reports for publication in the open, scientific literature.

  5. The use of dose-response data in a margin of exposure approach to carcinogenic risk assessment for genotoxic chemicals in food.

    PubMed

    Benford, Diane J

    2016-05-01

    Genotoxic substances are generally not permitted for deliberate use in food production. However, an appreciable number of known or suspected genotoxic substances occur unavoidably in food, e.g. from natural occurrence, environmental contamination and generation during cooking and processing. Over the past decade a margin of exposure (MOE) approach has increasingly been used in assessing the exposure to substances in food that are genotoxic and carcinogenic. The MOE is defined as a reference point on the dose-response curve (e.g. a benchmark dose lower confidences limit derived from a rodent carcinogenicity study) divided by the estimated human intake. A small MOE indicates a higher concern than a very large MOE. Whilst the MOE cannot be directly equated to risk, it supports prioritisation of substances for further research or for possible regulatory action, and provides a basis for communicating to the public. So far, the MOE approach has been confined to substances for which carcinogenicity data are available. In the absence of carcinogenicity data, evidence of genotoxicity is used only in hazard identification. The challenge to the genetic toxicology community is to develop approaches for characterising risk to human health based on data from genotoxicity studies. In order to achieve wide acceptance, it would be important to further address the issues that have been discussed in the context of dose-response modelling of carcinogenicity data in order to assign levels of concern to particular MOE values, and also whether it is possible to make generic conclusions on how potency in genotoxicity assays relates to carcinogenic potency. PMID:26297741

  6. Prevalence of Hyperthyroidism Following Exposure During Childhood or Adolescence to Radioiodines from the Chornobyl Nuclear Accident: Dose-Response Results from the Ukrainian-American Cohort Study

    PubMed Central

    Hatch, M.; Furukawa, K.; Brenner, A.; Olinjyk, V.; Ron, E.; Zablotska, L.; Terekhova, G.; McConnell, R.; Markov, V.; Shpak, V.; Ostroumova, E.; Bouville, A.; Tronko, M.

    2013-01-01

    Relatively few data are available on the prevalence of hyperthyroidism (TSH concentrations of < 0.3 mIU/L, with normal or elevated concentrations of free T4) in individuals exposed to radioiodines at low levels. The accident at the Chornobyl (Chernobyl) nuclear plant in Ukraine on April 26, 1986 exposed large numbers of residents to radioactive fallout, principally to iodine-131 (I-131) (mean and median doses = 0.6 Gray (Gy) and 0.2 Gy). We investigated the relationship of I-131 and prevalent hyperthyroidism among 11,853 individuals exposed as children or adolescents in Ukraine who underwent an in-depth, standardized thyroid gland screening examination 12–14 years later. Radioactivity measurements taken shortly after the accident were available for all subjects and were used to estimate individual thyroid doses. We identified 76 cases of hyperthyroidism (11 overt, 65 subclinical). Using logistic regression, we tested a variety of continuous risk models and conducted categorical analyses for all subjects combined and for females (53 cases, n=5,767) and males (23 cases, n=6,086) separately, but found no convincing evidence of a dose response relationship between I-131 and hyperthyroidism. There was some suggestion of elevated risk among females in an analysis based on a dichotomous dose model with a threshold of 0.5 Gy chosen empirically (OR=1.86, P=0.06), but the statistical significance level was reduced (P=0.13) in a formal analysis with an estimated threshold. In summary, after a thorough exploration of the data, we found no statistically significant dose response relationship between individual I-131 thyroid doses and prevalent hyperthyroidism. PMID:21128800

  7. Usage and Dose Response of a Mobile Acceptance and Commitment Therapy App: Secondary Analysis of the Intervention Arm of a Randomized Controlled Trial

    PubMed Central

    Lappalainen, Raimo; Välkkynen, Pasi; Sairanen, Essi; Lappalainen, Päivi; Karhunen, Leila; Peuhkuri, Katri; Korpela, Riitta; Kolehmainen, Marjukka; Ermes, Miikka

    2016-01-01

    Background Mobile phone apps offer a promising medium to deliver psychological interventions. A mobile app based on Acceptance and Commitment Therapy (ACT) was developed and studied in a randomized controlled trial (RCT). Objective To study usage metrics of a mobile ACT intervention and dose-response relationship between usage and improvement in psychological flexibility. Methods An RCT was conducted to investigate the effectiveness of different lifestyle interventions for overweight people with psychological stress. This paper presents a secondary analysis of the group that received an 8-week mobile ACT intervention. Most of the analyzed 74 participants were female (n=64, 86%). Their median age was 49.6 (interquartile range, IQR 45.4-55.3) years and their mean level of psychological flexibility, measured with the Acceptance and Action Questionnaire II, was 20.4 (95% confidence interval 18.3-22.5). Several usage metrics describing the intensity of use, usage of content, and ways of use were calculated. Linear regression analyses were performed to study the dose-response relationship between usage and the change in psychological flexibility and to identify the usage metrics with strongest association with improvement. Binary logistic regression analyses were further used to assess the role of usage metrics between those who showed improvement in psychological flexibility and those who did not. In addition, associations between usage and baseline participant characteristics were studied. Results The median number of usage sessions was 21 (IQR 11.8-35), the number of usage days was 15 (IQR 9.0-24), and the number of usage weeks was 7.0 (IQR 4.0-8.0). The participants used the mobile app for a median duration of 4.7 (IQR 3.2-7.2) hours and performed a median of 63 (IQR 46-98) exercises. There was a dose-response relationship between usage and the change in psychological flexibility. The strongest associations with psychological flexibility (results adjusted with gender

  8. Dose-response curve of EBT, EBT2, and EBT3 radiochromic films to synchrotron-produced monochromatic x-ray beams

    SciTech Connect

    Brown, Thomas A. D.; Hogstrom, Kenneth R.; Alvarez, Diane; Matthews, Kenneth L. II; Ham, Kyungmin; Dugas, Joseph P.

    2012-12-15

    Purpose: This work investigates the dose-response curves of GAFCHROMIC{sup Registered-Sign} EBT, EBT2, and EBT3 radiochromic films using synchrotron-produced monochromatic x-ray beams. EBT2 film is being utilized for dose verification in photoactivated Auger electron therapy at the Louisiana State University Center for Advanced Microstructures and Devices (CAMD) synchrotron facility. Methods: Monochromatic beams of 25, 30, and 35 keV were generated on the tomography beamline at CAMD. Ion chamber depth-dose measurements were used to determine the dose delivered to films irradiated at depths from 0.7 to 8.5 cm in a 10 Multiplication-Sign 10 Multiplication-Sign 10-cm{sup 3} polymethylmethacrylate phantom. AAPM TG-61 protocol was applied to convert measured ionization into dose. Films were digitized using an Epson 1680 Professional flatbed scanner and analyzed using the net optical density (NOD) derived from the red channel. A dose-response curve was obtained at 35 keV for EBT film, and at 25, 30, and 35 keV for EBT2 and EBT3 films. Calibrations of films for 4 MV x-rays were obtained for comparison using a radiotherapy accelerator at Mary Bird Perkins Cancer Center. Results: The sensitivity (NOD per unit dose) of EBT film at 35 keV relative to that for 4-MV x-rays was 0.73 and 0.76 for doses 50 and 100 cGy, respectively. The sensitivity of EBT2 film at 25, 30, and 35 keV relative to that for 4-MV x-rays varied from 1.09-1.07, 1.23-1.17, and 1.27-1.19 for doses 50-200 cGy, respectively. For EBT3 film the relative sensitivity was within 3% of unity for all three monochromatic x-ray beams. Conclusions: EBT and EBT2 film sensitivity showed strong energy dependence over an energy range of 25 keV-4 MV, although this dependence becomes weaker for larger doses. EBT3 film shows weak energy dependence, indicating that it would be a better dosimeter for kV x-ray beams where beam hardening effects can result in large changes in the effective energy.

  9. Dose-Response on the Chemopreventive Effects of Sarcophine-Diol on UVB-Induced Skin Tumor Development in SKH-1 Hairless Mice

    PubMed Central

    Guillermo, Ruth F.; Zhang, Xiaoying; Kaushik, Radhey S.; Zeman, David; Ahmed, Safwat A.; Khalifa, Sherief; Fahmy, Hesham; Dwivedi, Chandradhar

    2012-01-01

    Sarcophine-diol (SD) is a lactone ring-opened analogue of sarcophine. It has shown chemopreventive effects on chemically-induced skin tumor development in female CD-1 mice, as well as in a UVB-induced skin tumor development model in hairless SKH-1 mice at a dose of 30 μg SD applied topically and 180 mJ/cm2 UVB. The objective of this study was to determine the dose-response on the chemopreventive effects of SD on SKH-1 hairless mice when exposed to a UVB radiation dose of 30 mJ/cm2. This UVB dose better represents chronic human skin exposure to sunlight leading to skin cancer than previous studies applying much higher UVB doses. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into five groups. The control group was topically treated with 200 μL of acetone (vehicle), and the SD treatment groups were topically treated with SD (30 μg, 45 μg, and 60 μg dissolved in 200 μL of acetone) 1 h before UVB radiation (30 mJ/cm2). The last group of animals received 60 μg SD/200 μL acetone without UVB exposure. These treatments were continued for 27 weeks. Tumor multiplicity and tumor volumes were recorded on a weekly basis for 27 weeks. Weight gain and any signs of toxicity were also closely monitored. Histological characteristics and the proliferating cell nuclear antigen (PCNA) were evaluated in the mice skin collected at the end of the experiment. The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose. SD reduced the number of cells positively stained with PCNA proliferation marker in mice skin. The study also showed that SD application without UVB exposure has no effect on the structure of skin. The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects. PMID:23118725

  10. Self-Fluid Management in Prevention of Kidney Stones: A PRISMA-Compliant Systematic Review and Dose-Response Meta-Analysis of Observational Studies.

    PubMed

    Xu, Chang; Zhang, Chao; Wang, Xiao-Long; Liu, Tong-Zu; Zeng, Xian-Tao; Li, Shen; Duan, Xiao-Wen

    2015-07-01

    Epidemiologic studies have suggested that daily fluid intake that achieves at least 2.5 L of urine output per day is protective against kidney stones. However, the precise quantitative nature of the association between fluid intake and kidney stone risk, as well as the effect of specific types of fluids on such risk, are not entirely clear.We conducted a systematic review and dose-response meta-analysis to quantitatively assess the association between fluid intake and kidney stone risk. Based on a literature search of the PubMed, Embase, and Cochrane Library databases, 15 relevant studies (10 cohort and 5 case-control studies) were selected for inclusion in the meta-analysis with 9601 cases and 351,081 total participants.In the dose-response meta-analysis, we found that each 500 mL increase in water intake was associated with a significantly reduced risk of kidney stone formation (relative risk (RR) = 0.93; 95% CI: 0.87, 0.98; P < 0.01). Protective associations were also found for an increasing intake of tea (RR = 0.96; 95% CI: 0.93, 0.99; P = 0.02) and alcohol (RR = 0.80, 95% CI: 0.75, 0.85; P < 0.01). A borderline reverse association were observed on coffee intake and risk of kidney stone (RR = 0.88; 95% CI: 0.76, 1.00; P = 0.05). The risk of kidney stones was not significantly related to intake of juice (RR = 1.02, 95% CI: 0.95, 1.10; P = 0.64), soda (RR = 1.03; 95% CI: 0.90, 1.17; P = 0.65), or milk (RR = 0.96; 95% CI: 0.88, 1.03; P = 0.21). Subgroup analysis and sensitivity analyses showed inconsistent results on coffee, alcohol, and milk intake.Increased water intake is associated with a reduced risk of kidney stones; increased consumption of tea and alcohol may reduce kidney stone risk. An average daily water intake was recommended for kidney stone prevention. PMID:26166074

  11. Automated Dose-Response Analysis and Comparative Toxicogenomic Evaluation of the Hepatic Effects Elicited by TCDD, TCDF, and PCB126 in C57BL/6 Mice

    PubMed Central

    Kopec, Anna K.; Burgoon, Lyle D.; Ibrahim-Aibo, Daher; Burg, Ashley R.; Lee, Andrea W.; Tashiro, Colleen; Potter, Dave; Sharratt, Bonnie; Harkema, Jack R.; Rowlands, J. Craig; Budinsky, Robert A.; Zacharewski, Timothy R.

