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Sample records for agonist dose-response curves

  1. 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

  2. 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.

  3. 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.

  4. Dose-Response Curves for Radish Seedling Phototropism 12

    PubMed Central

    Everett, Marylee

    1974-01-01

    Radish seedlings (Raphanus sativus L.) were grown for 4 days in complete darkness, or in white light, or for 3 days in darkness followed by 1 day of red light. Phototropic dose-response curves for the seedlings grown in these three ways were determined with 460-nm light. The dark-grown and red light-treated seedlings responded with positive curvatures of no more than 10° to energy doses in the first positive range and with larger positive curvatures in the second positive dose range. No indifferent or negative curvature was seen with the light intensity used. White light-grown seedlings did not respond to first positive energy doses, but responded as strongly to second positive doses as the other types of seedlings. PMID:16658864

  5. Differential right shifts in the dose-response curve for intrathecal morphine and sufentanil as a function of stimulus intensity.

    PubMed

    Dirig, D M; Yaksh, T L

    1995-09-01

    To assess effects of stimulus intensity, dose-response curves in rats for radiant heat-evoked withdrawal of the hind paw was assessed after the intrathecal (i.t.) injection of sufentanil and morphine, mu-opioid agonists differing in intrinsic activity, at Low, Medium, and High stimulus intensities. Baseline latencies observed at the 3 intensities were: low = +/- 0.3; medium = 8.9 +/- 0.2; high = 5.7 +/- 0.1 sec. After i.t. administration of sufentanil or morphine, there was a right shift in the dose-response curves with morphine exhibiting a greater magnitude right shift than that of sufentanil. Dose ratios (ED 50 Medium/ED 50 Low and ED 50 High/ED 50 Low) with 95% CI for sufentanil were, respectively, 2.5 (2.2-2.9) and 7.7 (6.7-8.9), and the dose ratio for morphine (ED 50 Medium/ED 50 Low) was 34 (28-41). At the highest intensity, due to a plateau in the morphine dose-response curve, ED 50 and dose ratio calculations could not be performed. The present study supports the pharmacological model of receptor occupancy, such that the higher efficacy receptor agonist, sufentanil, demonstrated a lesser magnitude right shift than the lower efficacy agonist, morphine, while at the high stimulus intensity, morphine but not sufentanil, was a partial agonist.

  6. USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES

    EPA Science Inventory

    Use of Mechanistic Data to Help Define Dose-Response Curves

    The cancer risk assessment process described by the U.S. EPA necessitates a description of the dose-response curve for tumors in humans at low (environmental) exposures. This description can either be a default l...

  7. 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...

  8. 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.

  9. 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

  10. 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...

  11. 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.

  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.

  13. 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...

  14. Environmental standards for ionizing radiation: theoretical basis for dose-response curves.

    PubMed

    Upton, A C

    1983-10-01

    The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell.

  15. 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.

  16. 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.

  17. 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.

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

    NASA Astrophysics Data System (ADS)

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

    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 disrupts a variety of behaviors that are dependent upon the integrity of the dopaminergic system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, spatial learning and memory (Morris water maze), 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 presentation will review the data relevant to the degree to which these characteristics are in fact common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity. Supported by N.A.S.A. Grant NAG9-1190.

  19. 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.

  20. 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

  1. 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.

  2. Population variability in biological adaptive responses to DNA damage and the shapes of carcinogen dose-response curves

    SciTech Connect

    Conolly, Rory B. . E-mail: Conolly.Rory@epa.gov; Gaylor, David W.; Lutz, Werner K.

    2005-09-01

    Carcinogen dose-response curves for both ionizing radiation and chemicals are typically assumed to be linear at environmentally relevant doses. This assumption is used to ensure protection of the public health in the absence of relevant dose-response data. A theoretical justification for the assumption has been provided by the argument that low dose linearity is expected when an exogenous agent adds to an ongoing endogenous process. Here, we use computational modeling to evaluate (1) how two biological adaptive processes, induction of DNA repair and cell cycle checkpoint control, may affect the shapes of dose-response curves for DNA-damaging carcinogens and (2) how the resulting dose-response behaviors may vary within a population. Each model incorporating an adaptive process was capable of generating not only monotonic dose-responses but also nonmonotonic (J-shaped) and threshold responses. Monte Carlo analysis suggested that all these dose-response behaviors could coexist within a population, as the spectrum of qualitative differences arose from quantitative changes in parameter values. While this analysis is largely theoretical, it suggests that (a) accurate prediction of the qualitative form of the dose-response requires a quantitative understanding of the mechanism (b) significant uncertainty is associated with human health risk prediction in the absence of such quantitative understanding and (c) a stronger experimental and regulatory focus on biological mechanisms and interindividual variability would allow flexibility in regulatory treatment of environmental carcinogens without compromising human health.

  3. 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

  4. 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...

  5. 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...

  6. Curvilinearity in the dose-response curve for cancer in Japanese atomic bomb survivors.

    PubMed

    Little, M P; Muirhead, C R

    1997-12-01

    Recently released data on cancer incidence in Japanese atomic bomb survivors are analyzed using a variety of relative risk models that take account of errors in estimates of dose to assess the dose response at low doses. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Among solid cancer subtypes there is strong evidence for a possible dose threshold only for nonmelanoma skin cancer. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to the leukemia data, a threshold of more than about 0.3 Sv is inconsistent with the data. In contrast to the estimates for the threshold level for solid cancer data, the best estimate for the threshold level in the leukemia data is significantly different from zero even when allowance is made for a possible quadratic term in the dose response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukemia dose response from 0.2 Sv upwards. However, possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes interpretation of this finding questionable.

  7. 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

  8. 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.

  9. Construction of antagonist dose-response curves for estimation of pA2-values by Schild-plot analysis and detection of allosteric interactions.

    PubMed Central

    Pöch, G.; Brunner, F.; Kühberger, E.

    1992-01-01

    1. One aim of this paper is to show an alternative approach for the determination of antagonist affinity estimates, KB and pA2, by construction and evaluation of antagonist dose-response curves (DRCs), using the curve-fitting programme, ALLFIT. 2. Parallel antagonist DRCs were derived by vertical analysis of families of conventional agonist DRCs in the presence and absence of an antagonist at a certain agonist concentration above its ED50. The latter represents a chosen, i.e. fixed dose-ratio (DR). The antagonist concentration that reduces an agonist effect to its Emax/2 was termed Bx. It corresponds to B, the fixed antagonist concentration, tested to obtain DR-1, conventionally. 3. The dissociation constant was calculated as KB = Bx/DR-1, analogous to the conventional approach (KB = B/DR-1). Likewise, pA2-values were estimated by plotting log Bx, obtained by the alternative approach, vs log (DR-1) in an 'alternative Schild plot'. 4. Experimental agonist DRCs from our laboratory and from the literature were analysed and KB- and pA2-values obtained by the alternative approach were compared with those obtained by the conventional method. The results showed a very good agreement (correlation) between the pA2-values obtained by either method (slope = 1.02, r = 0.99, n = 9), in agreement with theoretical DRCs. 5. Besides estimation of KB and pA2, antagonist DRCs were also evaluated qualitatively. The most important finding was that allosteric antagonists or competitive antagonists with an allosteric component, such as gallamine, showed a significant reduction in the maximum of the antagonist DRCs (Imax). The evaluation of antagonist DRCs appears to be a sensitive procedure to detect allosteric interactions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1504755

  10. 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.

  11. Accumulation of cocaine in maternal and fetal hair; the dose response curve.

    PubMed

    Forman, R; Schneiderman, J; Klein, J; Graham, K; Greenwald, M; Koren, G

    1992-01-01

    Cocaine and its major metabolites are incorporated into hair during the growth of the shaft and stay there for the whole life of the hair. Cocaine crosses the placenta and its metabolites for example Benzoylecgonine (BZ), have been found in neonatal urine, meconium and hair. In order to utilize hair measurements of cocaine as a biological marker of systemic exposure, we conducted both animal and human investigations on the dose response characteristics of this phenomenon. Our data suggest that both maternal and fetal accumulation of cocaine and its metabolite follow a linear pattern within the clinically used doses. Similarly, a good correlation was observed in animals between maternal dose and fetal hair accumulation.

  12. 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

  13. The cytokinesis-blocked micronucleus assay: dose-response calibration curve, background frequency in the population and dose estimation.

    PubMed

    Rastkhah, E; Zakeri, F; Ghoranneviss, M; Rajabpour, M R; Farshidpour, M R; Mianji, F; Bayat, M

    2016-03-01

    An in vitro study of the dose responses of human peripheral blood lymphocytes was conducted with the aim of creating calibrated dose-response curves for biodosimetry measuring up to 4 Gy (0.25-4 Gy) of gamma radiation. The cytokinesis-blocked micronucleus (CBMN) assay was employed to obtain the frequencies of micronuclei (MN) per binucleated cell in blood samples from 16 healthy donors (eight males and eight females) in two age ranges of 20-34 and 35-50 years. The data were used to construct the calibration curves for men and women in two age groups, separately. An increase in micronuclei yield with the dose in a linear-quadratic way was observed in all groups. To verify the applicability of the constructed calibration curve, MN yields were measured in peripheral blood lymphocytes of two real overexposed subjects and three irradiated samples with unknown dose, and the results were compared with dose values obtained from measuring dicentric chromosomes. The comparison of the results obtained by the two techniques indicated a good agreement between dose estimates. The average baseline frequency of MN for the 130 healthy non-exposed donors (77 men and 55 women, 20-60 years old divided into four age groups) ranged from 6 to 21 micronuclei per 1000 binucleated cells. Baseline MN frequencies were higher for women and for the older age group. The results presented in this study point out that the CBMN assay is a reliable, easier and valuable alternative method for biological dosimetry.

  14. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator

    PubMed Central

    Lemos-Pinto, M.M.P.; Cadena, M.; Santos, N.; Fernandes, T.S.; Borges, E.; Amaral, A.

    2015-01-01

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. PMID:26445334

  15. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.

    PubMed

    Lemos-Pinto, M M P; Cadena, M; Santos, N; Fernandes, T S; Borges, E; Amaral, A

    2015-10-01

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.

  16. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.

    PubMed

    Lemos-Pinto, M M P; Cadena, M; Santos, N; Fernandes, T S; Borges, E; Amaral, A

    2015-10-01

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. PMID:26445334

  17. Calculating slope and ED50 of additive dose-response curves, and application of these tabulated parameter values.

    PubMed

    Pöch, G; Pancheva, S N

    1995-06-01

    Comparing dose-response curves (DRCs) of a compound A in the absence and presence of a fixed dose of an antagonist B is standard in pharmacology and toxicology. When B qualitatively resembles A in its action, it is often useful to construct theoretical DRCs of additive and independent combinations. Theoretical curves are calculated from experimental values by the program ALLFIT, which uses the four parameter logistic equation. DRCs of theoretical, additive DRCs are obtained by using the respective values for slope and ED50, which were taken from tables presented here compiled on the basis of the slope of the DRC of A alone (0.6-14) and of the effect of B alone (1-75%). These tables are unnecessary for the construction of theoretical curves if A acts by an independent mechanism, giving values for slope and ED50 identical to those of the DRC of A alone. Experimental DRCs of antiviral and other effects (the latter taken from data in the literature) are compared with theoretical curves by an F-test analysis provided by ALLFIT. The method can be used successfully for the construction of theoretical curves for additive and independent DRCs and comparison with experimental curves. This comparison may help clarify the mode of interaction of A with B. PMID:7640393

  18. 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.

  19. Construction of a cytogenetic dose-response curve for low-dose range gamma-irradiation in human peripheral blood lymphocytes using three-color FISH.

    PubMed

    Suto, Yumiko; Akiyama, Miho; Noda, Takashi; Hirai, Momoki

    2015-12-01

    In order to estimate biological doses after low-dose ionizing radiation exposure, fluorescence in situ hybridization (FISH) using three differentially colored chromosome painting probes was employed to detect exchange-type chromosome aberrations. A reference dose response curve was constructed using blood samples from a female donor whose lymphocytes consistently exhibited a low frequency of cells at the second mitosis under routine culture conditions. Aberration yields were studied for a total of about 155 thousand metaphases obtained from seven dose-points of gamma irradiations (0, 50, 100, 150, 200, 250 and 300mGy). In situ hybridization was performed using commercially available painting probes for chromosomes 1, 2 and 4. With the aid of an automated image-capturing method, exchange-type aberrations involving painted chromosomes were detected with considerable accuracy and speed. The results on the exchange-type aberrations (dicentrics plus translocations) at the seven dose-points showed a good fit to the linear-quadratic model (y=0.0023+0.0015x+0.0819x(2), P=0.83). A blind test proved the reproducibility of the reference dose-response relationship. In the control experiments using blood samples from another donor, the estimated doses calculated on the basis of the present reference curve were proved to be in good agreement with the actual physical doses applied. The present dose-response curve may serve as a means to assess the individual differences in cytogenetical radio-sensitivities.

  20. Equivalent intraperitoneal doses of ibuprofen supplemented in drinking water or in diet: a behavioral and biochemical assay using antinociceptive and thromboxane inhibitory dose-response curves in mice.

    PubMed

    Salama, Raghda A M; El Gayar, Nesreen H; Georgy, Sonia S; Hamza, May

    2016-01-01

    Background. Ibuprofen is used chronically in different animal models of inflammation by administration in drinking water or in diet due to its short half-life. Though this practice has been used for years, ibuprofen doses were never assayed against parenteral dose-response curves. This study aims at identifying the equivalent intraperitoneal (i.p.) doses of ibuprofen, when it is administered in drinking water or in diet. Methods. Bioassays were performed using formalin test and incisional pain model for antinociceptive efficacy and serum TXB2 for eicosanoid inhibitory activity. The dose-response curve of i.p. administered ibuprofen was constructed for each test using 50, 75, 100 and 200 mg/kg body weight (b.w.). The dose-response curves were constructed of phase 2a of the formalin test (the most sensitive phase to COX inhibitory agents), the area under the 'change in mechanical threshold'-time curve in the incisional pain model and serum TXB2 levels. The assayed ibuprofen concentrations administered in drinking water were 0.2, 0.35, 0.6 mg/ml and those administered in diet were 82, 263, 375 mg/kg diet. Results. The 3 concentrations applied in drinking water lay between 73.6 and 85.5 mg/kg b.w., i.p., in case of the formalin test; between 58.9 and 77.8 mg/kg b.w., i.p., in case of the incisional pain model; and between 71.8 and 125.8 mg/kg b.w., i.p., in case of serum TXB2 levels. The 3 concentrations administered in diet lay between 67.6 and 83.8 mg/kg b.w., i.p., in case of the formalin test; between 52.7 and 68.6 mg/kg b.w., i.p., in case of the incisional pain model; and between 63.6 and 92.5 mg/kg b.w., i.p., in case of serum TXB2 levels. Discussion. The increment in pharmacological effects of different doses of continuously administered ibuprofen in drinking water or diet do not parallel those of i.p. administered ibuprofen. It is therefore difficult to assume the equivalent parenteral daily doses based on mathematical calculations.

  1. Equivalent intraperitoneal doses of ibuprofen supplemented in drinking water or in diet: a behavioral and biochemical assay using antinociceptive and thromboxane inhibitory dose-response curves in mice.

    PubMed

    Salama, Raghda A M; El Gayar, Nesreen H; Georgy, Sonia S; Hamza, May

    2016-01-01

    Background. Ibuprofen is used chronically in different animal models of inflammation by administration in drinking water or in diet due to its short half-life. Though this practice has been used for years, ibuprofen doses were never assayed against parenteral dose-response curves. This study aims at identifying the equivalent intraperitoneal (i.p.) doses of ibuprofen, when it is administered in drinking water or in diet. Methods. Bioassays were performed using formalin test and incisional pain model for antinociceptive efficacy and serum TXB2 for eicosanoid inhibitory activity. The dose-response curve of i.p. administered ibuprofen was constructed for each test using 50, 75, 100 and 200 mg/kg body weight (b.w.). The dose-response curves were constructed of phase 2a of the formalin test (the most sensitive phase to COX inhibitory agents), the area under the 'change in mechanical threshold'-time curve in the incisional pain model and serum TXB2 levels. The assayed ibuprofen concentrations administered in drinking water were 0.2, 0.35, 0.6 mg/ml and those administered in diet were 82, 263, 375 mg/kg diet. Results. The 3 concentrations applied in drinking water lay between 73.6 and 85.5 mg/kg b.w., i.p., in case of the formalin test; between 58.9 and 77.8 mg/kg b.w., i.p., in case of the incisional pain model; and between 71.8 and 125.8 mg/kg b.w., i.p., in case of serum TXB2 levels. The 3 concentrations administered in diet lay between 67.6 and 83.8 mg/kg b.w., i.p., in case of the formalin test; between 52.7 and 68.6 mg/kg b.w., i.p., in case of the incisional pain model; and between 63.6 and 92.5 mg/kg b.w., i.p., in case of serum TXB2 levels. Discussion. The increment in pharmacological effects of different doses of continuously administered ibuprofen in drinking water or diet do not parallel those of i.p. administered ibuprofen. It is therefore difficult to assume the equivalent parenteral daily doses based on mathematical calculations. PMID:27547547

  2. Dose-response relationships in chemical carcinogenesis: superposition of different mechanisms of action, resulting in linear-nonlinear curves, practical thresholds, J-shapes.

    PubMed

    Lutz, W K

    1998-09-20

    The shape of a carcinogen dose-cancer incidence curve is discussed as the result of a superposition of dose-response relationships for various effects of the carcinogen on the process of carcinogenesis. Effects include direct DNA damage, e.g., by covalent binding, indirect DNA damage, e.g., by increased formation of reactive oxygen species or interaction with DNA replication or chromosome integrity. The 'fixation' of a DNA adduct as a heritable mutation depends on its pro-mutagenic potency and on the rates of DNA repair and DNA replication. Endogenous and unavoidable DNA damage is responsible for a background rate of the process of mutagenesis and carcinogenesis and forms the basis of spontaneous cancer incidence. For DNA-reactive carcinogens, linearity of the dose response at the low-dose end is expected. With increasing dose, saturation of DNA repair can introduce a sublinearity (example: dimethylnitrosamine). Stimulation of cell division as a result of high-dose toxicity and regenerative proliferation also results in a sublinear deviation from low-dose linearity. If the DNA-damaging potency of the carcinogen is low in comparison with the high-dose effects, the linear part of the low dose-cancer incidence curve might be hidden within the background variability. Under such conditions, 'practical thresholds' could be discussed (formaldehyde). If a carcinogen increases the rate of cell division or the level of oxidative stress at high dose but has an antimitogenic or antioxidative effect at low dose, a J-shaped (or: U-shaped) curve with a decrease of the spontaneous tumor incidence at low dose could result (caffeic acid; TCDD). This phenomenon has been observed even under conditions of a genotoxic contribution (ionizing radiation; diesel exhaust particles). For a mechanism-based assessment of a low-dose cancer risk, information on the various modes of action and modulations should be available over the full dose range, and models should be refined to incorporate the

  3. High-precision, in vitro validation of the sequestration mechanism for generating ultrasensitive dose-response curves in regulatory networks.

    PubMed

    Ricci, Francesco; Vallée-Bélisle, Alexis; Plaxco, Kevin W

    2011-10-01

    Our ability to recreate complex biochemical mechanisms in designed, artificial systems provides a stringent test of our understanding of these mechanisms and opens the door to their exploitation in artificial biotechnologies. Motivated by this philosophy, here we have recapitulated in vitro the "target sequestration" mechanism used by nature to improve the sensitivity (the steepness of the input/output curve) of many regulatory cascades. Specifically, we have employed molecular beacons, a commonly employed optical DNA sensor, to recreate the sequestration mechanism and performed an exhaustive, quantitative study of its key determinants (e.g., the relative concentrations and affinities of probe and depletant). We show that, using sequestration, we can narrow the pseudo-linear range of a traditional molecular beacon from 81-fold (i.e., the transition from 10% to 90% target occupancy spans an 81-fold change in target concentration) to just 1.5-fold. This narrowing of the dynamic range improves the sensitivity of molecular beacons to that equivalent of an oligomeric, allosteric receptor with a Hill coefficient greater than 9. Following this we have adapted the sequestration mechanism to steepen the binding-site occupancy curve of a common transcription factor by an order of magnitude over the sensitivity observed in the absence of sequestration. Given the success with which the sequestration mechanism has been employed by nature, we believe that this strategy could dramatically improve the performance of synthetic biological systems and artificial biosensors.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Acute effect of pretreatment with single conventional dose of salmeterol on dose-response curve to oxitropium bromide in chronic obstructive pulmonary disease

    PubMed Central

    Cazzola, M.; Di, P; Centanni, S.; Califano, C.; Donner, C. F.; D'Amato, M.; D'Amato, G.

    1999-01-01

    BACKGROUND—An earlier study documented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the clinically recommended dose (40 µg) does not produce any further bronchodilation than that achieved with salmeterol 50 µg alone. However, the dose of ipratropium bromide needed to produce near maximal bronchodilation is several times higher than the customary dosage. The full therapeutic potential of combined salmeterol plus an anticholinergic drug can therefore only be established using doses higher than those currently recommended in the marketing of these agents. A study was undertaken to examine the possible acute effects of higher than conventional doses of an anticholinergic agent on the single dose salmeterol induced bronchodilation in patients with stable and partially reversible COPD.
METHODS—Thirty two outpatients received 50 µg salmeterol or placebo. Two hours after inhalation a dose-response curve to inhaled oxitropium bromide (100 µg/puff) or placebo was constructed using one puff, one puff, two puffs, and two puffs—that is, a total cumulative dose of 600 µg oxitropium bromide. Dose increments were given at 20 minute intervals with measurements being made 15 minutes after each dose. On four separate days all patients received one of the following: (1) 50 µg salmeterol + 600 µg oxitropium bromide; (2) 50 µg salmeterol + placebo; (3) placebo + 600 µg oxitropium bromide; (4) placebo +placebo.
RESULTS—Salmeterol induced a good bronchodilation (mean increase 0.272 l; 95% CI 0.207 to 0.337) two hours after its inhalation. Oxitropium bromide elicited an evident dose-dependent increase in forced expiratory volume in one second (FEV1) and this occurred also after pretreatment with salmeterol with a further mean maximum increase of 0.152 l (95% CI of differences 0.124 to 0.180).
CONCLUSIONS—This study shows that acute pretreatment with 50 µg salmeterol does not block the possibility of

  9. Chronic ethanol (EtOH) feeding increases muscarinic receptor (mAChR) density in esophagus without parallel change in dose response (D-R) to cholinergic agonists

    SciTech Connect

    Keshavarzian, A.; Gordon, J.H.; Urban, G.; Fields, J.Z. VA Hospital, Hines, IL )

    1991-03-11

    The mAChR/effector pathway for signal transduction is important in the physiology of esophagus and mAChR alterations are involved in EtOH induced changes in several organs. To see if EtOH-induced increases in lower esophageal sphincter pressure (LESP) are due to upregulation of mAChR, the authors evaluated mAChR binding and D-R curves for bethanechol (IV) induced increases in LESP, and compared these values to changes in LESP after acute and chronic EtOH. EtOH was given to cats acutely or chronically. The number of mAChR sites (Bmax) in esophagus was lowered by acute EtOH, withdrawal from chronic EtOH raised Bmax. Acute injection of EtOH to cats in withdrawal reversed this increase in mAChR density. These changes correlated with the earlier data on EtOH-induced changes in LESP. In contrast, the D-R curve for bethanechol shifted to the right. Thus, the withdrawal-associated increase in Bmax is more likely to be a compensatory response to deficits distal to the receptor recognition site than to proximal deficits and doesn't cause LESP hyperactivity. Also, receptor binding changes do not necessarily translate into physiological changes.

  10. The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope

    PubMed Central

    Chang, Shuai; Zhuang, Daomin; Guo, Wei; Li, Lin; Zhang, Wenfu; Liu, Siyang; Li, Hanping; Liu, Yongjian; Bao, Zuoyi; Han, Jingwan

    2016-01-01

    Objectives This study was designed to identify common HIV-1 mutation complexes affecting the slope of inhibition curve, and to propose a new parameter incorporating both the IC50 and the slope to evaluate phenotypic resistance. Methods Utilizing site-directed mutagenesis, we constructed 22 HIV-1 common mutation complexes. IC50 and slope of 10 representative approved drugs and a novel agent against these mutations were measured to determine the resistance phenotypes. The values of new parameter incorporating both the IC50 and the slope of the inhibition curve were calculated, and the correlations between parameters were assessed. Results Depending on the class of drug, there were intrinsic differences in how the resistance mutations affected the drug parameters. All of the mutations resulted in large increases in the IC50s of nucleoside reverse transcriptase inhibitors. The effects of the mutations on the slope were the most apparent when examining their effects on the inhibition of non-nucleoside reverse transcriptase inhibitors and protease inhibitors. For example, some mutations, such as V82A, had no effect on IC50, but reduced the slope. We proposed a new concept, termed IIPatoxic, on the basis of IC50, slope and the maximum limiting concentrations of the drug. The IIPatoxic values of 10 approved drugs and 1 novel agent were calculated, and were closely related to the IIPmax values (r > 0.95, p < 0.001). Conclusions This study confirms that resistance mutations cannot be accurately assessed by IC50 alone, because it tends to underestimate the degree of resistance. The slope parameter is of very importance in the measurement of drug resistance and the effect can be applied to more complex patterns of resistance. This is the most apparent when testing the effects of the mutations on protease inhibitors activity. We also propose a new index, IIPatoxic, which incorporates both the IC50 and the slope. This new index could complement current IIP indices, thereby

  11. Extracting the normal lung dose-response curve from clinical DVH data: a possible role for low dose hyper-radiosensitivity, increased radioresistance

    NASA Astrophysics Data System (ADS)

    Gordon, J. J.; Snyder, K.; Zhong, H.; Barton, K.; Sun, Z.; Chetty, I. J.; Matuszak, M.; Ten Haken, R. K.

    2015-09-01

    In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence. Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP. Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (<20 Gy), a flat contribution from doses in the range ~20-40 Gy, then a further enhanced contribution from doses above 40 Gy. These features resemble the hyper-radiosensitivity / increased radioresistance (HRS/IRR) observed in some cell survival curves, which can be modeled using Joiner’s induced repair model. A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk.

  12. 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.

  13. 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

  14. A FLEXIBLE APPROACH FOR EVALUATING FIXED RATIO MIXTURES OF FULL AND PARTIAL AGONISTS FOR MIXTURES OF MANY CHEMICALS.

    EPA Science Inventory

    Detecting interaction in chemical mixtures can be complicated by differences in the shapes of the dose-response curves of the individual components (e.g. mixtures of full and partial agonists with differing response maxima). We present an analysis scheme where flexible single che...

  15. 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.

  16. 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

  17. The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells.

    PubMed

    Dornbos, Peter; Crawford, Robert B; Kaminski, Norbert E; Hession, Sarah L; LaPres, John J

    2016-10-01

    The influence of interindividual variability is not typically assessed in traditional toxicological studies. Given that chemical exposures occur in heterogeneous populations, this knowledge gap has the potential to cause undue harm within the realms of public health and industrial and municipal finances. A recent report from the National Research Council (NRC) suggests that when accounting for interindividual variation in responses, traditionally assumed nonlinear dose-response relationships (DRRs) for noncancer-causing endpoints would better be explained with a linear relationship within the low-dose region. To address this knowledge gap and directly test the NRC's assumption, this study focused on assessing the DRR between 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) exposure and immune suppression in a cohort of unique human donors. Human B cells were isolated from 51 individual donors and treated with logarithmically increasing concentrations of TCDD (0-30 nM TCDD). Two endpoints sensitive to TCDD were assessed: (1) number of IgM-secreting B cells and (2) quantity of IgM secreted. The results show that TCDD significantly suppressed both the number of IgM-secreting B cells and the quantity of IgM secreted (P < .05). Statistical model comparisons indicate that the low-dose region of the two DRRs is best explained with a nonlinear relationship. Rather than assuming low-dose linearity for all noncancer-causing DRRs, our study suggests the need to consider the specific mode of action of toxicants and pharmaceuticals during risk-management decision making. PMID:27473338

  18. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

  19. Exploring the dose response of radiochromic dosimeters

    NASA Astrophysics Data System (ADS)

    Skyt, P. S.; Wahlstedt, I.; Yates, E. S.; Muren, L. P.; Petersen, J. B. B.; Balling, P.

    2013-06-01

    The aim of this study was to explore the dose response of a newly developed radio-chromic hydrogel dosimeter based on leuco malachite green dye in a gelatine matrix. The original dosimeter composition was first investigated in terms of dose response and dose-rate dependence. In addition, the initiating compounds producing chlorine radicals were substituted with compounds producing fluorine radicals, oxygen-centered radicals, carbon-centered radicals and bromine radicals. Also the surfactant was substituted by other compounds of different molecular size and charge. The original composition gave a dose response of 3.5·10-3 Gy-1cm-1 at 6 Gy/min with a dose rate dependence giving a 27 % increase when decreasing the dose rate to 1 Gy/min. None of the substituted initiating components contributed to an increase in dose response while only one surfactant increased the dose response slightly.

  20. 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

  1. Analytical modelling of regional radiotherapy dose response of lung

    NASA Astrophysics Data System (ADS)

    Lee, Sangkyu; Stroian, Gabriela; Kopek, Neil; AlBahhar, Mahmood; Seuntjens, Jan; El Naqa, Issam

    2012-06-01

    Knowledge of the dose-response of radiation-induced lung disease (RILD) is necessary for optimization of radiotherapy (RT) treatment plans involving thoracic cavity irradiation. This study models the time-dependent relationship between local radiation dose and post-treatment lung tissue damage measured by computed tomography (CT) imaging. Fifty-eight follow-up diagnostic CT scans from 21 non-small-cell lung cancer patients were examined. The extent of RILD was segmented on the follow-up CT images based on the increase of physical density relative to the pre-treatment CT image. The segmented RILD was locally correlated with dose distribution calculated by analytical anisotropic algorithm and the Monte Carlo method to generate the corresponding dose-response curves. The Lyman-Kutcher-Burman (LKB) model was fit to the dose-response curves at six post-RT time periods, and temporal change in the LKB parameters was recorded. In this study, we observed significant correlation between the probability of lung tissue damage and the local dose for 96% of the follow-up studies. Dose-injury correlation at the first three months after RT was significantly different from later follow-up periods in terms of steepness and threshold dose as estimated from the LKB model. Dependence of dose response on superior-inferior tumour position was also observed. The time-dependent analytical modelling of RILD might provide better understanding of the long-term behaviour of the disease and could potentially be applied to improve inverse treatment planning optimization.

  2. 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

  3. Dose-response-a challenge for allelopathy?

    PubMed

    Belz, Regina G; Hurle, Karl; Duke, Stephen O

    2005-04-01

    The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.