    2010-01-01

    The toxic equivalency factor (TEF) approach recommended by the World Health Organization is used to quantify dioxin-like exposure concentrations for mixtures of polychlorinated dibenzo-dioxins, -furans, and polychlorinated biphenyls (PCBs), including 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Whole-genome microarrays were used to evaluate the hepatic gene expression potency of TCDF and PCB126 relative to TCDD with complementary histopathology, tissue level analysis, and ethoxyresorufin-O-deethylase (EROD) assay results. Immature ovariectomized C57BL/6 mice were gavaged with 0.001, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, and 300 μg/kg TCDD and TEF-adjusted doses (TEF for TCDF and PCB126 is 0.1) of TCDF or PCB126 (1, 3, 10, 30, 100, 300, 1000, and 3000 μg/kg of TCDF or PCB126) or sesame oil vehicle and sacrificed 24 h post dose. In general, TCDD, TCDF, and PCB126 tissue levels, as well as histopathological effects, were comparable when comparing TEF-adjusted doses. Automated dose-response modeling (ToxResponse Modeler) of the microarray data identified 210 TCDF and 40 PCB126 genes that exhibited sigmoidal dose-response curves with comparable slopes when compared with TCDD. These similar responses were used to calculate a median TCDF gene expression relative potency (REP) of 0.06 and a median PCB126 gene expression REP of 0.02. REPs of 0.02 were also calculated for EROD induction for both compounds. Collectively, these data suggest that differences in the ability of the liganded aryl hydrocarbon receptor:AhR nuclear translocator complex to elicit differential hepatic gene expression, in addition to pharmacokinetic differences between ligands, influence their potency in immature ovariectomized C57BL/6 mice. PMID:20702594

  12. SU-D-16A-02: A Novel Methodology for Accurate, Semi-Automated Delineation of Oral Mucosa for Radiation Therapy Dose-Response Studies

    SciTech Connect

    Dean, J; Welsh, L; Gulliford, S; Harrington, K; Nutting, C

    2014-06-01

    Purpose: The significant morbidity caused by radiation-induced acute oral mucositis means that studies aiming to elucidate dose-response relationships in this tissue are a high priority. However, there is currently no standardized method for delineating the mucosal structures within the oral cavity. This report describes the development of a methodology to delineate the oral mucosa accurately on CT scans in a semi-automated manner. Methods: An oral mucosa atlas for automated segmentation was constructed using the RayStation Atlas-Based Segmentation (ABS) module. A radiation oncologist manually delineated the full surface of the oral mucosa on a planning CT scan of a patient receiving radiotherapy (RT) to the head and neck region. A 3mm fixed annulus was added to incorporate the mucosal wall thickness. This structure was saved as an atlas template. ABS followed by model-based segmentation was performed on four further patients sequentially, adding each patient to the atlas. Manual editing of the automatically segmented structure was performed. A dose comparison between these contours and previously used oral cavity volume contours was performed. Results: The new approach was successful in delineating the mucosa, as assessed by an experienced radiation oncologist, when applied to a new series of patients receiving head and neck RT. Reductions in the mean doses obtained when using the new delineation approach, compared with the previously used technique, were demonstrated for all patients (median: 36.0%, range: 25.6% – 39.6%) and were of a magnitude that might be expected to be clinically significant. Differences in the maximum dose that might reasonably be expected to be clinically significant were observed for two patients. Conclusion: The method developed provides a means of obtaining the dose distribution delivered to the oral mucosa more accurately than has previously been achieved. This will enable the acquisition of high quality dosimetric data for use in

  13. WE-D-BRE-06: Quantification of Dose-Response for High Grade Esophagtis Patients Using a Novel Voxel-To-Voxel Method

    SciTech Connect

    Niedzielski, J; Martel, M; Tucker, S; Gomez, D; Court, L; Yang, J; Briere, T

    2014-06-15

    Purpose: Radiation induces an inflammatory response in the esophagus, discernible on CT studies. This work objectively quantifies the voxel esophageal radiation-response for patients with acute esophagitis. This knowledge is an important first-step towards predicting the effect of complex dose distributions on patient esophagitis symptoms. Methods: A previously validated voxel-based methodology of quantifying radiation esophagitis severity was used to identify the voxel dose-response for 18 NSCLC patients with severe esophagitis (CTCAE grading criteria, grade2 or higher). The response is quantified as percent voxel volume change for a given dose. During treatment (6–8 weeks), patients had weekly 4DCT studies and esophagitis scoring. Planning CT esophageal contours were deformed to each weekly CT using a demons DIR algorithm. An algorithm using the Jacobian Map from the DIR of the planning CT to all weekly CTs was used to quantify voxel-volume change, along with corresponding delivered voxel dose, to the planning voxel. Dose for each voxel for each time-point was calculated on each previous weekly CT image, and accumulated using DIR. Thus, for each voxel, the volume-change and delivered dose was calculated for each time-point. The data was binned according to when the volume-change first increased by a threshold volume (10%–100%, in 10% increments), and the average delivered dose calculated for each bin. Results: The average dose resulting in a voxel volume increase of 10–100% was 21.6 to 45.9Gy, respectively. The mean population dose to give a 50% volume increase was 36.3±4.4Gy, (range:29.8 to 43.5Gy). The average week of 50% response was 4.1 (range:4.9 to 2.8 weeks). All 18 patients showed similar dose to first response curves, showing a common trend in the initial inflammatoryresponse. Conclusion: We extracted the dose-response curve of the esophagus on a voxel-to-voxel level. This may be useful for estimating the esophagus response (and patient symptoms

  14. Dose-response effects of Lepidium meyenii (Maca) aqueous extract on testicular function and weight of different organs in adult rats.

    PubMed

    Chung, Francisco; Rubio, Julio; Gonzales, Carla; Gasco, Manuel; Gonzales, Gustavo F

    2005-04-01

    Lepidium meyenii (Brassicaceae) known as Maca grows exclusively between 4000 and 4500 m over the sea level in the Peruvian central Andes. The dried hypocotyls of Maca are traditionally used as food and for its supposed fertility-enhancing properties. A dose-response study was performed to determine the effect of 7 days oral administration of an aqueous lyophilized extract of Maca at 0.01-5 g/kg (corresponding to 0.022-11 g dry hypocotyls of Maca/kg) on body and different organ weights, stages of the seminiferous tubules, epididymal sperm count and motility, and serum testosterone and estradiol levels in rats. In doses up to 5 g extract/kg, no toxicity was observed. Almost all organ weights were similar in controls and in the Maca extract-treated groups. Seminal vesicles weight was significantly reduced at 0.01 and 0.10 g extract/kg. Maca increased in length of stages VII-VIII of the seminiferous tubules in a dose-response fashion, with highest response at 1.0 g/kg, while caput/corpus epididymal sperm count increased at the 1.0 g dose. Cauda epididymal sperm count, sperm motility, and serum estradiol level were not affected at any of the doses studied. Serum testosterone was lower at 0.10 g extract/kg. Low-seminal vesicle weights correlated with low-serum testosterone levels (R2=0.33; P<0.0001) and low-testosterone/estradiol ratio (R2=0.35; P<0.0001). Increase in epididymal sperm count was related to lengths of stages VII-VIII. Highest effect on stages VII-VIII of the seminiferous tubules was observed at 1.0 g Maca aqueous extract/kg. The present study demonstrated that Maca extract in doses up to 5 g/kg (equivalent to the intake of 770 g hypocotyls in a man of 70 kg) was safe and that higher effect on reproductive parameters was elicited with a dose of 1 g extract/kg corresponding to 2.2 g dry Maca hypocotyls/kg. PMID:15763375

  15. CANCER DOSE-RESPONSE STUDIES

    EPA Science Inventory

    Bromate- Ozone has been proposed for water disinfection because it is more efficient in killing microbes than chlorine and results in much lower levels of carcinogenic trihalomethanes than chlorination. Ozone leads to formation of hypobromous acid in surface waters with high brom...

  16. 5-ASA Dose-Response

    PubMed Central

    Katz, Seymour; Lichtenstein, Gary R; Safdi, Michael A

    2010-01-01

    Mesalamine (5-aminosalicylic acid; 5-ASA) represents the cornerstone of first-line therapy for mild-to-moderate ulcerative colitis (UC). Current guidelines suggest that the combination of oral and rectal therapies provide optimal symptom resolution and effectively maintain remission in the majority of these patients. Although effective, most oral 5-ASA formulations have a high pill burden and rectal therapies are associated with low adherence. Recent research has examined patterns of compliance, as well as the efficacy of different dose levels of 5-ASA in terms of symptom resolution, the maintenance of remission, and improvements in quality of life. The ASCEND I, II, and III trials found that doses of 4.8 g/day are more effective than 2.4 g/day doses in patients with moderate disease, those with previous steroid use, and those with a history of multiple medications. The benefits of effective long-term 5-ASA therapy include the avoidance of more costly and potentially toxic drugs (such as corticosteroids and biologic therapies), as well as improvements in quality of life, reductions in the need for future colectomy, and a lower risk of developing colorectal cancer. PMID:20567558

  17. The Dose-response of Intrathecal Ropivacaine Co-administered with Sufentanil for Cesarean Delivery under Combined Spinal-epidural Anesthesia in Patients with Scarred Uterus

    PubMed Central

    Xiao, Fei; Xu, Wen-Ping; Zhang, Yin-Fa; Liu, Lin; Liu, Xia; Wang, Li-Zhong

    2015-01-01

    Background: Spinal anesthesia is considered as a reasonable anesthetic option in lower abdominal and lower limb surgery. This study was to determine the dose-response of intrathecal ropivacaine in patients with scarred uterus undergoing cesarean delivery under combined spinal-epidural anesthesia. Methods: Seventy-five patients with scarred uterus undergoing elective cesarean delivery under combined spinal-epidural anesthesia were enrolled in this randomized, double-blinded, dose-ranging study. Patients received 6, 8, 10, 12, or 14 mg intrathecal hyperbaric ropivacaine with 5 μg sufentanil. Successful spinal anesthesia was defined as a T4 sensory level achieved with no need for epidural supplementation. The 50% effective dose (ED50) and 95% effective dose (ED95) were calculated with a logistic regression model. Results: ED50 and ED95 of intrathecal hyperbaric ropivacaine for patients with scarred uterus undergoing cesarean delivery under combined spinal-epidural anesthesia (CSEA) were 8.28 mg (95% confidence interval [CI]: 2.28–9.83 mg) and 12.24 mg (95% CI: 10.53–21.88 mg), respectively. Conclusion: When a CSEA technique is to use in patients with scarred uterus for an elective cesarean delivery, the ED50 and ED95 of intrathecal hyperbaric ropivacaine along with 5 μg sufentanil were 8.28 mg and 12.24 mg, respectively. In addition, this local anesthetic is unsuitable for emergent cesarean delivery, but it has advantages for ambulatory patients. PMID:26415793

  18. Dose-Response Analysis in the Joint Action of Two Effectors. A New Approach to Simulation, Identification and Modelling of Some Basic Interactions

    PubMed Central

    Murado García, Miguel Anxo; Prieto Lage, Miguel Ángel

    2013-01-01

    In systems with several effectors, the results of dose-response (DR) experiments are usually assessed by checking them against two hypotheses: independent action (IA) and concentration addition (CA). Both are useful simplifications, but do not represent the only possible responses, and avoid to a large extent the analysis of the interactions that are possible in the system. In addition, these are often applied in such a way that they produce insufficient descriptions of the problem that raises them, frequent inconclusive cases and doubtful decisions. In this work a generative approach is attempted, starting from some simple mechanisms necessarily underlying the response of an elementary biological entity to an effector agent. A set of simulations is formulated next through an equally simple system of logical rules, and several families of virtual responses are thus generated. These families include typical responses of IA and CA modes of action, other ones not less probable from a physiological point of view, and even other derived from common and expectable forms of interactions. The analysis of these responses enabled, firstly, to relate some phenomenological regularities with some general mechanistic principles, and to detect several causes by which the IA-CA dualism is necessarily ambiguous. Secondly, it allowed identifying different forms of synergy and antagonism that contribute to explain some controversial aspects of these notions. Finally, it led to propose two sets of explicit algebraic equations that describe accurately a wide diversity of possible and realistic responses. PMID:23637825

  19. Energy dependence and dose response of Gafchromic EBT2 film over a wide range of photon, electron, and proton beam energies

    SciTech Connect

    Arjomandy, Bijan; Tailor, Ramesh; Anand, Aman; Sahoo, Narayan; Gillin, Michael; Prado, Karl; Vicic, Milos

    2010-05-15

    Purpose: Since the Gafchromic film EBT has been recently replaced by the newer model EBT2, its characterization, especially energy dependence, has become critically important. The energy dependence of the dose response of Gafchromic EBT2 film is evaluated for a broad range of energies from different radiation sources used in radiation therapy. Methods: The beams used for this study comprised of kilovoltage x rays (75, 125, and 250 kVp), {sup 137}Cs gamma (662 KeV), {sup 60}Co gamma (1.17-1.33 MeV), megavoltage x rays (6 and 18 MV), electron beams (6 and 20 MeV), and proton beams (100 and 250 MeV). The film's response to each of the above energies was measured over the dose range of 0.4-10 Gy, which corresponds to optical densities ranging from 0.05 to 0.74 for the film reader used. Results: The energy dependence of EBT2 was found to be relatively small within measurement uncertainties (1{sigma}={+-}4.5%) for all energies and modalities. Conclusion: For relative and absolute dosimetry of radiation therapy beams, the weak energy dependence of the EBT2 makes it most suitable for clinical use compared to other films.

  20. ESR dosimetry of fossil enamel: some comments about measurement precision, long-term signal fading and dose-response curve fitting.

    PubMed

    Duval, M; Guilarte Moreno, V; Grün, R

    2013-12-01

    This work deals with the specific studies of three main sources of uncertainty in electron spin resonance (ESR) dosimetry/dating of fossil tooth enamel: (1) the precision of the ESR measurements, (2) the long-term signal fading the selection of the fitting function. They show a different influence on the equivalent dose (D(E)) estimates. Repeated ESR measurements were performed on 17 different samples: results show a mean coefficient of variation of the ESR intensities of 1.20 ± 0.23 %, inducing a mean relative variability of 3.05 ± 2.29 % in the D(E) values. ESR signal fading over 5 y was also observed: its magnitude seems to be quite sample dependant but is nevertheless especially important for the most irradiated aliquots. This fading has an apparent random effect on the D(E) estimates. Finally, the authors provide new insights and recommendations about the fitting of ESR dose-response curves of fossil enamel with a double saturating exponential (DSE) function. The potential of a new variation of the DSE was also explored. Results of this study also show that the choice of the fitting function is of major importance, maybe more than the other sources previously mentioned, in order to get accurate final D(E) values. PMID:23832975

  1. Campylobacteriosis outbreak associated with consumption of undercooked chicken liver pâté in the East of England, September 2011: identification of a dose-response risk.

    PubMed

    Edwards, D S; Milne, L M; Morrow, K; Sheridan, P; Verlander, N Q; Mulla, R; Richardson, J F; Pender, A; Lilley, M; Reacher, M

    2014-02-01

    A foodborne outbreak with 49 cases (22 culture positive for Campylobacter sp.) following a wedding party in the East of England was investigated. A retrospective cohort study identified an association between consumption of chicken liver pâté and infection with Campylobacter jejuni/coli. There was a statistically significant association between dose (amount of chicken liver pâté eaten) and the risk of disease ['tasted': odds ratio (OR) 1·5, 95% confidence interval (CI) 0·04-∞; 'partly eaten': OR 8·4, 95% CI 1·4-87·5; 'most or all eaten': OR 36·1, 95% CI 3·3-2119). The local authority found evidence that the preparation of chicken livers breached Food Standards Agency's guidelines. This epidemiological investigation established a clear dose-response relationship between consumption of chicken liver pâté and the risk of infection with Campylobacter. The continuing need to raise public awareness of the risk to human health posed by undercooked chicken liver is evident. PMID:23711104

  2. Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.

    PubMed

    Nielsen, Jace C; Hutmacher, Matthew M; Wesche, David L; Tolbert, Dwain; Patel, Mahlaqa; Kowalski, Kenneth G

    2015-01-01

    Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose-response analysis used seizure-count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6 g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively. PMID:25117853

  3. Dose-response and failure pattern for bulky or barrel-shaped stage IB cervical cancer treated by combined photon irradiation and extrafascial hysterectomy

    SciTech Connect

    Maruyama, Y.; van Nagell, J.R.; Yoneda, J.; Donaldson, E.; Gallion, H.H.; Higgins, R.; Powell, D.; Kryscio, R.; Berner, B.

    1989-01-01

    From 1975 to 1987, 80 patients with bulky or barrel-shaped Stage IB cervical cancer were treated with preoperative irradiation and Cs-137 intracavitary implant therapy, before a planned extrafascial abdominal hysterectomy, using a consistent treatment policy. Of the hysterectomy specimens obtained, 37% were positive histologically at 89 +/- 2.3 days after the start of radiotherapy and at 4 to 6 weeks after the completion of radiation therapy. Sixty-three percent were negative after a total external and internal cervix irradiation dose of 9642 cGy at point T. The average point A dose contributed by intracavitary therapy was 2104 cGy. The survival rate at 5 years was 84%: At 10 years the survival rate was 78%. The failure pattern was analyzed for patients who had positive and negative specimens. The patients with positive specimens failed pelvically or pelvically and distantly. Patients with negative specimens failed in extrapelvic or distant metastatic sites. Preoperative radiotherapy led to excellent local and pelvic control of tumor, and the failures became predominantly distant metastases. The combined radiosurgical therapy was tolerated well and allowed surgical staging of disease. This permitted earlier and selective consideration of adjunctive therapy (i.e., paraaortic irradiation, chemotherapy, or chemoradiotherapy). The dose-response data give insight into the effects of photon radiotherapy on bulky or barrel Stage IB cervical cancers and correlate histologic status with failure pattern, outcome, and long-term survival.

  4. Tooth loss is associated with increased risk of esophageal cancer: evidence from a meta-analysis with dose-response analysis

    PubMed Central

    Chen, Qi-Lin; Zeng, Xian-Tao; Luo, Zhi-Xiao; Duan, Xiao-Li; Qin, Jie; Leng, Wei-Dong

    2016-01-01

    Epidemiological studies have revealed the association between tooth loss and the risk of esophageal cancer (EC); however, consistent results were not obtained from different single studies. Therefore, we conducted the present meta-analysis to evaluate the association between tooth loss and EC. We conducted electronic searches of PubMed until to February 10, 2015 to identify relevant observational studies that examined the association between tooth loss and the risk of EC. Study selection and data extraction from eligible studies were independently performed by two authors. The meta-analysis was conducted using Stata 12.0 software. Finally eight eligible publications with ten studies involving 3 cohort studies, 5 case-control studies, and 1 cross-sectional study were yielded. Meta-analysis identified tooth loss increased risk of EC 1.30 times (Relative risk = 1.30, 95% confidence interval = 1.06–1.60, I2 = 13.5%). Dose-response analysis showed linear relationship between tooth loss and risk of EC (RR = 1.01, 95%CI = 1.00–1.03; P for non-linearity test was 0.45). Subgroup analysis proved similar results and publication bias was not detected. In conclusion, tooth loss could be considered to be a significant and dependent risk factor for EC based on the current evidence. PMID:26742493

  5. Integrating in vitro sensitivity and dose-response slope is predictive of clinical response to ABL kinase inhibitors in chronic myeloid leukemia.

    PubMed

    Vainstein, Vladimir; Eide, Christopher A; O'Hare, Thomas; Shukron, Ofir; Druker, Brian J

    2013-11-01

    BCR-ABL mutations result in clinical resistance to ABL tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Although in vitro 50% inhibitory concentration (IC(50)) values for specific mutations have been suggested to guide TKI choice in the clinic, the quantitative relationship between IC(50) and clinical response has never been demonstrated. We used Hill's equation for in vitro response of Ba/F3 cells transduced with various BCR-ABL mutants to determine IC(50) and the slope of the dose-response curve. We found that slope variability between mutants tracked with in vitro TKI resistance, provides particular additional interpretive value in cases where in vitro IC(50) and clinical response are disparate. Moreover, unlike IC(50) alone, higher inhibitory potential at peak concentration (IPP), which integrates IC(50), slope, and peak concentration (Cmax), correlated with improved complete cytogenetic response (CCyR) rates in CML patients treated with dasatinib. Our findings suggest a metric integrating in vitro and clinical data may provide an improved tool for BCR-ABL mutation-guided TKI selection. PMID:24062017

  6. Neuroprotective effects of selective β-1 adrenoceptor antagonists, landiolol and esmolol, on transient forebrain ischemia in rats; a dose-response study.

    PubMed

    Goyagi, Toru; Horiguchi, Takashi; Nishikawa, Toshiaki; Tobe, Yoshitsugu; Masaki, Yoko

    2012-06-21

    Although selective beta-1 adrenoceptor antagonists are known to provide neuroprotective effects after brain ischemia, dose-response relationships of their neuroprotective effects have not been examined. The present study was conducted to evaluate whether the degree of brain protection against transient forebrain ischemia would be influenced by different doses of selective beta-1 adrenoceptor antagonists, esmolol and landiolol, in rats. Adult male S.D. rats received intravenous infusion of saline 0.5 ml/h, esmolol 20, 200, 2,000 μg/kg/min, or landiolol 5, 50, 500 μg/kg/min. Infusion was initiated 30 min prior to ischemia and continued for 24h. Ten-minute forebrain ischemia was induced by hemorrhagic hypotension and occlusion of the bilateral carotid arteries. Neurological and histological examinations were performed. Neurological deficit scores at 1, 4 and 7 days were lower, and the number of intact neurons in CA1 hippocampal region was larger in the rats treated with esmolol and landiolol after ischemia, compared with saline-treated rats (P<0.05), whereas no difference was found among different doses of esmolol and landiolol. These results suggested that selective beta-1 adrenoceptor antagonists improved neurological and histological outcomes following forebrain ischemia in rats, irrespective of their doses. PMID:22583856

  7. Derivation of the critical effect size/benchmark response for the dose-response analysis of the uptake of radioactive iodine in the human thyroid.

    PubMed

    Weterings, Peter J J M; Loftus, Christine; Lewandowski, Thomas A

    2016-08-22

    Potential adverse effects of chemical substances on thyroid function are usually examined by measuring serum levels of thyroid-related hormones. Instead, recent risk assessments for thyroid-active chemicals have focussed on iodine uptake inhibition, an upstream event that by itself is not necessarily adverse. Establishing the extent of uptake inhibition that can be considered de minimis, the chosen benchmark response (BMR), is therefore critical. The BMR values selected by two international advisory bodies were 5% and 50%, a difference that had correspondingly large impacts on the estimated risks and health-based guidance values that were established. Potential treatment-related inhibition of thyroidal iodine uptake is usually determined by comparing thyroidal uptake of radioactive iodine (RAIU) during treatment with a single pre-treatment RAIU value. In the present study it is demonstrated that the physiological intra-individual variation in iodine uptake is much larger than 5%. Consequently, in-treatment RAIU values, expressed as a percentage of the pre-treatment value, have an inherent variation, that needs to be considered when conducting dose-response analyses. Based on statistical and biological considerations, a BMR of 20% is proposed for benchmark dose analysis of human thyroidal iodine uptake data, to take the inherent variation in relative RAIU data into account. Implications for the tolerated daily intakes for perchlorate and chlorate, recently established by the European Food Safety Authority (EFSA), are discussed. PMID:27268963

  8. Maternal care alterations induced by repeated ethanol leads to heightened consumption of the drug and motor impairment during adolescence: a dose-response analysis.

    PubMed

    Ponce, Luciano F; Pautassi, Ricardo Marcos; Spear, Norman E; Molina, Juan C

    2011-07-01

    Maternal ethanol exposure during lactation induces behavioral alterations in offspring, including disruptions in motor skills and heightened ethanol ingestion during adolescence. These behavioral outcomes appear to partially depend on ethanol-induced disruptions in maternal care. The present study assessed motor skills and ethanol intake in adolescent rats raised by dams that had been repeatedly given ethanol during lactation. Female rats (postpartum days [PDs] 3-13) were administered ethanol (0.5, 1.5, or 2.5 g/kg) or vehicle every other day and allowed to freely interact with their pups. During adolescence, the offspring were evaluated for motor coordination (accelerating rotarod test) and oral ethanol self administration. The lowest maternal ethanol dose (0.5 g/kg) mildly affected motor performance, whereas the higher doses (1.5 and 2.5 g/kg) resulted in motor coordination impairment and greater ethanol intake. Maternal care behavior was affected by ethanol in a dose-dependent fashion. These results indicate that early experience with ethanol during lactation, even when the drug dosage is kept relatively low, leads to long-term consequences in offspring. Dose-response effects on maternal care behavior (i.e., nest building, crouching) may underlie disruptions in motor development and greater ethanol intake resulting from these early ethanol experiences. PMID:21334354

  9. Radiation carcinogenesis in man: influence of dose-response models and risk projection models in the estimation of risk coefficients following exposure to low-level radiation

    SciTech Connect

    Fabrikant, J.I.

    1982-02-01

    The somatic effects of concern in human populations exposed to low doses and low dose rates of ionizing radiations are those that may be induced by mutation in individual cells, singly or in small numbers. The most important of these is considered to be cancer induction. Current knowledge of the carcinogenic effect of radiation in man has been reviewed in two recent reports: the 1977 UNSCEAR Report; and the 1980 BEIR-III Report. Both reports emphasize that cancers of the breast, thyroid, hematopoietic tissues, lung, and bone can be induced by radiation. Other cancers, including the stomach, pancreas, pharynx, lymphatic, and perhaps all tissues of the body, may also be induced by radiation. Both reports calculate risk estimates in absolute and relative terms for low-dose, low-LET whole-body exposure, and for leukemia, breast cancer, thyroid cancer, lung cancer, and other cancers. These estimates derive from exposure and cancer incidence data at high doses and at high dose rates. There are no compelling scientific reasons to apply these values of risk to the very low doses and low dose rates of concern in human radiation protection. In the absence of reliable human data for calculating risk estimates, dose-response models have been constructed from extrapolations of animal data and high-dose-rate human data for projection of estimated risks at low doses and low dose rates. (ERB)

  10. Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.

    PubMed

    Mao, Zhongping Lily; Modi, Nishit B

    2016-08-01

    Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double-blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention. PMID:26632091

  11. Low-dose neutron dose response of zebrafish embryos obtained from the Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility

    NASA Astrophysics Data System (ADS)

    Ng, C. Y. P.; Kong, E. Y.; Konishi, T.; Kobayashi, A.; Suya, N.; Cheng, S. H.; Yu, K. N.