  4. Characterization of Statin Dose-response within Electronic Medical Records

    PubMed Central

    Wei, Wei-Qi; Feng, Qiping; Jiang, Lan; Waitara, Magarya S.; Iwuchukwu, Otito F.; Roden, Dan M.; Jiang, Min; Xu, Hua; Krauss, Ronald M.; Rotter, Jerome I.; Nickerson, Deborah A.; Davis, Robert L.; Berg, Richard L.; Peissig, Peggy L.; McCarty, Catherine A.; Wilke, Russell A.; Denny, Joshua C.

    2013-01-01

    Efforts to define the genetic architecture underlying variable statin response have met with limited success possibly because previous studies were limited to effect based on one-single-dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 pre-selected variants. Two large biobanks were used to construct dose-response curves for 2,026 (simvastatin) and 2,252 subjects (atorvastatin). Atorvastatin was more efficacious, more potent, and demonstrated less inter-individual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in homozygous for the minor allele versus 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand of genetic factors contributing to drug response. PMID:24096969

  5. Modeling Dose-response at Low Dose: A Systems Biology Approach for Ionization Radiation

    PubMed Central

    Zhao, Yuchao; Ricci, Paolo F.

    2010-01-01

    For ionization radiation (IR) induced cancer, a linear non-threshold (LNT) model at very low doses is the default used by a number of national and international organizations and in regulatory law. This default denies any positive benefit from any level of exposure. However, experimental observations and theoretical biology have found that both linear and J-shaped IR dose-response curves can exist at those very low doses. We develop low dose J-shaped dose-response, based on systems biology, and thus justify its use regarding exposure to IR. This approach incorporates detailed, molecular and cellular descriptions of biological/toxicological mechanisms to develop a dose-response model through a set of nonlinear, differential equations describing the signaling pathways and biochemical mechanisms of cell cycle checkpoint, apoptosis, and tumor incidence due to IR. This approach yields a J-shaped dose response curve while showing where LNT behaviors are likely to occur. The results confirm the hypothesis of the J-shaped dose response curve: the main reason is that, at low-doses of IR, cells stimulate protective systems through a longer cell arrest time per unit of IR dose. We suggest that the policy implications of this approach are an increasingly correct way to deal with precautionary measures in public health. PMID:21191485

  6. 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.

  7. 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

  8. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  9. The effects of heating rate on the dose response characteristics of TLD-200, TLD-300 and TLD-400

    NASA Astrophysics Data System (ADS)

    Kafadar, V. Emir; Necmeddin Yazici, A.; Güler Yildirim, R.

    2009-10-01

    In the given study; the effects of heating rates on the dose response characteristics of CaF 2:Dy (TLD-200), CaF 2:Tm (TLD-300) and CaF 2:Mn (TLD-400) crystals have been investigated using the dose dependence curve and dose response function f( D). It was observed from the dose response functions that the linearity and behaviour of the TL glow peaks of TLD-200 and TLD-400 are affected, but the TLD-300 is not affected from the heating rate.

  10. Injection route and TLR9 agonist addition significantly impact heroin vaccine efficacy.

    PubMed

    Bremer, Paul T; Schlosburg, Joel E; Lively, Jenny M; Janda, Kim D

    2014-03-01

    Active immunization is an effective means of blocking the pharmacodynamic effects of drugs and holds promise as a treatment for heroin addiction. Previously, we demonstrated the efficacy of our first-generation vaccine in blocking heroin self-administration in rats, however, many vaccine components can be modified to further improve performance. Herein we examine the effects of varying heroin vaccine injection route and adjuvant formulation. Mice immunized via subcutaneous (sc) injection exhibited inferior anti-heroin titers compared to intraperitoneal (ip) and sc/ip coadministration injection routes. Addition of TLR9 agonist cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826) to the original alum adjuvant elicited superior antibody titers and opioid affinities compared to alum alone. To thoroughly assess vaccine efficacy, full dose-response curves were generated for heroin-induced analgesia in both hot plate and tail immersion tests. Mice treated with CpG ODN 1826 exhibited greatly shifted dose-response curves (10-13-fold vs unvaccinated controls) while non-CpG ODN vaccine groups did not exhibit the same robust effect (2-7-fold shift for ip and combo, 2-3-fold shift for sc). Our results suggest that CpG ODN 1826 is a highly potent adjuvant, and injection routes should be considered for development of small molecule-protein conjugate vaccines. Lastly, this study has established a new standard for assessing drugs of abuse vaccines, wherein a full dose-response curve should be performed in an appropriate behavioral task.

  11. Dose response of alanine detectors irradiated with carbon ion beams

    SciTech Connect

    Herrmann, Rochus; Jaekel, Oliver; Palmans, Hugo; Sharpe, Peter; Bassler, Niels

    2011-04-15

    Purpose: The dose response of the alanine detector shows a dependence on particle energy and type when irradiated with ion beams. The purpose of this study is to investigate the response behavior of the alanine detector in clinical carbon ion beams and compare the results to model predictions. Methods: Alanine detectors have been irradiated with carbon ions with an energy range of 89-400 MeV/u. The relative effectiveness of alanine has been measured in this regime. Pristine and spread out Bragg peak depth-dose curves have been measured with alanine dosimeters. The track structure based alanine response model developed by Hansen and Olsen has been implemented in the Monte Carlo code FLUKA and calculations were compared to experimental results. Results: Calculations of the relative effectiveness deviate less than 5% from the measured values for monoenergetic beams. Measured depth-dose curves deviate from predictions in the peak region, most pronounced at the distal edge of the peak. Conclusions: The used model and its implementation show a good overall agreement for quasimonoenergetic measurements. Deviations in depth-dose measurements are mainly attributed to uncertainties of the detector geometry implemented in the Monte Carlo simulations.

  12. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.

    2003-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

  13. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Cureri, Peter A. (Technical Monitor)

    2002-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of cAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of cAMP by either epinephrine or isoproterenol.

  14. Dose Effects of Ion Beam Exposure on Deinococcus Radiodurans: Survival and Dose Response

    NASA Astrophysics Data System (ADS)

    Song, Dao-jun; Wu, Li-fang; Wu, Li-jun; Yu, Zeng-liang

    2001-02-01

    To explore the survival and dose response of organism for different radiation sources is of great importance in the research of radiobiology. In this study, the survival-dose response of Deinococcus radiodurans (E.coli, as the control) for ultra-violet (UV), γ-rays radiation and ion beam exposure was investigated. The shoulder type of survival curves were found for both UV and γ-ray ionizing radiation, but the saddle type of survival curves were shown for H+, N+(20keV and 30keV) and Ar+ beam exposure. This dose effect of the survival initially decreased with the increase in dose and then increased in the high dose range and finally decreased again in the higher dose range. Our experimental results suggest that D. radiodurans, which is considerably radio-resistant to UV and x-ray and γ-ray ionizing radiation, do not resist ion beam exposure.

  15. Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy

    SciTech Connect

    Mossman, K.L.

    1983-08-01

    A quantitative dose-response curve for salivary gland function in patients during radiotherapy is presented. Salivary-function data used in this study were obtained from four previously published reports. All patients were treated with /sup 60/Co teletherapy to the head and neck using conventional treatment techniques. Salivary dysfunction was determined at specific dose levels by comparing salivary flow rates before therapy with flow rates at specific dose intervals during radiotherapy up to a total dose of 6000 cGy. Fifty percent salivary dysfunction occurred after 1000 cGy and eighty percent dysfunction was observed by the end of the therapy course (6000 cGy). The salivary-function curve was also compared to the previously published dose-response curve for taste function. Comparisons of the two curves indicate that salivary dysfunction precedes taste loss and that the shapes of the dose-response curves are different. A new term, tissue tolerance ratio, defined as the ratio of responses of two tissues given the same radiation dose, was used to make the comparisons between gustatory and salivary gland tissue effects. Measurements of salivary gland function and analysis of dose-response curves may be useful in evaluating chemical modifiers of radiation response.

  16. Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy

    SciTech Connect

    Mossman, K.L.

    1983-08-01

    A quantitative dose-response curve for salivary gland function in patients during radiotherapy is presented. Salivary-function data used in this study were obtained from four previously published reports. All patients were treated wih /sup 60/Co teletherapy to the head and neck using conventional treatment techniques. Salivary dysfunction was determined at specific dose levels by comparing salivary flow rates before therapy with flow rates at specific dose intervals during radiotherapy up to a total dose of 6000 cGy. Fifty percent salivary dysfunction occurred after 1000 cGy and eighty percent dysfunction was observed by the end of the therapy course (6000 cGy). The salivary-function curve was also compared to the previously published dose-response curve for taste function. Comparisons of the two curves indicate that salivary dysfunction precedes taste loss and that the shapes of the dose-response curves are different. A new term, tissue tolerance ratio, defined as the ratio of responses of two tissues given the same radiation dose, was used to make the comparisons between gustatory and salivary gland tissue effects. Measurements of salivary gland function and analysis of dose-response curves may be useful in evaluating chemical modifiers of radiation response.

  17. Biologically Based Dose-Response Modeling. What is the potential for accurate description of the biological linkages in the applied dose - tissue dose-health effect continuum?

    EPA Science Inventory

    Given knowledge of exposure, the shape of the dose response curve is the key to predicting health risk, which in turn determines allowable levels of exposure and the associated economic costs of compliance.

  18. Dose-response investigation into glucose facilitation of memory performance and mood in healthy young adults.

    PubMed

    Sünram-Lea, Sandra I; Owen, Lauren; Finnegan, Yvonne; Hu, Henglong

    2011-08-01

    It has been suggested that the memory enhancing effect of glucose follows an inverted U-shaped curve, with 25 g resulting in optimal facilitation in healthy young adults. The aim of this study was to further investigate the dose dependency of the glucose facilitation effect in this population across different memory domains and to assess moderation by interindividual differences in glucose regulation and weight. Following a double-blind, repeated measures design, 30 participants were administered drinks containing five different doses of glucose (0 g, 15 g, 25 g, 50 g, and 60 g) and were tested across a range of memory tasks. Glycaemic response and changes in mood state were assessed following drink administration. Analysis of the data showed that glucose administration did not affect mood, but significant glucose facilitation of several memory tasks was observed. However, dose-response curves differed depending on the memory task with only performance on the long-term memory tasks adhering largely to the previously observed inverted U-shaped dose-response curve. Moderation of the response profiles by interindividual differences in glucose regulation and weight was observed. The current data suggest that dose-response function and optimal dose might depend on cognitive domain and are moderated by interindividual differences in glucose regulation and weight.

  19. A Method to Evaluate Hormesis in Nanoparticle Dose-Responses

    PubMed Central

    Nascarella, Marc A.; Calabrese, Edward J.

    2012-01-01

    The term hormesis describes a dose-response relationship that is characterized by a response that is opposite above and below the toxicological or pharmacological threshold. Previous reports have shown that this relationship is ubiquitous in the response of pharmaceuticals, metals, organic chemicals, radiation, and physical stressor agents. Recent reports have also indicated that certain nanoparticles (NPs) may also exhibit a hormetic dose-response. We describe the application of three previously described methods to quantify the magnitude of the hormetic biphasic dose-responses in nanotoxicology studies. This methodology is useful in screening assays that attempt to parse the observed toxicological dose-response data into categories based on the magnitude of hormesis in the evaluation of NPs. For example, these methods may be used to quickly identify NP induced hormetic responses that are either desirably enhanced (e.g., neuronal cell viability) or undesirably stimulated (e.g., low dose stimulation of tumor cells). PMID:22942868

  20. Quantitative radiation dose-response relationships for normal tissues in man - I. Gustatory tissues response during photon and neutron radiotherapy

    SciTech Connect

    Mossman, K.L.

    1982-08-01

    Quantitative radiation dose-response curves for normal gustatory tissue in man were studied. Taste function, expressed as taste loss, was evaluated in 84 patients who were given either photon or neutron radiotherapy for tumors in the head and neck region. Patients were treated to average tumor doses of 6600 cGy (photon) or 2200 cGy intervals for photon patients and 320-cGy intervals for neutron patients during radiotherapy. The dose-response curves for photons and neutrons were analyzed by fitting a four-parameter logistic equation to the data. Photon and neutron curves differed principally in their relative position along the dose axis. Comparison of the dose-response curves were made by determination of RBE. At 320 cGy, the lowest neutron dose at which taste measurements were made, RBE = 5.7. If this RBE is correct, then the therapeutic gain factor may be equal to or less than 1, indicating no biological advantage in using neutrons over photons for this normal tissue. These studies suggest measurements of taste function and evaluation of dose-response relationships may also be useful in quantitatively evaluating the efficacy of chemical modifiers of radiation response such as hypoxic cell radiosensitizers and radioprotectors.

  1. 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.

  2. 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

  3. Dose-response characteristics of insulin action on glucose metabolism: a non-steady-state approach.

    PubMed

    Natali, A; Gastaldelli, A; Camastra, S; Sironi, A M; Toschi, E; Masoni, A; Ferrannini, E; Mari, A

    2000-05-01

    The traditional methods for the assessment of insulin sensitivity yield only a single index, not the whole dose-response curve information. This curve is typically characterized by a maximally insulin-stimulated glucose clearance (Cl(max)) and an insulin concentration at half-maximal response (EC(50)). We developed an approach for estimating the whole dose-response curve with a single in vivo test, based on the use of tracer glucose and exogenous insulin administration (two steps of 20 and 200 mU x min(-1) x m(-2), 100 min each). The effect of insulin on plasma glucose clearance was calculated from non-steady-state data by use of a circulatory model of glucose kinetics and a model of insulin action in which glucose clearance is represented as a Michaelis-Menten function of insulin concentration with a delay (t(1/2)). In seven nondiabetic subjects, the model predicted adequately the tracer concentration: the model residuals were unbiased, and their coefficient of variation was similar to the expected measurement error (approximately 3%), indicating that the model did not introduce significant systematic errors. Lean (n = 4) and obese (n = 3) subjects had similar half-times for insulin action (t(1/2) = 25 +/- 9 vs. 25 +/- 8 min) and maximal responses (Cl(max) = 705 +/- 46 vs. 668 +/- 259 ml x min(-1) x m(-2), respectively), whereas EC(50) was 240 +/- 84 microU/ml in the lean vs. 364 +/- 229 microU/ml in the obese (P < 0.04). EC(50) and the insulin sensitivity index (ISI, initial slope of the dose-response curve), but not Cl(max), were related to body adiposity and fat distribution with r of 0.6-0.8 (P < 0.05). Thus, despite the small number of study subjects, we were able to reproduce information consistent with the literature. In addition, among the lean individuals, t(1/2) was positively related to the ISI (r = 0.72, P < 0.02). We conclude that the test here presented, based on a more elaborate representation of glucose kinetics and insulin action, allows a

  4. Statistical methods for clinical verification of dose response parameters related to esophageal stricture and AVM obliteration from radiotherapy

    NASA Astrophysics Data System (ADS)

    Mavroidis, Panayiotis; Lind, Bengt K.; Theodorou, Kyriaki; Laurell, Göran; Fernberg, Jan-Olof; Lefkopoulos, Dimitrios; Kappas, Constantin; Brahme, Anders

    2004-08-01

    The purpose of this work is to provide some statistical methods for evaluating the predictive strength of radiobiological models and the validity of dose-response parameters for tumour control and normal tissue complications. This is accomplished by associating the expected complication rates, which are calculated using different models, with the clinical follow-up records. These methods are applied to 77 patients who received radiation treatment for head and neck cancer and 85 patients who were treated for arteriovenous malformation (AVM). The three-dimensional dose distribution delivered to esophagus and AVM nidus and the clinical follow-up results were available for each patient. Dose-response parameters derived by a maximum likelihood fitting were used as a reference to evaluate their compatibility with the examined treatment methodologies. The impact of the parameter uncertainties on the dose-response curves is demonstrated. The clinical utilization of the radiobiological parameters is illustrated. The radiobiological models (relative seriality and linear Poisson) and the reference parameters are validated to prove their suitability in reproducing the treatment outcome pattern of the patient material studied (through the probability of finding a worse fit, area under the ROC curve and khgr2 test). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed, and the total volume of AVM. The estimated confidence intervals of the dose-response curves appear to have a significant supporting role on their clinical implementation and use.

  5. 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.

  6. DOSE RESPONSE DEETERMINATION OF NMDA ANTAGONISTS AND GABA AGONIST ON SUSTAINED ATTENTION.

    EPA Science Inventory

    We have shown that acute inhalation of toluene impairs sustained attention as assessed with a visual signal detection task (SDT). In vitro studies indicate that the NMDA and GABA systems are primary targets of anesthetic agents and organic solvents such as toluene. Pharmacologica...

  7. Calcium uptake studies of 1,4-dihydropyridine agonists into rabbit aortic smooth muscle cells in culture

    SciTech Connect

    Papaioannou, S.; Panzer-Knodle, S.; Yang, P.C.

    1989-01-01

    The effects of the three dihydropyridine calcium channel agonists (/plus minus/)BAY K 8644, (+)202-791 and (/plus minus/)CGP 28392 on /sup 45/Ca/sup + +/ uptake were studied in cultures of rabbit aortic smooth muscle cells. At 10/sup /minus/7/M each agonist enhanced /sup 45/Ca/sup + +/ uptake in 15-50 mM K/sup +/ but had no effect on the basal /sup 45/Ca/sup + +/ uptake at 5 mM K/sup +/. At the uptake threshold of 15 mM K/sup +/ each agonist potentiated /sup 45/Ca/sup + +/ uptake in a dose-dependent manner with half maximal effects at 2.4 nM for (/plus minus/)BAY K 8644, 22 nM for (+)202-791 and 18 nM for (/plus minus/)CGP 28392. The agonists showed no significant antagonistic activity. Responses were antagonized competitively by nifedipine and non-competitively by (/plus minus/)D-600. The /sup 45/Ca/sup + +/ uptake-dose response curves and the half maximal effects of the three agonists were over the same range of concentrations as their inhibition of (/sup 3/H)nitrendipine binding to rat ventricular receptor membrane preparations. The data suggest that these cells mimic the calcium uptake by the intact aorta better than commercial vascular smooth muscle lines or cardiac cells.

  8. 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.

  9. 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)

  10. A Bayesian network model for biomarker-based dose response.

    PubMed

    Hack, C Eric; Haber, Lynne T; Maier, Andrew; Shulte, Paul; Fowler, Bruce; Lotz, W Gregory; Savage, Russell E

    2010-07-01

    A Bayesian network model was developed to integrate diverse types of data to conduct an exposure-dose-response assessment for benzene-induced acute myeloid leukemia (AML). The network approach was used to evaluate and compare individual biomarkers and quantitatively link the biomarkers along the exposure-disease continuum. The network was used to perform the biomarker-based dose-response analysis, and various other approaches to the dose-response analysis were conducted for comparison. The network-derived benchmark concentration was approximately an order of magnitude lower than that from the usual exposure concentration versus response approach, which suggests that the presence of more information in the low-dose region (where changes in biomarkers are detectable but effects on AML mortality are not) helps inform the description of the AML response at lower exposures. This work provides a quantitative approach for linking changes in biomarkers of effect both to exposure information and to changes in disease response. Such linkage can provide a scientifically valid point of departure that incorporates precursor dose-response information without being dependent on the difficult issue of a definition of adversity for precursors.

  11. 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 ...

  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. 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…

  14. The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure.

    PubMed Central

    Andersen, M E; Barton, H A

    1998-01-01

    Biomarkers based on alterations in molecular and biochemical parameters may be useful in chemical risk assessment for establishing the presence of an exposure, ranking relative risks among exposed individuals, and estimating risks at low levels of exposure. Because it is unlikely that the relation between toxic responses and the degree of alteration in the biomarker is equivalent at all doses, quantification of risks at low levels is not necessarily more accurate using these biomarkers for extrapolation. The application of response biomarkers for risk evaluation at low levels of exposure is discussed in relation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound that causes induction of cytochromes CYP1A1 and CYP1A2 in liver and other tissues. CYP1A1 induction in liver increases monotonically with TCDD dosage; however, several of the dose-response curves for hepatic effects of TCDD are U-shaped. The U-shaped dose-response curve for hepatic tumor promotion appears to result because the integrated toxicologic response depends on multiple underlying processes--mitosuppression, toxicity, and cell proliferation--each of which has a different dose-response relationship with respect to TCDD. Although dose-response relationships for the biomarkers are not expected to duplicate the complex shapes seen with the integrated responses, measurements and pharmacodynamic modeling of the changes in these molecular and biochemical parameters can still be useful for obtaining an upperbound risk estimate at low levels of exposure. Images Figure 2 PMID:9539029

  15. 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

  16. 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).

  17. 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.

  18. 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

  19. Dose response of chlorhexidine against plaque and comparison with triclosan.

    PubMed

    Jenkins, S; Addy, M; Newcombe, R G

    1994-04-01

    The optimum dose of chlorhexidine delivered by mouthrinse, which balances efficacy against local side-effects, is generally considered to be in the region of 20 mg 2 x daily. Unfortunately, there have been few dose-response studies for chlorhexidine mouthrinses and for these, only limited details are published. The aims of this study were to determine the dose response of chlorhexidine to plaque inhibition and position a 0.1% triclosan rinse within this model. 28 subjects took part in this 7-treatment, double-blind, randomised cross-over 4-day plaque regrowth study. The rinses were 0.01%, 0.05%, 0.1% and 0.2% chlorhexidine, 0.1% triclosan and minus active controls for chlorhexidine and triclosan. On day 1 from a zero plaque baseline, volunteers suspended tooth-cleaning and commenced supervised 2 x daily rinsing with 10 ml volumes of the allocated rinses. On Day 5, plaque was scored by index and area. Treatment differences between the 7 rinses were highly significant. A clear dose-response pattern was seen for chlorhexidine with mean plaque scores decreasing with increasing dose. Even at 0.01%, chlorhexidine showed considerable and significant plaque inhibition compared to control. Triclosan at 0.1% showed limited plaque inhibition and less than 0.01% chlorhexidine. The findings of this study suggest that consideration could be given to low concentration chlorhexidine rinses as adjuncts to oral hygiene.

  20. Molecular circuits, biological switches, and nonlinear dose-response relationships.

    PubMed Central

    Andersen, Melvin E; Yang, Raymond S H; French, C Tenley; Chubb, Laura S; Dennison, James E

    2002-01-01

    Signaling motifs (nuclear transcriptional receptors, kinase/phosphatase cascades, G-coupled protein receptors, etc.) have composite dose-response behaviors in relation to concentrations of protein receptors and endogenous signaling molecules. "Molecular circuits" include the biological components and their interactions that comprise the workings of these signaling motifs. Many of these molecular circuits have nonlinear dose-response behaviors for endogenous ligands and for exogenous toxicants, acting as switches with "all-or-none" responses over a narrow range of concentration. In turn, these biological switches regulate large-scale cellular processes, e.g., commitment to cell division, cell differentiation, and phenotypic alterations. Biologically based dose-response (BBDR) models accounting for these biological switches would improve risk assessment for many nonlinear processes in toxicology. These BBDR models must account for normal control of the signaling motifs and for perturbations by toxic compounds. We describe several of these biological switches, current tools available for constructing BBDR models of these processes, and the potential value of these models in risk assessment. PMID:12634127

  1. 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.

  2. Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model.

    PubMed

    Yadav, Bhagwan; Wennerberg, Krister; Aittokallio, Tero; Tang, Jing

    2015-01-01

    Rational design of multi-targeted drug combinations is a promising strategy to tackle the drug resistance problem for many complex disorders. A drug combination is usually classified as synergistic or antagonistic, depending on the deviation of the observed combination response from the expected effect calculated based on a reference model of non-interaction. The existing reference models were proposed originally for low-throughput drug combination experiments, which make the model assumptions often incompatible with the complex drug interaction patterns across various dose pairs that are typically observed in large-scale dose-response matrix experiments. To address these limitations, we proposed a novel reference model, named zero interaction potency (ZIP), which captures the drug interaction relationships by comparing the change in the potency of the dose-response curves between individual drugs and their combinations. We utilized a delta score to quantify the deviation from the expectation of zero interaction, and proved that a delta score value of zero implies both probabilistic independence and dose additivity. Using data from a large-scale anticancer drug combination experiment, we demonstrated empirically how the ZIP scoring approach captures the experimentally confirmed drug synergy while keeping the false positive rate at a low level. Further, rather than relying on a single parameter to assess drug interaction, we proposed the use of an interaction landscape over the full dose-response matrix to identify and quantify synergistic and antagonistic dose regions. The interaction landscape offers an increased power to differentiate between various classes of drug combinations, and may therefore provide an improved means for understanding their mechanisms of action toward clinical translation.

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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.

  8. Nonmonotonic Dose Response Curves (NMDRCs) Common after Estrogen or Androgen Signaling Pathway Disruption: Fact or Falderal?

    EPA Science Inventory

    EDCs appear to induce some effects that do not appear to display a threshold (apparent Linear No Threshold responses) NMDRCs for EDCs Biologically plausible Occur frequently in vitro, but these are generally not relevant to in vivo effects and do not occur at low concentrations ...

  9. IncucyteDRC: An R package for the dose response analysis of live cell imaging data

    PubMed Central

    Chapman, Philip J.; James, Dominic I.; Watson, Amanda J.; Hopkins, Gemma V.; Waddell, Ian D.; Ogilvie, Donald J.

    2016-01-01

    We present IncucyteDRC, an R package for the analysis of data from live cell imaging cell proliferation experiments carried out on the Essen Biosciences IncuCyte ZOOM instrument. The package provides a simple workflow for summarising data into a form that can be used to calculate dose response curves and EC50 values for small molecule inhibitors. Data from different cell lines, or cell lines grown under different conditions, can be normalised as to their doubling time. A simple graphical web interface, implemented using shiny, is provided for the benefit of non-R users. The software is potentially useful to any research group studying the impact of small molecule inhibitors on cell proliferation using the IncuCyte ZOOM.

  10. IncucyteDRC: An R package for the dose response analysis of live cell imaging data

    PubMed Central

    Chapman, Philip J.; James, Dominic I.; Watson, Amanda J.; Hopkins, Gemma V.; Waddell, Ian D.; Ogilvie, Donald J.

    2016-01-01

    We present IncucyteDRC, an R package for the analysis of data from live cell imaging cell proliferation experiments carried out on the Essen Biosciences IncuCyte ZOOM instrument. The package provides a simple workflow for summarising data into a form that can be used to calculate dose response curves and EC50 values for small molecule inhibitors. Data from different cell lines, or cell lines grown under different conditions, can be normalised as to their doubling time. A simple graphical web interface, implemented using shiny, is provided for the benefit of non-R users. The software is potentially useful to any research group studying the impact of small molecule inhibitors on cell proliferation using the IncuCyte ZOOM. PMID:27703665

  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. Generalized Concentration Addition Modeling Predicts Mixture Effects of Environmental PPARγ Agonists.

    PubMed

    Watt, James; Webster, Thomas F; Schlezinger, Jennifer J

    2016-09-01

    The vast array of potential environmental toxicant combinations necessitates the development of efficient strategies for predicting toxic effects of mixtures. Current practices emphasize the use of concentration addition to predict joint effects of endocrine disrupting chemicals in coexposures. Generalized concentration addition (GCA) is one such method for predicting joint effects of coexposures to chemicals and has the advantage of allowing for mixture components to have differences in efficacy (ie, dose-response curve maxima). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays a central role in regulating lipid homeostasis, insulin sensitivity, and bone quality and is the target of an increasing number of environmental toxicants. Here, we tested the applicability of GCA in predicting mixture effects of therapeutic (rosiglitazone and nonthiazolidinedione partial agonist) and environmental PPARγ ligands (phthalate compounds identified using EPA's ToxCast database). Transcriptional activation of human PPARγ1 by individual compounds and mixtures was assessed using a peroxisome proliferator response element-driven luciferase reporter. Using individual dose-response parameters and GCA, we generated predictions of PPARγ activation by the mixtures, and we compared these predictions with the empirical data. At high concentrations, GCA provided a better estimation of the experimental response compared with 3 alternative models: toxic equivalency factor, effect summation and independent action. These alternatives provided reasonable fits to the data at low concentrations in this system. These experiments support the implementation of GCA in mixtures analysis with endocrine disrupting compounds and establish PPARγ as an important target for further studies of chemical mixtures.

  13. Dose response of CaF2:Tm to charged particles of different LET.

    PubMed

    Moyers, M F; Nelson, G A

    2009-08-01

    Thermoluminescent dosimeters are well established for performing calibrations in radiotherapy and for monitoring dose to personnel exposed to low linear energy transfer (LET) ionizing radiation. Patients undergoing light ion therapy and astronauts engaged in space flight are, however, exposed to radiation fields consisting of a mix of low- and high-LET charged particles. In this study, glow curves from CaF2:Tm chips were examined after exposure to various electron and ion beams. The annealing and readout procedures for these chips were optimized for these beams. After a 10 min prereadout annealing at 100 degrees C, the optimized glow curve samples the light output between 95 and 335 degrees C with a heating rate of 2 degrees C/s. The ratio of the integral of the glow curve under peaks 4-6 to the integral under peak 3 was approximately 0.9 for electrons, 1.0 for entrance protons, 1.6 for peak protons, and 2.2 for entrance carbon, silicon, and iron ions. The integral light output per unit dose in water for the iron exposures was about half as much as for the electron exposures. The peak-area-ratio can be used to determine a dose response factor for different LET radiations. PMID:19746804

  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

    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.

  16. Dose-response relationships for radium-induced bone sarcomas

    SciTech Connect

    Rowland, R.E.; Stehney, A.F.; Lucas, H.F. Jr.

    1981-01-01

    The incidence of bone sarcomas among 3055 female radium-dial workers who entered the dial industry before 1950 was used to determine dose-response relationships for the induction of bone sarcomas by radium. Two subpopulations were analyzed: all measured cases who survived at last five years after the start of employment and all cases who survived at least two years after first measurement. The first constituted a group based on year of entry; it contained 1468 women who experienced 42 bone sarcomas; the expected number was 0.4. The second comprised a group based on first measurement; it contained 1257 women who experienced 13 bone sarcomas; the expected number was 0.2. The dose-response function, I = (C + ..cap alpha..D + ..beta..D/sup 2/)e/sup -..gamma..D/, and simplifications of this general form, were fit to each data set. Two functions, I = (C + ..cap alpha..D + ..beta..D/sup 2/)e/sup -..gamma..D/ and I = (C + ..beta..D/sup 2/)e/sup -..gamma..D/, fit the data for year of entry (p greater than or equal to 0.05); both these functions and I = (C + ..cap alpha..D) fit the data for first measurement. The function I = (C + ..beta..D/sup 2/)e/sup -..gamma..D/ was used to predict the number of bone sarcomas in all other pre-1950 radium cases (medical, laboratory, and other exposure); fewer were actually observed than the fit of this function to the female dial workers predicted.

  17. 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

  18. 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.

  19. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship.

    PubMed

    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.

  20. Dose-response analysis of cadmium in man: body burden vs kidney dysfunction

    SciTech Connect

    Ellis, K.J.; Yuen, K.; Yasumura, S.; Cohn, S.H.