    2015-09-01

    The dose response of embryos of the zebrafish, Danio rerio, irradiated at 5 h post fertilization (hpf) by 2-MeV neutrons with ≤100 mGy was determined. The neutron irradiations were made at the Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility in the National Institute of Radiological Sciences (NIRS), Chiba, Japan. A total of 10 neutron doses ranging from 0.6 to 100 mGy were employed (with a gamma-ray contribution of 14% to the total dose), and the biological effects were studied through quantification of apoptosis at 25 hpf. The responses for neutron doses of 10, 20, 25, and 50 mGy approximately fitted on a straight line, while those for neutron doses of 0.6, 1 and 2.5 mGy exhibited neutron hormetic effects. As such, hormetic responses were generically developed by different kinds of ionizing radiations with different linear energy transfer (LET) values. The responses for neutron doses of 70 and 100 mGy were significantly below the lower 95% confidence band of the best-fit line, which strongly suggested the presence of gamma-ray hormesis.

  12. REDUCING UNCERTAINTY IN AIR TOXICS RISK ASSESSMENT: A MECHANISTIC EXPOSURE-DOSE-RESPONSE (EDR) MODEL FOR ASSESSING THE ACUTE NEUROTOXICITY OF VOLATILE ORGANIC COMPOUNDS (VOCS) BASED UPON A RECEPTOR-MEDIATED MODE OF ACTION

    EPA Science Inventory

    SUMMARY: The major accomplishment of NTD’s air toxics program is the development of an exposure-dose- response model for acute exposure to volatile organic compounds (VOCs), based on momentary brain concentration as the dose metric associated with acute neurological impairments...

  13. Kinetic modeling of Fluorine vacancy/F center creation in LiF:Mg,Ti including vacancy-interstitial recombination: Evaluating the factors leading to the lack of supralinearity in the optical absorption F center concentration dose response

    NASA Astrophysics Data System (ADS)

    Eliyahu, I.; Horowitz, Y. S.; Oster, L.; Mardor, I.; Druzhyna, S.; Biderman, S.

    2015-01-01

    Kinetic model simulations of charge carrier transport following irradiation of LiF:Mg,Ti (TLD-100) including Fluorine vacancy/F center creation by the radiation and dose-dependent vacancy-interstitial recombination are presented which describe the experimentally measured linear/exponentially saturating optical absorption dose response of the electron trapping centers at 4.0 eV, 4.77 eV, 5.08 eV (F band) and 5.45 eV. Linear/exponentially saturating dose response is commonly observed for centers which are not created by the radiation. The creation of Fluorine vacancies by the radiation could therefore be expected to lead to a supralinear dose response of the F center before the onset of saturation. Nonetheless, the dose response is linear from 10 Gy to 500 Gy and can be fitted with a dose-filling constant β = 6.1 · 10-5 Gy-1 corresponding to a 5% and 25% decrease from linearity at 103 Gy and 5 · 103 Gy respectively. The model attempts to resolve a central question concerning the mechanisms leading to the linear/exponentially saturating dose response of the F band even though Fluorine vacancies are being continuously created during the irradiation. The electron-trapping characteristics of the created vacancies are assumed to differ somewhat from the vacancies originally present in un-irradiated samples due to differences in their immediate environment. Vacancy-interstitial recombination for separation distances less than a critical distance, dc is demonstrated to be significant for D > 500 Gy (dc = 36 Å) and is an important mechanism contributing to the F center saturation at high dose-levels. The kinetic model accurately simulates the experimentally observed F center dose response over the entire investigated dose range of 10-105 Gy under the following conditions: (i) The concentration of vacancies initially present is unexpectedly high at ∼1023 m-3, possibly due to the highly doped, non-crystalline and hot-pressed nature of the LiF:Mg,Ti samples. (ii) The

  14. A dose-response study of consuming high-fructose corn syrup–sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults123456

    PubMed Central

    Medici, Valentina; Bremer, Andrew A; Lee, Vivien; Lam, Hazel D; Nunez, Marinelle V; Chen, Guoxia X; Keim, Nancy L; Havel, Peter J

    2015-01-01

    Background: National Health and Nutrition Examination Survey data show an increased risk of cardiovascular disease (CVD) mortality with an increased intake of added sugar. Objective: We determined the dose-response effects of consuming beverages sweetened with high-fructose corn syrup (HFCS) at zero, low, medium, and high proportions of energy requirements (Ereq) on circulating lipid/lipoprotein risk factors for CVD and uric acid in adults [age: 18–40 y; body mass index (in kg/m2): 18–35]. Design: We conducted a parallel-arm, nonrandomized, double-blinded intervention study in which adults participated in 3.5 inpatient days of baseline testing at the University of California Davis Clinical and Translational Science Center’s Clinical Research Center. Participants then consumed beverages sweetened with HFCS at 0% (aspartame sweetened, n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) of Ereq during 13 outpatient days and during 3.5 inpatient days of intervention testing at the research center. We conducted 24-h serial blood collections during the baseline and intervention testing periods. Results: Consuming beverages containing 10%, 17.5%, or 25% Ereq from HFCS produced significant linear dose-response increases of lipid/lipoprotein risk factors for CVD and uric acid: postprandial triglyceride (0%: 0 ± 4; 10%: 22 ± 8; 17.5%: 25 ± 5: 25%: 37 ± 5 mg/dL, mean of Δ ± SE, P < 0.0001 effect of HFCS-dose), fasting LDL cholesterol (0%: −1.0 ± 3.1; 10%: 7.4 ± 3.2; 17.5%: 8.2 ± 3.1; 25%: 15.9 ± 3.1 mg/dL, P < 0.0001), and 24-h mean uric acid concentrations (0%: −0.13 ± 0.07; 10%: 0.15 ± 0.06; 17.5%: 0.30 ± 0.07; 25%: 0.59 ± 0.09 mg/dL, P < 0.0001). Compared with beverages containing 0% HFCS, all 3 doses of HFCS-containing beverages increased concentrations of postprandial triglyceride, and the 2 higher doses increased fasting and/or postprandial concentrations of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, apolipoprotein CIII, and

  15. DOSE-RESPONSE Relationships Between Whole-Body Vibration and Lumbar Disk DISEASE—A Field Study on 388 Drivers of Different Vehicles

    NASA Astrophysics Data System (ADS)

    Schwarze, S.; Notbohm, G.; Dupuis, H.; Hartung, E.

    1998-08-01

    In a longitudinal study, the dose-response relationships between long term occupational exposure to whole-body vibration and degenerative processes in the lumbar spine caused by the lumbar disks were examined. From 1990 to 1992, 388 vibration-exposed workers from different driving jobs were examined medically and by lumbar X-ray. For each individual, a history of all exposure conditions was recorded, and a cumulative vibration dose was calculated allowing comparisons between groups of low, middle, and high intensity of exposure. 310 subjects were selected for a follow-up four years later, of whom 90·6% (n=281) agreed to participate. In comparing the exposure groups, the results indicate that the limit value ofazw(8h)=0·8 m/s2should be reviewed. The best fit between the lifelong vibration dose and the occurrence of a lumbar syndrome was obtained by applying a daily reference ofazw(8h)=0·6 ms2as a limit value. The results became more distinct still when only those subjects were included in the statistical analysis who had had no lumbar symptoms up to the end of the first year of exposure. The prevalence of lumbar syndrome is 1·55 times higher in the highly exposed group when compared to the reference group with low exposure (CI95%=1·24/1·95). Calculating the cumulative incidence of new cases of lumbar syndrome in the follow-up period yields a relative risk ofRRMH=1·37 (CI95%=0·86/2·17) for the highly exposed group. It is concluded that the limit value for the calculation of an individual lifelong vibration dose should be based on a daily reference exposure ofazw(8h)=0·6 m/s2. With increasing dose it is more and more probable that cases of lumbar syndrome are caused by exposure to vibration.

  16. Meta-analysis for deriving age- and gender-specific dose-response relationships between urinary cadmium concentration and {beta} {sub 2}-microglobulinuria under environmental exposure

    SciTech Connect

    Gamo, Masashi . E-mail: masashi-gamo@aist.go.jp; Ono, Kyoko; Nakanishi, Junko

    2006-05-15

    A meta-analysis was conducted to derive age- and gender-specific dose-response relationships between urinary cadmium (Cd) concentration and {beta} {sub 2}-microglobulinuria ({beta}2MG-uria) under environmental exposure. {beta}2MG-uria was defined by a cutoff point of 1000 {mu}g {beta} {sub 2}-microglobulin/g creatinine. We proposed a model for describing the relationships among the interindividual variabilities in urinary Cd concentration, the ratio of Cd concentrations in the target organ and in urine, and the threshold Cd concentration in the target organ. The parameters in the model were determined so that good agreement might be achieved between the prevalence rates of {beta}2MG-uria reported in the literature and those estimated by the model. In this analysis, only the data from the literature on populations environmentally exposed to Cd were used. Using the model and estimated parameters, the prevalence rate of {beta}2MG-uria can be estimated for an age- and gender-specific subpopulation for which the distribution of urinary Cd concentrations is known. The maximum permissible level of urinary Cd concentration was defined as the maximum geometric mean of the urinary Cd concentration in an age- and gender-specific subpopulation that would not result in a statistically significant increase in the prevalence rate of {beta}2MG-uria. This was estimated to be approximately 3 {mu}g/g creatinine for a population in a small geographical area and approximately 2 {mu}g/g creatinine for a nationwide population.

  17. Tenuous dose-response correlations for common disease states: case study of cholesterol and perfluorooctanoate/sulfonate (PFOA/PFOS) in the C8 Health Project.

    PubMed

    Kerger, Brent D; Copeland, Teri L; DeCaprio, Anthony P

    2011-10-01

    Persistent organic chemicals, such as perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), dioxins, and polychlorinated biphenyls, pose investigative challenges because they are found in virtually everyone (there is no unexposed control group). To overcome this problem, outcome data in some studies are sorted by chemical dose level and findings in low-end dose groups are compared to sequential higher dose groups. An example is the C8 Health Project that evaluated serum PFOA/PFOS (C8) and total cholesterol among 46,294 West Virginia residents who lived, worked, or went to school for at least 1 year in a C8 contaminated drinking-water district and were over age 18 in 2005-2006. The risk for high total cholesterol (>240 mg/dL) measured via odds ratios (ORs) in logistic regression models showed sequential OR increases with PFOA quartile, in comparison to the lowest quartile (OR = 1.00), that were each significantly elevated (OR = 1.21, 1.33, and 1.40, respectively), but age, sex, and body mass index were stronger correlates. Importantly, the magnitude of cholesterol increase was small (12 mg/dL from lowest to highest exposure deciles) and comparison to similar statistics for the general U.S. population showed the C8 cohort had lower rates of high cholesterol. This suggests that inadvertent selection bias may have affected the lowest exposure quartile (control group), making tenuous the dose-response relationship between PFOA/PFOS and risk of high cholesterol. This case illustrates the substantial difficulties in assigning toxicological importance to statistical comparisons for common disease states that utilize subgroups with low exposures as an effective control group. PMID:21770727

  18. Role of type II pneumocytes in pathogenesis of radiation pneumonitis: dose response of radiation-induced lung changes in the transient high vascular permeability period.

    PubMed

    Osterreicher, Jan; Pejchal, Jaroslav; Skopek, Jirí; Mokrỳ, Jaroslav; Vilasová, Zdena; Psutka, Jan; Vávrová, Jirina; Mazurová, Yvona

    2004-12-01

    We studied the dose response of pulmonary changes at 3 weeks after 1-25 Gy irradiation and we investigated the effects of an anti-inflammatory drug. Wistar rats were given a single dose of 1-25Gy irradiation to the thorax. Group one was treated with saline only, while group two was administered subcutaneously a combination of pentoxifylline (35 mg/kg) and dexamethasone (1 mg/kg) twice per week. Lungs were examined histochemically and number of neutrophile granulocytes, alveolar septal thickness, air/tissue ratio, number of alveoli per field, number of type II pneumocytes per alveolus, and occludin 1 expression were measured. A significant dose-dependent depletion of type II pneumocytes was found after irradiation with a dose of 1 Gy and higher. Alveolar neutrophils increased after 1 Gy with a dose dependency noted after 10-25Gy and alveolar septa thickening followed 5-25 Gy. A lower occludin 1 expression was observed in animals irradiated with the doses of 5 20 Gy, indicating an effect on vascular permeability. Anti-inflammatory therapy partially inhibited the increase of neutrophils at all radiation doses and the depletion of type II pneumocytes after doses of 1, 10, and 15 Gy. Occludin 1 did not decrease in the lungs of rats treated with the anti-inflammatory drugs as it did in most rats treated only with saline. Our results suggest that pneumocytes depletion is a major factor responsible for radiation pneumonitis development and that these changes may be compensated for provided radiation doses are below the threshold. PMID:15625787

  19. Photodynamic Therapy Using Intra-Articular Photofrin for Murine MRSA Arthritis: Biphasic Light Dose Response for Neutrophil-Mediated Antibacterial Effect

    PubMed Central

    Tanaka, Masamitsu; Kinoshita, Manabu; Yoshihara, Yasuo; Shinomiya, Nariyoshi; Seki, Shuhji; Nemoto, Koichi; Hamblin, Michael R.; Morimoto, Yuji

    2011-01-01

    Background and Objective Bacterial arthritis does not respond well to antibiotics and moreover multidrug resistance is spreading. We previously tested photodynamic therapy (PDT) mediated by systemic Photofrin® in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) arthritis, but found that neutrophils were killed by PDT and therefore the infection was potentiated. Study Design/Materials and Methods The present study used an intra-articular injection of Photofrin® and optimized the light dosimetry in order to maximize bacterial killing and minimize killing of host neutrophils. MRSA (5 × 107 CFU) was injected into the mouse knee followed 3 days later by 1 μg of Photofrin® and 635-nm diode laser illumination with a range of fluences within 5 minutes. Synovial fluid was sampled 6 hours or 1–3, 5, and 7 days after PDT to determine MRSA colony-forming units (CFU), neutrophil numbers, and levels of cytokines. Results A biphasic light dose response was observed with the greatest reduction of MRSA CFU seen with a fluence of 20 J cm−2, whereas lower antibacterial efficacy was observed with fluences that were either lower or higher. Consistent with these results, a significantly higher concentration of macrophage inflammatory protein-2, a CXC chemokine, and greater accumulation of neutrophils were seen in the infected knee joint after PDT with a fluence of 20 J cm−2 compared to fluences of 5 or 70 J cm−2. Conclusion PDT for murine MRSA arthritis requires appropriate light dosimetry to simultaneously maximize bacterial killing and neutrophil accumulation into the infected site, while too little light does not kill sufficient bacteria and too much light kills neutrophils and damages host tissue as well as bacteria and allows bacteria to grow unimpeded by host defense. PMID:21412806

  20. Coupling a continuous watershed-scale microbial fate and transport model with a stochastic dose-response model to estimate risk of illness in an urban watershed.

    PubMed

    Liao, Hehuan; Krometis, Leigh-Anne H; Kline, Karen

    2016-05-01

    Within the United States, elevated levels of fecal indicator bacteria (FIB) remain the leading cause of surface water-quality impairments requiring formal remediation plans under the federal Clean Water Act's Total Maximum Daily Load (TMDL) program. The sufficiency of compliance with numerical FIB criteria as the targeted endpoint of TMDL remediation plans may be questionable given poor correlations between FIB and pathogenic microorganisms and varying degrees of risk associated with exposure to different fecal pollution sources (e.g. human vs animal). The present study linked a watershed-scale FIB fate and transport model with a dose-response model to continuously predict human health risks via quantitative microbial risk assessment (QMRA), for comparison to regulatory benchmarks. This process permitted comparison of risks associated with different fecal pollution sources in an impaired urban watershed in order to identify remediation priorities. Results indicate that total human illness risks were consistently higher than the regulatory benchmark of 36 illnesses/1000 people for the study watershed, even when the predicted FIB levels were in compliance with the Escherichia coli geometric mean standard of 126CFU/100mL. Sanitary sewer overflows were associated with the greatest risk of illness. This is of particular concern, given increasing indications that sewer leakage is ubiquitous in urban areas, yet not typically fully accounted for during TMDL development. Uncertainty analysis suggested the accuracy of risk estimates would be improved by more detailed knowledge of site-specific pathogen presence and densities. While previous applications of the QMRA process to impaired waterways have mostly focused on single storm events or hypothetical situations, the continuous modeling framework presented in this study could be integrated into long-term water quality management planning, especially the United States' TMDL program, providing greater clarity to watershed

  1. Long-Term Coffee Consumption and Risk of Cardiovascular Disease: A Systematic Review and a Dose-Response Meta-Analysis of Prospective Cohort Studies

    PubMed Central

    Ding, Ming; Bhupathiraju, Shilpa N; Satija, Ambika; van Dam, Rob M; Hu, Frank B

    2013-01-01

    Background Considerable controversy exists regarding the association between coffee consumption and cardiovascular disease (CVD) risk. A meta-analysis was performed to assess the dose-response relationship of long-term coffee consumption with CVD risk. Methods and Results Pubmed and EMBASE were searched for prospective cohort studies of the relationship between coffee consumption and CVD risk, which included coronary heart disease, stroke, heart failure, and CVD mortality. Thirty-six studies were included with 1,279,804 participants and 36,352 CVD cases. A non-linear relationship of coffee consumption with CVD risk was identified (P for heterogeneity = 0.09, P for trend < 0.001, P for non-linearity < 0.001). Compared with the lowest category of coffee consumption (median: 0 cups/d), the relative risk of CVD was 0.95 (95% CI, 0.87 to 1.03) for the highest (median: 5 cups/d) category, 0.85 (0.80 to 0.90) for the second highest (median: 3.5 cups/d), and 0.89 (0.84 to 0.94) for the third highest category (median: 1.5 cups/d). Looking at separate outcomes, coffee consumption was non-linearly associated with both CHD (P for heterogeneity = 0.001, P for trend < 0.001, P for non-linearity < 0.001) and stroke risks (P for heterogeneity = 0.07, P for trend < 0.001, P for non-linearity< 0.001) (P for trend differences > 0.05). Conclusions A non-linear association between coffee consumption with CVD risk was observed in this meta-analysis. Moderate coffee consumption was inversely significantly associated with CVD risk, with the lowest CVD risk at 3 to 5 cups/d, and heavy coffee consumption was not associated with elevated CVD risk. PMID:24201300

  2. Effect of iron salt counter ion in dose-response curves for inactivation of Fusarium solani in water through solar driven Fenton-like processes

    NASA Astrophysics Data System (ADS)

    Aurioles-López, Verónica; Polo-López, M. Inmaculada; Fernández-Ibáñez, Pilar; López-Malo, Aurelio; Bandala, Erick R.

    2016-02-01

    The inactivation of Fusarium solani in water was assessed by solar driven Fenton-like processes using three different iron salts: ferric acetylacetonate (Fe(acac)3), ferric chloride (FeCl3) and ferrous sulfate (FeSO4). The experimental conditions tested were [Fe] ≈ 5 mg L-1, [H2O2] ≈ 10 mg L-1 and [Fe] ≈ 10 mg L-1; [H2O2] ≈ 20 mg L-1 mild and high, respectively, and pH 3.0 and 5.0, under solar radiation. The highest inactivation rates were observed at high reaction conditions for the three iron salts tested at pH 5.0 with less than 3.0 kJ L-1 of accumulate energy (QUV) to achieve over 99.9% of F. solani inactivation. Fe(acac)3 was the best iron salt to accomplishing F. solani inactivation. The modified Fermi equation was used to fix the experimental inactivation, data showed it was helpful for modeling the process, adequately describing dose-response curves. Inactivation process using FeSO4 at pH 3.0 was modeled fairly with r2 = 0.98 and 0.99 (mild and high concentration, respectively). Fe(acac)3, FeCl3 and FeSO4 at high concentration (i.e. [Fe] ≈ 10 mg L-1; [H2O2] ≈ 20 mg L-1) and pH 5.0 showed the highest fitting values (r2 = 0.99). Iron salt type showed a remarkable influence on the Fenton-like inactivation process.

  3. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    SciTech Connect

    O'Neill, Peter; Anderson, Jennifer

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  4. Mysteries of LiF TLD response following high ionisation density irradiation: nanodosimetry and track structure theory, dose response and glow curve shapes.

    PubMed

    Horowitz, Y; Fuks, E; Datz, H; Oster, L; Livingstone, J; Rosenfeld, A

    2011-06-01

    Three outstanding effects of ionisation density on the thermoluminescence (TL) mechanisms giving rise to the glow peaks of LiF:Mg,Ti (TLD-100) are currently under investigation: (1) the dependence of the heavy charged particle (HCP) relative efficiency with increasing ionisation density and the effectiveness of its modelling by track structure theory (TST), (2) the behaviour of the TL efficiency, f(D), as a function of photon energy and dose. These studies are intended to promote the development of a firm theoretical basis for the evaluation of relative TL efficiencies to assist in their application in mixed radiation fields. And (3) the shape of composite peak 5 in the glow curve for various HCP types and energies and following high-dose electron irradiation, i.e. the ratio of the intensity of peak 5a to peak 5. Peak 5a is a low-temperature satellite of peak 5 arising from electron-hole capture in a spatially correlated trapping centre/luminescent centre (TC/LC) complex that has been suggested to possess a potential as a solid-state nanodosemeter due to the preferential electron/hole population of the TC/LC at high ionisation density. It is concluded that (1) the predictions of TST are very strongly dependent on the choice of photon energy used in the determination of f(D); (2) modified TST employing calculated values of f(D) at 2 keV is in agreement with 5-MeV alpha particle experimental results for composite peak 5 but underestimates the 1.5-MeV proton relative efficiencies. Both the proton and alpha particle relative TL efficiencies of the high-temperature TL (HTTL) peaks 7 and 8 are underestimated by an order of magnitude suggesting that the HTTL efficiencies are affected by other factors in addition to radial electron dose; (3) the dose-response supralinearity of peaks 7 and 8 change rapidly with photon energy: this behaviour is explained in the framework of the unified interaction model as due to a very strong dependence on photon energy of the relative

  5. The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers

    PubMed Central

    Ekwaru, John Paul; Zwicker, Jennifer D.; Holick, Michael F.; Giovannucci, Edward; Veugelers, Paul J.

    2014-01-01

    Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P<0.001). We did not observe any increase in the risk for hypercalcemia with increasing vitamin D supplementation. We recommend vitamin D supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for overweight subjects relative to normal weight subjects. This observational study provides body weight specific recommendations to achieve 25(OH)D targets. PMID:25372709

  6. Evidence of a Non-Linear Dose-Response Relationship between Training Load and Stress Markers in Elite Female Futsal Players

    PubMed Central

    Milanez, Vinicius F.; Ramos, Solange P.; Okuno, Nilo M.; Boullosa, Daniel A.; Nakamura, Fabio Y.

    2014-01-01

    The aim of this study was: to describe typical training load (TL) carried out by a professional female futsal team for a period of 5 weeks; and to verify the relationship between TL, stress symptoms, salivary secretory immunoglobulin A (SIgA) levels, and symptoms of upper respiratory infections (URI). Over 45 sessions, the TL of the athletes was monitored daily by means of session-RPE method during the in-season period prior to the main national competition. Stress symptoms were measured weekly by means of the “Daily Analysis of Life Demands in Athletes Questionnaire” (DALDA), SIgA levels, and by symptoms of URI by the “Wisconsin Upper Respiratory Symptom Survey-21” (WURSS). There was a significant increase in TL, monotony, and training strain in week 3, with a concomitant and significant reduction in percentage variation (Δ%) of SIgA concentration and secretion rate (p < 0.05). Additionally, a second order regression model showed a high goodness of fit (R2 = 0.64 - 0.89) between TL and strain with SIgA concentration, secretion rate, and “worse than normal” responses of stress symptoms from the questionnaire. In conclusion, a link between TL and SIgA levels, and stress symptoms in female futsal players was evident in a non linear fashion. There appears to be an optimal range of values of daily TL between ~343 and ~419 AU and strain between ~2639 and 3060 AU, because at levels below and above these values there was an increase in stress symptoms and above ~435 and ~3160 AU to TL and strain there were a decrease in SIgA levels. In contrast, symptoms of URI failed to demonstrate relationship with the variables studied. Key Points There is a dose-response relationship between SIgA levels and stress symptoms with TL. For the athletes of the present study, values of ~436 AU and ~3161 AU to TL and strain training would be desirable because higher values would decrease responses of SIgA levels. An optimal range of values of TL between ~336 and ~412 AU to TL

  7. Development of dose response to Y-90 microsphere treatment of metastatic liver cancer by quantitative analysis of SPECT and PET images

    NASA Astrophysics Data System (ADS)

    Campbell, Janice M.

    Y-90 microsphere radiotherapy is an option for treating inoperable metastatic liver tumors. This takes advantage of the differing vascular supply of the tumor and normal liver. The radiation dosimetry can be complex due to the non-uniform distribution of the particles. Because of this difficulty, the recorded treatment absorbed dose is often calculated assuming a uniform distribution throughout the entire liver segment. This work represents a retrospective analysis of twelve consecutive patients treated with Y-90 microspheres for colorectal liver metastasis. Absorbed dose to tumor and normal liver tissue was calculated by two methods for comparison. Both were partition methods, one using an average tumor to normal liver vascularity ratio and the other a patient specific vascularity ratio derived from SPECT scans performed pre-treatment. Tumor response was quantitatively evaluated from pre and post treatment PET scans. Site-specific thresholding ROI volumes were used to determine tumor SUV in the image analysis. PET analysis showed a significant response as a whole with an average of 52% +/- 22% decrease in total tumor burden. The range of decrease, representing tumor response in size and metabolism was 17-91%. Dose versus response curves were generated based on the above calculations. The results and statistical analysis indicate that there is a significant difference in the tumor absorbed dose value when calculated by the traditional partition method using an average tumor to normal liver ratio as compared to use of a patient specific tumor to normal liver ratio derived from SPECT images. The paired t-test result demonstrated a significant difference with the t value of 3.06 corresponding to a P of 0.009. A linear regression analysis of each dose response curve allowed a comparison of each dose calculation method as well. There was an increase in the r value for the absorbed dose calculated by the patient specific method in all response parameters. The best fits

  8. N7-glycidamide-guanine DNA adduct formation by orally ingested acrylamide in rats: a dose-response study encompassing human diet-related exposure levels.