    1984-02-01

    The primary objective of this study was to develop dose-response relationships of cadmium in human beings. In vivo measurements of kidney, liver, urine, and blood cadmium, and urinary levels of ..beta../sub 2/-microglobulin and total protein were obtained in 82 industrially exposed workers and 30 control subjects. The values of 200 ..mu..g/g creatinine for urinary ..beta../sub 2/-microglobulin and 250 mg/g creatinine for urinary total protein were used to define the upper limit for normal kidney function. Forty-one of the cadmium workers (18 active, 23 retired) were classified as having abnormal kidney function; all control subjects had normal kidney function. Most workers with Cd above 70 ppm in the liver were judged to have some evidence of kidney abnormalities. The dose-response relationship for liver cadmium for the actively employed workers could be described by a linear logistic regression model: In p/(1-p) = 0.118 x liver cadmium (ppm) - 5.00 where p is the individual's probability of having kidney dysfunction. The loss of cadmium from the kidney following dysfunction prohibited a direct logistic analysis of the kidney cadmium data. However, when the linear relationship between kidney and liver cadmium for the subjects with normal kidney function was combined with the logistic equation for the liver, a predicted-response curve was obtained for the kidney. The logistic models predict a 50% probability of having kidney dysfunction at 38.4 mg for the kidney and 42.3 ppm for the liver, respectively.

  1. The niacin skin flush abnormality in schizophrenia: a quantitative dose-response study.

    PubMed

    Messamore, Erik; Hoffman, William F; Janowsky, Aaron

    2003-08-01

    Niacin dilates cutaneous blood vessels, resulting in a pronounced skin flush in most people. The flush response to niacin is attenuated in schizophrenia, but the quantification and physiological mechanism of this abnormality have not been described in detail. It is not clear whether the mechanism involves changes in the pharmacological sensitivity to niacin, or whether there is a reduced ability of the vasculature to dilate adequately in subjects with schizophrenia. We address this question in the present study by characterizing the dose-response relationship between topically applied alpha-methylnicotinate (AMN) and cutaneous blood flow changes, which were quantified by laser Doppler flowmetry. The dose-response curve was shifted to the right in subjects with schizophrenia. The EC(50) value of AMN was significantly increased in the schizophrenia group (mean: 1.66 mM; 95% confidence interval: 1.04-2.65 mM) as compared to the control group (mean: 0.38 mM; 95% confidence interval: 0.263-0.547 mM). The blood flow responses to higher AMN doses were lower in the schizophrenics; however, there was no statistically significant difference in the extrapolated maximal blood flow response value (F(max)) between the two groups. The results suggest that the skin flush abnormality in schizophrenia primarily reflects reduced pharmacological sensitivity to niacin rather than an inadequate cutaneous vasodilatory response to the stimulus. Since vasodilatation in response to niacin requires the release of prostaglandins, the data from this study suggest that schizophrenia is associated with abnormalities in enzymes, receptors, or signal transduction mechanisms that affect the synthesis, release, or response to vasodilatory prostaglandins.

  2. Non-linear dose-response of DNA-reactive genotoxins: recommendations for data analysis.

    PubMed

    Johnson, George E; Doak, Shareen H; Griffiths, Sioned M; Quick, Emma L; Skibinski, David O F; Zaïr, Zoulikha M; Jenkins, Gareth J

    2009-08-01

    Until recently, there has only been a limited amount of data available on the kinetics of mutation induction in the low dose region of exposure. In our publication Doak et al. [S.H. Doak, G.J. Jenkins, G.E. Johnson, E. Quick, E.M. Parry, J.M. Parry, Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens, Cancer Res. 67 (2007) 3904-3911] we showed that the two alkylating agents methyl-methanesulfonate (MMS) and ethyl-methanesulfonate (EMS) possess non-linear dose-response curves with no observed effect levels (NOEL) for mutation or chromosomal damage in vitro. These experiments were carried out in the AHH-1 human lymphoblastoid cell line, using the hypoxanthine phosphoribosyl transferase (HPRT) assay and the cytokinesis-block micronucleus (CBMN) assay, respectively. We have now carried out more advanced statistical analyses to define threshold values, which is critical as it has a dramatic impact on hazard and risk assessment. To do this, we re-analysed the data to see if the linear model or a more complex model (hockey stick or quadratic) gave a significant better fit of the data. For both EMS and MMS cytokinesis-block micronucleus data sets, the hockey stick model gave the most significant fit. The same was true for EMS, MMS and surprisingly ethylnitrosourea (ENU) in the HPRT assay in human AHH-1 cells. However, methylnitrosourea (MNU) was linear in both assays. These further analyses have shown that EMS and MMS have clear thresholds for both gene mutation and chromosome damage, as does ENU for gene mutation in AHH-1 cells. MNU was linear for gene and chromosome mutation and so was ENU for chromosome mutations at the concentrations tested. These findings correlate closely with those in vivo findings of Gocke et al. [E. Gocke, L. Müller, In vivo studies in the mouse to define a threshold for the genotoxicity of EMS and ENU, Mutat. Res. (this issue)] and together these data show a true threshold for EMS both in vitro and in

  3. A nicotinic acetylcholine receptor mutation (Y151S) causes reduced agonist potency to a range of neonicotinoid insecticides.

    PubMed

    Liu, Zewen; Williamson, Martin S; Lansdell, Stuart J; Han, Zhaojun; Denholm, Ian; Millar, Neil S

    2006-11-01

    Neonicotinoid insecticides are potent selective agonists of insect nicotinic acetylcholine receptors (nAChRs). Since their introduction in 1991, resistance to neonicotinoids has been slow to develop, but it is now established in some insect field populations such as the planthopper, Nilaparvata lugens, a major rice pest in many parts of Asia. We have reported recently the identification of a target-site mutation (Y151S) within two nAChR subunits (Nlalpha1 and Nlalpha3) from a laboratory-selected field population of N. lugens. In the present study, we have examined the influence of this mutation upon the functional properties of recombinant nAChRs expressed in Xenopus oocytes (as hybrid nAChRs, co-expressed with a rat beta2 subunit). The agonist potency of several nicotinic agonists has been examined, including all of the neonicotinoid insecticides that are currently licensed for either crop protection or animal health applications (acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid and thiamethoxam). The Y151S mutation was found to have no significant effect on the maximal current (I(max)) observed with the endogenous agonist, acetylcholine. In contrast, a significant reduction in I(max) was observed for all neonicotinoids (the I(max) for mutant nAChRs ranged from 13 to 81% of that observed on wild-type receptors). In addition, nAChRs containing the Y151S mutation caused a significant rightward shift in agonist dose-response curves for all neonicotinoids, but of varying magnitude (shifts in EC(50) values ranged from 1.3 to 3.6-fold). The relationship between neonicotinoid structure and their potency on nAChRs containing the Y151S target-site mutation is discussed.

  4. 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.

  5. 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.

  6. Characterization of a developmental toxicity dose-response model

    SciTech Connect

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

    1989-02-01

    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.

  7. Characteristics of dose-response relationships for late radiation effects: an analysis of skin telangiectasia and of head and neck morbidity.

    PubMed

    Turesson, I

    1991-03-01

    The dose-response characteristics were analysed for late skin telangiectasia in patients for 1, 2 and 5 fractions per week and 3 to 4 dose levels per schedule. Altogether 286 fields were used. Skin telangiectasia was scored on an arbitrary scale and dose-response analysis was performed at 10 year's follow-up for various degrees of telangiectasia, score greater than or equal to 1 to greater than or equal to 4. The following parameters were determined for each schedule and the equivalent single dose-response curves for each endpoint using probit analysis: the ED50, the absolute steepness, measured as the probit width, K, the relative steepness, K/ED50, and the normalised effect gradient, gamma 50. The inverse radiosensitivity, Doeff or Do, was estimated using the Poisson and LQ-models for tissue response. The alpha/beta value was found to be independent of the degree of telangiectasia used as endpoint. The absolute steepness of the dose-incidence curve increased with increasing dose per fraction and was correlated to the degree of damage. The relative steepness was independent of the dose per fraction when the dose-response curve was generated by a fixed dose per fraction, and was less than if generated by a fixed number of fractions. The relative steepness increased with higher degree of damage. Doeff decreased with increasing dose per fraction, and also with higher degree of telangiectasia. The highest steepness determined for telangiectasia score greater than or equal to 4 (partially confluent or more) at 10 years corresponded to K = 0.8 Gy, K/ED50 = 5%, gamma 50 = 7 and Do = 0.7 Gy. The dose-response characteristics found for late skin telangiectasia score greater than or equal to 2 to greater than or equal to 4 were consistent with those determined for necrosis and fatal complications 5 years after radiotherapy to head and neck tumours in our department.

  8. Analysis of the dose-response relationship between high-risk human papillomavirus viral load and cervical lesions.

    PubMed

    Huang, Min-Zhu; Li, Hong-Bo; Nie, Xin-Min; Jiang, Xiao-Man; Ming, Hui; Li, Deng-Qing; Wu, Xin-Yin

    2009-08-01

    The aims of this study were to explore the dose-response relationship between high-risk human papillomavirus (hrHPV) load and cervical lesions; the relationship between hrHPV viral load and the severity of cervical lesions; and the clinical application of the hybrid capture II (HC-II) system in the secondary prevention of cervical cancer. HrHPV viral load was detected by the HC-II system and cervical lesions were diagnosed from biopsied tissue. Curve estimation and Mantel trend analysis were used to explore the dose-response relationship between hrHPV viral load and cervical lesions. Spearman's rank correlation analysis and ordinal regression model were used for the analysis of hrHPV viral load and the severity of cervical lesions. Curve estimation showed good correlation between cervical lesion rates and hrHPV viral load (r=0.775, P=0.008); the rate of cervical lesions increased with hrHPV viral load (chi(trend)=8.000, P<0.001). Medium intensity rank correlation was found between hrHPV viral load grades and the severity of cervical lesions (r(s)=0.321, P<0.001); a correlation appeared between hrHPV viral load and the severity of cervical lesions (P<0.001). These results suggest a dose-response relationship between hrHPV viral load and the severity of cervical lesions. This dependence has important clinical applications and shows the potential value of the HC-II system in cervical cancer prevention.

  9. Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of mu-opioid receptors and dynamin-2.

    PubMed

    Pawar, Mohit; Kumar, Priyank; Sunkaraneni, Soujanya; Sirohi, Sunil; Walker, Ellen A; Yoburn, Byron C

    2007-06-01

    It has been proposed that opioid agonist efficacy may play a role in tolerance and the regulation of opioid receptor density. To address this issue, the present studies estimated the in vivo efficacy of three opioid agonists and then examined changes in spinal mu-opioid receptor density following chronic treatment in the mouse. In addition, tolerance and regulation of the trafficking protein dynamin-2 were determined. To evaluate efficacy, the method of irreversible receptor alkylation was employed and the efficacy parameter tau estimated. Mice were injected with the irreversible mu-opioid receptor antagonist clocinnamox (0.32-25.6 mg/kg, i.p), and 24 h later, the analgesic potency of s.c. morphine, oxycodone and etorphine were determined. Clocinnamox dose-dependently antagonized the analgesic effects of morphine, etorphine and oxycodone. The shift to the right of the dose-response curves was greater for morphine and oxycodone compared to etorphine and the highest dose of clocinnamox reduced the maximal effect of morphine and oxycodone, but not etorphine. The order of efficacy calculated from these results was etorphine>morphine>oxycodone. Other mice were infused for 7 days with oxycodone (10-150 mg/kg/day, s.c.) or etorphine (50-250 microg/kg/day, s.c.) and the analgesic potency of s.c. morphine determined. The low efficacy agonist (oxycodone) produced more tolerance than the high efficacy agonist (etorphine) at equi-effective infusion doses. In saturation binding experiments, the low efficacy opioid agonists (morphine, oxycodone) did not regulate the density of spinal mu-opioid receptors, while etorphine produced approximately 40% reduction in mu-opioid receptor density. Furthermore, etorphine increased spinal dynamin-2 abundance, while oxycodone did not produce any significant change in dynamin-2 abundance. Overall, these data indicate that high efficacy agonists produce less tolerance at equi-effective doses. Furthermore, increased efficacy was associated with

  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. 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.

  12. Chronic periodontitis and smoking Prevalence and dose-response relationship

    PubMed Central

    Khan, Shahrukh; Khalid, Taimur; Awan, Kamran H.

    2016-01-01

    Objectives: To determine the prevalence and dose-response relationship of chronic periodontitis among smokers in Pakistan. Methods: This is a cross-sectional study among participants seeking dental care in Karachi Medical and Dental College, Karachi, Pakistan. A total of 443 participants with a mean age of 44.3 (±6.5) participated in the study from April 2011 to December 2011. Males comprised 64.7%, and females comprised 35.2%. Participants were interviewed on social demographics and oral habits. Participants with shallow pockets (3.5-5.5 mm) and deep pockets (>5.5 mm) were considered suffering from chronic periodontitis. The characteristics of participants were assessed using frequency distribution for categorical variables and mean (standard deviation) for continuous variables. Results: Among 443 participants, smokers were distributed as 55.1% and non-smokers as 44.9%. Smoking was found to be significantly related to young adults (p<0.007), male gender (p<0.001), and lower education level (p<0.01). Overall prevalence of chronic periodontitis among smokers was estimated at 81.6%. Heavy smoking was found to have significantly high prevalence (p<0.001) and severity (p<0.001) of periodontitis as compared with moderate and light smokers. The multivariate unadjusted model depicted 3.5 times higher risk of chronic periodontitis among smokers (p<0.001). Conclusion: Chronic periodontitis had a high prevalence among smokers. Heavy smoking was found to have a higher risk for having periodontitis. PMID:27464867

  13. 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.

  14. Shared dosimetry error in epidemiological dose-response analyses

    DOE PAGES

    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

  15. 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

  16. 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.

  17. 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

  18. 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 role of nitrate as a promoter of germination of Sisymbrium officinale seeds was examined in optimal light conditions. It was shown that the requirement for nitrate was absolute. This was true for all seed lots used. The probit of germination in water was log-linearly related to the level of endogenous nitrate. Preincubation at 15°C resulted in an immediate decrease in germination, whereas in 25 millimolar KNO3 the decrease was delayed. The decline of germination in water was strongly correlated with the rate at which nitrate leached from the seeds. The germination response to a range of KNO3 concentrations was followed during preincubation at 24-hour intervals. During the entire 264-hour preincubation period increasingly higher nitrate concentrations were required to maintain a response. This resulted in a right-hand shift of the dose-response curve parallel to the x axis. After 120 hours the high maximum germination level started to decline. The dose-response curves could be simulated by an equation from the receptor-occupancy theory. It is proposed that induction of secondary dormancy is a result of a decrease of the number of nitrate receptors. After 24 and 48 hours of preincubation, the nitrate-response curves were biphasic. The biphasic character could be related to the level of endogenous nitrate and to a differential requirement for nitrate of two fractions of the seed population. Similarities with the behavior of fluence-response curves after prolonged dark incubation led to the hypothesis that phytochrome and nitrate share the same site of action. PMID:16667802

  19. 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...

  20. 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...

  1. 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...

  2. 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...

  3. Statistical strategies for averaging EC50 from multiple dose-response experiments.

    PubMed

    Jiang, Xiaoqi; Kopp-Schneider, Annette

    2015-11-01

    In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

  4. 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...

  5. 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...

  6. Effect of composition interactions on the dose response of an N-isopropylacrylamide gel dosimeter.

    PubMed

    Chang, Yuan-Jen; Hsieh, Bor-Tsung

    2012-01-01

    In this study, a two-level full factorial design was used to identify the effects of the interactions between compositions in an N-isopropylacrylamide (NIPAM) gel dosimeter involving the following variables: (A) gelatin, (B) NIPAM, (C) the crosslinker N, N'-methylene-bis-acrylamide (Bis), and (D) the antioxidant tetrakis (hydroxymethyl) phosphonium chloride (THPC). The dose range was from 0 Gy to 5 Gy. Optical computed tomography was used to scan the polymer gel dosimeter. Each component was set to two levels for all four variables, including (A) 4% and 6%, (B) 4% and 6%, (C) 2% and 4%, as well as (D) 5 and 15 mM. Response surface methodology and a central composite design were adopted for the quantitative investigation of the respective interaction effects on the dose response curve of the gel. The results showed that the contributions of the interaction effects, i.e., AB (6.22%), AC (8.38%), AD (7.74%), BC (9.44%), ABC (18.24%), BCD (12.66%), and ABCD (13.4%), were greater than those of the four main effects, accounting for over 76.08% of the total variability. These results also indicated that the NIPAM gel recipe with the highest sensitivity was at 40%C (mass fraction of Bis). PMID:23077487

  7. Effect of Composition Interactions on the Dose Response of an N-Isopropylacrylamide Gel Dosimeter

    PubMed Central

    Chang, Yuan-Jen; Hsieh, Bor-Tsung

    2012-01-01

    In this study, a two-level full factorial design was used to identify the effects of the interactions between compositions in an N-isopropylacrylamide (NIPAM) gel dosimeter involving the following variables: (A) gelatin, (B) NIPAM, (C) the crosslinker N, N′-methylene-bis-acrylamide (Bis), and (D) the antioxidant tetrakis (hydroxymethyl) phosphonium chloride (THPC). The dose range was from 0 Gy to 5 Gy. Optical computed tomography was used to scan the polymer gel dosimeter. Each component was set to two levels for all four variables, including (A) 4% and 6%, (B) 4% and 6%, (C) 2% and 4%, as well as (D) 5 and 15 mM. Response surface methodology and a central composite design were adopted for the quantitative investigation of the respective interaction effects on the dose response curve of the gel. The results showed that the contributions of the interaction effects, i.e., AB (6.22%), AC (8.38%), AD (7.74%), BC (9.44%), ABC (18.24%), BCD (12.66%), and ABCD (13.4%), were greater than those of the four main effects, accounting for over 76.08% of the total variability. These results also indicated that the NIPAM gel recipe with the highest sensitivity was at 40%C (mass fraction of Bis). PMID:23077487

  8. 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

  9. Longitudinal FEV1 dose-response model for inhaled PF-00610355 and salmeterol in patients with chronic obstructive pulmonary disease.

    PubMed

    Nielsen, Jace C; Hutmacher, Matthew M; Cleton, Adriaan; Martin, Steven W; Ribbing, Jakob

    2012-12-01

    The objective of this work was to characterize the dose-response relationship between two inhaled long-acting beta agonists (PF-00610355 and salmeterol) and the forced expiratory volume in one second (FEV1) in order to inform dosing recommendations for future clinical trials in patients with chronic obstructive pulmonary disease (COPD). This meta-analysis of four studies included 8,513 FEV1 measurements from 690 patients with moderate COPD. A longitudinal kinetic-pharmacodynamic (K-PD) model was developed and adequately described changes in FEV1 measurements over time, including circadian patterns within a day, as well as changes in FEV1 measurements elicited from administration of PF-00610355 or salmeterol. The fine-particle dose, the amount of drug present in particles small enough for lung delivery, was used as the exposure measure for PF-00610355. Greater reversibility following administration of a short-acting beta agonist during run-in was associated with increased FEV1 response to long-acting beta agonists (through an increased maximal response, E(max)). Simulations were conducted to better understand the response to PF-00610355 relative to placebo and salmeterol. The results of the simulations show that once daily fine-particle doses of 28.1 μg versus placebo have a moderate probability of providing an average improvement above 100 mL at trough. The 50 μg fine-particle dose, on the other hand, has a greater than 0.78 probability of achieving a 120 mL improvement versus placebo at trough. From an efficacy perspective and assuming a fine-particle fraction of 25 % for the Phase 3 formulation; 100 and 200 μg once daily nominal doses would be of interest to investigate in future Phase 3 trials.

  10. Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys.

    PubMed

    Ko, Mei-Chuan; Woods, James H; Fantegrossi, William E; Galuska, Chad M; Wichmann, Jürgen; Prinssen, Eric P

    2009-08-01

    Behavioral effects of a nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64-6198, have not been studied in primate species. The aim of the study was to verify the receptor mechanism underlying the behavioral effects of Ro 64-6198 and to systematically compare behavioral effects of Ro 64-6198 with those of a mu-opioid receptor agonist, alfentanil, in monkeys. Both Ro 64-6198 (0.001-0.06 mg/kg, s.c.) and alfentanil (0.001-0.06 mg/kg, s.c.) produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced allodynia. An NOP receptor antagonist, J-113397 (0.01-0.1 mg/kg, s.c.), dose-dependently produced rightward shifts of the dose-response curve of Ro 64-6198-induced antinociception. The apparent pA(2) value of J-113397 was 8.0. Antagonist studies using J-113397 and naltrexone revealed that Ro 64-6198 produced NOP receptor-mediated antinociception independent of mu-opioid receptors. In addition, alfentanil dose-dependently produced respiratory depression and itch/scratching responses, but antinociceptive doses of Ro 64-6198 did not produce such effects. More important, Ro 64-6198 did not produce reinforcing effects comparable with those of alfentanil, cocaine, or methohexital under self-administration procedures in monkeys. These results provide the first functional evidence that the activation of NOP receptors produces antinociception without reinforcing effects in primates. Non-peptidic NOP receptor agonists may have therapeutic value as novel analgesics without abuse liability in humans. PMID:19279568

  11. Administration of mu-, kappa- or delta2-receptor agonists via osmotic minipumps suppresses murine splenic antibody responses.

    PubMed

    Rahim, R T; Meissler, J J; Cowan, A; Rogers, T J; Geller, E B; Gaughan, J; Adler, M W; Eisenstein, T K

    2001-10-01

    Previously, our laboratory has shown that morphine given by implantation of a 75-mg slow-release pellet for 48 h suppresses murine splenic antibody responses to sheep red blood cells (SRBCs) in a plaque-forming cell (PFC) assay. However, the use of slow-release pellets for such studies is limited, as these pellets are only available in fixed doses and similar pellets for kappa and delta agonists have not been developed. In the present study, we investigated the feasibility of administering opioids via Alzet osmotic minipumps to assess their immunomodulatory effects. Groups of mice received minipumps dispensing morphine sulfate, which has primary activity at the mu opioid receptor; U50,488H, which is a kappa-selective agonist; deltorphin II, which is a delta2-selective agonist; or DPDPE, which has greater selectivity for delta1 than delta, receptors. Morphine, U50,488H and deltorphin II were all immunosuppressive, with biphasic dose-response curves exhibiting maximal (approximately 50%) suppression of the PFC response at doses of 0.5 to 2 mg/kg/day 48 h after pump implantation. Further, immunosuppression by morphine sulfate, U50,488H or deltorphin II was blocked by simultaneous implantation of a minipump administering the opioid receptor-selective antagonists CTAP (1 mg/kg/day), nor-binaltorphimine (5 mg/kg/day), or naltriben (3 mg/kg/day), respectively. DPDPE was inactive at doses lower than 10 mg/kg/day. We conclude that osmotic minipumps are a practical and useful way of administering opioids to study their effects on the immune system, and give further evidence that immunosuppression induced in vivo by opioid agonists is mediated not only via mu, but also via kappa and delta2 opioid receptors. PMID:11606031

  12. The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.

    PubMed

    Yohn, Samantha E; Santerre, Jessica L; Nunes, Eric J; Kozak, Rouba; Podurgiel, Samantha J; Correa, Mercè; Salamone, John D

    2015-08-01

    Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of ecopipam, and in each case the D1 agonist significantly attenuated the effects of ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists.

  13. The role of dopamine D1 receptor transmission in effort-related choice behavior: Effects of D1 agonists.

    PubMed

    Yohn, Samantha E; Santerre, Jessica L; Nunes, Eric J; Kozak, Rouba; Podurgiel, Samantha J; Correa, Mercè; Salamone, John D

    2015-08-01

    Mesolimbic dopamine (DA), particularly in the nucleus accumbens, is a critical component of the brain circuitry involved in behavioral activation and effort-related processes. Although much is known about the characteristics of DA D2 receptor antagonism on effort-related choice behavior, less is known about the effects of D1 antagonism, and agonist/antagonist interactions. The highly selective D1 antagonist ecopipam was studied for its effects on effort-related choice behavior using the concurrent fixed ratio (FR) 5/chow feeding choice and T-maze barrier choice procedures. In rats tested on the FR5/chow feeding choice task, ecopipam shifted choice behavior, decreasing lever pressing for preferred high carbohydrate pellets but increasing consumption of lab chow. Also, ecopipam decreased selection of the high effort option (i.e., climbing the barrier to obtain a larger reward) in rats tested on the T-maze task, but did not disrupt arm preference or discrimination when no barrier was present. The D1 agonists SKF38393, SKF81297 and A77636 were assessed for their ability to reverse the effects of ecopipam, and in each case the D1 agonist significantly attenuated the effects of ecopipam, typically with an inverted-u shaped dose/response curve. SKF81297 also was able to reverse the effects of the catecholamine depleting agent tetrabenazine on T-maze performance. In summary, the present results implicate DA D1 receptors in the regulation of behavioral activation and effort-related functions, and demonstrate the utility of using tests of effort-related choice behavior for assessing the effects of D1 agonists. PMID:26022661

  14. 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

  15. 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

  16. [The dose-response of unstable chromosome exchanges in lymphocytes of cancer patients undergone whole-body fractionated gamma-rays exposure at the total dose 1.15 Gy].

    PubMed

    Semenov, A V; Vorobtsova, I E; Zharinov, G M

    2010-01-01

    The dose-response of unstable chromosome exchanges (UCE) in lymphocytes of 4 cancer patients undergone whole-body fractionated gamma-rays exposure (at the daily dose of 0.115 Gy up to the total dose 1.15 Gy) was compared with corresponding dose-response for lymphocytes of the same patients, irradiated in vitro at the same dose range. In vivo irradiation yielded lower frequency of UCE on the dose unit than in vitro irradiation. It was shown that the in vivo dose-response curve gives more adequate dose estimation than in vitro one. This curve could be used for reconstruction of absorbed dose in the cases of analogous character of in-controlled irradiation of people.

  17. 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

  18. 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

  19. Generalized Concentration Addition Modeling Predicts Mixture Effects of Environmental PPARγ Agonists.

    PubMed

    Watt, James; Webster, Thomas F; Schlezinger, Jennifer J

    2016-09-01

    The vast array of potential environmental toxicant combinations necessitates the development of efficient strategies for predicting toxic effects of mixtures. Current practices emphasize the use of concentration addition to predict joint effects of endocrine disrupting chemicals in coexposures. Generalized concentration addition (GCA) is one such method for predicting joint effects of coexposures to chemicals and has the advantage of allowing for mixture components to have differences in efficacy (ie, dose-response curve maxima). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays a central role in regulating lipid homeostasis, insulin sensitivity, and bone quality and is the target of an increasing number of environmental toxicants. Here, we tested the applicability of GCA in predicting mixture effects of therapeutic (rosiglitazone and nonthiazolidinedione partial agonist) and environmental PPARγ ligands (phthalate compounds identified using EPA's ToxCast database). Transcriptional activation of human PPARγ1 by individual compounds and mixtures was assessed using a peroxisome proliferator response element-driven luciferase reporter. Using individual dose-response parameters and GCA, we generated predictions of PPARγ activation by the mixtures, and we compared these predictions with the empirical data. At high concentrations, GCA provided a better estimation of the experimental response compared with 3 alternative models: toxic equivalency factor, effect summation and independent action. These alternatives provided reasonable fits to the data at low concentrations in this system. These experiments support the implementation of GCA in mixtures analysis with endocrine disrupting compounds and establish PPARγ as an important target for further studies of chemical mixtures. PMID:27255385

  20. Microbial dose response modeling: past, present, and future.

    PubMed

    Haas, Charles N

    2015-02-01

    The understanding of the risk to humans from exposure to pathogens has been firmly put into a risk assessment framework. A key element of applying this approach is the understanding of the relationship between dose and response for particular pathogens. This understanding has progressed from early use of threshold concepts ("minimal infectious dose") thru multiple generations of models. Generation 1 models describe probability of response to exposed dose. Generation 2 models incorporate host factors (e.g., age) and/or pathogen factors (e.g., particle size of inhaled agents). Generation 3 models describe the rate at which effects develop, i.e. the epidemic curve. These (generation 1 through three models) have been developed and used in multiple contexts. Beyond Generation 3 lies an opportunity for the deep incorporation of in vivo physiological responses and the coupling of the individual host dynamics to the dynamics of spread of contagious diseases in the population. This would enable more direct extrapolation from controlled dosing studies to estimate population level effects. There remain also needs to understand broader categories of infectious agents, including pathogenic amoebae and fungi. More advanced models need to be validated against well-characterized human outbreak data.

  1. Dose response of elastase-induced emphysema in hamsters.

    PubMed

    Raub, J A; Mercer, R R; Miller, F J; Graham, J A; O'Neil, J J

    1982-04-01

    Elastase-induced emphysema in hamsters was studied using pulmonary function tests in an effort to develop techniques for determining the effects of air pollutants on the progression of this disease. Single intratracheal injections of 6, 12, or 24 units of porcine pancreatic elastase produced dose-related changes in pulmonary function after 4 wk when compared with sham-injected control animals. Boyle's law end-expiratory volume and residual volume, measured by gas dilution, increased (p less than 0.05) at 12 and 24 units, respectively, whereas vital capacity, determined plethysmographically, and total lung capacity wee increased (p less than 0.05) at all 3 elastase doses. Respiratory system compliance, calculated by a nonlinear least squares regression fit of the deflation pressure-volume curve, increased (p less than 0.05) at 24 units only. The multiple-breath nitrogen washout slope (N2 slope) and the single-breath diffusing capacity for carbon monoxide (DLCO) decreased (p less than 0.05) at all 3 doses of elastase. Both histologic and physiologic evaluation showed dose-related pulmonary impairment. It appears, therefore, that as little as 6 units of elastase produces mild emphysema in hamsters, which is detectable by pulmonary function testing. Of these tests, the DLCO and N2 slope were the most effective in detecting the degree of impairment. PMID:6918202

  2. 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...

  3. Toward a unified approach to dose-response modeling in ecotoxicology.

    PubMed

    Ritz, Christian

    2010-01-01

    This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.

  4. 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...

  5. 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.

  6. 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.

  7. 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.

  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. Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli.

    PubMed

    Chatterjee, Manash S; Purvis, Jeremy E; Brass, Lawrence F; Diamond, Scott L

    2010-07-01

    Prediction of cellular response to multiple stimuli is central to evaluating patient-specific clinical status and to basic understanding of cell biology. Cross-talk between signaling pathways cannot be predicted by studying them in isolation and the combinatorial complexity of multiple agonists acting together prohibits an exhaustive exploration of the complete experimental space. Here we describe pairwise agonist scanning (PAS), a strategy that trains a neural network model based on measurements of cellular responses to individual and all pairwise combinations of input signals. We apply PAS to predict calcium signaling responses of human platelets in EDTA-treated plasma to six different agonists (ADP, convulxin, U46619, SFLLRN, AYPGKF and PGE(2)) at three concentrations (0.1, 1 and 10 x EC(50)). The model predicted responses to sequentially added agonists, to ternary combinations of agonists and to 45 different combinations of four to six agonists (R = 0.88). Furthermore, we use PAS to distinguish between the phenotypic responses of platelets from ten donors. Training neural networks with pairs of stimuli across the dose-response regime represents an efficient approach for predicting complex signal integration in a patient-specific disease milieu. PMID:20562863

  10. 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.

  11. Dose-response relationship of dicentric chromosomes in human lymphocytes obtained for the fission neutron therapy facility MEDAPP at the research reactor FRM II.

    PubMed

    Schmid, E; Wagner, F M; Romm, H; Walsh, L; Roos, H

    2009-02-01

    The biological effectiveness of neutrons from the neutron therapy facility MEDAPP (mean neutron energy 1.9 MeV) at the new research reactor FRM II at Garching, Germany, has been analyzed, at different depths in a polyethylene phantom. Whole blood samples were exposed to the MEDAPP beam in special irradiation chambers to total doses of 0.14-3.52 Gy at 2-cm depth, and 0.18-3.04 Gy at 6-cm depth of the phantom. The neutron and gamma-ray absorbed dose rates were measured to be 0.55 Gy min(-1) and 0.27 Gy min(-1) at 2-cm depth, while they were 0.28 and 0.25 Gy min(-1) at 6-cm depth. Although the irradiation conditions at the MEDAPP beam and the RENT beam of the former FRM I research reactor were not identical, neutrons from both facilities gave a similar linear-quadratic dose-response relationship for dicentric chromosomes at a depth of 2 cm. Different dose-response curves for dicentrics were obtained for the MEDAPP beam at 2 and 6 cm depth, suggesting a significantly lower biological effectiveness of the radiation with increasing depth. No obvious differences in the dose-response curves for dicentric chromosomes estimated under interactive or additive prediction between neutrons or gamma-rays and the experimentally obtained dose-response curves could be determined. Relative to (60)Co gamma-rays, the values for the relative biological effectiveness at the MEDAPP beam decrease from 5.9 at 0.14 Gy to 1.6 at 3.52 Gy at 2-cm depth, and from 4.1 at 0.18 Gy to 1.5 at 3.04 Gy at 6-cm depth. Using the best possible conditions of consistency, i.e., using blood samples from the same donor and the same measurement techniques for about two decades, avoiding the inter-individual variations in sensitivity or the differences in methodology usually associated with inter-laboratory comparisons, a linear-quadratic dose-response relationship for the mixed neutron and gamma-ray MEDAPP field as well as for its fission neutron part was obtained. Therefore, the debate on whether the fission

  12. The hormetic dose-response model is more common than the threshold model in toxicology.

    PubMed

    Calabrese, Edward J; Baldwin, Linda A

    2003-02-01

    The threshold dose-response model is widely viewed as the most dominant model in toxicology. The present study was designed to test the validity of the threshold model by assessing the responses of doses below the toxicological NOAEL (no observed adverse effect level) in relationship to the control response (i.e., unexposed group). Nearly 1,800 doses below the NOAEL, from 664 dose-response relationships derived from a previously published database that satisfied a priori entry criteria, were evaluated. While the threshold model predicts a 1:1 ratio of responses "greater than" to "less than" the control response (i.e., a random distribution), a 2.5:1 ratio (i.e., 1171:464) was observed, reflecting 31% more responses above the control value than expected (p < 0.0001). The mean response (calculated as % control response) of doses below the NOAEL was 115.0% +/- 1.5 standard error of the mean (SEM). These findings challenge the long-standing belief in the primacy of the threshold model in toxicology (and other areas of biology involving dose-response relationships) and provide strong support for the hormetic-like biphasic dose-response model characterized by a low-dose stimulation and a high-dose inhibition. These findings may affect numerous aspects of toxicological and biological/biomedical research related to dose-response relationships, including study design, risk assessment, as well as chemotherapeutic strategies.

  13. 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.

  14. Calmodulin regulation of basal and agonist-stimulated G protein coupling by the mu-opioid receptor (OP(3)) in morphine-pretreated cell.

    PubMed

    Wang, D; Surratt, C K; Sadée, W

    2000-08-01

    Calmodulin (CaM) has been shown to suppress basal G protein coupling and attenuate agonist-stimulated G protein coupling of the mu-opioid receptor (OP(3)) through direct interaction with the third intracellular (i3) loop of the receptor. Here we have investigated the role of CaM in regulating changes in OP(3)-G protein coupling during morphine treatment, shown to result in CaM release from plasma membranes. Basal and agonist-stimulated G protein coupling by OP(3) was measured before and after morphine pretreatment by incorporation of guanosine 5'-O-(3-[(35)S]thiotriphosphate) into membranes, obtained from HEK 293 cells transfected with human OP(3) cDNA. The opioid antagonist beta-chlornaltrexamine fully suppressed basal G protein coupling of OP(3), providing a direct measure of basal signaling. Pretreatment of the cells with morphine enhanced basal G protein coupling (sensitization). In contrast, agonist-stimulated coupling was diminished (desensitization), resulting in a substantially flattened morphine dose-response curve. To test whether CaM is involved in these changes, we constructed OP(3)-i3 loop mutants with reduced affinity for CaM (K273A, R275A, and K273A/R275A). Basal signaling of these mutant OP(3) receptors was higher than that of the wild-type receptor and, moreover, unaffected by morphine pretreatment, whereas desensitization to agonist stimulation was only slightly attenuated. Therefore, CaM-OP(3) interactions appear to play only a minor role in the desensitization of OP(3). In contrast, release of CaM from the plasma membrane appears to enhance the inherent basal G protein coupling of OP(3), thereby resolving the paradox that OP(3) displays both desensitization and sensitization during morphine treatment.

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

    PubMed

    Koplovitz, I; Menton, R; Matthews, C; Shutz, M; Nalls, C; Kelly, S

    1995-01-01

    HI-6 (1-2-hydroxyiminomethyl-1-pyridino-3-(4-carbamoyl-1-pyridino -2- oxapropane dichloride) 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 HI6 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. It is concluded that 1) ATR has a large effect on the efficacy of HI-6 against OP poisoning, 2) the dose of ATR must be carefully selected in studies investigating the efficacy of HI-6 against OP poisoning, 3) the effective dose of ATR in the guinea pig is approximately 16 mg/kg, and 4) diazepam is a useful

  16. Dopamine agonist-induced penile erection and yawning: a comparative study in outbred Roman high- and low-avoidance rats.

    PubMed

    Sanna, Fabrizio; Corda, Maria Giuseppa; Melis, Maria Rosaria; Piludu, Maria Antonietta; Löber, Stefan; Hübner, Harald; Gmeiner, Peter; Argiolas, Antonio; Giorgi, Osvaldo

    2013-08-01

    The effects on penile erection and yawning of subcutaneous (SC) injections of the mixed dopamine D1/D2-like agonist apomorphine (0.02-0.2 mg/kg) were studied in outbred Roman high- (RHA) and low-avoidance (RLA) male rats, two lines selectively bred for their respectively rapid versus poor acquisition of the active avoidance response in the shuttle-box, and compared with the effects observed in male Sprague-Dawley (SD) rats. Apomorphine dose-response curves were bell-shaped in all rat lines/strains. Notably, more penile erections and yawns were recorded mainly in the ascending part of these curves (e.g., apomorphine 0.02-0.08 mg/kg) in both RLA and RHA rats compared to SD rats, with RLA rats showing the higher response (especially for yawning) with respect to RHA rats. Similar results were found with PD-168,077 (0.02-0.2 mg/kg SC), a D4 receptor agonist, which induced penile erection but not yawning. In all rat lines/strains, apomorphine responses were markedly reduced by the D2 antagonist L-741,626, but not by the D3 antagonist, SB277011A, whereas the D4 antagonists L-745,870 and FAUC213 elicited a partial, yet statistically significant, inhibitory effect. In contrast, the pro-erectile effect of PD-168,077 was completely abolished by L-745,870 and FAUC213, as expected. The present study confirms and extends previously reported differences in dopamine transmission between RLA and RHA rats and between the SD strain and the Roman lines. Moreover, it confirms previous studies supporting the view that dopamine receptors of the D2 subtype play a predominant role in the pro-yawning and pro-erectile effect of apomorphine, and that the selective stimulation of D4 receptors induces penile erection.

  17. 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...

  18. 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…

  19. 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, ...

  20. 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...

  1. A dose-response study of triclosan mouthrinses on plaque regrowth.

    PubMed

    Jenkins, S; Addy, M; Newcombe, R J

    1993-09-01

    Triclosan is used in toothpastes and mouthrinses as a plaque inhibitory agent. The concentrations used and therefore the dose of triclosan varies between products and there is, as with most plaque inhibitory agents, little information on the dose response of this agent. The purpose of this investigation was to measure the plaque inhibitory properties of triclosan in a simple mouthrinse formulation over a range of concentrations and therefore doses. The study was a 5 treatment, double-blind, Latin-square randomised, minus-active controlled design balanced for residual effects. The formulations were 0.01%, 0.05%, 0.1% and 0.2% triclosan in 0.5% sodium carbonate and 5% alcohol aqueous solutions, used as 10 ml, 1-min rinses 2 x daily, without tooth-brushing. 2 groups each of 15 healthy volunteers rinsed during alternate 4-day treatment, 1-week washout periods with the allocated rinses. From a zero-plaque baseline on Day 1, plaque was scored by index and area on Day 5. A dose response pattern of decreasing plaque indices and particularly areas, with increasing triclosan dose was observed. However, by far the largest sequential drop in plaque scores occurred between 0.1% and 0.2% triclosan treatments. Extending the dose-response study to higher concentrations is considered impractical if not unjustifiable, because of potential harmful local side-effects and compliance difficulties. Dose-response studies to assess the agents thought to potentiate triclosan would seem warranted.

  2. 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...

  3. 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.)…

  4. 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...

  5. 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.

  6. 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...

  7. 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:…

  8. 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...

  9. 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 ...

  10. Evaluating quantitative formulas for dose-response assessment of chemical mixtures.

    PubMed Central

    Hertzberg, Richard C; Teuschler, Linda K

    2002-01-01

    Risk assessment formulas are often distinguished from dose-response models by being rough but necessary. The evaluation of these rough formulas is described here, using the example of mixture risk assessment. Two conditions make the dose-response part of mixture risk assessment difficult, lack of data on mixture dose-response relationships, and the need to address risk from combinations of chemicals because of public demands and statutory requirements. Consequently, the U.S. Environmental Protection Agency has developed methods for carrying out quantitative dose-response assessment for chemical mixtures that require information only on the toxicity of single chemicals and of chemical pair interactions. These formulas are based on plausible ideas and default parameters but minimal supporting data on whole mixtures. Because of this lack of mixture data, the usual evaluation of accuracy (predicted vs. observed) cannot be performed. Two approaches to the evaluation of such formulas are to consider fundamental biological concepts that support the quantitative formulas (e.g., toxicologic similarity) and to determine how well the proposed method performs under simplifying constraints (e.g., as the toxicologic interactions disappear). These ideas are illustrated using dose addition and two weight-of-evidence formulas for incorporating toxicologic interactions. PMID:12634126

  11. 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...

  12. Duration of Exposure and the Dose-Response Model of PTSD

    ERIC Educational Resources Information Center

    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…

  13. 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...

  14. 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 ...

  15. 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.

  16. Evidence for curvilinearity in the cancer incidence dose-response in the Japanese atomic bomb survivors.

    PubMed

    Little, M P; Muirhead, C R

    1996-07-01

    The recently released data on cancer incidence in the Japanese atomic bomb survivors are analysed using a variety of relative risk models which take account of errors in estimates of dose to assess the dose-response at low doses. For all solid cancers analysed together there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Linear-quadratic models and linear-quadratic models with an exponential cell-sterilization term provide no better fit than the linear model. For the three main radiation-inducible leukaemia subtypes analysed together (acute lymphatic leukaemia, acute myeloid leukaemia and chronic myeloid leukaemia) there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the leukaemia data, a thresh-old of more than about 0.3 Sv is inconsistent with the data. In contrast with the solid cancer data, the best estimate for the threshold level in the leukaemia data is significantly different from zero, even when allowance is made for a possible quadratic term in the dose-response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukaemia dose-response from 0.2 Sv upwards. However, the possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken

  17. Dose-Responsive Gene Expression in Suberoylanilide Hydroxamic Acid (SAHA) Treated Resting CD4+ T Cells

    PubMed Central

    Reardon, Brian; Beliakova-Bethell, Nadejda; Spina, Celsa A.; Singhania, Akul; Margolis, David M.; Richman, Douglas R.; Woelk, Christopher H.

    2015-01-01

    Design Persistent latently infected CD4+ T cells represent a major obstacle to HIV eradication. Histone deacetylase inhibitors (HDACis) are a proposed activation therapy. However, off-target effects on expression in host immune cells are poorly understood. We hypothesized that HDACi-modulated genes would be best identified with dose-response analysis. Methods Resting primary CD4+ T cells were treated with 0.34, 1, 3, or 10 μM of the HDACi, SAHA, for 24 hours and subjected to microarray gene expression analysis. Genes with dose-correlated expression were filtered to identify a subset with consistent up or downregulation at each SAHA dose. Histone modifications were characterized in 6 SAHA dose-responsive genes by chromatin immunoprecipitation (ChIP-RT-qPCR). Results A large number of genes were shown to be up (N=657) or downregulated (N=725) by SAHA in a dose-responsive manner (FDR p-value < 0.05, fold change ≥ |2|). Several genes (CTNNAL1, DPEP2, H1F0, IRGM, PHF15, and SELL) are potential in vivo biomarkers of SAHA activity. SAHA dose-responsive genes included transcription factors, HIV restriction factors, histone methyltransferases, and host proteins that interact with HIV. Pathway analysis suggested net downregulation of T cell activation with increasing SAHA dose. Histone acetylation was not correlated with host gene expression, but plausible alternative mechanisms for SAHA-modulated gene expression were identified. Conclusions Numerous genes in CD4+ T cells are modulated by SAHA in a dose-responsive manner, including genes that may negatively influence HIV activation from latency. Our study suggests that SAHA influences gene expression through a confluence of several mechanisms, including histone modification, and altered expression and activity of transcription factors. PMID:26258524

  18. 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

  19. 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

  20. TOWARD A BIOLOGICALLY BASED DOSE-RESPONSE MODEL FOR DEVELOPMENTAL TOXICITY OF 5-FLUOROURACIL IN THE RAT: A MATHEMATICAL CONSTRUCT

    EPA Science Inventory

    Biologically based dose-response (BBDR) models comprise one way to incorporate mechanistic information into a dose-response assessment to be used for risk assessments. The chemotherapeutic drug 5-fluorouracil (5-FU) has been used as a prototypic compound for the construction of ...

  1. 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

  2. Dose-response relationship between amphibole fiber lung burden and mesothelioma.

    PubMed

    Rödelsperger, K; Woitowitz, H J; Brückel, B; Arhelger, R; Pohlabeln, H; Jöckel, K H

    1999-01-01

    In a mesothelioma case-control study, asbestos and other mineral fibers from lung burden were examined as causal factors. Diagnosis was confirmed by a panel of pathologists. For 66 cases and 66 controls from hospitals in five German towns, lung tissue fiber analysis by transmission electron microscopy was available. Control patients were treated by a surgical lung resection mostly because of lung cancer. For chrysotile and other mineral fibers a significantly increased odds ratio (OR) was not observed. A clear dose-response relationship was demonstrated for the concentration CA of amphibole fibers longer than 5 microm. Between 0.025 and 2.5 fibers/microg dry weight (f/microg) the relationship can be approximated as OR = CA/(0. 025 f/microg). Similar but less distinct dose-response relationships were found in a Canadian and an Australian study. It is concluded that among German mesothelioma patients factors not associated with amphibole fiber concentration are not predominating.

  3. 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

  4. 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

  5. A novel method of estimating dose responses for polymer gels using texture analysis of scanning electron microscopy images.

    PubMed

    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 R (2) 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

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

    PubMed

    El Naqa, I; Suneja, G; Lindsay, P E; Hope, A J; Alaly, J R; Vicic, M; Bradley, J D; Apte, A; Deasy, J O

    2006-11-21

    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.

  7. 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.

  8. Cytogenetic dose-response in vitro for biological dosimetry after exposure to high doses of gamma-rays.

    PubMed

    Vinnikov, Volodymyr A; Maznyk, Nataliya A

    2013-04-01

    The dose response for dicentrics plus centric rings and total unstable chromosome-type aberrations was studied in the first mitoses of cultured human peripheral blood lymphocytes irradiated in vitro to doses of ∼2, 4, 6, 8, 10, 16 and 20 Gy of acute (60)Со gamma-rays. A dose-dependent increase of aberration yield was accompanied by a tendency to the underdispersion of dicentrics and centric rings among cells distributions compared with Poisson statistics at doses ≥6 Gy. The formal fitting of the data to a linear-quadratic model resulted in an equation with the linear and quadratic coefficients ranged 0.098-0.129×cell(-1)×Gy(-1) and 0.039-0.034×cell(-1)×Gy(-2), respectively, depending on the fitting method. The actual radiation-induced aberration yield was markedly lower than expected from a calibration curve, generated earlier within a lower dose range. Interlaboratory variations in reported dicentric yields induced by medium-to-high radiation doses in vitro are discussed.

  9. Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol A as a Case Study

    PubMed Central

    Vandenberg, Laura N.

    2014-01-01

    Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not ‘common enough’ to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where ‘safe’ low doses are predicted from high dose exposures. PMID:24910584

  10. Dose-response effect of a novel functional fibre, PolyGlycopleX(®), PGX(®), on satiety.

    PubMed

    Solah, Vicky A; Brand-Miller, Jennie C; Atkinson, Fiona S; Gahler, Roland J; Kacinik, Veronica; Lyon, Michael R; Wood, Simon

    2014-06-01

    The objective of this research was to determine the dose-response effects of a palatable, viscous and gel forming fibre, PolyGlycopleX(®) (PGX(®)), [(α-D-glucurono-α-manno-β-D-manno-β-D-gluco), (α-Lgulurono-β-D mannurono), (β-D-gluco-β-D-mannan)] on satiety, and to gain insight into the underlying mechanisms that lead to appetite inhibition. Healthy subjects (n = 10), aged between 20.3 and 29.2 years, consumed PGX(®), in granular form at 2.5, 5.0 and 7.5 g, and a 5g inulin control, with a standard breakfast. The PGX(®) doses of 2.5 and 7.5 g mixed with water at the start of breakfast increased satiety (iAUC of 140.0 and 157.7, P = 0.025 and 0.001, respectively) compared to the control. The most effective dose (7.5g) was palatable and corresponded to a 34% increase in fullness, measured using a visual analogue scale and incremental area under the curve, and resulted in a delayed postprandial glycaemic response when compared with the control. PMID:24631638

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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

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

    NASA Astrophysics Data System (ADS)

    Pedersen, Eja; Persson Waye, Kerstin

    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. .

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

    PubMed

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

    2015-12-02

    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.

  19. 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

  20. 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

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

    PubMed

    Rosier, Bob T; Lazova, Milena D

    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 attractant

  2. Joint detection of important biomarkers and optimal dose-response model using penalties.

    PubMed

    Vandenhende, F; Eilers, P; Ledent, E; Renard, D; Tibaldi, F

    2007-11-30

    We propose a method to jointly detect influential biomarkers and estimate how they change with dose. The assessment is made in dose-ranging trials collecting multiple outcomes for efficacy, safety, pharmacokinetics or pharmacodynamics. We regress all these outcomes versus a non-parametric transformation of the dose. The regression coefficients and the parameters from the dose-response model are simultaneously estimated using a penalized alternating least-squares method. We illustrate the technique with a phase I clinical trial and a metabonomic experiment in rats. PMID:17579922

  3. Agonist-sensitive calcium pool in the pancreatic acinar cell. I. Permeability properties

    SciTech Connect

    Muallem, S.; Schoeffield, M.S.; Fimmel, C.J.; Pandol, S.J.

    1988-08-01

    45Ca2+ fluxes and free cytosolic Ca2+ (( Ca2+)i) were used to describe the Ca2+ permeability and Ca2+ reloading of the agonist-sensitive pool at rest, during stimulation, and at termination of stimulation. A sequence of stimulation with carbachol, inhibition with atropine (cycling), and restimulation with cholecystokinin octapeptide (CCK-8) was used to follow Ca2+ reloading. Reloading of the pool required extracellular Ca2+ and was measured as an increased rate and extent of 45Ca2+ uptake into the acini. The 45Ca2+ incorporated into cycled acini could be completely released with CCK-8. The dose-response curves for 45Ca uptake and release were identical to those of the hormonally evoked (Ca2+)i increase. The increased 45Ca2+ uptake during reloading was not due to an expansion of any intracellular pool size but reflects the labeling of the pool to isotopic equilibrium in cycled acini. The rate constant of Ca2+ efflux from the pool of resting cells was approximately 0.67 +/- 0.01/h. With stimulation, the Ca2+ permeability of the pool membrane rapidly increased, resulting in Ca2+ release into the cytosol and an increase in (Ca2+)i. With termination of stimulation, the Ca2+ permeability of the pool membrane rapidly decreased while the pool continued to reload with extracellular Ca2+. Labeling of the pool to isotopic equilibrium allowed determination of the amount of Ca2+ released from the pool, which was 2.94 +/- 0.06 nmol/mg protein. This indicates that total Ca2+ concentration in the pool is in the millimolar range.

  4. 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...

  5. Dose-response relationship between ingested arsenic and cataracts among residents in Southwestern Taiwan.

    PubMed

    See, Lai-Chu; Chiou, Hung-Yi; Lee, Jiahn-Shing; Hsueh, Yu-Mei; Lin, Shu-Mei; Tu, Ming-Chang; Yang, Meng-Ling; Chen, Chien-Jen

    2007-10-01

    This association study was carried out to examine the effect of long-term exposure to ingested arsenic on various types of cataract. A total of 349 residents living in arseniasis-hyperendemic villages of southwestern Taiwan were recruited. Cumulative arsenic exposure was derived from the history of consuming artesian well water and the arsenic level in well water. The Lens Opacities System III was used to classify different types of cataract. The cataract surgery prevalence was 10% for the age group of 50 or more years. Cortical opacity was most common (35%), while nuclear and posterior subcapsular opacities were observed in 24% and 22% of subjects, respectively. Diabetes mellitus was a significant risk factor for all types of cataract. Occupational sunlight exposure was associated with cortical and posterior subcapsular opacities in a dose-response relationship. The cumulative exposure to arsenic from artesian well water and the duration of consuming artesian well water were associated with an increased risk of all types of lens opacity. But statistically significant dose-response relations with the cumulative arsenic exposure and the duration of consuming artesian well water were observed only for posterior subcapsular opacity (P=0.014 and P=0.023, respectively) after adjustment for age, sex, diabetes status, and occupational sunlight exposure. It was concluded that there was an increasing prevalence of posterior subcapsular opacity with the increase in exposure to ingested arsenic.

  6. 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

  7. Dose-response analyses of the carcinogenic effects of trichloroethylene in experimental animals.

    PubMed Central

    Rhomberg, L R

    2000-01-01

    In lifetime bioassays, trichloroethylene (TCE, CAS No. 79-01-6) causes liver tumors in mice following gavage, liver and lung tumors in mice following inhalation, and kidney tumors in rats following gavage or inhalation. Recently developed pharmacokinetic models provide estimates of internal, target-organ doses of the TCE metabolites thought responsible for these tumor responses. Dose-response analyses following recently proposed methods for carcinogen risk assessment from the U.S. Environmental Protection Agency (U.S. EPA) are conducted on the animal tumor data using the pharmacokinetic dosimeters to derive a series of alternative projections of the potential carcinogenic potency of TCE in humans exposed to low environmental concentrations. Although mechanistic considerations suggest action of possibly nonlinear processes, dose-response shapes in the observable range of tumor incidence evince little sign of such patterns. Results depend on which of several alternative pharmacokinetic analyses are used to define target-organ doses. Human potency projections under the U.S. EPA linear method based on mouse liver tumors and internal dosimetry equal or somewhat exceed calculations based on administered dose, and projections based on mouse liver tumors exceed those from mouse lung or rat kidney tumors. Estimates of the carcinogenic potency of the two primary oxidative metabolites of TCE--trichloroacetic acid and dichloroacetic acid, which are mouse liver carcinogens in their own right--are also made, but it is not clear whether the carcinogenic potency of TCE can be quantitatively ascribed to metabolic generation of these metabolites. PMID:10807564

  8. A prototype microfluidic platform for miniaturization and automation of serial dilution and dose-response assays.

    PubMed

    Koehler, Jeffrey; Vajjhala, Surekha; Coyne, Courtney; Flynn, Terence; Pezzuto, Marci; Williams, Manda; Levine, Leanna

    2002-11-01

    A novel microfluidic device was designed and developed to miniaturize, multiplex, and automate serial dilution and three-reagent dose-response assays using submicroliter quantities of reagents. This prototype microfluidic device can be used to measure enzyme kinetics and to test a chemical lead's response to a target by fluorescent readout using common plate readers and detection systems. The prototype microfluidic system yielded serial dilution and dose-response assay data comparable to results obtained from manual titrations and reagent additions performed using a microwell plate. Enzyme kinetics were highly reproducible using these devices, although Michaelis-Menten kinetics results differed from those obtained in the microwell plate. In all cases reported here, assays performed on the microfluidic format required lower volumes of reagents compared with the microwell plate. In addition to savings in reagent consumption, the microfluidic devices and bench-top instruments offer additional advantages over conventional solutions, including a small footprint and compatibility with commercially available fluorescence detectors. Future directions for the prototype technology are discussed.

  9. Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model.

    PubMed

    Schachtel, Bernard P; Homan, Harvey D; Gibb, Iain A; Christian, Jenny

    2002-05-01

    The dose response of flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). The 2.5-mg flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent.

  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. Quantitative mechanistically based dose-response modeling with endocrine-active compounds.

    PubMed Central

    Andersen, M E; Conolly, R B; Faustman, E M; Kavlock, R J; Portier, C J; Sheehan, D M; Wier, P J; Ziese, L

    1999-01-01

    A wide range of toxicity test methods is used or is being developed for assessing the impact of endocrine-active compounds (EACs) on human health. Interpretation of these data and their quantitative use in human and ecologic risk assessment will be enhanced by the availability of mechanistically based dose-response (MBDR) models to assist low-dose, interspecies, and (italic)in vitro(/italic) to (italic)in vivo(/italic) extrapolations. A quantitative dose-response modeling work group examined the state of the art for developing MBDR models for EACs and the near-term needs to develop, validate, and apply these models for risk assessments. Major aspects of this report relate to current status of these models, the objectives/goals in MBDR model development for EACs, low-dose extrapolation issues, regulatory inertia impeding acceptance of these approaches, and resource/data needs to accelerate model development and model acceptance by the research and the regulatory community. PMID:10421774

  12. Does a dose-response relation exist between spinal pain and temporomandibular disorders?

    PubMed Central

    Wiesinger, Birgitta; Malker, Hans; Englund, Erling; Wänman, Anders

    2009-01-01

    Background The aim of this study was to test whether a reciprocal dose-response relation exists between frequency/severity of spinal pain and temporomandibular disorders (TMD). Methods A total of 616 subjects with varying severity of spinal pain or no spinal pain completed a questionnaire focusing on symptoms in the jaw, head and spinal region. A subset of the population (n = 266) were sampled regardless of presence or absence of spinal pain. We used two different designs, one with frequency/severity of spinal pain, and the other, with frequency/severity of TMD symptoms as independent variable. All 616 participants were allocated to four groups, one control group without spinal pain and three spinal pain groups. The subjects in the subset were allocated to one control group without TMD symptoms and three TMD groups. Odds ratios (ORs) were calculated for presence of frequent TMD symptoms in the separate spinal pain groups as well as for frequent spinal pain in the separate TMD groups. Results The analysis showed increasing ORs for TMD with increasing frequency/severity of spinal pain. We also found increasing ORs for spinal pain with increasing frequency/severity of TMD symptoms. Conclusion This study shows a reciprocal dose-response-like relationship between spinal pain and TMD. The results indicate that these two conditions may share common risk factors or that they may influence each other. Studies on the temporal sequence between spinal pain and TMD are warranted. PMID:19254384

  13. Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model.

    PubMed

    Schachtel, Bernard P; Homan, Harvey D; Gibb, Iain A; Christian, Jenny

    2002-05-01

    The dose response of flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). The 2.5-mg flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent. PMID:12011823

  14. Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose-response meta-analysis.

    PubMed

    Greenwood, Darren C; Thatcher, Natalie J; Ye, Jin; Garrard, Lucy; Keogh, Georgina; King, Laura G; Cade, Janet E

    2014-10-01

    Caffeine is commonly consumed during pregnancy, crosses the placenta, with fetal serum concentrations similar to the mother's, but studies of birth outcome show conflicting findings. We systematically searched Medline and Embase for relevant publications. We conducted meta-analysis of dose-response curves for associations between caffeine intake and spontaneous abortion, stillbirth, preterm delivery, low birth weight and small for gestational age (SGA) infants. Meta-analyses included 60 unique publications from 53 cohort and case-control studies. An increment of 100 g caffeine was associated with a 14 % (95 % CI 10-19 %) increase in risk of spontaneous abortion, 19 % (5-35 %) stillbirth, 2 % (-2 to 6 %) preterm delivery, 7 % (1-12 %) low birth weight, and 10 % (95 % CI 6-14 %) SGA. There was substantial heterogeneity in all models, partly explained by adjustment for smoking and previous obstetric history, but not by prospective assessment of caffeine intake. There was evidence of small-study effects such as publication bias. Greater caffeine intake is associated with an increase in spontaneous abortion, stillbirth, low birth weight, and SGA, but not preterm delivery. There is no identifiable threshold below which the associations are not apparent, but the size of the associations are generally modest within the range of usual intake and are potentially explained by bias in study design or publication. There is therefore insufficient evidence to support further reductions in the maximum recommended intake of caffeine, but maintenance of current recommendations is a wise precaution.

  15. Spatial distribution and dose-response relationship for different operation modes in a reaction-diffusion model of the MAPK cascade

    NASA Astrophysics Data System (ADS)

    Zhao, Qi; Yi, Ming; Liu, Yan

    2011-10-01

    The mitogen-activated protein kinase (MAPK) cascade plays a critical role in the control of cell growth. Deregulation of this pathway contributes to the development of many cancers. To better understand its signal transduction, we constructed a reaction-diffusion model for the MAPK pathway. We modeled the three layers of phosphorylation-dephosphorylation reactions and diffusion processes from the cell membrane to the nucleus. Based on different types of feedback in the MAPK cascade, four operation modes are introduced. For each of the four modes, spatial distributions and dose-response curves of active kinases (i.e. ppMAPK) are explored by numerical simulation. The effects of propagation length, diffusion coefficient and feedback strength on the pathway dynamics are investigated. We found that intrinsic bistability in the MAPK cascade can generate a traveling wave of ppMAPK with constant amplitude when the propagation length is short. ppMAPK in this mode of intrinsic bistability decays more slowly than it does in all other modes as the propagation length increases. Moreover, we examined the global and local responses to Ras-GTP of these four modes, and demonstrated how the shapes of these dose-response curves change as the propagation length increases. Also, we found that larger diffusion constant gives a higher response level on the zero-order regime and makes the ppMAPK profiles flatter under strong Ras-GTP stimulus. Furthermore, we observed that spatial responses of ppMAPK are more sensitive to negative feedback than to positive feedback in the broader signal range. Finally, we showed how oscillatory signals pass through the kinase cascade, and found that high frequency signals are damped faster than low frequency ones.