    PubMed

    Watzek, Nico; Böhm, Nadine; Feld, Julia; Scherbl, Denise; Berger, Franz; Merz, Karl Heinz; Lampen, Alfonso; Reemtsma, Thorsten; Tannenbaum, Steven R; Skipper, Paul L; Baum, Matthias; Richling, Elke; Eisenbrand, Gerhard

    2012-02-20

    Acrylamide (AA) is formed during the heating of food and is classified as a genotoxic carcinogen. The margin of exposure (MOE), representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be of concern. After ingestion, AA is converted by P450 into the genotoxic epoxide glycidamide (GA). GA forms DNA adducts, primarily at N7 of guanine (N7-GA-Gua). We performed a dose-response study with AA in female Sprague-Dawley (SD) rats. AA was given orally in a single dosage of 0.1-10 000 μg/kg bw. The formation of urinary mercapturic acids and of N7-GA-Gua DNA adducts in liver, kidney, and lung was measured 16 h after application. A mean of 37.0 ± 11.5% of a given AA dose was found as mercapturic acids (MAs) in urine. MA excretion in urine of untreated controls indicated some background exposure from endogenous AA. N7-GA-Gua adduct formation was not detectable in any organ tested at 0.1 μg AA/kg bw. At a dose of 1 μg/kg bw, adducts were found in kidney (around 1 adduct/10(8) nucleotides) and lung (below 1 adduct/10(8) nucleotides) but not in liver. At 10, respectively, 100 μg/kg bw, adducts were found in all three organs, at levels close to those found at 1 μg AA/kg, covering a range of about 1-2 adducts/10(8) nucleotides. As compared to DNA adduct levels from electrophilic genotoxic agents of various origin found in human tissues, N7-GA-Gua adduct levels within the dose range of 0.1-100 μg AA/kg bw were at the low end of this human background. We propose to take the background level of DNA lesions in humans more into consideration when doing risk assessment of food-borne genotoxic carcinogens. PMID:22211389

  9. Dose response of multiple parameters for calyculin A-induced premature chromosome condensation in human peripheral blood lymphocytes exposed to high doses of cobalt-60 gamma-rays.

    PubMed

    Lu, Xue; Zhao, Hua; Feng, Jiang-Bin; Zhao, Xiao-Tao; Chen, De-Qing; Liu, Qing-Jie

    2016-09-01

    Many studies have investigated exposure biomarkers for high dose radiation. However, no systematic study on which biomarkers can be used in dose estimation through premature chromosome condensation (PCC) analysis has been conducted. The present study aims to screen the high-dose radiation exposure indicator in calyculin A-induced PCC. The dose response of multiple biological endpoints, including G2/A-PCC (G2/M and M/A-PCC) index, PCC ring (PCC-R), ratio of the longest/shortest length (L/L ratio), and length and width ratio of the longest chromosome (L/B ratio), were investigated in calyculin A-induced G2/A-PCC spreads in human peripheral blood lymphocytes exposed to 0-20Gy (dose-rate of 1Gy/min) cobalt-60 gamma-rays. The G2/A-PCC index was decreased with enhanced absorbed doses of 4-20Gy gamma-rays. The G2/A PCC-R at 0-12Gy gamma-rays conformed to Poisson distribution. Three types of PCC-R were scored according to their shape and their solidity or hollowness. The frequencies of hollow PCC-R and PCC-R including or excluding solid ring in G2/A-PCC spreads were enhanced with increased doses. The length and width of the longest chromosome, as well as the length of the shortest chromosome in each G2/M-PCC or M/A-PCC spread, were measured. All L/L or L/B ratios in G2/M-PCC or M/A-PCC spread increased with enhanced doses. A blind test with two new irradiated doses was conducted to validate which biomarker could be used in dose estimation. Results showed that hollow PCC-R and PCC-R including solid ring can be utilized for accurate dose estimation, and that hollow PCC-R was optimal for practical application. PMID:27542714

  10. [Dose-Response Dependences for Frequency of RET/PTC Gene Rearrangements in Papillary Thyroid Carcinoma after Irradiation. Simple Pooling Analysis of Molecular Epidemiological Data].

    PubMed

    Koterov, A N; Ushenkova, L N; Biryukov, A P

    2016-01-01

    reduce the strength of associations for RET/PTC in total. On the basis of ordinal scale doses (background, "low" (0.1 Gy), "middle" (0.1-1 Gy) and "large" (1-10 Gy) dose) also found was a significant correlation (Spearman) with the dose for the frequency RET/PTC in total (r = 0.736; p = 0.0098), but for certain types of rearrangements the results were reverse to the previous analysis (the effect was significant only for the RET/PTC3: r = 0.731; p = 0.024). The linear dose-response trends of the Cochrane-Armitage-test for the frequency of RET/PTC in total, RET/PTC1 and RET/PTC3 depending on the dose to the thyroid in the ordinal scale were registered (p, respectively: < 0.0001 < 0.0001 and 0.007). Thus; after more than 20 years of the molecular and epidemiological research of RET/PTC in thyroid radiogenic carcinomas the comprehensive evidence of the dose-effect dependence existence indicating a real relationship between the studied parameters and a radiation factor was obtained for the first time. PMID:27245001

  11. Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose-response study.

    PubMed

    Pasquali, Renato; Ambrosi, Bruno; Armanini, Decio; Cavagnini, Francesco; Uberti, Ettore Degli; Del Rio, Graziano; de Pergola, Giovanni; Maccario, Mauro; Mantero, Franco; Marugo, Mario; Rotella, Carlo Maria; Vettor, Roberto

    2002-01-01

    There is increasing evidence that the abdominal obesity phenotype may be associated with multiple alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in both sexes. Our hypothesis is that the lack of adequate cortisol suppression after the dexamethasone test may constitute an indirect marker of HPA axis hyperactivity in the presence of the abdominal obesity phenotype. A total of 34 normal-weight (13 men and 21 women) and 87 obese (36 men and 51 women), healthy, nondepressed subjects therefore underwent four different dexamethasone suppression tests randomly performed at varying intervals of at least 1 wk between each test. After a standard overnight 1-mg dexamethasone test, which served as a reference, three other tests were randomly performed at 1-wk intervals by administering 0.0035, 0.0070, and 0.015 mg oral dexamethasone per kilogram of body weight overnight. Blood samples were obtained for cortisol, ACTH, and dexamethasone. Results were analyzed separately in men and women as well as in normal-weight [body mass index (BMI) < or = 25 kg/m(2)] and overweight or obese (BMI > 25 kg/m(2)) subjects. The waist circumference and the waist to hip ratio (WHR) were used as markers of body fat distribution. After the standard 1-mg test, cortisol suppression was greater than 90% in all subjects. However, after each test, obese women had significantly higher values of percent cortisol and percent ACTH suppression than normal-weight women without any difference between obese and normal-weight men. Considering the response to the three variable-dose tests, a clear dose- response pattern (P < 0.001 for trend analysis) in percent cortisol and percent ACTH suppression was found in all subjects. After each test men had significantly higher dexamethasone levels than women, regardless of BMI. However, obese women, but not men, had significantly higher dexamethasone levels after each test than their normal-weight counterpart. Plasma dexamethasone

  12. Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies

    PubMed Central

    Keum, NaNa; Giovannucci, Edward; Fadnes, Lars T; Boffetta, Paolo; Greenwood, Darren C; Tonstad, Serena; Vatten, Lars J; Riboli, Elio; Norat, Teresa

    2016-01-01

    Objective To quantify the dose-response relation between consumption of whole grain and specific types of grains and the risk of cardiovascular disease, total cancer, and all cause and cause specific mortality. Data sources PubMed and Embase searched up to 3 April 2016. Study selection Prospective studies reporting adjusted relative risk estimates for the association between intake of whole grains or specific types of grains and cardiovascular disease, total cancer, all cause or cause specific mortality. Data synthesis Summary relative risks and 95% confidence intervals calculated with a random effects model. Results 45 studies (64 publications) were included. The summary relative risks per 90 g/day increase in whole grain intake (90 g is equivalent to three servings—for example, two slices of bread and one bowl of cereal or one and a half pieces of pita bread made from whole grains) was 0.81 (95% confidence interval 0.75 to 0.87; I2=9%, n=7 studies) for coronary heart disease, 0.88 (0.75 to 1.03; I2=56%, n=6) for stroke, and 0.78 (0.73 to 0.85; I2=40%, n=10) for cardiovascular disease, with similar results when studies were stratified by whether the outcome was incidence or mortality. The relative risks for morality were 0.85 (0.80 to 0.91; I2=37%, n=6) for total cancer, 0.83 (0.77 to 0.90; I2=83%, n=11) for all causes, 0.78 (0.70 to 0.87; I2=0%, n=4) for respiratory disease, 0.49 (0.23 to 1.05; I2=85%, n=4) for diabetes, 0.74 (0.56 to 0.96; I2=0%, n=3) for infectious diseases, 1.15 (0.66 to 2.02; I2=79%, n=2) for diseases of the nervous system disease, and 0.78 (0.75 to 0.82; I2=0%, n=5) for all non-cardiovascular, non-cancer causes. Reductions in risk were observed up to an intake of 210-225 g/day (seven to seven and a half servings per day) for most of the outcomes. Intakes of specific types of whole grains including whole grain bread, whole grain breakfast cereals, and added bran, as well as total bread and total breakfast cereals were also associated

  13. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation

    NASA Technical Reports Server (NTRS)

    Van Dongen, Hans P A.; Maislin, Greg; Mullington, Janet M.; Dinges, David F.

    2003-01-01

    OBJECTIVES: To inform the debate over whether human sleep can be chronically reduced without consequences, we conducted a dose-response chronic sleep restriction experiment in which waking neurobehavioral and sleep physiological functions were monitored and compared to those for total sleep deprivation. DESIGN: The chronic sleep restriction experiment involved randomization to one of three sleep doses (4 h, 6 h, or 8 h time in bed per night), which were maintained for 14 consecutive days. The total sleep deprivation experiment involved 3 nights without sleep (0 h time in bed). Each study also involved 3 baseline (pre-deprivation) days and 3 recovery days. SETTING: Both experiments were conducted under standardized laboratory conditions with continuous behavioral, physiological and medical monitoring. PARTICIPANTS: A total of n = 48 healthy adults (ages 21-38) participated in the experiments. INTERVENTIONS: Noctumal sleep periods were restricted to 8 h, 6 h or 4 h per day for 14 days, or to 0 h for 3 days. All other sleep was prohibited. RESULTS: Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days resulted in significant cumulative, dose-dependent deficits in cognitive performance on all tasks. Subjective sleepiness ratings showed an acute response to sleep restriction but only small further increases on subsequent days, and did not significantly differentiate the 6 h and 4 h conditions. Polysomnographic variables and delta power in the non-REM sleep EEG-a putative marker of sleep homeostasis--displayed an acute response to sleep restriction with negligible further changes across the 14 restricted nights. Comparison of chronic sleep restriction to total sleep deprivation showed that the latter resulted in disproportionately large waking neurobehavioral and sleep delta power responses relative to how much sleep was lost. A statistical model revealed that, regardless of the mode of sleep deprivation, lapses in behavioral alertness

  14. Dose-response relationship between alcohol consumption before and during pregnancy and the risks of low birth weight, preterm birth and small-size-for-gestational age (SGA) – A systematic review and meta-analyses

    PubMed Central

    Patra, Jayadeep; Bakker, Rachel; Irving, Hyacinth; Jaddoe, Vincent W.V.; Malini, Shobha; Rehm, Jürgen

    2011-01-01

    Background The effects of moderate alcohol consumption during pregnancy on adverse pregnancy outcomes have been inconsistent. Objective To review systematically and perform meta-analyses on the effect of maternal alcohol exposure on the risk of low birth weight, preterm birth and small-size-for-gestational age (SGA). Search Strategy Using Medical Subject Headings, a literature search of MEDLINE, EMBASE, CINAHL, CABS, WHOlist, SIGLE, ETOH, and Web of Science between 1 January 1980 and 1 August 2009 was performed followed by manual searches. Selection Criteria Case control or cohort studies were assessed for quality (STROBE), 36 available studies were included. Data collection and Analysis Two reviewers independently extracted the information on low birth weight, preterm birth and SGA using a standardized protocol. Meta-analyses on dose-response relationship were performed using linear as well as first-order and second-order fractional polynomial regressions to estimate best fitting curves to the data. Main Results Compared to abstainers, the overall dose-response relationships for low birth weight and SGA had no effect up to 10 g/day (an average of about 1 drink/day) and preterm birth had no effect up to 18 g/day (an average of 1.5 drinks/day) of pure alcohol consumption; thereafter, the relationship had monotonically increasing risk for increasing maternal alcohol consumption. Moderate consumption during pre-pregnancy was associated with reduced risks for both outcomes. Conclusions Dose-response relationship indicates that heavy alcohol consumption during pregnancy increases the risks of all three outcomes while light to moderate alcohol consumption shows no effect. Preventive measures during antenatal consults should be initiated. PMID:21729235

  15. Identification of bound nitro musk-protein adducts in fish liver by gas chromatography-mass spectrometry: biotransformation, dose-response and toxicokinetics of nitro musk metabolites protein adducts in trout liver as biomarkers of exposure.