  16. 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

  17. 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

  18. Bradford Curves.

    ERIC Educational Resources Information Center

    Rousseau, Ronald

    1994-01-01

    Discussion of informetric distributions shows that generalized Leimkuhler functions give proper fits to a large variety of Bradford curves, including those exhibiting a Groos droop or a rising tail. The Kolmogorov-Smirnov test is used to test goodness of fit, and least-square fits are compared with Egghe's method. (Contains 53 references.) (LRW)

  19. Dose-response and risk assessment of airborne hexavalent chromium and lung cancer mortality.

    PubMed

    Crump, Casey; Crump, Kenny; Hack, Eric; Luippold, Rose; Mundt, Kenneth; Liebig, Elizabeth; Panko, Julie; Paustenbach, Dennis; Proctor, Deborah

    2003-12-01

    This study evaluates the dose-response relationship for inhalation exposure to hexavalent chromium [Cr(VI)] and lung cancer mortality for workers of a chromate production facility, and provides estimates of the carcinogenic potency. The data were analyzed using relative risk and additive risk dose-response models implemented with both Poisson and Cox regression. Potential confounding by birth cohort and smoking prevalence were also assessed. Lifetime cumulative exposure and highest monthly exposure were the dose metrics evaluated. The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to 1 microg/m3 Cr(VI) (occupational exposure unit risk) was 0.00205 (90%CI: 0.00134, 0.00291) for the relative risk model and 0.00216 (90%CI: 0.00143, 0.00302) for the additive risk model assuming a linear dose response for cumulative exposure with a five-year lag. Extrapolating these findings to a continuous (e.g., environmental) exposure scenario yielded an environmental unit risk of 0.00978 (90%CI: 0.00640, 0.0138) for the relative risk model [e.g., a cancer slope factor of 34 (mg/kg-day)-1] and 0.0125 (90%CI: 0.00833, 0.0175) for the additive risk model. The relative risk model is preferred because it is more consistent with the expected trend for lung cancer risk with age. Based on statistical tests for exposure-related trend, there was no statistically significant increased lung cancer risk below lifetime cumulative occupational exposures of 1.0 mg-yr/m3, and no excess risk for workers whose highest average monthly exposure did not exceed the current Permissible Exposure Limit (52 microg/m3). It is acknowledged that this study had limited power to detect increases at these low exposure levels. These cancer potency estimates are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI).

  20. A natural history of "agonist".

    PubMed

    Russo, Ruth

    2002-01-01

    This paper constructs a brief history of the biochemical term agonist by exploring the multiple meanings of the root agôn in ancient Greek literature and describing how agonist first appeared in the scientific literature of the 20th century in the context of neurophysiologists' debates about the existence and properties of cellular receptors. While the narrow scientific definition of agonist may appear colorless and dead when compared with the web of allusions spun by the ancient Greek agôn, the scientific power and creativity of agonist actually resides precisely in its exact, restricted meaning for biomedical researchers.

  1. 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

  2. A dose-response relation of headers and concussions with cognitive impairment in professional soccer players.

    PubMed

    Matser, J T; Kessels, A G; Lezak, M D; Troost, J

    2001-12-01

    The purpose of this study was to determine the effects of headers and concussions on cognitive impairment in professional soccer players. A group of 84 active professional soccer players from several premier league soccer clubs underwent neuropsychological evaluations. The dose-response relation between the number of headers in one professional season and the number of soccer-related concussions on cognitive functioning was investigated. It was found that the number of headers in one season was related to poorer results on tests measuring focused attention and visual/verbal memory. Soccer-related concussions were related to poorer results on tests measuring sustained attention and visuoperceptual processing. The findings suggest that headers as well as concussions separately contribute to cognitive impairment.

  3. 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.

  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 relationships between pollination and fruiting refine pollinator comparisons for cranberry (Vaccinium macrocarpon [Ericaceae]).

    PubMed

    Cane, James H; Schiffhauer, Daniel

    2003-10-01

    Comparisons of pollinator efficacy using pollen received on stigmas can be refined by incorporating experimental dose-response relationships for pollen deposition and fruiting responses. A range of discrete pollen doses applied to cranberry stigmas resulted in decelerating curvilinear responses for fruiting, berry size, and seed set. Minimum thresholds and maximum asymptotes bounded reproductive responses to incremental stigmatic pollen loads. Four bee species were compared for their pollination efficacies on commercial cranberries, using counts of pollen received by stigmas during single bee visits to previously virgin flowers. Differences between these bee species were found to be exaggerated when raw pollen counts were used for comparison because foragers of some species often delivered pollen in excess of that needed to maximize fruit and seed production. Sixfold differences between species in mean pollen deposition translated into 1.5-2-fold differences in predicted cranberry fruit set and size. Implications for pollen tube competition and agricultural production are discussed.

  6. 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.

  7. Dose response of xylitol and sorbitol for EPR retrospective dosimetry with applications to chewing gum.

    PubMed

    Israelsson, A; Gustafsson, H; Lund, E

    2013-04-01

    The purpose of this investigation was to study the radiation-induced electron paramagnetic resonance signal in sweeteners xylitol and sorbitol for use in retrospective dosimetry. For both sweeteners and chewing gum, the signal changed at an interval of 1-84 d after irradiation with minimal changes after 4-8 d. A dependence on storage conditions was noticed and the exposure of the samples to light and humidity was therefore minimised. Both the xylitol and sorbitol signals showed linearity with dose in the measured dose interval, 0-20 Gy. The dose-response measurements for the chewing gum resulted in a decision threshold of 0.38 Gy and a detection limit of 0.78 Gy. A blind test illustrated the possibility of using chewing gums as a retrospective dosemeter with an uncertainty in the dose determination of 0.17 Gy (1 SD).

  8. 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

  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.

  10. 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.

  11. Assessing dose-response relationships for endocrine disrupting chemicals (EDCs): a focus on non-monotonicity.

    PubMed

    Zoeller, R Thomas; Vandenberg, Laura N

    2015-01-01

    The fundamental principle in regulatory toxicology is that all chemicals are toxic and that the severity of effect is proportional to the exposure level. An ancillary assumption is that there are no effects at exposures below the lowest observed adverse effect level (LOAEL), either because no effects exist or because they are not statistically resolvable, implying that they would not be adverse. Chemicals that interfere with hormones violate these principles in two important ways: dose-response relationships can be non-monotonic, which have been reported in hundreds of studies of endocrine disrupting chemicals (EDCs); and effects are often observed below the LOAEL, including all environmental epidemiological studies examining EDCs. In recognition of the importance of this issue, Lagarde et al. have published the first proposal to qualitatively assess non-monotonic dose response (NMDR) relationships for use in risk assessments. Their proposal represents a significant step forward in the evaluation of complex datasets for use in risk assessments. Here, we comment on three elements of the Lagarde proposal that we feel need to be assessed more critically and present our arguments: 1) the use of Klimisch scores to evaluate study quality, 2) the concept of evaluating study quality without topical experts' knowledge and opinions, and 3) the requirement of establishing the biological plausibility of an NMDR before consideration for use in risk assessment. We present evidence-based logical arguments that 1) the use of the Klimisch score should be abandoned for assessing study quality; 2) evaluating study quality requires experts in the specific field; and 3) an understanding of mechanisms should not be required to accept observable, statistically valid phenomena. It is our hope to contribute to the important and ongoing debate about the impact of NMDRs on risk assessment with positive suggestions. PMID:25971795

  12. Meta-analysis on occupational exposure to pesticides--neurobehavioral impact and dose-response relationships.

    PubMed

    Meyer-Baron, Monika; Knapp, Guido; Schäper, Michael; van Thriel, Christoph

    2015-01-01

    While the health impact of high exposures to pesticides is acknowledged, the impact of chronic exposures in the absence of acute poisonings is controversial. A systematic analysis of dose-response relationships is still missing. Its absence may provoke alternative explanations for altered performances. Consequently, opportunities for health prevention in the occupational and environmental field may be missed. Objectives were (1) quantification of the neurotoxic impact of pesticides by an analysis of functional alterations in workers measured by neuropsychological performance tests, (2) estimates of dose-response relationships on the basis of exposure duration, and (3) exploration of susceptible subgroups. The meta-analysis employed a random effects model to obtain overall effects for individual performance tests. Twenty-two studies with a total of 1758 exposed and 1260 reference individuals met the inclusion criteria. At least three independent outcomes were available for twenty-six performance variables. Significant performance effects were shown in adults and referred to both cognitive and motor performances. Effect sizes ranging from dRE=-0.14 to dRE=-0.67 showed consistent outcomes for memory and attention. Relationships between effect sizes and exposure duration were indicated for individual performance variables and the total of measured performances. Studies on adolescents had to be analyzed separately due to numerous outliers. The large variation among outcomes hampered the analysis of the susceptibility in this group, while data on female workers was too scant for the analysis. Relationships exist between the impact of pesticides on performances and exposure duration. A change in test paradigms would help to decipher the impact more specifically. The use of biomarkers appropriate for lower exposures would allow a better prevention of neurotoxic effects due to occupational and environmental exposure. Intervention studies in adolescents seem warranted to

  13. 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

  14. Triphasic low-dose response in zebrafish embryos irradiated by microbeam protons.

    PubMed

    Choi, Viann Wing Yan; Yum, Emily Hoi Wa; Konishi, Teruaki; Oikawa, Masakazu; Cheng, Shuk Han; Yu, Kwan Ngok

    2012-01-01

    The microbeam irradiation system (Single-Particle Irradiation System to Cell, acronym as SPICE) at the National Institute of Radiological Sciences (NIRS), Japan, was employed to irradiate dechorionated zebrafish embryos at the 2-cell stage at 0.75 h post fertilization (hpf) by microbeam protons. Either one or both of the cells of the embryos were irradiated with 10, 20, 40, 50, 80, 100, 160, 200, 300 and 2000 protons each with an energy of 3.37 MeV. The embryos were then returned back to the incubator until 24 hpf for analyses. The levels of apoptosis in zebrafish embryos at 25 hpf were quantified through terminal dUTP transferase-mediated nick end-labeling (TUNEL) assay, with the apoptotic signals captured by a confocal microscope. The results revealed a triphasic dose-response for zebrafish embryos with both cells irradiated at the 2-cell stage, namely, (1) increase in apoptotic signals for < 200 protons (< 30 mGy), (2) hormesis to reduce the apoptotic signals below the spontaneous number for 200-400 protons (at doses of 30-60 mGy), and (3) increase in apoptotic signals again for > 600 protons (at doses > 90 mGy). The dose response for zebrafish embryos with only one cell irradiated at the 2-cell stage was also likely a triphasic one, but the apoptotic signals in the first zone (< 200 protons or < 30 mGy) did not have significant differences from those of the background. At the same time, the experimental data were in line with induction of radiation-induced bystander effect as well as rescue effect in the zebrafish embryos, particular in those embryos with unirradiated cells.

  15. Forecasting Cell Death Dose-Response from Early Signal Transduction Responses In Vitro

    PubMed Central

    Vrana, Julie A.; Currie, Holly N.; Han, Alice A.; Boyd, Jonathan

    2014-01-01

    The rapid pharmacodynamic response of cells to toxic xenobiotics is primarily coordinated by signal transduction networks, which follow a simple framework: the phosphorylation/dephosphorylation cycle mediated by kinases and phosphatases. However, the time course from initial pharmacodynamic response(s) to cell death following exposure can have a vast range. Viewing this time lag between early signaling events and the ultimate cellular response as an opportunity, we hypothesize that monitoring the phosphorylation of proteins related to cell death and survival pathways at key, early time points may be used to forecast a cell's eventual fate, provided that we can measure and accurately interpret the protein responses. In this paper, we focused on a three-phased approach to forecast cell death after exposure: (1) determine time points relevant to important signaling events (protein phosphorylation) by using estimations of adenosine triphosphate production to reflect the relationship between mitochondrial-driven energy metabolism and kinase response, (2) experimentally determine phosphorylation values for proteins related to cell death and/or survival pathways at these significant time points, and (3) use cluster analysis to predict the dose-response relationship between cellular exposure to a xenobiotic and plasma membrane degradation at 24 h post-exposure. To test this approach, we exposed HepG2 cells to two disparate treatments: a GSK-3β inhibitor and a MEK inhibitor. After using our three-phased approach, we were able to accurately forecast the 24 h HepG2 plasma membrane degradation dose-response from protein phosphorylation values as early as 20 min post-MEK inhibitor exposure and 40 min post-GSK-3β exposure. PMID:24824809

  16. 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.

  17. Origin of the linearity no threshold (LNT) dose-response concept.

    PubMed

    Calabrese, Edward J

    2013-09-01

    This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673-674, 1928) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201-213, 1929; Oliver in Science 71:44-46, 1930), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose-response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide. PMID:23887208

  18. Forecasting cell death dose-response from early signal transduction responses in vitro.

    PubMed

    Vrana, Julie A; Currie, Holly N; Han, Alice A; Boyd, Jonathan

    2014-08-01

    The rapid pharmacodynamic response of cells to toxic xenobiotics is primarily coordinated by signal transduction networks, which follow a simple framework: the phosphorylation/dephosphorylation cycle mediated by kinases and phosphatases. However, the time course from initial pharmacodynamic response(s) to cell death following exposure can have a vast range. Viewing this time lag between early signaling events and the ultimate cellular response as an opportunity, we hypothesize that monitoring the phosphorylation of proteins related to cell death and survival pathways at key, early time points may be used to forecast a cell's eventual fate, provided that we can measure and accurately interpret the protein responses. In this paper, we focused on a three-phased approach to forecast cell death after exposure: (1) determine time points relevant to important signaling events (protein phosphorylation) by using estimations of adenosine triphosphate production to reflect the relationship between mitochondrial-driven energy metabolism and kinase response, (2) experimentally determine phosphorylation values for proteins related to cell death and/or survival pathways at these significant time points, and (3) use cluster analysis to predict the dose-response relationship between cellular exposure to a xenobiotic and plasma membrane degradation at 24 h post-exposure. To test this approach, we exposed HepG2 cells to two disparate treatments: a GSK-3β inhibitor and a MEK inhibitor. After using our three-phased approach, we were able to accurately forecast the 24 h HepG2 plasma membrane degradation dose-response from protein phosphorylation values as early as 20 min post-MEK inhibitor exposure and 40 min post-GSK-3β exposure.

  19. Kidney dysfunction and cadmium exposure--factors influencing dose-response relationships.

    PubMed

    Nordberg, Gunnar; Jin, Taiyi; Wu, Xunwei; Lu, Jian; Chen, Liang; Liang, Yihuai; Lei, Lijian; Hong, Feng; Bergdahl, Ingvar A; Nordberg, Monica

    2012-06-01

    Our early toxicological studies showed that metallothionein (MT) is a protein that carries cadmium (Cd) to the kidney, explaining why Cd exposures during long time periods may give rise to kidney dysfunction. This dysfunction is usually considered to be the critical effect, i.e. the adverse effect that occurs at the lowest exposure level. MT also provides intracellular protection against cadmium toxicity. In studies of population groups in cadmium contaminated areas in China, we investigated factors that affected the relationship between internal dose of Cd, as indicated by blood Cd (BCd) or urinary Cd (UCd), and the prevalence of kidney dysfunction. We found dose-response relationships between UCd and the prevalence of increased levels of biomarkers of renal tubular dysfunction (urinary beta-2-microglobulin, B2M, or N-acetyl-beta-d-glucosaminidase - NAG) or urinary albumin (UAlb), a biomarker of glomerular kidney dysfunction. Two years after Cd intake from contaminated rice was diminished, renal tubular dysfunction appeared unchanged or aggravated among those with higher UCd; Another 8 years later, i.e. 10 years after Cd intake was decreased, the prevalence of renal tubular dysfunction was still increased but UAlb had returned to normal. Factors that influenced the dose-response relationships were: (1) time after maximum exposure. (2) Concomitant exposure to other nephrotoxic agents such as inorganic arsenic. (3) Cd induced metallothionein mRNA levels in peripheral blood lymphocytes, used as a biomarker of the ability of each person, to synthesize MT. (4) The occurrence of increased levels in blood plasma of autoantibodies against MT. The two last points further support a role in humans of MT as a protective protein against tissue damage from cadmium and gives support to previous ideas developed partly in experimental systems.

  20. Recent odour regulation developments in Flanders: ambient odour quality standards based on dose-response relationships.

    PubMed

    Van Broeck, G; Van Langenhove, H; Nieuwejaers, B

    2001-01-01

    Until now there has been little uniformity in the approach of odour nuisance problems in Flanders. A switch to a standardised and scientifically underpinned approach is essential and is currently in full development. This paper mainly discusses the results of five year research on odour concentration standard developments in Flanders, executed in the period 1996-2000. The research was focused on five pilot sectors: pig farms, slaughterhouses, paint spray installations, sewage treatment plants and textile plants. The general approach of the method to determine the dose-response relation was found to be sufficient. The methodology used is fully described in the paper presented by Van Broeck and Van Langenhove at the CIWEM and IAWO Joint International Conference on Control and Prevention of Odours in the Water Industry in September 1999. For each location (16 locations in total) an unambiguous dose-response relation could be derived (rising nuisance for rising concentrations). In most cases, a "no effect" level could be determined. The background percentage nuisance fluctuated between 0 and 15%. For the sectors of the slaughterhouses, paint spray installations and sewage treatment plants a no effect level was 0.5, 2.0 and 0.5 sniffing units m(-3) as 98th percentile (sniffing units are odour concentrations measured by means of sniffing measurements on the field) was determined. For the sectors of the textile plants and pig farms, no unambiguous no effect level was found. Currently research is undertaken to translate the no effect levels to odour standards. Other initiatives, taken to underpin the Flemish odour regulations, such as the development of an odour source inventory and a complaint handling system, are also briefly discussed. PMID:11762449

  1. 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.

  2. Bayesian dose-response analysis for epidemiological studies with complex uncertainty in dose estimation.

    PubMed

    Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian E; Simon, Steven L

    2016-02-10

    Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure.

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

    PubMed Central

    Wali, Bushra; Ishrat, Tauheed; Won, Soonmi; Stein, Donald G.

    2014-01-01

    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

  4. Time and dose-response effects of honokiol on UVB-induced skin cancer development.

    PubMed

    Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

    2012-06-01

    Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

  5. Pharmacokinetics and dose response of anti-TB drugs in rat infection model of tuberculosis.

    PubMed

    Kumar, Naveen; Vishwas, K G; Kumar, Mahesh; Reddy, Jitendar; Parab, Manish; Manikanth, C L; Pavithra, B S; Shandil, R K

    2014-05-01

    Robust and physiologically relevant infection models are required to investigate pharmacokinetic-pharmacodynamic (PK/PD) correlations for anti-tuberculosis agents at preclinical discovery. We have validated an inhalation-based rat infection model of tuberculosis harbouring mycobacteria in a replicating state, that is suitable for investigating pharmacokinetics and drug action of anti-tubercular agents. A reproducible and actively replicating lung infection was established in Wistar rats by inhalation of a series of graded inocula of Mycobacterium tuberculosis. Following an initial instillation of ∼10(5) log10 CFU/lung, M. tuberculosis grew logarithmically for the first 3 weeks, and then entered into a chronic phase with no net increase in pulmonary bacterial loads. Dose response of front-line anti-TB drugs was investigated following pharmacokinetic measurements in the plasma of infected rats. Rifampicin, Isoniazid, and Ethambutol dosed per orally exhibited bactericidality and good dose response with maximal effect of 5.66, 4.66, and 4.80 log10 CFU reductions in the lungs, respectively. In contrast, Pyrazinamide was merely bacteriostatic with 1.92 log10 CFU/lung reduction and did not reduce the bacterial burden beyond the initial bacterial loads present at beginning of treatment in spite of high Pyrazinamide blood levels. Rat infection model with actively replicating bacilli provides a physiologically distinct and pharmacologically relevant model that can be exploited to distinguish investigational compounds in to bacteriostatic or bactericidal scaffolds. We propose that this rat infection model though need more drug substance, can be used in early discovery settings to investigate pharmacology of novel anti-tubercular agents for the treatment of active pulmonary tuberculosis.

  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.

  7. 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

  8. Hierarchical dose response of E. coli O157:H7 from human outbreaks incorporating heterogeneity in exposure.

    PubMed

    Teunis, P F M; Ogden, I D; Strachan, N J C

    2008-06-01

    The infectivity of pathogenic microorganisms is a key factor in the transmission of an infectious disease in a susceptible population. Microbial infectivity is generally estimated from dose-response studies in human volunteers. This can only be done with mildly pathogenic organisms. Here a hierarchical Beta-Poisson dose-response model is developed utilizing data from human outbreaks. On the lowest level each outbreak is modelled separately and these are then combined at a second level to produce a group dose-response relation. The distribution of foodborne pathogens often shows strong heterogeneity and this is incorporated by introducing an additional parameter to the dose-response model, accounting for the degree of overdispersion relative to Poisson distribution. It was found that heterogeneity considerably influences the shape of the dose-response relationship and increases uncertainty in predicted risk. This uncertainty is greater than previously reported surrogate and outbreak models using a single level of analysis. Monte Carlo parameter samples (alpha, beta of the Beta-Poisson model) can be readily incorporated in risk assessment models built using tools such as S-plus and @ Risk.

  9. 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.

  10. Inorganic arsenic in drinking water and bladder cancer: a meta-analysis for dose-response assessment.

    PubMed

    Chu, Huei-An; Crawford-Brown, Douglas J

    2006-12-01

    Most arsenic cancer risk assessments have been based solely on epidemiological studies to characterize the dose-response relationship for arsenic-associated cancer and to perform risk calculations. However, current epidemiological evidence is too inconsistent and fraught with uncertainty regarding arsenic exposure to provide reliable estimates. This makes it hard to draw a firm conclusion about the shape and slope of the dose-response relationship from individual studies. Meta-analysis is a statistical approach to combining results across studies and offers expanded opportunities for obtaining an improved dose-response relationship. In this study, a meta-analysis of arsenic studies was conducted by combining seven epidemiological studies from different regions to get an overall dose-response relationship between the amount of arsenic intake and the excess probability of bladder cancer. Both the fixed-effect and random-effect models were used to calculate the averaged coefficient of the linear-logistic regression model. A homogeneity test was also conducted. The final product of this research is an aggregated dose-response model in the range of empirical observation of arsenic. Considering the most recent arsenic MCL (maximum contaminant level, i.e. 10microg/L), the associated bladder cancer risk (lifetime excess probability) at this MCL is 2.29 x 10-5.

  11. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  12. Different serotonin receptor agonists have distinct effects on sound-evoked responses in inferior colliculus.

    PubMed

    Hurley, Laura M

    2006-11-01

    The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing. PMID:16870843

  13. The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats.

    PubMed

    Sirviö, J; Riekkinen, P; Ekonsalo, T; Lammintausta, R; Riekkinen, P J

    1992-02-01

    The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 micrograms/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 micrograms/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 microgram/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 micrograms/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3-9.0 micrograms/kg) increased swimming speed in rats. Only a large dose (300 micrograms/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.

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

    PubMed

    Calabrese, Edward J; 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; Keller, John G; Klaunig, James E; Knudsen, Thomas B; Kozumbo, Walter J; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I; Masoro, Edward J; McClellan, Roger O; Mehendale, Harihara M; Mothersill, Carmel; Newlin, David B; Nigg, Herbert N; Oehme, Frederick W; Phalen, Robert F; Philbert, Martin A; Rattan, Suresh I S; Riviere, Jim E; Rodricks, Joseph; Sapolsky, Robert M; Scott, Bobby R; Seymour, Colin; Sinclair, David A; Smith-Sonneborn, Joan; Snow, Elizabeth T; Spear, Linda; Stevenson, Donald E; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M; Mattson, Mark P

    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.

  15. Dose-response in an outbreak of non-bacterial food poisoning traced to a mixed seafood cocktail.

    PubMed Central

    Gray, S. F.; Evans, M. R.

    1993-01-01

    An outbreak of non-bacterial food poisoning presumed due to small round, structured viruses (SRSV) occurred at a national conference. A detailed postal survey of all conference attenders was carried out to ascertain the cause of the outbreak and 355 questionnaires were returned. Univariate analysis showed that mussels in the seafood cocktail were the likely vehicle of infection. A dose-response relationship between the amount of seafood cocktail consumed and the risk of illness was demonstrated. Dose-response has not previously been documented in a food-borne outbreak due to small round structured virus. Detailed quantitative food histories can be useful in eliciting dose-response relationships and may be crucial in establishing the vehicle of infection when investigating food poisoning following consumption of a set-menu meal. Their use should be considered in other outbreak situations. PMID:8519323

  16. 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.

  17. Predictive Bayesian microbial dose-response assessment based on suggested self-organization in primary illness response: Cryptosporidium parvum.

    PubMed

    Englehardt, James D; Swartout, Jeff

    2006-04-01

    The probability of illness caused by very low doses of pathogens cannot generally be tested due to the numbers of subjects that would be needed, though such assessments of illness dose response are needed to evaluate drinking water standards. A predictive Bayesian dose-response assessment method was proposed previously to assess the unconditional probability of illness from available information and avoid the inconsistencies of confidence-based approaches. However, the method uses knowledge of the conditional dose-response form, and this form is not well established for the illness endpoint. A conditional parametric dose-response function for gastroenteric illness is proposed here based on simple numerical models of self-organized host-pathogen systems and probabilistic arguments. In the models, illnesses terminate when the host evolves by processes of natural selection to a self-organized critical value of wellness. A generalized beta-Poisson illness dose-response form emerges for the population as a whole. Use of this form is demonstrated in a predictive Bayesian dose-response assessment for cryptosporidiosis. Results suggest that a maximum allowable dose of 5.0 x 10(-7) oocysts/exposure (e.g., 2.5 x 10(-7) oocysts/L water) would correspond with the original goals of the U.S. Environmental Protection Agency Surface Water Treatment Rule, considering only primary illnesses resulting from Poisson-distributed pathogen counts. This estimate should be revised to account for non-Poisson distributions of Cryptosporidium parvum in drinking water and total response, considering secondary illness propagation in the population. PMID:16573639

  18. 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.

  19. 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

  20. UV-induced unscheduled DNA synthesis in human skin: dose response, correlation with erythema, time course and split dose exposure in vivo.

    PubMed

    Hönigsmann, H; Brenner, W; Tanew, A; Ortel, B

    1987-09-01

    Unscheduled DNA synthesis (UDS) has been shown to be saturated above a threshold dose of UV-C in human fibroblasts in vitro. We have investigated by autoradiography whether a similar saturation occurs in human skin in vivo with UV-B and whether this phenomenon correlates with the erythemal response. In addition, we determined the time course of UDS at 24 h after exposure and the effect of dual exposures separated by 24 h. The dose-response curve was established by exposure to 1/16, 1/8, 1/4, 1/2, 1, 2, 3, 4 and 6 MEDs UV-B. For the time-course study, areas exposed to 1/2 and 2 MEDs were biopsied after 1, 3, 6, 12 and 24 h. Autoradiography was performed in vitro. The dose-response curve showed a significant increase in UDS from 1/16 to 1 minimal erythema dose (MED), whereas no significant difference was observed between 1 MED and the higher UV-B doses tested. The 24 h time sequence revealed a gradual decrease in UDS activity. The 1/2 MED curve declined more rapidly and reached the zero-level between 12 h and 24 h, whereas about 50% of the initial UDS value was still retained 24 h after 2 MEDs. The dual-dose study revealed that a second hit of fractions of the MED resulted in lower levels of UDS than induced by these fractions alone in previously untreated areas. UDS increases with the erythemal dose between 1/16 and 1 MED. It reaches a plateau after 1 MED and cannot be increased by doses up to 6 MEDs, suggesting a saturation of excision repair in vivo. Time course studies support such a saturation phenomenon. The failure to increase significantly UDS by a second irradiation 24 h after the first exposure needs further clarification. Since persistence of DNA lesions may lead to an accumulation after repeated exposures, additional mechanisms other than excision repair may protect human skin by error-free removal of possibly mutagenic sites. Photoreactivation may be important in this respect.

  1. Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  2. 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

  3. 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

  4. Leisure Time Physical Activity and Mortality: A Detailed Pooled Analysis of the Dose-Response Relationship

    PubMed Central

    Arem, Hannah; Moore, Steven C.; Patel, Alpa; Hartge, Patricia; de Gonzalez, Amy Berrington; Visvanathan, Kala; Campbell, Peter T.; Freedman, Michal; Weiderpass, Elisabete; Adami, Hans Olov; Linet, Martha S.; Lee, I-Min; Matthews, Charles E.

    2015-01-01

    Importance The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic equivalent hours per week (MET h/wk)) of aerobic activity for “substantial” health benefit, and suggested “additional” benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. Objective To quantify the dose-response association between leisure-time physical activity and mortality, and to define the upper limit of benefit or harm associated with more physical activity. Design We pooled data from six studies in the NCI Cohort Consortium (baseline 1992–2003). We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). Median follow-up time was 14.2 years. Setting Population-based prospective cohorts in the U.S. and Europe with self-reported physical activity. Participants 661,137 men and women (116,686 deaths); median age 62 (range 21–98) years. Exposure Leisure-time moderate- to vigorous-intensity physical activity Main Outcome Mortality Results Compared to those reporting no leisure-time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended 7.5 MET h/wk minimum (HR=0.80, 95% CI 0.78–0.82), a 31% lower risk at 1–2 times the recommended minimum (0.69, 0.67–0.70), and a 37% lower risk at 2–3 times the minimum (0.63, 0.62–0.65). An upper threshold for mortality benefit occurred at 3–5 times the physical activity recommendation (0.61, 0.59–0.62), but compared to the recommended minimum, the additional benefit was modest (31% vs. 39%). There was no evidence of harm at 10+ times the recommended minimum (0.68, 0.59–0.78). A similar dose-response was observed for mortality due to cardiovascular disease and to cancer. Conclusions and

  5. Dose-response characteristics of nebulized albuterol in the treatment of acutely ill, hospitalized asthmatics.

    PubMed

    Ciccolella, D E; Brennan, K; Kelsen, S G; Criner, G J

    1999-09-01

    We investigated the bronchodilator dose-response to nebulized albuterol and the dose of albuterol which produces maximal bronchodilation in the acutely ill, hospitalized asthmatic. Consecutively admitted patients from the emergency room in status asthmaticus who fulfilled the inclusion criteria (age <41 years old and <12 pack-years of smoking) were studied. Albuterol was administered by nebulizer (Puritan-Bennett Raindrop) in repeated 2.5-mg treatments up to a total dose of 10 mg and the bronchodilator response was measured by a computerized spirometer. Twenty-two patients were studied. Baseline spirometry showed a (mean +/- SE) forced expiratory volume in 1 sec (FEV1) of 1.26 +/- 0.14 L (42 +/- 4.0% predicted), which increased significantly (p < 0.05) during albuterol titration to a maximum FEV1 of 1.70 +/- 0.19 L (57 +/- 5% of predicted). After cumulative doses of 2.5, 5.0, 7.5, and 10.0 mg of nebulized albuterol, 27%, 45%, 72%, and 77% of patients, respectively, attained maximum bronchodilation. The remaining 23% of patients did not respond to doses up to 10 mg of albuterol. The maximum FEV1 response to albuterol did not correlate with the initial severity of airflow obstruction (r = 0.36, p > 0.05). Pulse rate and arterial oxygen saturation were not significantly affected by nebulized albuterol up to a total dose of 10 mg. No arrhythmias were noted. In summary, most hospitalized asthmatics (72%) required a cumulative dose of 7.5 mg of nebulized albuterol to achieve maximum bronchodilation and a large fraction (50%) required higher albuterol doses than the standard 2.5 mg. The bronchodilatory response to nebulized albuterol varied widely among patients in status asthmaticus and could not be predicted from the initial severity of airflow obstruction. Because side effects were minimal, it would be reasonable to use 7.5 mg of nebulized albuterol as initial therapy. Alternatively, dose-response titration with albuterol would be advantageous.