    PubMed

    Mottaleb, M Abdul; Osemwengie, Lantis I; Islam, M Rafiq; Sovocool, G Wayne

    2012-01-15

    Ubiquitous occurrences of synthetic nitro musks are evident in the literature. The in vivo analysis of musk xylene (MX) and musk ketone (MK)-protein adducts in trout liver has been performed by gas chromatography-mass spectrometry using selected ion monitoring (GC-SIM-MS). Biotransformation, dose-response and toxicokinetics studies of 2-amino-MX (2-AMX), 2-amino-MK (2-AMK) and 4-amino-MX (4-AMX) metabolites, covalently bound to cysteine amino acids in proteins in fish liver, formed by enzymatic nitro-reduction of MX and MK, have been described. Trouts were exposed to single exposures of 0.010, 0.030, 0.10, and 0.30 mg/g MX and/or MK. Forty-two fish liver samples were collected from exposed- and control-fish subsequent to exposure intervals of 1 day, 3 days, and 7 days and were composited as per exposure schedules and times. Alkaline hydrolysis released bound metabolites from exposed liver composites that were extracted into n-hexane and then concentrated and analyzed by GC-SIM-MS. The presence of the metabolites in liver extracts was confirmed based on agreement of similar mass spectral properties and retention times with standards. In the dose-response study, the maximum adduct formation was 492.0 ng/g for 2-AMX, 505.5 ng/g for 2-AMK and 12588.5 ng/g for 4-AMX in liver at 0.03 mg/g MX and MK fish in 1 day after exposure. For toxicokinetics investigation, the highest amount of the target metabolites was found to be the same concentration as observed in the dose-response study for 1 day after exposure with 0.03 mg/g MX and MK fish and the half-lives of the metabolites were estimated to be 2-9 days based on assumption of first-order kinetics. Average recoveries exceeded 95% with a relative standard deviation (RSD) around 9%, and the limit of detection (LOD) ranged from 0.91 to 3.8 ng/g based on a signal to noise ratio of 10 (S/N=10) could be achieved for the metabolites. No metabolites were detected in the controls and exposed non-hydrolyzed liver extracts. This is

  16. The supra-additive hyperactivity caused by an amphetamine-chlordiazepoxide mixture exhibits an inverted-U dose response: negative implications for the use of a model in screening for mood stabilizers.

    PubMed

    Kelly, Michele P; Logue, Sheree F; Dwyer, Jason M; Beyer, Chad E; Majchrowski, Heather; Cai, Zhang; Liu, Zhi; Adedoyin, Adedayo; Rosenzweig-Lipson, Sharon; Comery, Thomas A

    2009-06-01

    One of the few preclinical models used to identify mood stabilizers is an assay in which amphetamine-induced hyperactivity (AMPH) is potentiated by the benzodiazepine chlordiazepoxide (CDP), an effect purportedly blocked by mood stabilizers. Our data here challenge this standard interpretation of the AMPH-CDP model. We show that the potentiating effects of AMPH-CDP are not explained by a pharmacokinetic interaction as both drugs have similar brain and plasma exposures whether administered alone or in combination. Of concern, however, we find that combining CDP (1-12 mg/kg) with AMPH (3 mg/kg) results in an inverted-U dose response in outbred CD-1 as well as inbred C57Bl/6N and 129S6 mice (peak hyperactivity at 3 mg/kg CDP+3 mg/kg AMPH). Such an inverted-U dose response complicates interpreting whether a reduction in hyperactivity produced by a mood stabilizer reflects a "blockade" or a "potentiation" of the mixture. In fact, we show that the prototypical mood stabilizer valproic acid augments the effects of CDP on hypolocomotion and anxiolytic-like behavior (increases punished crossings by Swiss-Webster mice in the four-plate test). We argue that these data, in addition to other practical and theoretical concerns surrounding the model, limit the utility of the AMPH-CDP mixture model in drug discovery. PMID:19303035

  17. Radiotherapy of abdomen with precise renal assessment with SPECT/CT imaging (RAPRASI): design and methodology of a prospective trial to improve the understanding of kidney radiation dose response

    PubMed Central

    2013-01-01

    Background The kidneys are a principal dose-limiting organ in radiotherapy for upper abdominal cancers. The current understanding of kidney radiation dose response is rudimentary. More precise dose-volume response models that allow direct correlation of delivered radiation dose with spatio-temporal changes in kidney function may improve radiotherapy treatment planning for upper-abdominal tumours. Our current understanding of kidney dose response and tolerance is limited and this is hindering efforts to introduce advanced radiotherapy techniques for upper-abdominal cancers, such as intensity-modulated radiotherapy (IMRT). The aim of this study is to utilise radiotherapy and combined anatomical/functional imaging data to allow direct correlation of radiation dose with spatio-temporal changes in kidney function. The data can then be used to develop a more precise dose-volume response model which has the potential to optimise and individualise upper abdominal radiotherapy plans. Methods/design The Radiotherapy of Abdomen with Precise Renal Assessment with SPECT/CT Imaging (RAPRASI) is an observational clinical research study with participating sites at Sir Charles Gairdner Hospital (SCGH) in Perth, Australia and the Peter MacCallum Cancer Centre (PMCC) in Melbourne, Australia. Eligible patients are those with upper gastrointestinal cancer, without metastatic disease, undergoing conformal radiotherapy that will involve incidental radiation to one or both kidneys. For each patient, total kidney function is being assessed before commencement of radiotherapy treatment and then at 4, 12, 26, 52 and 78 weeks after the first radiotherapy fraction, using two procedures: a Glomerular Filtration Rate (GFR) measurement using the 51Cr-ethylenediamine tetra-acetic acid (EDTA) clearance; and a regional kidney perfusion measurement assessing renal uptake of 99mTc-dimercaptosuccinic acid (DMSA), imaged with a Single Photon Emission Computed Tomography / Computed Tomography (SPECT

  18. Dose-Response Effects of a Web-Based Physical Activity Program on Body Composition and Metabolic Health in Inactive Older Adults: Additional Analyses of a Randomized Controlled Trial

    PubMed Central

    Vroege, David P; Wijsman, Carolien A; Broekhuizen, Karen; de Craen, Anton JM; van Heemst, Diana; van der Ouderaa, Frans JG; van Mechelen, Willem; Slagboom, P Eline; Catt, Michael; Westendorp, Rudi GJ; Verhagen, Evert ALM

    2014-01-01

    Background Low physical activity is a major risk factor for several age-related diseases. Recently, we showed in a randomized controlled trial that a 12-week Web-based intervention (Philips DirectLife) to increase physical activity was effective in increasing physical activity levels and metabolic health in an inactive population aged 60-70 years. Objective The goal of this paper was to assess how many participants successfully reached the physical activity level as targeted by the intervention and what the effects of the intervention on body composition and metabolic health in these successful individuals were to provide insight in the maximum attainable effect of the intervention. Methods Among the 235 participants in a randomized controlled trial of the Actief en Gezond Oud (AGO) study, we assessed the effects of the intervention on metabolic parameters in those who had successfully reached their personalized physical activity target compared with the entire intervention group. Furthermore, we studied the dose-response effect of increase in physical activity on metabolic outcome within the intervention group. Results Of the intervention group, 50 of 119 (42.0%) participants successfully reached the physical activity target (corresponding to a 10% increased daily physical activity on average). This group showed markedly higher effects of the intervention compared to the entire intervention group, with greater decreases in body weight (2.74 vs 1.49 kg), waist circumference (3.74 vs 2.33 cm), insulin resistance (HOMA index: 0.23 vs 0.20), and in cholesterol/HDL ratio (0.39 vs 0.20) and Framingham risk score (0.90% vs 0.54%). We found that men compared to women were more likely to be successful. The dose-response analysis showed that there was a significant association between increase in minutes spent in moderate-to-vigorous activity and body weight loss, BMI reduction, waist circumference reduction, HDL cholesterol increasing, and cholesterol/HDL ratio lowering

  19. Deviation from additivity in mixture toxicity: relevance of nonlinear dose-response relationships and cell line differences in genotoxicity assays with combinations of chemical mutagens and gamma-radiation.

    PubMed Central

    Lutz, Werner K; Vamvakas, Spyros; Kopp-Schneider, Annette; Schlatter, Josef; Stopper, Helga

    2002-01-01

    Sublinear dose-response relationships are often seen in toxicity testing, particularly with bioassays for carcinogenicity. This is the result of a superimposition of various effects that modulate and contribute to the process of cancer formation. Examples are saturation of detoxification pathways or DNA repair with increasing dose, or regenerative hyperplasia and indirect DNA damage as a consequence of high-dose cytotoxicity and cell death. The response to a combination treatment can appear to be supra-additive, although it is in fact dose-additive along a sublinear dose-response curve for the single agents. Because environmental exposure of humans is usually in a low-dose range and deviation from linearity is less likely at the low-dose end, combination effects should be tested at the lowest observable effect levels (LOEL) of the components. This principle has been applied to combinations of genotoxic agents in various cellular models. For statistical analysis, all experiments were analyzed for deviation from additivity with an n-factor analysis of variance with an interaction term, n being the number of components tested in combination. Benzo[a]pyrene, benz[a]anthracene, and dibenz[a,c]anthracene were tested at the LOEL, separately and in combination, for the induction of revertants in the Ames test, using Salmonella typhimurium TA100 and rat liver S9 fraction. Combined treatment produced no deviation from additivity. The induction of micronuclei in vitro was investigated with ionizing radiation from a 137Cs source and ethyl methanesulfonate. Mouse lymphoma L5178Y cells revealed a significant 40% supra-additive combination effect in an experiment based on three independent replicates for controls and single and combination treatments. On the other hand, two human lymphoblastoid cell lines (TK6 and WTK1) as well as a pilot study with human primary fibroblasts from fetal lung did not show deviation from additivity. Data derived from one cell line should therefore

  20. In vitro excitation of purified membrane fragments by cholinergic agonists : III. Comparison of the dose-response curves to decamethonium with the corresponding binding curves of decamethonium to the cholinergic receptor.

    PubMed

    Kasai, M; Changeux, J P

    1971-03-01

    The reversible binding of(14)C-decamethonium (Deca) to excitable microsacs prepared from the electric tissue ofElectrophorus electricus is followed by an ultracentrifugal assay. α-Bungarotoxin, a snake venom toxin, blocks irreversibly the binding of(14)C-Deca. The displacement is partial. The fraction of(14)C-Deca displaced by α-bungarotoxin corresponds to molecules of Deca bound to the cholinergic receptor site, whereas the fraction of(14)C-Deca bound in the presence of α-bungarotoxin corresponds to molecules bound to the catalytic site of acetylcholinesterase (AcChE). The total number of cholinergic receptor sites is found to be close but not identical to the total number of catalytic sites of AcChE.On the same preparation of microsacs, the binding of(14)C-Deca and the permeability response corresponding to a given concentration of Deca are measured as a function of increased concentration of Deca. The dose-response curve and the binding curve superimpose almost exactly; in other words, the "apparent" affinity of Deca coincides with its "real" affinity. Displacement of(14)C-Deca byd-tubocurarine gives an "apparent" affinity ford-tubocurarine which coincides as well with its "real" affinity.The transport properties of the ionophore controlled by one Deca binding site are estimated. PMID:24173289

  1. A cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: dose-response analysis of thyroid follicular adenomas detected during first screening in Ukraine (1998-2000).

    PubMed

    Zablotska, Lydia B; Bogdanova, Tetyana I; Ron, Elaine; Epstein, Ovsiy V; Robbins, Jacob; Likhtarev, Illya A; Hatch, Maureen; Markov, Valentyn V; Bouville, Andre C; Olijnyk, Valery A; McConnell, Robert J; Shpak, Victor M; Brenner, Alina; Terekhova, Galina N; Greenebaum, Ellen; Tereshchenko, Valery P; Fink, Daniel J; Brill, Aaron B; Zamotayeva, Galina A; Masnyk, Ihor J; Howe, Geoffrey R; Tronko, Mykola D

    2008-02-01

    The Chornobyl (Chernobyl) accident in 1986 exposed many individuals to radioactive iodines, chiefly (131)I, the effects of which on benign thyroid diseases are largely unknown. To investigate the risk of follicular adenoma in relation to radiation dose after Chornobyl, the authors analyzed the baseline data from a prospective screening cohort study of those exposed as children or adolescents. A stratified random sample was selected from all individuals who were younger than 18 years, had thyroid radioactivity measurements taken within 2 months after the accident, and resided in the three heavily contaminated areas in Ukraine. This analysis is based on the 23 cases diagnosed in 12,504 subjects for whom personal history of thyroid diseases was known. The dose-response relation was linear with an excess relative risk of 2.07 per gray (95% confidence interval: 0.28, 10.31). The risk was significantly higher in women compared with men, with no clear modifying effects of age at exposure. In conclusion, persons exposed to radioactive iodines as children and adolescents have an increased risk of follicular adenoma, though it is smaller than the risk of thyroid cancer in the same cohort. Compared with results from other studies, this estimate is somewhat smaller, but confidence intervals overlap, suggesting compatibility. PMID:17989057

  2. El control biologico de plagas(Biological control of pests)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this work some ecological principles that drive applied biocontrol and agent selection are discussed. Subjects such as specificity evaluations, host shifts and species invasiveness are analyzed under the light of ecological theory. The main assertions are: 1. biological control is a safe and bene...