  6. The ligand-receptor-G-protein ternary complex as a GTP-synthase. steady-state proton pumping and dose-response relationships for beta -adrenoceptors.

    PubMed

    Broadley, K J; Nederkoorn, P H; Timmerman, H; Timms, D; Davies, R H

    2000-07-21

    Steady-state solutions are developed for the rate of G alpha.GTP production in a synthase model of the ligand-receptor-G-protein ternary complex activated by a ligand-receptor proton pumping mechanism. The effective rate, k(31), defining the proton transfer, phosphorylation and G alpha.GTP release is a controlling rate of the synthase in the presence of a ligand with an efficient mode of signal activation, the ligand-receptor interaction taking place under effectively equilibrium conditions. The composite rate, however, becomes an amplifying factor in any dose-response relationship. The amplification is a triple product of the rate, k(31), the equilibrium constant associated with the activation of the proton signal, K(act)and the fraction of agonist conformer transmitting the signal, f(*). Where the rate of activation of the proton signal becomes critically inefficient, the rate of activation, k(act 1)replaces k(31)K(act). A correlation between beta(1)-adrenergic receptor-stimulated GDP release and adenylate cyclase activation shows that this correlation is not unique to an exchange reaction. Within the initiating Tyr-Arg-Tyr receptor proton shuttle mechanism, the position of Arg(r156) paralleldictates the high-(R(p)) and low-(R(u)) ligand-binding affinities. These states are close to R(*)and R(0)of the equilibrium model (De Lean et al., 1980, J. Biol. Chem.255, 7108-7117). An increased rate of hydrogen ion diffusion into a receptor mutant can give rise to constitutive activity while increased rates of G-protein release and changes in receptor state balance can contribute to the resultant level of action. Constitutive action will arise from a faster rate of G-protein release alone if proton diffusion in the wild-type receptor contributes to a basal level of G-protein activation. Competitive ligand-receptor occupancy for constitutive mutants shows that, where the rate of G-protein activation from the proportion of ligand-occupied receptors is less than the

  7. Autoantibodies enhance agonist action and binding to cardiac muscarinic receptors in chronic Chagas' disease.

    PubMed

    Hernandez, Ciria C; Nascimento, Jose H; Chaves, Elen A; Costa, Patricia C; Masuda, Masako O; Kurtenbach, Eleonora; Campos DE Carvalho, Antonio C; Gimenez, Luis E

    2008-01-01

    Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M(2)-muscarinic acetylcholine receptors (M(2)AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M(2)AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M(2)AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [(3)H]-N-methyl scopolamine ([(3)H]-NMS) in allosterism binding assays. A peptide corresponding to the M(2)AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [(3)H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [(3)H]-NMS dissociation right shifted from an IC(50) of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 x 10(- 8), 1.33 x 10(- 7), and 2.0 x 10(- 7) mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M(2)AChRs as a positive cooperativity effect on acetylcholine action. PMID:18702010

  8. Autoantibodies Enhance Agonist Action and Binding to Cardiac Muscarinic Receptors in Chronic Chagas’ Disease

    PubMed Central

    Hernández, Ciria C.; Nascimento, José H.; Chaves, Elen A.; Costa, Patrícia C.; Masuda, Masako O.; Kurtenbach, Eleonora; Campos de Carvalho, Antônio C.; Giménez, Luis E.

    2009-01-01

    Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M2-muscarinic acetylcholine receptors (M2AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M2AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M2AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [3H]-N-methyl scopolamine ([3H]-NMS) in allosterism binding assays. A peptide corresponding to the M2AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [3H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [3H]-NMS dissociation right shifted from an IC50 of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 × 10−8, 1.33 × 10−7, and 2.0 × 10−7 mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M2AChRs as a positive cooperativity effect on acetylcholine action. PMID:18702010

  9. Threshold estimation based on a p-value framework in dose-response and regression settings.

    PubMed

    Mallik, A; Sen, B; Banerjee, M; Michailidis, G

    2011-12-01

    We use p-values to identify the threshold level at which a regression function leaves its baseline value, a problem motivated by applications in toxicological and pharmacological dose-response studies and environmental statistics. We study the problem in two sampling settings: one where multiple responses can be obtained at a number of different covariate levels, and the other the standard regression setting involving limited number of response values at each covariate. Our procedure involves testing the hypothesis that the regression function is at its baseline at each covariate value and then computing the potentially approximate p-value of the test. An estimate of the threshold is obtained by fitting a piecewise constant function with a single jump discontinuity, known as a stump, to these observed p-values, as they behave in markedly different ways on the two sides of the threshold. The estimate is shown to be consistent and its finite sample properties are studied through simulations. Our approach is computationally simple and extends to the estimation of the baseline value of the regression function, heteroscedastic errors and to time series. It is illustrated on some real data applications. PMID:23049132

  10. Threshold estimation based on a p-value framework in dose-response and regression settings

    PubMed Central

    Mallik, A.; Sen, B.; Banerjee, M.; Michailidis, G.

    2011-01-01

    Summary We use p-values to identify the threshold level at which a regression function leaves its baseline value, a problem motivated by applications in toxicological and pharmacological dose-response studies and environmental statistics. We study the problem in two sampling settings: one where multiple responses can be obtained at a number of different covariate levels, and the other the standard regression setting involving limited number of response values at each covariate. Our procedure involves testing the hypothesis that the regression function is at its baseline at each covariate value and then computing the potentially approximate p-value of the test. An estimate of the threshold is obtained by fitting a piecewise constant function with a single jump discontinuity, known as a stump, to these observed p-values, as they behave in markedly different ways on the two sides of the threshold. The estimate is shown to be consistent and its finite sample properties are studied through simulations. Our approach is computationally simple and extends to the estimation of the baseline value of the regression function, heteroscedastic errors and to time series. It is illustrated on some real data applications. PMID:23049132

  11. Dose response effect of Paracoccidioides brasiliensis in an experimental model of arthritis.

    PubMed

    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.

  12. Treatment of porcine cysticercosis with oxfendazole: a dose-response trial.

    PubMed

    Gonzalez, A E; Falcon, N; Gavidia, C; Garcia, H H; Tsang, V C; Bernal, T; Romero, M; Gilman, R H

    1997-10-18

    Taenia solium cysticercosis is an important public health problem in developing countries. Oxfendazole has been shown to be highly effective against porcine cysticercosis, when given as a single dose at 30 mg/kg bodyweight. This dose, however, was estimated from experience with albendazole. A controlled dose-response trial was therefore undertaken to determine the efficacy and safety of three concentrations of oxfendazole. Twenty-four naturally parasitised pigs were divided into four groups and treated with oxfendazole at 10 mg/kg, 20 mg/kg or 30 mg/kg, or left untreated. Eight to 10 weeks later the pigs were killed and the viability of the parasites assessed by evagination. No side-effects of oxfendazole treatment were observed. In the control group more than 90 per cent of the cysts were viable. Viable cysts were found in the muscle and brain of the pigs treated with 10 or 20 mg/kg oxfendazole. At 30 mg/kg there were no viable cysts in any of the tissues examined, indicating that this concentration of oxfendazole provided an effective treatment against porcine cysticercosis.

  13. 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

  14. 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

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

    PubMed Central

    Yu, Winifred W.; Schmid, Christopher H.; Lichtenstein, Alice H.; Lau, Joseph; Trikalinos, Thomas A.

    2014-01-01

    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 topic, we performed meta-analyses of odds ratios with five approaches: using extreme exposure categories only, two-step approach (first calculated study-specific effects then combined across studies) using unadjusted data, two-step approach using adjusted data, one-step approach (analyzed all data in one regression model) using unadjusted data, and one-step approach using adjusted data. Meta-analyses including only extreme exposure categories gave consistently bigger effects and wider confidence intervals than meta-analyses using all data. Confidence intervals of effect sizes were generally wider in meta-analyses with the two-step approach, compared with the one-step approach. Meta-analyses using unadjusted data and adjusted data differed, with no consistent pattern of discordance in direction, statistical significance, or magnitude of effect. We discourage using meta-analysis approaches that only use data from extreme exposure categories. The one step approach generally has higher precision than the two-step approach. Sensitivity analysis comparing results between meta-analyses of adjusted and unadjusted data may be useful in indicating the presence of confounding. PMID:25379059

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

    PubMed

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

    2014-06-01

    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.

  17. Intramuscular relative dose response (RDR) determination of liver vitamin A stores in rats.

    PubMed

    Zachman, R D; Chen, X M

    1991-02-01

    This study questioned whether the relative dose response (RDR) method to detect liver stores of vitamin A could be used by intramuscular administration of the vitamin. Vitamin A-deficient and reference rat serum retinol levels were determined by HPLC at zero time and then again 5 h after an intramuscular injection of 5.25 mumol/kg retinyl palmitate. The RDR percentage was calculated: [(A5-A0)/(A5)] x 100. The 5-h RDR was determined in 20 deficient and 16 reference diet rats and a clear relationship to liver retinyl palmitate concentration was demonstrated. At a liver retinyl palmitate concentration of less than 0.105 mumol/g, all RDR values were greater than 20%. When the liver retinyl palmitate was greater than 0.122 mumol/g the RDR was less than 20%. This study suggests that the intramuscular RDR is a valid tool for estimating liver retinyl palmitate in populations in which the oral RDR cannot be administered. PMID:1825326

  18. 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.

  19. dose-response functions and mapping of risk for materials in urban polluted atmosphere

    NASA Astrophysics Data System (ADS)

    Laurans, E.; Ausset, P.; Chabas, A.; Lefevre, R.-A.

    2003-04-01

    The French field test-site of the United-Nations International Co-operative Programme "Influence of Atmospheric Pollution on Materials, including Historic and Cultural Monuments" (ICP-Materials) located at the top of the Saint-Eustache Church in a pedestrian area in the center of Paris allows to expose various materials (stone, glass, metals, polymers...) and to measure simultaneously the atmospheric parameters (gases, particles, rain, temperature, relative humidity, time of wetness...). The dose-response functions are calculated from the doses recorded on the 30 test-sites of the ICP-Materials network and from the responses analyzed on exposed samples. The critical or acceptable levels and loads are then determined and illustrated by means of mapping. The map of risk for Portland limestone, on the entire French territory and only on Ile-de-France are then given. In conclusion, an improvement of the method is proposed for stone: the mapping of the risk has no meaning except for the area of utilization. Nevertheless, the map of risk for entire Europe concerning materials universally used, like Carrara marble, Portland cement based mortars and Si-Ca-Na modern glass are of better utility.

  20. 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.

  1. Parity and Cardiovascular Disease Mortality: a Dose-Response Meta-Analysis of Cohort Studies.

    PubMed

    Lv, Haichen; Wu, Hongyi; Yin, Jiasheng; Qian, Juying; Ge, Junbo

    2015-08-24

    Parity has been shown to inversely associate with cardiovascular disease (CVD) mortality, but the evidence of epidemiological studies is still controversial. Therefore, we quantitatively assessed the relationship between parity and CVD mortality by summarizing the evidence from prospective studies. We searched MEDLINE (PubMed), EMBASE and ISI Web of Science databases for relevant prospective studies of parity and CVD mortality through the end of March 2015. Fixed- or random-effects models were used to estimate summary relative risks (RRs) and 95% confidence intervals (CIs). Heterogeneity among studies was assessed using the I(2) statistics. All statistical tests were two-sided. Ten prospective studies were included with a total of 994,810 participants and 16,601 CVD events. A borderline significant inverse association was observed while comparing parity with nulliparous, with summarized RR = 0.79 (95% CI: 0.60-1.06; I(2) = 90.9%, P < 0.001). In dose-response analysis, we observed a significant nonlinear association between parity number and CVD mortality. The greatest risk reduction appeared when the parity number reached four. The findings of this meta-analysis suggests that ever parity is inversely related to CVD mortality. Furthermore, there is a statistically significant nonlinear inverse association between parity number and CVD mortality.

  2. 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

  3. 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

  4. Meta-analysis of dioxin cancer dose response for three occupational cohorts.

    PubMed Central

    Crump, Kenny S; Canady, Richard; Kogevinas, Manolis

    2003-01-01

    This article presents a meta analysis of data from three cohorts occupationally exposed to TCDD and related compounds. A statistically significant (p = 0.02) trend was found in total cancer mortality with increasing dioxin exposure. The trend tests show an increase in total cancer at cumulative TEQ (unit of measurement for TCDD-like compounds that is defined as the amount of TCDD that would produce the same toxicity as a mixture of TCDD-like compounds) serum levels that would result from lifetime intake of 7 pg TEQ/kg body weight/day, with no increase at 6 pg/kg/day. A linear dose response provided a good fit to the combined data and predicted an ED(01) (dioxin exposure resulting in a 0.01 increase in lifetime risk of cancer mortality) of 45 pg/kg/day (95% confidence interval, 21-324). The U.S. Environmental Protection Agency estimates that current lifetime human exposures to dioxin average approximately 1 pg/kg/day (99% percentile: 3 pg/kg/day). Although it appears unlikely that current exposures through foods would reach either 7 pg/kg/day or the ED(01), our analysis argues for careful consideration of the upper ranges of long-term average exposures for dioxins. PMID:12727594

  5. 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 ...

  6. 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...

  7. 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...

  8. Skin sensitization in chemical risk assessment: report of a WHO/IPCS international workshop focusing on dose-response assessment.

    PubMed

    van Loveren, Henk; Cockshott, Amanda; Gebel, Tom; Gundert-Remy, Ursula; de Jong, Wim H; Matheson, Joanna; McGarry, Helen; Musset, Laurence; Selgrade, Maryjane K; Vickers, Carolyn

    2008-03-01

    An international workshop was held in 2006 to evaluate experimental techniques for hazard identification and hazard characterization of sensitizing agents in terms of their ability to produce data, including dose-response information, to inform risk assessment. Human testing to identify skin sensitizers is discouraged for ethical reasons. Animal-free alternatives, such as quantitative structure-activity relationships and in vitro testing approaches, have not been sufficiently developed for such application. Guinea pig tests do not generally include dose-response assessment and are therefore not designed for the assessment of potency, defined as the relative ability of a chemical to induce sensitization in a previously naive individual. In contrast, the mouse local lymph node assay does include dose-response assessment and is appropriate for this purpose. Epidemiological evidence can be used only under certain circumstances for the evaluation of the sensitizing potency of chemicals, as it reflects degree of exposure as well as intrinsic potency. Nevertheless, human diagnostic patch test data and quantitative elicitation data have provided very important information in reducing allergic contact dermatitis risk and sensitization in the general population. It is therefore recommended that clinical data, particularly dose-response data derived from sensitized patients, be included in risk assessment.

  9. Household physical activity and cancer risk: a systematic review and dose-response meta-analysis of epidemiological studies.

    PubMed

    Shi, Yun; Li, Tingting; Wang, Ying; Zhou, Lingling; Qin, Qin; Yin, Jieyun; Wei, Sheng; Liu, Li; Nie, Shaofa

    2015-10-07

    Controversial results of the association between household physical activity and cancer risk were reported among previous epidemiological studies. We conducted a meta-analysis to investigate the relationship of household physical activity and cancer risk quantitatively, especially in dose-response manner. PubMed, Embase, Web of science and the Cochrane Library were searched for cohort or case-control studies that examined the association between household physical activity and cancer risks. Random-effect models were conducted to estimate the summary relative risks (RRs), nonlinear or linear dose-response meta-analyses were performed to estimate the trend from the correlated log RR estimates across levels of household physical activity quantitatively. Totally, 30 studies including 41 comparisons met the inclusion criteria. Total cancer risks were reduced 16% among the people with highest household physical activity compared to those with lowest household physical activity (RR = 0.84, 95% CI = 0.76-0.93). The dose-response analyses indicated an inverse linear association between household physical activity and cancer risk. The relative risk was 0.98 (95% CI = 0.97-1.00) for per additional 10 MET-hours/week and it was 0.99 (95% CI = 0.98-0.99) for per 1 hour/week increase. These findings provide quantitative data supporting household physical activity is associated with decreased cancer risk in dose-response effect.

  10. 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...

  11. 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...

  12. 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…

  13. Dose response of micronuclei induced by combination radiation of α-particles and γ-rays in human lymphoblast cells.

    PubMed

    Ren, Ruiping; He, Mingyuan; Dong, Chen; Xie, Yuexia; Ye, Shuang; Yuan, Dexiao; Shao, Chunlin

    2013-01-01

    Combination radiation is a real situation of both nuclear accident exposure and space radiation environment, but its biological dosimetry is still not established. This study investigated the dose-response of micronuclei (MN) induction in lymphocyte by irradiating HMy2.CIR lymphoblast cells with α-particles, γ-rays, and their combinations. Results showed that the dose-response of MN induced by γ-rays was well-fitted with the linear-quadratic model. But for α-particle irradiation, the MN induction had a biphasic phenomenon containing a low dose hypersensitivity characteristic and its dose response could be well-stimulated with a state vector model where radiation-induced bystander effect (RIBE) was involved. For the combination exposure, the dose response of MN was similar to that of α-irradiation. However, the yield of MN was closely related to the sequence of irradiations. When the cells were irradiated with α-particles at first and then γ-rays, a synergistic effect of MN induction was observed. But when the cells were irradiated with γ-rays followed by α-particles, an antagonistic effect of MN was observed in the low dose range although this combination radiation also yielded a synergistic effect at high doses. When the interval between two irradiations was extended to 4h, a cross-adaptive response against the other irradiation was induced by a low dose of γ-rays but not α-particles.

  14. 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...

  15. 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 ...

  16. 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...

  17. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    SciTech Connect

    Molenaar, P.; Malta, E.

    1986-04-01

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-(/sup 125/I)iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants.

  18. 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

  19. 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

  20. 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

  1. Effects and dose--response relationships of skin cancer and blackfoot disease with arsenic.

    PubMed

    Tseng, W P

    1977-08-01

    In a limited area on the southwest coast of Taiwan, where artesian well water with a high concentration of arsenic has been used for more than 60 years, a high prevalence of chronic arsenicism has been observed in recent years. The total population of this "endemic" area is approximately 100,000. A general survey of 40,421 inhabitants and follow-up of 1,108 patients with blackfoot disease were made. Blackfoot disease, so-termed locally, is a peripheral vascular disorder resulting in gangrene of the extremities, especially the feet. The overall prevalence rates for skin cancer was 10.6 per 1000, and for blackfoot disease 8.9 per 1000. Generally speaking, the prevalence increased steadily with age in both diseases. The prevalence rates for skin cancer and blackfoot disease increased with the arsenic content of well water, i.e., the higher the arsenic content, the more patients with skin cancer and blackfoot disease. A dose-response relationship between blackfoot disease and the duration of water intake was also noted. Furthermore, the degree of permanent impairment of function in the patient was directly related to duration of intake of arsenical water and to duration of such intake at the time of onset. The most common cause of death in the patients with skin cancer and blackfoot disease was carcinoma of various sites. The 5-year survival rate after the onset of blackfoot disease was 76.3%; the 10-year survival rate was 63.3% and 15-year survival rate, 52.2%. The 50% survival point was 16 years after onset of the disease.

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

    PubMed

    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 30 g/day increment intake was 0.98 (95%CI = 0.95-1.001; I(2) = 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; I(2) = 0%; n = 5) and animal-based fat (summary RR = 1.17, 95%CI = 0.92-1.36; I(2) = 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.

  3. Use of the intramuscular relative-dose-response test to predict bronchopulmonary dysplasia in premature infants.

    PubMed

    Zachman, R D; Samuels, D P; Brand, J M; Winston, J F; Pi, J T

    1996-01-01

    We tested the hypothesis that an intramuscular relative dose response (IM-RDR) on day 1 of life would more accurately predict which premature infants would develop bronchopulmonary dysplasia (BPD) than single measurements of retinol, retinyl palmitate (RP), or retinol binding protein (RBP). Seventy-five premature infants < or = 32 wk gestation had the IM-RDR on day 1 of life. An RDR > or = 25% occurred in 6 of 37 infants who did not develop BPD compared with 15 of 38 infants who developed BPD (P = 0.025). Retinol, RP, and RBP on day 1 were not different between the groups. BPD infants who received postnatal dexamethasone during their hospital course had a higher day-28 baseline retinol concentration (1.19 +/- 0.15 mumol/L) than did the group with no BPD (0.82 +/- 0.06 mumol/L) (P = 0.03). However, the effect of postnatal dexamethasone on serum retinol was biphasic, rising initially, and then declining after 8-12 d. RP values at time 0 and 5 h on day 28 were higher than day 1 values in both infants without BPD and infants with BPD who did not receive dexamethasone. Retrospective analysis also revealed a significant correlation between a day-1 RDR > or = 25% and the incidence of intraventricular hemorrhage in these premature infants. Because the IM-RDR is more helpful in predicting the development of BPD than single serum retinol and RP analyses, this test could be useful in determining which premature infants might benefit from supplemental vitamin A for BPD. PMID:8604659

  4. Dose - response relationship between noise exposure and the risk of occupational injury.

    PubMed

    Yoon, Jin-Ha; Hong, Jeong-Suk; Roh, Jaehoon; Kim, Chi-Nyon; Won, Jong-Uk

    2015-01-01

    Many workers worldwide experience fatality and disability caused by occupational injuries. This study examined the relationship between noise exposure and occupational injuries at factories in Korea. A total of 1790 factories located in northern Gyeonggi Province, Korea was evaluated. The time-weighted average levels of dust and noise exposure were taken from Workplace Exposure Assessment data. Apart occupational injuries, sports events, traffic accidents, and other accidents occurring outside workplaces were excluded. The incidences of occupational injury in each factory were calculated by data from the Korea Workers' Compensation and Welfare Services. Workplaces were classified according to the incidence of any occupational injuries (incident or nonincident workplaces, respectively). Workplace dust exposure was classified as <1 or ≥ 1 mg/m³ , and noise exposure as <80, 80-89, or >90 dB. Workplaces with high noise exposure were significantly associated with being incident workplaces, whereas workplaces with high dust exposure were not. The odds ratios (95% confidence intervals) derived from a logistic regression model were 1.68 (1.27-2.24) and 3.42 (2.26-5.17) at 80-89 dB and ≥ 90 dB versus <80 dB. These associations remained significant when in a separate analysis according to high or low dust exposure level. Noise exposure increases the risk of occupational injury in the workplace. Furthermore, the risk of occupational injury increases with noise exposure level in a dose-response relationship. Therefore, strategies for reducing noise exposure level are required to decrease the risk of occupational injury.

  5. 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

  6. Surgical Results of Symmetric and Asymmetric Surgeries and Dose-Response in Patients with Infantile Esotropia

    PubMed Central

    Yurdakul, Nazife Sefi; Bodur, Seda; Koç, Feray

    2015-01-01

    Objectives: To evaluate the results of symmetric and asymmetric surgery and responses to surgical amounts in patients with infantile esotropia. Materials and Methods: The records of patients with infantile esotropia who underwent bilateral medial rectus recession (symmetric surgery) and unilateral medial rectus recession with lateral rectus resection (asymmetric surgery) were analyzed. The results of the cases with symmetric (group 1) and asymmetric (group 2), successful (group 3) and failed (group 4) surgeries were compared, and responses to the amount of surgery were investigated. Results: There were no significant differences between group 1 (n=71) and group 2 (n=13) cases in terms of gender, refraction, preoperative distance deviation, anisometropia and postoperative deviation angles, binocular vision, surgical success or follow-up period (p>0.05). The rate of amblyopia, near deviation and amount of surgery were higher in group 2 cases (p<0.05). Between group 3 (n=64) and group 4 subjects (n=20), no significant differences were detected in terms of gender, surgical age, refraction, amblyopia, anisometropia, preoperative deviation angles, the number of symmetric and asymmetric surgeries, the amount of surgery, or postoperative binocular vision (p>0.05). The average postoperative follow-up period was 15.41±19.93 months (range, 6-98 months) in group 3 cases and 40.45±40.06 months (range, 6-143 months) in group 4 cases (p=0.000). No significant difference was detected in the amount of deviation corrected per 1 mm of surgical procedure between the successful cases in the symmetric and asymmetric groups (p>0.05). Conclusion: Symmetric or asymmetric surgery may be preferable in patients with infantile esotropia according to the clinical features. It is necessary for every clinic to review its own dose-response results. PMID:27800232

  7. Simulated and measured dose response characteristics of detectors used for CT dosimetry

    NASA Astrophysics Data System (ADS)

    Hakanen, Arvi

    2012-08-01

    A CT-SD16 semiconductor detector was calibrated in terms of the computed tomography (CT) air kerma index for the integration length L = 100 mm, CK,PMMA,100, in the cylindrical CT head and body dosimetry phantoms using a DCT10 pencil ionization chamber as a reference instrument. Using IEC RQT 9 120-kV x-ray radiation quality and 25-62.5 mm nominal beam widths free in air, a CK,PMMA,100(DCT10)/CK,PMMA,100(CT-SD16) ratio of 0.97 was observed, while in the centre of 300 mm long CT head and body dosimetry phantoms, CK,PMMA,100(DCT10)/CK,PMMA,100(CT-SD16) ratios ranged from 1.02 to 1.09. Using IEC RQT 8-10 radiation qualities free in air, Monte Carlo simulated dose response characteristics of CT-SD16 and DCT10 were comparable with those obtained from the measurements. Simulations were also used to determine CK,PMMA,100(DCT10) in the centre of the CT head and body phantoms. At IEC RQT 9 and 25-62.5 mm nominal beam widths, the relative values of the simulated dose agreed with the measured values within 2-10% for the head and body phantoms, respectively. A kq correction factor between dose measurements in the phantom and free in air was determined for the model of DCT10 and for the real detectors using measured CK,PMMA,100 data. Simulations were performed using the EGSnrc CAVRZ code.

  8. 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

  9. Late Dose-Response Effects of Prenatal Cocaine Exposure on Newborn Neurobehavioral Performance

    PubMed Central

    Tronick, Edward Z.; Frank, Deborah A.; Cabral, Howard; Mirochnick, Mark; Zuckerman, Barry

    2008-01-01

    Objective To determine in a representative sample of full-term urban newborns of English-speaking mothers whether an immediate or late dose-response effect could be demonstrated between prenatal cocaine exposure and newborn neurobehavioral performance, controlling for confounding factors. Methods The Neonatal Behavioral Assessment Scale (NBAS) was administered by masked examiners to a total sample of 251 clinically healthy, full-term infants at 2 days and/or 17 days. Three in utero cocaine exposure groups were defined: heavily exposed (n = 44, >75th percentile self-reported days of use during pregnancy and/or >75th percentile of meconium benzoylecognine concentration); lightly exposed (n = 79, less than both 75th percentiles); and unexposed (n = 101, no positive biological or self-report marker). At the 3-week examination there were 38 heavily exposed, 73 lightly exposed, and 94 unexposed infants. Controlling for infant birth weight, gestational age, infant age at the time of examination, mothers’ age, perinatal risk, obstetric medication, and alcohol, marijuana, and cigarette use, a regression analysis evaluated the effects of levels of cocaine exposure on NBAS performance. Results No neurobehavioral effects of exposure on the newborn NBAS cluster scores or on the qualifier scores were found when confounders were controlled for at 2 to 3 days of age. At 3 weeks, after controlling for covariates, a significant dose effect was observed, with heavily exposed infants showing poorer state regulation and greater excitability. Conclusions These findings demonstrate specific dose-related effects of cocaine on 3-week neurobehavioral performance, particularly for the regulation of arousal, which was not observed in the first few days of life. PMID:8668416

  10. Exposure-dose-response of Tellina deltoidalis to metal contaminated estuarine sediments 2. Lead spiked sediments.

    PubMed

    Taylor, Anne M; Maher, William A

    2014-01-01

    Lead accumulation in estuarine sediments, as a result of activities such as mining and ore smelting, and through urban runoff is a continuing problem in the increasingly developed world. Marine organisms accumulate lead, which is known to be highly toxic to biological processes and to degrade organism and ecosystem health. Here the relationship between lead exposure, dose and response was investigated in the sediment dwelling, deposit feeding, marine bivalve Tellina deltoidalis. Bivalves were exposed in the laboratory to individual lead spiked sediments at < 0.01, 100 and 300 μg/g dry mass, for 28 days and accumulated total tissue lead concentrations of 4, 96 and 430 μg/g, respectively. Subcellular fractionation indicated that around 70% of the total accumulated tissue lead was detoxified, three quarters of the detoxified lead fraction was converted into metal rich granules, with the remainder in the metallothionein like protein fraction. The majority of biologically active lead was associated with the mitochondrial fraction with up to a 128 fold increase in lead burden in exposed organisms compared to controls. This indicates lead detoxification was occurring but the organism was unable to prevent lead interacting with sensitive organelles. With increased lead exposure T. deltoidalis showed a suppression in glutathione peroxidase activity, total glutathione concentration and reduced GSH:GSSG ratios, however, these differences were not significant. Lead exposed T. deltoidalis had a significantly reduced total antioxidant capacity which corresponded with increased lipid peroxidation, lysosomal destabilisation and micronuclei frequency. The exposure-dose-response relationships demonstrated for lead exposed T. deltoidalis supports its potential for the development of sublethal endpoints in lead toxicity assessment. PMID:24100051

  11. Differences in Radiation Dose Response between Small and Large Intestinal Crypts.

    PubMed

    Otsuka, Kensuke; Suzuki, Keiji

    2016-09-01

    The protection of intestinal epithelial cells from the lethal effects induced by high-dose radiation is an important issue in radiotherapy and in the treatment of acute radiation syndrome. However, the effects of middle- and low-dose radiation on intestinal epithelial cells remain unclear. Because the accumulation of DNA damage in intestinal stem cells may be crucial for the development of cancer-initiating cells, it is important to understand the kinetics of DNA repair and tissue response (which are involved in the elimination of damaged cells and tissue injury repair) to middle- to low-dose irradiation. In this study, mice were X-ray irradiated with 0.1, 1 or 4 Gy, after which the small intestine (duodenum and ileum) and colon were harvested from the animals. DNA damage repair and the elimination of damaged cells were quantified by measuring the number of foci of 53BP1, a surrogate marker for DNA double-strand breaks. Tissue-proliferative response was evaluated by determining the number of Ki-67(+) and mitotic cells. Intra-crypt response differed considerably between the small intestine and the colon. In the small intestine, 53BP1 foci were detected immediately after irradiation, but rapidly disappeared thereafter, especially noticeable in Lgr5(+) stem cells. Cellular growth was temporally arrested; however, cell numbers and mitotic cell numbers in the crypt did not change. The kinetics of DNA damage repair in Lgr5(+) stem cells were similar to those in the small intestines, while the colon was more susceptible to radiation-induced damage. Preferential cell loss in the lower crypt was clearly observed in the colon; and after low-dose X-ray irradiation, only the colon exhibited considerably reduced cell numbers and dramatic induction of mitosis. These results suggest that differences in radiation dose response between the small and the large intestine may depend on the growth activity of stem cells after DNA repair.

  12. 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.

  13. 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

  14. Differences in Radiation Dose Response between Small and Large Intestinal Crypts.

    PubMed

    Otsuka, Kensuke; Suzuki, Keiji

    2016-09-01

    The protection of intestinal epithelial cells from the lethal effects induced by high-dose radiation is an important issue in radiotherapy and in the treatment of acute radiation syndrome. However, the effects of middle- and low-dose radiation on intestinal epithelial cells remain unclear. Because the accumulation of DNA damage in intestinal stem cells may be crucial for the development of cancer-initiating cells, it is important to understand the kinetics of DNA repair and tissue response (which are involved in the elimination of damaged cells and tissue injury repair) to middle- to low-dose irradiation. In this study, mice were X-ray irradiated with 0.1, 1 or 4 Gy, after which the small intestine (duodenum and ileum) and colon were harvested from the animals. DNA damage repair and the elimination of damaged cells were quantified by measuring the number of foci of 53BP1, a surrogate marker for DNA double-strand breaks. Tissue-proliferative response was evaluated by determining the number of Ki-67(+) and mitotic cells. Intra-crypt response differed considerably between the small intestine and the colon. In the small intestine, 53BP1 foci were detected immediately after irradiation, but rapidly disappeared thereafter, especially noticeable in Lgr5(+) stem cells. Cellular growth was temporally arrested; however, cell numbers and mitotic cell numbers in the crypt did not change. The kinetics of DNA damage repair in Lgr5(+) stem cells were similar to those in the small intestines, while the colon was more susceptible to radiation-induced damage. Preferential cell loss in the lower crypt was clearly observed in the colon; and after low-dose X-ray irradiation, only the colon exhibited considerably reduced cell numbers and dramatic induction of mitosis. These results suggest that differences in radiation dose response between the small and the large intestine may depend on the growth activity of stem cells after DNA repair. PMID:27556352

  15. 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.

  16. 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

  17. 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.

  18. Bioactivity screening and mass spectrometric confirmation for the detection of PPARδ agonists that increase type 1 muscle fibres.

    PubMed

    Bovee, Toine F H; Blokland, Marco; Kersten, Sander; Hamers, Astrid R M; Heskamp, Henri H; Essers, Martien L; Nielen, Michel W F; van Ginkel, Leendert A

    2014-01-01

    Sensitive and robust bioassays able to detect nuclear receptor activation are very useful for veterinary and doping control, pharmaceutical industry and environmental scientists. Here, we used bioassays based on human leukemic monocyte lymphoma U937 and human liver hepatocellular carcinoma HepG2 cell lines to detect the ligand-induced activation of the peroxisome proliferator-activated receptor delta (PPARδ). Exposure of U937 cells to the PPARδ agonist GW501516 resulted in a marked increase in mRNA expression of the PPARδ target gene Angptl4 which was quantified by qRT-PCR analysis. Exposure of HepG2 cells transiently transfected with a PPARδ expression plasmid and a PPAR-response element-driven luciferase reporter plasmid to PPARδ agonists GW501516, GW610742 and L-165041 resulted in clear dose-response curves. Although the qRT-PCR resulted in higher fold inductions, the luciferase assay with transfected HepG2 cells is cheaper and quicker and about ten times more sensitive to GW501516 compared to analysis of Angptl4 mRNA expression in U937 cells by qRT-PCR. The HepG2-based luciferase assay was therefore used to screen GW501516-spiked supplements and feed and water samples. After liquid extraction and clean-up by solid phase extraction using a weak anion exchange column, extracts were screened in the HepG2 bioassay followed by confirmation with a newly developed UPLC-MS/MS method, using two transitions for each compound, i.e., for GW501516, 454.07>188.15 (collision energy (CE) 46 V) and 454.07>257.08 (CE 30 V); for GW610742, 472.07>206.2 (CE 48 V) and 472.07>275.08 (CE 30 V); and for L-165041, 401.2>193.15 (CE 26 V) and 401.2>343.2 (CE 20 V).

  19. Dose-response relationships of rat fetal skeleton variations: Relevance for risk assessment.

    PubMed

    Chahoud, Ibrahim; Paumgartten, Francisco J R

    2009-10-01

    In developmental toxicity studies, skeleton abnormalities found in fetuses at term are classified as variations or malformations. The relevance of skeleton variations for human risk assessment, however, is a controversial issue. This paper is a contribution to the discussion on the interpretation of fetal skeleton variations in the context of risk assessment. Dose-response relationships of skeleton variations and malformations induced by three antineoplastic drugs (FUDR: 5-fluoro-2'-deoxyuridine, HU: hydroxyurea and 6-MPr: 6-mercaptopurine-riboside) were evaluated. FUDR (0, 3, 14, 25, 35, 45, 55 and 65mg/kg body wt sc) and HU (0, 250, 300, 350, 400, 450, 500 and 550mg/kg body wt ip) were administered to rats on gestation day 11 (GD 11) while 6-MPr (0, 3, 7, 10 and 14mg/kg body wt sc) was given on GD 11, or on GD 12. Caesarean sections were performed on GD 21 and all fetuses were cleared and stained with alizarin red S for skeleton examination. Drugs given on GD 11 increased the incidence of thoracic and lumbar vertebra (dumbbell-shaped and bipartite ossification center (o.c.) and sternum (misaligned sternebrae) variations in a dose-dependent manner. Occurrence of zygomatic bone fused with maxilla (a variation in our rats) was also increased by HU and 6-MPr (GD 11) but it was not altered by FUDR. Spontaneous occurrence of wavy ribs was reduced by all treatments. Malformations such as cleft palate, tympanic bone absent and tibia absent were also increased in a dose-dependent manner by the three compounds. No observed effect levels (NOEL) for variations, irrespective of the compound administered, were generally lower than NOELs for malformations. In the discussion, we supported the view that any dose-related increase in the incidence of variations should be taken into account for determination of NOELs in routine studies. Increased occurrences of skeleton variations in term fetuses are also to be considered in risk assessment, unless experimental evidence exists that

  20. Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure.

    PubMed

    Claussen, Catherine M; Dafny, Nachum

    2015-09-01

    The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long-term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization was also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals were observed for the 2.5 and 10.0mg/kg MPD exposed groups. For 2.5mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure and

  1. 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

  2. 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.

  3. Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure

    PubMed Central

    Claussen, Catherine M; Dafny, Nachum

    2016-01-01

    The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0 mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization were also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals was observed for the 2.5 and 10.0 mg/kg MPD exposed groups. For 2.5 mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0 mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0 mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure

  4. Is There a Dose-Response Relationship for Heart Disease With Low-Dose Radiation Therapy?

    SciTech Connect

    Chung, Eugene; Corbett, James R.; Moran, Jean M.; Griffith, Kent A.; Marsh, Robin B.; Feng, Mary; Jagsi, Reshma; Kessler, Marc L.; Ficaro, Edward C.; Pierce, Lori J.

    2013-03-15

    Purpose: To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer. Methods and Materials: On a randomized trial, 32 women with node-positive left-sided breast cancer underwent pre-RT stress single photon emission computed tomography (SPECT-CT) myocardial perfusion scans. Patients received RT to the breast/chest wall and regional lymph nodes to doses of 50 to 52.2 Gy. Repeat SPECT-CT scans were performed 1 year after RT. Perfusion defects (PD), summed stress defects scores (SSS), and ejection fractions (EF) were evaluated. Doses to the heart and coronary arteries were quantified. Results: The mean difference in pre- and post-RT PD was −0.38% ± 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% ± 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% ± 2.50% (P=.08) and 1.75% ± 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF. Conclusions: Using sensitive measures of cardiac function, no clinically significant defects were found after RT, with the average heart Dmean <5 Gy. Although a dose response may exist for measures of cardiac dysfunction at higher doses, no correlation was found in the present study for low doses delivered to cardiac structures and perfusion, SSS, or EF.

  5. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

  6. Curves and Their Properties.

    ERIC Educational Resources Information Center

    Yates, Robert C.

    This volume, a reprinting of a classic first published in 1952, presents detailed discussions of 26 curves or families of curves, and 17 analytic systems of curves. For each curve the author provides a historical note, a sketch or sketches, a description of the curve, a discussion of pertinent facts, and a bibliography. Depending upon the curve,…

  7. Microfluidic serial dilution cell-based assay for analyzing drug dose response over a wide concentration range.

    PubMed

    Sugiura, Shinji; Hattori, Koji; Kanamori, Toshiyuki

    2010-10-01

    In this paper we report a perfusion culture microchamber array chip with a serial dilution microfluidic network for analyzing drug dose response over a concentration range spanning 6 orders of magnitude, which is required for practical drug discovery applications. The microchamber array chip was equipped with a pressure-driven interface, in which medium and drug solution were added with a micropipet and delivered into the microfluidic network by pneumatic pressure. We demonstrated that the microchamber array chip could be used to estimate the 50% growth inhibitory concentration using the model anticancer drug paclitaxel and the model cancer cell line HeLa. The results obtained by using the microchamber array chip were consistent with those obtained by a conventional assay using microplates. The microchamber array chip, with its simple interface and well-designed microfluidic network, has potential as an efficient platform for high-throughput dose response assays in drug discovery applications.

  8. 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.

  9. 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.

  10. 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

  11. Light exposure at night, sleep duration, melatonin, and breast cancer: a dose-response analysis of observational studies.

    PubMed

    Yang, Wan-Shui; Deng, Qin; Fan, Wen-Yan; Wang, Wei-Ye; Wang, Xin

    2014-07-01

    Evidence from observational studies on light at night (LAN) exposure, sleep duration, endogenous melatonin levels, and risk for breast cancer in women is conflicting. This led us to conduct a dose-response analysis of published observational data. Pertinent studies were identified by searching Medline, Web of Science, and EMBASE through April 2013. The dose-response relationship between sleep duration, urinary 6-sulphatoxymelatonin levels, and breast cancer was assessed using the restricted cubic spline model and by multivariate random-effects metaregression. A separate meta-analysis was also carried out to calculate the relative risks (RRs) with 95% confidence intervals (CIs) for breast cancer for the comparable categories or highest levels of exposure versus the lowest levels. Twelve case-control and four cohort studies were included in the analysis. High artificial LAN exposure is associated with an increased risk for breast cancer (RR=1.17, 95% CI: 1.11-1.23), but not ambient LAN exposure (RR=0.91, 95% CI: 0.78-1.07). The summary RR for breast cancer is 1.00 (95% CI: 0.995-1.01) for an increment of 1 h of sleep per night. No significant dose-response relationship between sleep duration and breast cancer was found either for the linearity test (Ptrend=0.725) or for the nonlinearity (Ptrend=0.091) test. An increasein of 15 ng/mg creatinine in urinary 6-sulphatoxymelatonin is associated with a 14% reduced risk for breast cancer (RR=0.86, 95% CI: 0.78-0.95), with a linear dose-response trend (Ptrend=0.003). There was no evidence of substantial heterogeneity or publication bias in the analysis. Our study adds to the evidence of LAN breast cancer theory. Further research in this area is warranted.

  12. 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.

  13. 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,...

  14. 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.

  15. A meta-analysis on dose-response relationship between night shift work and the risk of breast cancer.

    PubMed

    Wang, F; Yeung, K L; Chan, W C; Kwok, C C H; Leung, S L; Wu, C; Chan, E Y Y; Yu, I T S; Yang, X R; Tse, L A

    2013-11-01

    This study aimed to conduct a systematic review to sum up evidence of the associations between different aspects of night shift work and female breast cancer using a dose-response meta-analysis approach. We systematicly searched all cohort and case-control studies published in English on MEDLINE, Embase, PSYCInfo, APC Journal Club and Global Health, from January 1971 to May 2013. We extracted effect measures (relative risk, RR; odd ratio, OR; or hazard ratio, HR) from individual studies to generate pooled results using meta-analysis approaches. A log-linear dose-response regression model was used to evaluate the relationship between various indicators of exposure to night shift work and breast cancer risk. Downs and Black scale was applied to assess the methodological quality of included studies. Ten studies were included in the meta-analysis. A pooled adjusted relative risk for the association between 'ever exposed to night shift work' and breast cancer was 1.19 [95% confidence interval (CI) 1.05-1.35]. Further meta-analyses on dose-response relationship showed that every 5-year increase of exposure to night shift work would correspondingly enhance the risk of breast cancer of the female by 3% (pooled RR = 1.03, 95% CI 1.01-1.05; Pheterogeneity < 0.001). Our meta-analysis also suggested that an increase in 500-night shifts would result in a 13% (RR = 1.13, 95% CI 1.07-1.21; Pheterogeneity = 0.06) increase in breast cancer risk. This systematic review updated the evidence that a positive dose-response relationship is likely to present for breast cancer with increasing years of employment and cumulative shifts involved in the work.

  16. Light exposure at night, sleep duration, melatonin, and breast cancer: a dose-response analysis of observational studies.

    PubMed

    Yang, Wan-Shui; Deng, Qin; Fan, Wen-Yan; Wang, Wei-Ye; Wang, Xin

    2014-07-01

    Evidence from observational studies on light at night (LAN) exposure, sleep duration, endogenous melatonin levels, and risk for breast cancer in women is conflicting. This led us to conduct a dose-response analysis of published observational data. Pertinent studies were identified by searching Medline, Web of Science, and EMBASE through April 2013. The dose-response relationship between sleep duration, urinary 6-sulphatoxymelatonin levels, and breast cancer was assessed using the restricted cubic spline model and by multivariate random-effects metaregression. A separate meta-analysis was also carried out to calculate the relative risks (RRs) with 95% confidence intervals (CIs) for breast cancer for the comparable categories or highest levels of exposure versus the lowest levels. Twelve case-control and four cohort studies were included in the analysis. High artificial LAN exposure is associated with an increased risk for breast cancer (RR=1.17, 95% CI: 1.11-1.23), but not ambient LAN exposure (RR=0.91, 95% CI: 0.78-1.07). The summary RR for breast cancer is 1.00 (95% CI: 0.995-1.01) for an increment of 1 h of sleep per night. No significant dose-response relationship between sleep duration and breast cancer was found either for the linearity test (Ptrend=0.725) or for the nonlinearity (Ptrend=0.091) test. An increasein of 15 ng/mg creatinine in urinary 6-sulphatoxymelatonin is associated with a 14% reduced risk for breast cancer (RR=0.86, 95% CI: 0.78-0.95), with a linear dose-response trend (Ptrend=0.003). There was no evidence of substantial heterogeneity or publication bias in the analysis. Our study adds to the evidence of LAN breast cancer theory. Further research in this area is warranted. PMID:24858716

  17. Different behavioral effect dose-response profiles in mice exposed to two-carbon chlorinated hydrocarbons: influence of structural and physical properties.

    PubMed

    Umezu, Toyoshi; Shibata, Yasuyuki

    2014-09-01

    The present study aimed to clarify whether dose-response profiles of acute behavioral effects of 1,2-dichloroethane (DCE), 1,1,1-trichloroethane (TCE), trichloroethylene (TRIC), and tetrachloroethylene (PERC) differ. A test battery involving 6 behavioral endpoints was applied to evaluate the effects of DCE, TCE, TRIC, and PERC in male ICR strain mice under the same experimental conditions. The behavioral effect dose-response profiles of these compounds differed. Regression analysis was used to evaluate the relationship between the dose-response profiles and structural and physical properties of the compounds. Dose-response profile differences correlated significantly with differences in specific structural and physical properties. These results suggest that differences in specific structural and physical properties of DCE, TCE, TRIC, and PERC are responsible for differences in behavioral effects that lead to a variety of dose-response profiles.

  18. Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases.

    PubMed

    Wu, M M; Kuo, T L; Hwang, Y H; Chen, C J

    1989-12-01

    Age-adjusted mortality rates were analyzed to examine the dose-response relation between ingested arsenic levels and risk of cancers and vascular diseases among residents in the endemic area of blackfoot disease, a unique peripheral vascular disease associated with long-term exposure to high-arsenic artesian well water and confined to the southwestern coast of Taiwan. The arsenic levels in well water determined in 1964-1966 were available in 42 villages of the study area, while mortality and population data during 1973-1986 were obtained from the local household registration offices and Taiwan Provincial Department of Health. Age-adjusted mortality rates from various cancers and vascular diseases by sex were calculated using the 1976 world population as the standard population. A significant dose-response relation was observed between arsenic levels in well water and cancers of the bladder, kidney, skin, and lung in both males and females, and cancers of the prostate and liver in males. However, there was no association for cancers of the nasopharynx, esophagus, stomach, colon, and uterine cervix, and for leukemia. Arsenic levels in well water were also associated with peripheral vascular diseases and cardiovascular diseases in a dose-response pattern, but not with cerebrovascular accidents. The dual effect of arsenic on carcinogenesis and arteriosclerosis and the interrelation between these two pathogenic mechanisms deserve more intensive study.

  19. Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose response using different monomers

    NASA Astrophysics Data System (ADS)

    Senden, R. J.; DeJean, P.; McAuley, K. B.; Schreiner, L. J.

    2006-07-01

    In this work, three new polymer gel dosimeter recipes were investigated that may be more suitable for widespread applications than polyacrylamide gel dosimeters, since the extremely toxic acrylamide has been replaced with the less harmful monomers N-isopropylacrylamide (NIPAM), diacetone acrylamide and N-vinylformamide. The new gel dosimeters studied contained gelatin (5 wt%), monomer (3 wt%), N,N'-methylene-bis-acrylamide crosslinker (3 wt%) and tetrakis (hydroxymethyl) phosphonium chloride antioxidant (10 mM). The NMR response (R2) of the dosimeters was analysed for conditions of varying dose, dose rate, time post-irradiation, and temperature during irradiation and scanning. It was shown that the dose-response behaviour of the NIPAM/Bis gel dosimeter is comparable to that of normoxic polyacrylamide gel (PAGAT) in terms of high dose-sensitivity and low dependence on dose rate and irradiation temperature, within the ranges considered. The dose-response (R2) of NIPAM/Bis appears to be linear over a greater dose range than the PAGAT gel dosimeter. The effects of time post-irradiation (temporal instability) and temperature during NMR scanning on the R2 response were more significant for NIPAM/Bis dosimeters. Diacetone acrylamide and N-vinylformamide gel dosimeters possessed considerably lower dose-sensitivities. The optical dose-response, measured in terms of the attenuation coefficient for each polymer gel dosimeter, showed potential for the use of optical imaging techniques in future studies.

  20. Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose-response using different monomers.

    PubMed

    Senden, R J; De Jean, P; McAuley, K B; Schreiner, L J

    2006-07-21

    In this work, three new polymer gel dosimeter recipes were investigated that may be more suitable for widespread applications than polyacrylamide gel dosimeters, since the extremely toxic acrylamide has been replaced with the less harmful monomers N-isopropylacrylamide (NIPAM), diacetone acrylamide and N-vinylformamide. The new gel dosimeters studied contained gelatin (5 wt%), monomer (3 wt%), N,N'-methylene-bis-acrylamide crosslinker (3 wt%) and tetrakis (hydroxymethyl) phosphonium chloride antioxidant (10 mM). The NMR response (R2) of the dosimeters was analysed for conditions of varying dose, dose rate, time post-irradiation, and temperature during irradiation and scanning. It was shown that the dose-response behaviour of the NIPAM/Bis gel dosimeter is comparable to that of normoxic polyacrylamide gel (PAGAT) in terms of high dose-sensitivity and low dependence on dose rate and irradiation temperature, within the ranges considered. The dose-response (R2) of NIPAM/Bis appears to be linear over a greater dose range than the PAGAT gel dosimeter. The effects of time post-irradiation (temporal instability) and temperature during NMR scanning on the R2 response were more significant for NIPAM/Bis dosimeters. Diacetone acrylamide and N-vinylformamide gel dosimeters possessed considerably lower dose-sensitivities. The optical dose-response, measured in terms of the attenuation coefficient for each polymer gel dosimeter, showed potential for the use of optical imaging techniques in future studies. PMID:16825731

  1. 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

  2. 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

  3. 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.

  4. 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

  5. Flexible dose-response models for Japanese atomic bomb survivor data: Bayesian estimation and prediction of cancer risk.

    PubMed

    Bennett, James; Little, Mark P; Richardson, Sylvia

    2004-12-01

    Generalised absolute risk models were fitted to the latest Japanese atomic bomb survivor cancer incidence data using Bayesian Markov Chain Monte Carlo methods, taking account of random errors in the DS86 dose estimates. The resulting uncertainty distributions in the relative risk model parameters were used to derive uncertainties in population cancer risks for a current UK population. Because of evidence for irregularities in the low-dose dose response, flexible dose-response models were used, consisting of a linear-quadratic-exponential model, used to model the high-dose part of the dose response, together with piecewise-linear adjustments for the two lowest dose groups. Following an assumed administered dose of 0.001 Sv, lifetime leukaemia radiation-induced incidence risks were estimated to be 1.11 x 10(-2) Sv(-1) (95% Bayesian CI -0.61, 2.38) using this model. Following an assumed administered dose of 0.001 Sv, lifetime solid cancer radiation-induced incidence risks were calculated to be 7.28 x 10(-2) Sv(-1) (95% Bayesian CI -10.63, 22.10) using this model. Overall, cancer incidence risks predicted by Bayesian Markov Chain Monte Carlo methods are similar to those derived by classical likelihood-based methods and which form the basis of established estimates of radiation-induced cancer risk.

  6. Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases

    SciTech Connect

    Wu, M.M.; Kuo, T.L.; Hwang, Y.H.; Chen, C.J. )

    1989-12-01

    Age-adjusted mortality rates were analyzed to examine the dose-response relation between ingested arsenic levels and risk of cancers and vascular diseases among residents in the endemic area of blackfoot disease, a unique peripheral vascular disease associated with long-term exposure to high-arsenic artesian well water and confined to the southwestern coast of Taiwan. The arsenic levels in well water determined in 1964-1966 were available in 42 villages of the study area, while mortality and population data during 1973-1986 were obtained from the local household registration offices and Taiwan Provincial Department of Health. Age-adjusted mortality rates from various cancers and vascular diseases by sex were calculated using the 1976 world population as the standard population. A significant dose-response relation was observed between arsenic levels in well water and cancers of the bladder, kidney, skin, and lung in both males and females, and cancers of the prostate and liver in males. However, there was no association for cancers of the nasopharynx, esophagus, stomach, colon, and uterine cervix, and for leukemia. Arsenic levels in well water were also associated with peripheral vascular diseases and cardiovascular diseases in a dose-response pattern, but not with cerebrovascular accidents. The dual effect of arsenic on carcinogenesis and arteriosclerosis and the interrelation between these two pathogenic mechanisms deserve more intensive study.

  7. 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

  8. Medical hypophysectomy: I. Dose-response using a gonadotropin-releasing hormone antagonist.

    PubMed

    Kenigsberg, D; Littman, B A; Hodgen, G D

    1984-07-01

    The hypothalamic-pituitary-ovarian axis can be "dissected" in a nonsurgical and reversible fashion by the administration of a potent gonadotropin-releasing hormone (GnRH) antagonist. We created a transient, functional lesion at the level of the pituitary gonadotrope by using a potent GnRH antagonist ([ Ac- pClPhe1 , pClDPhe2 , DTrp3 , DArg6 , DAla10 ]-GnRH). In long-term castrate cynomolgus monkeys, doses of 0.05 to 2.0 mg/kg/day intramuscularly were administered for a total of 32 days. At doses up to 0.2 mg/kg/day, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in circulation were only moderately suppressed; these subjects responded to an estradiol challenge by manifesting an LH elevation or surge within 48 hours. At doses of 0.5 to 1.0 mg/kg/day, FSH and LH secretion was suppressed to or below the limits of assay detection within 7 days, remaining in a severely hypogonadotropic state for the remainder of the treatment interval. Using 2 mg/kg/day, estradiol-positive feedback for midcycle-like LH/FSH surges was fully inhibited. This suppression of gonadotropin secretion was rapidly reversible, in that circulating gonadotropin levels had returned to pretreatment castrate levels within 60 days after termination of GnRH antagonist treatments. These findings suggest that potent GnRH antagonists can effectively create a hypogonadotropic milieu without the initial enhancement of gonadotropin secretion that occurs during initiation of GnRH agonist therapy. "Medical hypophysectomy" through GnRH antagonist administration may permit a more direct and controlled approach to gonadal therapies such as ovulation induction.

  9. Receptor mechanisms and dose-response models for the effects of dioxins.

    PubMed Central

    Lucier, G W; Portier, C J; Gallo, M A

    1993-01-01

    There is increasing evidence that receptor-mediated events impact one or more stages responsible for tumor development in experimental animals and humans. Although many chemicals and endogenous hormones require receptor interactions as a necessary event in their carcinogenic activity, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its structural analogs are the most visible examples of receptor-mediated carcinogens. TCDD, or dioxin as it is frequently called, interacts with the Ah receptor (AhR), which functions in a manner analogous to receptors for steroids. TCDD produces a wide spectrum of biochemical and toxic responses in in vitro and in vivo systems, and the Ah receptor is generally considered necessary for most if not all of these responses. Risk assessments for dioxin made by the United States and other countries throughout the world have been based on its carcinogenecity in experimental animals. Recently, epidemiology studies have indicated that TCDD is a human carcinogen at high doses. Because TCDD appears to be acting like a potent and persistent hormone agonist, it appears reasonable to incorporate mechanistic information on receptor-mediated events in risk assessments for TCDD. This information may be obtained from steroid receptor action and from molecular data on the Ah receptor. In this paper, we evaluate the scientific foundation on which mechanistic models for estimating dioxin's risks should be based. These models need to recognize the mechanisms possible for the diversity of biological responses that are initiated by a single receptor interacting with a single ligand. The U.S. EPA is currently reevaluating dioxin's risks by examining the possibility of developing biologically based models.(ABSTRACT TRUNCATED AT 250 WORDS) Images p36-a Figure 1. p42-a p42-b p42-c PMID:8390353

  10. 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

  11. Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

    PubMed Central

    2010-01-01

    Background The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia. Methods First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion. Results Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours. Conclusions Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia. PMID:20932337

  12. 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.

  13. Effects of beta 2-adrenoceptor agonists on anti-IgE-induced contraction and smooth muscle reactivity in human airways.

    PubMed Central

    Gorenne, I; Labat, C; Norel, X; De Montpreville, V; Guillet, M C; Cavero, I; Brink, C

    1995-01-01

    1. The beta 2-adrenoceptor agonists, salbutamol, salmeterol and RP 58802 relaxed basal tone of human isolated bronchial smooth muscle. Salmeterol- and RP 58802-induced relaxations persisted for more than 4 h when the medium was constantly renewed after treatment. 2. Salbutamol, salmeterol and RP 58802 reversed histamine-induced contractions in human airways (pD2 values: 6.15 +/- 0.21, 6.00 +/- 0.19 and 6.56 +/- 0.12, respectively). 3. Anti-IgE-induced contractions were significantly inhibited immediately after pretreatment of preparations with beta 2-adrenoceptor agonists (10 microM). However, when tissues were treated with beta 2-agonists and then washed for a period of 4 h, salmeterol was the only agonist which significantly inhibited the anti-IgE response. 4. Histamine response curves were shifted to the right immediately after pretreatment of tissues with the beta 2-adrenoceptor agonists (10 microM; 20 min), but maximal contractions were not affected. After a 4 h washing period, the histamine curves were not significantly different from controls. Concentration-effect curves to acetylcholine (ACh) or leukotriene C4 (LTC4) were not significantly modified after beta 2-agonist pretreatment. 5. These results suggest that beta 2-adrenoceptor agonists may prevent anti-IgE-induced contraction by inhibition of mediator release rather than alterations of those mechanisms involved in airway smooth muscle contraction. PMID:7780648

  14. The black agonist-receptor model of high potency sweeteners, and its implication to sweetness taste and sweetener design.

    PubMed

    Farkas, Attila; Híd, János

    2011-10-01

    The dose responses of the most commonly used high potency sweeteners (HPSs) have been measured by a more precise sensory procedure. The data were analyzed by Black's pharmacological model that takes into account not only agonist binding affinity but transduction efficiency as well. HPSs are clearly segregated into 2 groups depending on whether they bind to T1R2 or T1R3 of the receptor heterodimer. Surprisingly, the more potent sweeteners have lower transduction efficiencies. The implications of these on consumer product development and HPS design are discussed.

  15. The black agonist-receptor model of high potency sweeteners, and its implication to sweetness taste and sweetener design.

    PubMed

    Farkas, Attila; Híd, János

    2011-10-01

    The dose responses of the most commonly used high potency sweeteners (HPSs) have been measured by a more precise sensory procedure. The data were analyzed by Black's pharmacological model that takes into account not only agonist binding affinity but transduction efficiency as well. HPSs are clearly segregated into 2 groups depending on whether they bind to T1R2 or T1R3 of the receptor heterodimer. Surprisingly, the more potent sweeteners have lower transduction efficiencies. The implications of these on consumer product development and HPS design are discussed. PMID:22417603

  16. Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review.

    PubMed

    Yoshida, Takahiko; Yamauchi, Hiroshi; Fan Sun, Gui

    2004-08-01

    Chronic arsenic (As) poisoning has become a worldwide public health issue. Most human As exposure occurs from consumption of drinking water containing high amounts of inorganic As (iAs). In this paper, epidemiological studies conducted on the dose-response relationships between iAs exposure via the drinking water and related adverse health effects are reviewed. Before the review, the methods for evaluation of the individual As exposure are summarized and classified into two types, that is, the methods depending on As concentration of the drinking water and the methods depending on biological monitoring for As exposure; certain methods may be applied as optimum As exposure indexes to study dose-response relationship based on various As exposure situation. Chronic effects of iAs exposure via drinking water include skin lesions, neurological effects, hypertension, peripheral vascular disease, cardiovascular disease, respiratory disease, diabetes mellitus, and malignancies including skin cancer. The skin is quite sensitive to arsenic, and skin lesions are some of the most common and earliest nonmalignant effects related to chronic As exposure. The increase of prevalence in the skin lesions has been observed even at the exposure levels in the range of 0.005-0.01 mg/l As in drinking waters. Skin, lung, bladder, kidney, liver, and uterus are considered as sites As-induced malignancies, and the skin is though to be perhaps the most sensitive site. Prospective studies in large area of endemic As poisoning, like Bangladesh or China, where the rate of malignancies is expected to increase within the next several decades, will help to clarify the dose-response relationship between As exposure levels and adverse health effects with enhanced accuracy.