  3. BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants

    PubMed Central

    Sen, Abhijit; Prasad, Manya; Norat, Teresa; Janszky, Imre; Tonstad, Serena; Romundstad, Pål; Vatten, Lars J

    2016-01-01

    Objective To conduct a systematic review and meta-analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose-response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease. Data sources PubMed and Embase databases searched up to 23 September 2015. Study selection Cohort studies that reported adjusted risk estimates for at least three categories of BMI in relation to all cause mortality. Data synthesis Summary relative risks were calculated with random effects models. Non-linear associations were explored with fractional polynomial models. Results 230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738 144 deaths and >9 976 077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3 744 722 deaths among 30 233 329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18 (95% confidence interval 1.15 to 1.21; I2=95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I2=93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I2=89%, n=11) among healthy never smokers with exclusion of early follow-up, and 1.05 (1.04 to 1.07; I2=97%, n=198) among all participants. There was a J shaped dose-response relation in never smokers (Pnon-linearity <0.001), and the lowest risk was observed at BMI 23-24 in never smokers, 22-23 in healthy never smokers, and 20-22 in studies of never smokers with ≥20 years’ follow-up. In contrast there was a U shaped association between BMI and mortality in analyses with a greater potential for bias including all participants, current, former, or ever smokers, and in studies with a short duration of follow-up (<5 years or <10 years), or with moderate study quality scores. Conclusion Overweight and obesity is associated

  4. Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013

    PubMed Central

    Kyu, Hmwe H; Bachman, Victoria F; Alexander, Lily T; Mumford, John Everett; Afshin, Ashkan; Estep, Kara; Veerman, J Lennert; Delwiche, Kristen; Iannarone, Marissa L; Moyer, Madeline L; Cercy, Kelly; Vos, Theo; Murray, Christopher J L

    2016-01-01

    Objective To quantify the dose-response associations between total physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events. Design Systematic review and Bayesian dose-response meta-analysis. Data sources PubMed and Embase from 1980 to 27 February 2016, and references from relevant systematic reviews. Data from the Study on Global AGEing and Adult Health conducted in China, Ghana, India, Mexico, Russia, and South Africa from 2007 to 2010 and the US National Health and Nutrition Examination Surveys from 1999 to 2011 were used to map domain specific physical activity (reported in included studies) to total activity. Eligibility criteria for selecting studies Prospective cohort studies examining the associations between physical activity (any domain) and at least one of the five diseases studied. Results 174 articles were identified: 35 for breast cancer, 19 for colon cancer, 55 for diabetes, 43 for ischemic heart disease, and 26 for ischemic stroke (some articles included multiple outcomes). Although higher levels of total physical activity were significantly associated with lower risk for all outcomes, major gains occurred at lower levels of activity (up to 3000-4000 metabolic equivalent (MET) minutes/week). For example, individuals with a total activity level of 600 MET minutes/week (the minimum recommended level) had a 2% lower risk of diabetes compared with those reporting no physical activity. An increase from 600 to 3600 MET minutes/week reduced the risk by an additional 19%. The same amount of increase yielded much smaller returns at higher levels of activity: an increase of total activity from 9000 to 12 000 MET minutes/week reduced the risk of diabetes by only 0.6%. Compared with insufficiently active individuals (total activity <600 MET minutes/week), the risk reduction for those in the highly active category (≥8000 MET minutes/week) was 14% (relative risk 0.863, 95% uncertainty

  5. A Randomized, Double-Blind, Parallel Study to Evaluate the Dose-Response of Three Different Vitamin D Treatment Schemes on the 25-Hydroxyvitamin D Serum Concentration in Patients with Vitamin D Deficiency.

    PubMed

    Schleck, Marie-Louise; Souberbielle, Jean-Claude; Jandrain, Bernard; Da Silva, Stéphanie; De Niet, Sophie; Vanderbist, Francis; Scheen, André; Cavalier, Etienne

    2015-07-01

    Many people worldwide are vitamin D (VTD) deficient or insufficient, and there is still no consensus on the dose of VTD that should be administered to achieve a 25(OH)D concentration of 20 or 30 ng/mL. In this study, we aimed to determine an adapted supplementation of VTD able to quickly and safely increase the vitamin D status of healthy adults with low 25(OH)D. One hundred and fifty (150) subjects were randomized into three groups, each to receive, orally, a loading dose of 50,000, 100,000 or 200,000 IU of VTD3 at Week 0, followed by 25,000, 50,000 or 100,000 IU at Week 4 and Week 8. Whereas 25(OH)D baseline values were not different between groups (p = 0.42), a significant increase was observed at Week 12 (p < 0.0001) with a mean change from baseline of 7.72 ± 5.08, 13.3 ± 5.88 and 20.12 ± 7.79 ng/mL. A plateau was reached after eight weeks. No related adverse event was recorded. This study demonstrated a linear dose-response relationship with an increase in 25(OH)D levels proportional to the dose administered. In conclusion, a loading dose of 200,000 IU VTD3 followed by a monthly dose of 100,000 IU is the best dosing schedule to quickly and safely correct the VTD status. PMID:26151178

  6. Loss of cooperativity of secreted CD40L and increased dose-response to IL4 on CLL cell viability correlates with enhanced activation of NF-kB and STAT6.

    PubMed

    Bhattacharya, Nupur; Reichenzeller, Michaela; Caudron-Herger, Maiwen; Haebe, Sarah; Brady, Nathan; Diener, Susanne; Nothing, Maria; Döhner, Hartmut; Stilgenbauer, Stephan; Rippe, Karsten; Mertens, Daniel

    2015-01-01

    Chronic lymphocytic leukemia (CLL) cells fail to enter apoptosis in vivo as opposed to their non-malignant B-lymphocyte counterparts. The ability of CLL cells to escape apoptosis is highly dependent on their microenvironment. Compared to non-malignant B cells, CLL cells are more responsive to complex stimuli that can be reproduced in vitro by the addition of cytokines. To understand the molecular mechanism of the environment-dependent anti-apoptotic signaling circuitry of CLL cells, we quantified the effect of the SDF-1, BAFF, APRIL, anti-IgM, interleukin-4 (IL4) and secreted CD40L (sCD40L) on the survival of in vitro cultured CLL cells and found IL4 and sCD40L to be most efficient in rescuing CLL cells from apoptosis. In quantitative dose-response experiments using cell survival as readout, the binding affinity of IL4 to its receptor was similar between malignant and non-malignant cells. However, the downstream signaling in terms of the amount of STAT6 and its degree of phosphorylation was highly stimulated in CLL cells. In contrast, the response to sCD40L showed a loss of cooperative binding in CLL cells but displayed a largely increased ligand binding affinity. Although a high-throughput microscopy analysis did not reveal a significant difference in the spatial CD40 receptor organization, the downstream signaling showed an enhanced activation of the NF-kB pathway in the malignant cells. Thus, we propose that the anti-apoptotic phenotype of CLL involves a sensitized response for IL4 dependent STAT6 phosphorylation, and an activation of NF-kB signaling due to an increased affinity of sCD40L to its receptor. PMID:24828787

  7. Efficacy and Dose Response of Soil-Applied Neem Formulations in Substrates With Different Amounts of Organic Matter, in the Control of Whiteflies, Aleyrodes proletella and Trialeurodes vaporariorum (Hemiptera: Aleyrodidae).

    PubMed

    Karanja, Josephine; Poehling, Hans-Michael; Pallmann, Philip

    2015-06-01

    Neem products have been used frequently as an alternative to synthetic pesticides, because of their insecticidal, insect antifeedant, and growth-regulating effects. Moreover, new formulations are continually being developed and therefore, they have to be evaluated for their efficacy and persistence. In this regard, two soil-applied products-a liquid-based drenching solution NeemAzal-T and NeemAzal granules-were evaluated against two whitefly species, Aleyrodes proletella L. and Trialeurodes vaporariorum (West) on Brussels sprout and tomatoes, respectively. The plants were grown in two substrates: one was a commercial substrate (CS) composed of 15% humus, 35% clay, and 50% peat, and the other was a commercial substrate and sand mixture in 1:1 ratio. The main objective of the study was to evaluate the efficacy, persistence, and dose response of the two soil-applied NeemAzal formulations in substrates with different amount of organic matter. The results show that the efficacy of neem formulations was dose dependent, with the highest doses of NeemAzal granules (300 mg/kg=21 mg azadirachtin [AZA]/kg of substrate) and NeemAzal T (2 ml/kg=20 mg AZA/kg of substrate) achieving up to 100% mortality of immature stages of whiteflies. NeemAzal caused significantly higher mortality in immature stages of both whitefly species with CS + sand mixture than with pure CS. Persistence of the NeemAzal formulations was not influenced by the substrate type but rather by time span between treatment application and infestation, with significant decrease in efficacy when whiteflies were exposed 10 d after treatments. PMID:26470244

  8. A Randomized, Double-Blind, Parallel Study to Evaluate the Dose-Response of Three Different Vitamin D Treatment Schemes on the 25-Hydroxyvitamin D Serum Concentration in Patients with Vitamin D Deficiency

    PubMed Central

    Schleck, Marie-Louise; Souberbielle, Jean-Claude; Jandrain, Bernard; Da Silva, Stéphanie; De Niet, Sophie; Vanderbist, Francis; Scheen, André; Cavalier, Etienne

    2015-01-01

    Many people worldwide are vitamin D (VTD) deficient or insufficient, and there is still no consensus on the dose of VTD that should be administered to achieve a 25(OH)D concentration of 20 or 30 ng/mL. In this study, we aimed to determine an adapted supplementation of VTD able to quickly and safely increase the vitamin D status of healthy adults with low 25(OH)D. One hundred and fifty (150) subjects were randomized into three groups, each to receive, orally, a loading dose of 50,000, 100,000 or 200,000 IU of VTD3 at Week 0, followed by 25,000, 50,000 or 100,000 IU at Week 4 and Week 8. Whereas 25(OH)D baseline values were not different between groups (p = 0.42), a significant increase was observed at Week 12 (p < 0.0001) with a mean change from baseline of 7.72 ± 5.08, 13.3 ± 5.88 and 20.12 ± 7.79 ng/mL. A plateau was reached after eight weeks. No related adverse event was recorded. This study demonstrated a linear dose-response relationship with an increase in 25(OH)D levels proportional to the dose administered. In conclusion, a loading dose of 200,000 IU VTD3 followed by a monthly dose of 100,000 IU is the best dosing schedule to quickly and safely correct the VTD status. PMID:26151178

  9. Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[11C]verapamil PET

    PubMed Central

    Kuntner, Claudia; Bankstahl, Jens P.; Bankstahl, Marion; Stanek, Johann; Wanek, Thomas; Stundner, Gloria; Karch, Rudolf; Brauner, Rebecca; Meier, Martin; Ding, Xiaoqi; Müller, Markus; Löscher, Wolfgang; Langer, Oliver

    2013-01-01

    Purpose Overactivity of the multidrug efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) is believed to play an important role in resistance to central nervous system drug treatment. (R)-[11C]verapamil (VPM) PET can be used to measure the function of P-gp at the BBB, but low brain uptake of VPM hampers the mapping of regional differences in cerebral P-gp function and expression. The aim of this study was to evaluate the dose-response relationship of two potent P-gp inhibitors and to investigate if increased brain uptake of VPM mediated by P-gp inhibition can be used to assess regional differences in P-gp activity. Methods Two groups of Sprague-Dawley rats (n=12) underwent single VPM PET scans at 120 min after administration of different doses of the P-gp inhibitors tariquidar and elacridar. In an additional 6 rats, paired VPM PET scans were performed before and after administration of 3 mg/kg tariquidar. Results Inhibitor administration resulted in an up to 11-fold increase in VPM brain distribution volumes (DV) with ED50 values of 3.0±0.2 and 1.2±0.1 mg/kg for tariquidar and elacridar, respectively. In paired PET scans, 3 mg/kg tariquidar resulted in regionally different enhancement of brain activity distribution, with lowest DV in cerebellum and highest DV in thalamus. Conclusion Our data show that tariquidar and elacridar are able to increase VPM brain distribution in rat brain up to 11-fold over baseline at maximum effective doses, with elacridar being about 3 times more potent than tariquidar. Regional differences in tariquidar-induced modulation of VPM brain uptake point to regional differences in cerebral P-gp function and expression in rat brain. PMID:20016890

  10. Mean frequency and relative fluorescence intensity measurement of γ-H2AX foci dose response in PBL exposed to γ-irradiation: An inter- and intra-laboratory comparison and its relevance for radiation triage.

    PubMed

    Venkateswarlu, Raavi; Tamizh, Selvan G; Bhavani, Manivannan; Kumar, Arun; Alok, Amit; Karthik, Kanagaraj; Kalra, Namita; Vijayalakshmi, J; Paul, Solomon F D; Chaudhury, N K; Venkatachalam, Perumal

    2015-12-01

    Measurement of γ-H2AX protein changes in the peripheral blood lymphocytes (PBL) of individuals exposed to ionizing radiation is a simple, sensitive, and rapid assay for radiation triage and early marker of dose estimation. The qualitative and quantitative measurements of the protein changes were examined using flow cytometry and microscopy. Whole blood and isolated lymphocytes wer