  17. 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

  18. 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.

  19. Dairy consumption and incidence of hypertension: a dose-response meta-analysis of prospective cohort studies.

    PubMed

    Soedamah-Muthu, Sabita S; Verberne, Lisa D M; Ding, Eric L; Engberink, Mariëlle F; Geleijnse, Johanna M

    2012-11-01

    Observational and clinical studies suggest that dairy intake, particularly low-fat dairy, could have a beneficial effect on blood pressure. We performed a dose-response meta-analysis of prospective cohort studies on dairy intake and risk of hypertension in the general population. A systematic literature search for eligible studies was conducted until July 2011, using literature databases and hand search. Study-specific dose-response associations were computed according to the generalized least squares for trend estimation method, and linear and piecewise regression models were created. Random-effects models were performed with summarized dose-response data. We included 9 studies with a sample size of 57 256, a total of 15 367 incident hypertension cases, and a follow-up time between 2 and 15 years. Total dairy (9 studies; range of intake, ≈100-700 g/d), low-fat dairy (6 studies; ≈100-500 g/d), and milk (7 studies; ≈100-500 g/d) were inversely and linearly associated with a lower risk of hypertension. The pooled relative risks per 200 g/d were 0.97 (95% CI, 0.95-0.99) for total dairy, 0.96 (95% CI, 0.93-0.99) for low-fat dairy, and 0.96 (95% CI, 0.94-0.98) for milk. High-fat dairy (6 studies), total fermented dairy (4 studies), yogurt (5 studies), and cheese (8 studies) were not significantly associated with hypertension incidence (pooled relative risks of ≈1). This meta-analysis of prospective cohort studies suggests that low-fat dairy and milk could contribute to the prevention of hypertension, which needs confirmation in randomized controlled trials.

  20. Explicit superconic curves.

    PubMed

    Cho, Sunggoo

    2016-09-01

    Conics and Cartesian ovals are extremely important curves in various fields of science. In addition, aspheric curves based on conics are useful in optical design. Superconic curves, recently suggested by Greynolds, are extensions of both conics and Cartesian ovals and have been applied to optical design. However, they are not extensions of aspheric curves based on conics. In this work, we investigate another type of superconic curves. These superconic curves are extensions of not only conics and Cartesian ovals but also aspheric curves based on conics. Moreover, these are represented in explicit form, while Greynolds's superconic curves are in implicit form. PMID:27607506

  1. Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

    PubMed

    Craft, R M; Bernal, S A

    2001-08-01

    A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects. PMID:11418226

  2. Dose-response function for the soiling of silica-soda-lime glass due to dry deposition.

    PubMed

    Lombardo, T; Ionescu, A; Chabas, A; Lefèvre, R-A; Ausset, P; Candau, Y

    2010-01-15

    Several exposure campaigns of silica-soda-lime window glass have been performed in 30 European sites and 1 in Canada in order to understand, quantify and model the phenomenon of soiling. In this purpose samples were exposed sheltered from the rain. Parallel to exposure, several meteorological parameters and pollution concentrations have been monitored. This paper shows first results on the establishment of a dose-response function for glass soiling. Statistical analyses show that PM(10) is not the only parameter, but also SO(2) and NO(2) atmospheric concentrations seem to be responsible for the optical impairment of glass surfaces, expressed as haze.

  3. Non-Targeted Effects of Ionizing Radiation: Implications for Risk Assessment and the Radiation Dose Response Profile

    SciTech Connect

    Morgan, William F.; Sowa, Marianne B.

    2009-11-01

    Radiation risks at low doses remain a hotly debated topic. Recent experimental advances in our understanding of effects occurring in the progeny of irradiated cells, and/or the non-irradiated neighbors of irradiated cells, i.e., non-targeted effects associated with exposure to ionizing radiation, have influenced this debate. The goal of this document is to summarize the current status of this debate and speculate on the potential impact of non-targeted effects on radiation risk assessment and the radiation dose response profile.

  4. Biologically Effective Dose-Response Relationship for Breast Cancer Treated by Conservative Surgery and Postoperative Radiotherapy

    SciTech Connect

    Plataniotis, George A. Dale, Roger G.

    2009-10-01

    Purpose: To find a biologically effective dose (BED) response for adjuvant breast radiotherapy (RT) for initial-stage breast cancer. Methods and Materials: Results of randomized trials of RT vs. non-RT were reviewed and the tumor control probability (TCP) after RT was calculated for each of them. Using the linear-quadratic formula and Poisson statistics of cell-kill, the average initial number of clonogens per tumor before RT and the average tumor cell radiosensitivity (alpha-value) were calculated. An {alpha}/{beta} ratio of 4 Gy was assumed for these calculations. Results: A linear regression equation linking BED to TCP was derived: -ln[-ln(TCP)] = -ln(No) + {alpha}{sup *} BED = -4.08 + 0.07 * BED, suggesting a rather low radiosensitivity of breast cancer cells (alpha = 0.07 Gy{sup -1}), which probably reflects population heterogeneity. From the linear relationship a sigmoid BED-response curve was constructed. Conclusion: For BED values higher than about 90 Gy{sub 4} the radiation-induced TCP is essentially maximizing at 90-100%. The relationship presented here could be an approximate guide in the design and reporting of clinical trials of adjuvant breast RT.

  5. Dose-response relationships and statistical performance of a battery of bacterial gene profiling assays.

    PubMed

    Dardenne, F; Nobels, I; De Coen, W; Blust, R

    2007-05-01

    Because of increasing awareness and legislative demands, there is a demand for the development and use of biological assays for the assessment of the toxicity of chemicals, environmental samples. Recently, a growing number of bacterial reporter assays have been developed and implemented. Nevertheless, little data is published on the performance of these assays in terms of analytical parameters. We present results on a battery of 14 transgenic Escherichia coli strains carrying different promoter::reporter fusions. Growth characteristics and basal expression levels were modeled and fitted, data show that growth curves should be taken into account during test development. Our study shows that the induction profiles reflect the mode of action, e.g., paraquat clearly induces the soxRS operon. The sensitivity of the assay compares well to that of whole organism tests, e.g., fish and Daphnia for polar organics. Metal toxicity is detected less efficiently, e.g., cadmium is detected near the LC50 of carp, considered a relatively insensitive species towards cadmium. The assay variability ranges from 10 to 40% depending on the strain, comparable to that of other bioassays. The variability was shown to be determined by the intrinsic traits of the promoter-strain combination, not by operating conditions. PMID:17225096

  6. 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

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

    PubMed

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

    2016-07-01

    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.

  8. 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

  9. 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 ...

  10. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  11. Respiratory symptoms, lung function, and nasal cellularity in Indonesian wood workers: a dose-response analysis

    PubMed Central

    Borm, P; Jetten, M; Hidayat, S; van de Burgh, N; Leunissen, P; Kant, I; Houba, R; Soeprapto, H

    2002-01-01

    Objectives: It was hypothesised that inflammation plays a dominant part in the respiratory effects of exposure to wood dust. The purpose of this study was to relate the nasal inflammatory responses of workers exposed to meranti wood dust to (a) levels of exposure, (b) respiratory symptoms and (c) respiratory function. Methods: A cross sectional study was carried out in 1997 in a woodworking plant that used mainly meranti, among 982 workers exposed to different concentrations of wood dust. Personal sampling (n=243) of inhalable dust measurements indicated mean exposure in specific jobs, and enabled classification of 930 workers in three exposure classes (<2, 2–5, and >5 mg/m3) based on job title. Questionnaires were used to screen respiratory symptoms in the entire population. Lung function was measured with two different techniques, conventional flow-volume curves and the forced oscillation technique. Nasal lavage was done to assess inflammation in the upper respiratory tract. Results: A negative trend between years of employment and most flow-volume variables was found in men, but not in women workers. Current exposure, however, was not related to spirometric outcomes, respiratory symptoms, or nasal cellularity. Some impedance variables were related to current exposure but also with better function at higher exposure. Conclusions: Exposure to meranti wood dust did not cause an inflammation in the upper respiratory tract nor an increase of respiratory symptoms or decrease of lung function. These data do not corroborate the hypothesis that inflammation plays a part in airway obstruction induced by wood dust. PMID:11983850

  12. 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

  13. Dose response and post-irradiation characteristics of the Sunna 535-nm photo-fluorescent film dosimeter

    NASA Astrophysics Data System (ADS)

    Murphy, M. K.; Kovács, A.; Miller, S. D.; McLaughlin, W. L.

    2003-12-01

    Results of characterization studies on one of the first versions of the Sunna photo-fluorescent dosimeter™ have previously been reported, and the performance of the red fluorescence component described. This present paper describes dose response and post-irradiation characteristics of the green fluorescence component from the same dosimeter film ( Sunna Model γ), which is manufactured using the injection molding technique. This production method may supply batch sizes on the order of 1 million dosimeter film elements while maintaining a signal precision (1 σ) on the order of ±1% without the need to correct for variability of film thickness. The dosimeter is a 1 cm×3 cm polymeric film of 0.5-mm thickness that emits green fluorescence at intensities increasing almost linearly with dose. The data presented include dose response, post-irradiation growth, heat treatment, dosimeter aging, dose rate dependence, energy dependence, dose fractionation, variation of response within a batch, and the stability of the fluorimeter response. The results indicate that, as a routine dosimeter, the green signal provides a broad range of response at food irradiation (0.3-5 kGy), medical sterilization (5-40 kGy), and polymer cross-linking (40-250 kGy) dose levels.

  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. An in vitro dynamic microcosm biofilm model for caries lesion development and antimicrobial dose-response studies.

    PubMed

    Maske, T T; Brauner, K V; Nakanishi, L; Arthur, R A; van de Sande, F H; Cenci, M S

    2016-01-01

    Some dynamic biofilm models for dental caries development are limited as they require multiple experiments and do not allow independent biofilm growth units, making them expensive and time-consuming. This study aimed to develop and test an in vitro dynamic microcosm biofilm model for caries lesion development and for dose-response to chlorhexidine. Microcosm biofilms were grown under two different protocols from saliva on bovine enamel discs for up to 21 days. The study outcomes were as follows: the percentage of enamel surface hardness change, integrated hardness loss, and the CFU counts from the biofilms formed. The measured outcomes, mineral loss and CFU counts showed dose-response effects as a result of the treatment with chlorhexidine. Overall, the findings suggest that biofilm growth for seven days with 0.06 ml min(-1) salivary flow under exposure to 5% sucrose (3 × daily, 0.25 ml min(-1), 6 min) was suitable as a pre-clinical model for enamel demineralization and antimicrobial studies.

  16. 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

  17. Concentration- and flux-based ozone dose-response relationships for five poplar clones grown in North China.

    PubMed

    Hu, Enzhu; Gao, Feng; Xin, Yue; Jia, Huixia; Li, Kaihui; Hu, Jianjun; Feng, Zhaozhong

    2015-12-01

    Concentration- and flux-based O3 dose-response relationships were developed for poplars in China. Stomatal conductance (gs) of five poplar clones was measured to parameterize a Jarvis-type multiplicative gs model. The maximum gs and other model parameters varied between clones. The strongest relationship between stomatal O3 flux and total biomass was obtained when phytotoxic ozone dose (POD) was integrated using an uptake rate threshold of 7 nmol m(-2) s(-1). The R(2) value was similar between flux-based and concentration-based dose-response relationships. Ozone concentrations above 28-36 nmol mol(-1) contributed to reducing the biomass production of poplar. Critical levels of AOT40 (accumulated O3 exposure over 40 nmol mol(-1)) and POD7 in relation to 5% reduction in total biomass for poplar were 12 μmol mol(-1) h and 3.8 mmol m(-2), respectively.

  18. 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

  19. Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.

    PubMed

    Crippa, Alessio; Discacciati, Andrea; Larsson, Susanna C; Wolk, Alicja; Orsini, Nicola

    2014-10-15

    Several studies have analyzed the relationship between coffee consumption and mortality, but the shape of the association remains unclear. We conducted a dose-response meta-analysis of prospective studies to examine the dose-response associations between coffee consumption and mortality from all causes, cardiovascular disease (CVD), and all cancers. Pertinent studies, published between 1966 and 2013, were identified by searching PubMed and by reviewing the reference lists of the selected articles. Prospective studies in which investigators reported relative risks of mortality from all causes, CVD, and all cancers for 3 or more categories of coffee consumption were eligible. Results from individual studies were pooled using a random-effects model. Twenty-one prospective studies, with 121,915 deaths and 997,464 participants, met the inclusion criteria. There was strong evidence of nonlinear associations between coffee consumption and mortality for all causes and CVD (P for nonlinearity < 0.001). The largest risk reductions were observed for 4 cups/day for all-cause mortality (16%, 95% confidence interval: 13, 18) and 3 cups/day for CVD mortality (21%, 95% confidence interval: 16, 26). Coffee consumption was not associated with cancer mortality. Findings from this meta-analysis indicate that coffee consumption is inversely associated with all-cause and CVD mortality.

  20. Association between dietary vitamin C intake and risk of esophageal cancer: A dose-response meta-analysis.

    PubMed

    Bo, Yacong; Lu, Yan; Zhao, Yan; Zhao, Erjiang; Yuan, Ling; Lu, Weiquan; Cui, Lingling; Lu, Quanjun

    2016-04-15

    While several epidemiological studies have investigated the association between vitamin C and risk of esophageal cancer, the results remain inconsistent. In the present study, a meta-analysis was conducted to assess the impact of dietary vitamin C intake on esophageal cancer risk. Online databases were searched up to March 29, 2015, for studies on the association between dietary vitamin C intake and esophageal cancer risk. Pooled risk ratios (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Dose-response analyses were performed using the method of restricted cubic splines with four knots at percentiles of 5, 35, 65 and 95% of the distribution. Publication bias was estimated using Egger's tests and funnel plots. In all, 15 articles were included in this meta-analysis, including 20 studies, containing 7063 controls and 3955 cases of esophageal cancer. By comparing the highest vs. the lowest categories of vitamin C intake, we found that vitamin C was inversely associated with the risk of esophageal cancer [overall OR = 0.58, 95% CI = 0.49-0.68, I(2) = 56%]. A linear dose-response relationship was found. With an increase in dietary vitamin C intake of 50 mg/day, the risk of esophageal cancer statistically decreased by 13% (OR = 0.87, 95% CI = 0.80-0.93, p(linearity) = 0.0002). In conclusion, our analysis suggested that the higher intake of dietary vitamin C might have a protective effect against esophageal cancer.

  1. 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.

  2. An in vitro dynamic microcosm biofilm model for caries lesion development and antimicrobial dose-response studies.

    PubMed

    Maske, T T; Brauner, K V; Nakanishi, L; Arthur, R A; van de Sande, F H; Cenci, M S

    2016-01-01

    Some dynamic biofilm models for dental caries development are limited as they require multiple experiments and do not allow independent biofilm growth units, making them expensive and time-consuming. This study aimed to develop and test an in vitro dynamic microcosm biofilm model for caries lesion development and for dose-response to chlorhexidine. Microcosm biofilms were grown under two different protocols from saliva on bovine enamel discs for up to 21 days. The study outcomes were as follows: the percentage of enamel surface hardness change, integrated hardness loss, and the CFU counts from the biofilms formed. The measured outcomes, mineral loss and CFU counts showed dose-response effects as a result of the treatment with chlorhexidine. Overall, the findings suggest that biofilm growth for seven days with 0.06 ml min(-1) salivary flow under exposure to 5% sucrose (3 × daily, 0.25 ml min(-1), 6 min) was suitable as a pre-clinical model for enamel demineralization and antimicrobial studies. PMID:26905384

  3. Benchmarking B-cell epitope prediction with quantitative dose-response data on antipeptide antibodies: towards novel pharmaceutical product development.

    PubMed

    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.

  4. 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).

  5. 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.

  6. Effect of inorganic salts and glucose additives on dose-response, melting point and mass density of genipin gel dosimeters.

    PubMed

    Al-jarrah, A M; Abdul Rahman, Azhar; Shahrim, Iskandar; Razak, Nik Noor Ashikin Nik Ab; Ababneh, Baker; Tousi, Ehsan Taghizadeh

    2016-01-01

    Genipin gel dosimeters are hydrogels infused with a radiation-sensitive material which yield dosimetric information in three dimensions (3D). The effect of inorganic salts and glucose on the visible absorption dose-response, melting points and mass density of genipin gel dosimeters has been experimentally evaluated using 6-MV LINAC photons. As a result, the addition of glucose with optimum concentration of 10% (w/w) was found to improve the thermal stability of the genipin gel and increase its melting point (Tm) by 6 °C accompanied by a slight decrease of dose-response. Furthermore, glucose helps to adjust the gel mass density to obtain the desired tissue-equivalent properties. A drop of Tm was observed when salts were used as additives. As the salt concentration increased, gel Tm decreased. The mass density and melting point of the genipin gel could be adjusted using different amounts of glucose that improved the genipin gel suitability for 3D dose measurements without introducing additional toxicity to the final gel.

  7. A meta-analysis including dose-response relationship between night shift work and the risk of colorectal cancer.

    PubMed

    Wang, Xiao; Ji, Alin; Zhu, Yi; Liang, Zhen; Wu, Jian; Li, Shiqi; Meng, Shuai; Zheng, Xiangyi; Xie, Liping

    2015-09-22

    A meta-analysis was conducted to quantitatively evaluate the correlation between night shift work and the risk of colorectal cancer. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer via fixed- or random-effect models. A dose-response meta-analysis was performed as well. The pooled OR estimates of the included studies illustrated that night shift work was correlated with an increased risk of colorectal cancer (OR = 1.318, 95% CI 1.121-1.551). No evidence of publication bias was detected. In the dose-response analysis, the rate of colorectal cancer increased by 11% for every 5 years increased in night shift work (OR = 1.11, 95% CI 1.03-1.20). In conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms.

  8. Effects of folic acid supplementation on serum folate and plasma homocysteine concentrations in older adults: a dose-response trial.

    PubMed

    Anderson, Cheryl A M; Jee, Sun Ha; Charleston, Jeanne; Narrett, Matthew; Appel, Lawrence J

    2010-10-15

    The authors' objective in this study was to estimate the changes in serum folate and homocysteine concentration that resulted from 6 weeks of supplementation with folic acid. A randomized, double-blind, placebo-controlled, dose-response trial with a parallel-group design was conducted. A total of 133 participants aged 60-90 years (70% female, 19% nonwhite) were assigned to receive 0, 100, 400, 1,000, or 2,000 μg/day of folic acid for 6 weeks. Data were collected in the United States between June and September 1996. At baseline, median serum folate and plasma homocysteine concentrations were 5.7 ng/mL (interquartile range (25th-75th percentiles), 4.1-7.8) and 8.3 μmol/L (interquartile range, 7.1-10.0), respectively. As the folic acid dose increased, serum folate levels increased (P-trend < 0.001). There was no dose-response relation with homocysteine level among all participants. In analyses restricted to persons with the lowest serum folate concentration (<4.5 ng/mL) at baseline, there was a trend (P = 0.06) toward decreased homocysteine levels with increasing folic acid dose. In healthy, older adults with adequate folate status, folic acid supplementation is not beneficial for homocysteine reduction. However, for older adults with low serum folate levels, supplementation will improve folate status and may be beneficial for lowering homocysteine concentrations.

  9. Dietary magnesium intake and metabolic syndrome in the adult population: dose-response meta-analysis and meta-regression.

    PubMed

    Ju, Sang-Yhun; Choi, Whan-Seok; Ock, Sun-Myeong; Kim, Chul-Min; Kim, Do-Hoon

    2014-12-22

    ncreasing evidence has suggested an association between dietary magnesium intake and metabolic syndrome. However, previous research examining dietary magnesium intake and metabolic syndrome has produced mixed results. Our objective was to determine the relationship between dietary magnesium intake and metabolic syndrome in the adult population using a dose-response meta-analysis. We searched the PubMed, Embase and the Cochrane Library databases from August, 1965, to May, 2014. Observational studies reporting risk ratios with 95% confidence intervals (CIs) for metabolic syndrome in ≥ 3 categories of dietary magnesium intake levels were selected. The data extraction was performed independently by two authors, and the quality of the studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). Based on eight cross-sectional studies and two prospective cohort studies, the pooled relative risks of metabolic syndrome per 150 mg/day increment in magnesium intake was 0.88 (95% CI, 0.84-0.93; I(2) = 36.3%). The meta-regression model showed a generally linear, inverse relationship between magnesium intake (mg/day) and metabolic syndrome. This dose-response meta-analysis indicates that dietary magnesium intake is significantly and inversely associated with the risk of metabolic syndrome. However, randomized clinical trials will be necessary to address the issue of causality and to determine whether magnesium supplementation is effective for the prevention of metabolic syndrome.

  10. Blue light dose-responses of leaf photosynthesis, morphology, and chemical composition of Cucumis sativus grown under different combinations of red and blue light.

    PubMed

    Hogewoning, Sander W; Trouwborst, Govert; Maljaars, Hans; Poorter, Hendrik; van Ieperen, Wim; Harbinson, Jeremy

    2010-06-01

    The blue part of the light spectrum has been associated with leaf characteristics which also develop under high irradiances. In this study blue light dose-response curves were made for the photosynthetic properties and related developmental characteristics of cucumber leaves that were grown at an equal irradiance under seven different combinations of red and blue light provided by light-emitting diodes. Only the leaves developed under red light alone (0% blue) displayed dysfunctional photosynthetic operation, characterized by a suboptimal and heterogeneously distributed dark-adapted F(v)/F(m), a stomatal conductance unresponsive to irradiance, and a relatively low light-limited quantum yield for CO(2) fixation. Only 7% blue light was sufficient to prevent any overt dysfunctional photosynthesis, which can be considered a qualitatively blue light effect. The photosynthetic capacity (A(max)) was twice as high for leaves grown at 7% blue compared with 0% blue, and continued to increase with increasing blue percentage during growth measured up to 50% blue. At 100% blue, A(max) was lower but photosynthetic functioning was normal. The increase in A(max) with blue percentage (0-50%) was associated with an increase in leaf mass per unit leaf area (LMA), nitrogen (N) content per area, chlorophyll (Chl) content per area, and stomatal conductance. Above 15% blue, the parameters A(max), LMA, Chl content, photosynthetic N use efficiency, and the Chl:N ratio had a comparable relationship as reported for leaf responses to irradiance intensity. It is concluded that blue light during growth is qualitatively required for normal photosynthetic functioning and quantitatively mediates leaf responses resembling those to irradiance intensity.

  11. A study of [D-Pro2, D-Phe7, D-Trp9]-substance P and [D-Trp7,9]-substance P as tachykinin partial agonists in the rat colon.

    PubMed Central

    Bailey, S. J.; Jordan, C. C.

    1984-01-01

    Two substance P (SP) analogues, [D-Pro2, D-Phe7, D-Trp9]-SP (DPDPDT) and [D-Trp7,9]-SP (DT79), previously described as tachykinin antagonists, have been shown to contract the rat colon muscularis mucosae preparation. The maximum response exhibited by these analogues was about 30% that of the SP maximum, suggesting that they were acting as partial agonists relative to SP. The responses to DPDPDT were unaffected by pretreatment with mepyramine, methysergide or [Sar1, Ile5, Ala8]-angiotensin II, which abolished the responses to histamine, 5-hydroxytryptamine (5-HT) and angiotensin II, respectively. Methysergide also did not affect the responses to DT79; the other antagonists were not tested against this analogue. Indomethacin and cimetidine also had no inhibitory effect. Atropine (2 microM) was present in all experiments to prevent indirect muscarinic effects. Phenoxybenzamine did not affect the dose-response curves to SP, eledoisin-related peptide (ERP), kassinin, eledoisin or physalaemin, nor did it affect the responses to individual doses of DPDPDT or DT79. However, in the absence of atropine, it shifted the carbachol dose-response curve markedly to the right, and reduced its maximum. The tachykinin antagonist [D-Pro4, D-Trp7,9,10]-SP4-11 reduced the responses to individual matched doses of DPDPDT, DT79 and SP to the same degree, whilst leaving responses to 5-HT or angiotensin II unaffected. This suggested that DPDPDT and DT79 were acting at the same receptor as SP. The inhibitory effects of DPDPDT on responses to SP, ERP and kassinin, and that of DT79 on responses to SP, were analysed. All four combinations yielded data compatible with an interaction at only one receptor, although DPDPDT appeared slightly more potent at inhibiting responses to kassinin. The results are discussed in the light of the proposed existence of multiple tachykinin receptor subtypes. The possible influence of differential metabolism of tachykinin analogues is also considered. PMID:6203595

  12. Relationship between food intake and metabolic rate in rats treated with beta-adrenoceptor agonists.

    PubMed

    Yamashita, J; Onai, T; York, D A; Bray, G A

    1994-06-01

    The purpose of the present experiment was to clarify the interaction between food intake and activity of the thermogenic component of the sympathetic nervous system by studying the dose response relationships of typical beta 1-, beta 2-, and beta 3-adrenoceptor agonists on oxygen consumption and food intake. The data showed that the ED50 for the effects of Dobutamine (beta 1), Clenbuterol (beta 2) and ICI D7114 (beta 3) agonists on food intake were 8.9, 0.041 and > 1.1 mumol/kg respectively whereas the ED50 values for stimulation of metabolic rate were 7.1, 1.3 and 0.11 mumole/kg respectively. The marked differences in ED50 values for suppression of food intake and stimulation of metabolic rate for both clenbuterol and ICI D7114 suggest that the regulation of feeding and of metabolic rate in response to these agonists are independent of each other. The experiments also identified that Clenbuterol activated a very sensitive beta 2-adrenergic system for the regulation of feeding behavior. PMID:7915938

  13. Ozone fluxes and foliar injury development in the ozone-sensitive poplar clone Oxford (Populus maximowiczii x Populus berolinensis): a dose-response analysis.

    PubMed

    Marzuoli, Riccardo; Gerosa, Giacomo; Desotgiu, Rosanna; Bussotti, Filippo; Ballarin-Denti, Antonio

    2009-01-01

    Between 2004 and 2005 a combined open plot and open-top chamber (OTC) experiment was carried out at Curno (Northern Italy) with cuttings of the poplar clone Oxford (Populus maximowiczii Henry x Populus berolinensis Dippel) grown in open plots (OPs, ambient air), charcoal-filtered OTCs (CF, ozone concentration reduced to 50% of ambient) or non-filtered OTCs (NF, ozone concentration reduced to 95% of ambient). Plants in half of the chambers were kept well-watered (WET), and plants in the remaining chambers were not watered (DRY). The onset and development of visible foliar injury and the stomatal conductance to water vapor (g(w)) were assessed during each growing season. A stomatal conductance model was parameterized by the Jarvis approach, allowing the calculation of ozone stomatal fluxes of plants in each treatment. The pattern of visible symptoms was analyzed in relation to ozone exposure (AOT40, accumulated ozone over a threshold of 40 ppb) and accumulated ozone stomatal fluxes (AF(ST)). Symptoms became visible at an AOT40 between 9584 and 13,110 ppb h and an AF(ST) between 27.85 and 30.40 mmol O(3) m(-2). The development of symptoms was more widespread and faster in plants in WET plots than in DRY plots. A slightly higher dose of ozone was required to cause visible symptoms in plants in DRY plots than in WET plots. By the end of each growing season, plants in the CF OTCs had absorbed a high dose of ozone (31.60 mmol O(3) m(-2) in 2004 and 32.83 mmol O(3) m(-2) in 2005, for WET plots), without developing any visible symptoms. A reliable dose-response relationship was defined by a sigmoidal curve model. The shape of this curve expresses the change in leaf sensitivity and physiologic state over a prolonged ozone exposure. After the appearance of the first symptoms, foliar injury increased more rapidly than the increases in ozone exposure and ozone absorbed dose; however, when the injury incidence reached 75%, the plant response declined.

  14. Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans.

    PubMed

    Greer, Monte A; Goodman, Gay; Pleus, Richard C; Greer, Susan E

    2002-09-01

    Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect

  15. Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans.

    PubMed Central

    Greer, Monte A; Goodman, Gay; Pleus, Richard C; Greer, Susan E

    2002-01-01

    Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect

  16. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  17. Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.

    PubMed

    Marino, Dale J; Clewell, Harvey J; Gentry, P Robinan; Covington, Tammie R; Hack, C Eric; David, Raymond M; Morgott, David A

    2006-06-01

    The current USEPA cancer risk assessment for dichloromethane (DCM) is based on deterministic physiologically based pharmacokinetic (PBPK) modeling involving comparative metabolism of DCM by the GST pathway in the lung and liver of humans and mice. Recent advances in PBPK modeling include probabilistic methods and, in particular, Bayesian inference to quantitatively address variability and uncertainty separately. Although Bayesian analysis of human PBPK models has been published, no such efforts have been reported specifically addressing the mouse, apart from results included in the OSHA final rule on DCM. Certain aspects of the OSHA model, however, are not consistent with current approaches or with the USEPA's current DCM cancer risk assessment. Therefore, Bayesian analysis of the mouse PBPK model and dose-response modeling was undertaken to support development of an improved cancer risk assessment for DCM. A hierarchical population model was developed and prior parameter distributions were selected to reflect parameter values that were considered the most appropriate and best available. Bayesian modeling was conducted using MCSim, a publicly available software program for Markov Chain Monte Carlo analysis. Mean posterior values from the calibrated model were used to develop internal dose metrics, i.e., mg DCM metabolized by the GST pathway/L tissue/day in the lung and liver using exposure concentrations and results from the NTP mouse bioassay, consistent with the approach used by the USEPA for its current DCM cancer risk assessment. Internal dose metrics were 3- to 4-fold higher than those that support the current USEPA IRIS assessment. A decrease of similar magnitude was also noted in dose-response modeling results. These results show that the Bayesian PBPK model in the mouse provides an improved basis for a cancer risk assessment of DCM.

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

    PubMed

    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.

  19. Association between physical activity and all cancer mortality: Dose-response meta-analysis of cohort studies.

    PubMed

    Li, Yingjun; Gu, Mengjia; Jing, Fangyuan; Cai, Shaofang; Bao, Chengzhen; Wang, Jianbing; Jin, Mingjuan; Chen, Kun

    2016-02-15

    The relationship between physical activity (PA) before cancer diagnosis and all cancer mortality among the general population is not well defined because of inconsistent results from published studies. Thus, the lack of a meta-analysis that addresses that issue prompted the current report. We conducted a literature search of PubMed and Web of Science to identify all relevant epidemiological studies published before February 28, 2015. We performed categorical and dose-response meta-analyses to evaluate and quantify the association between pre-diagnosis PA and all cancer mortality. A total of 32 prospective cohort studies involving 59,362 cancer deaths were included in this meta-analysis. The pooled relative risks (RRs) of all cancer mortality were 0.80 [95% confidence interval (CI) = 0.76-0.85)] for highest versus lowest PA group and 0.85 (95% CI = 0.82-0.88) for PA versus non/occasional PA group. Dose-response analysis showed that the increment in pre-diagnosis PA level was associated with a decreased risk of cancer death continuously. Moreover, an increment of 10 MET-h/week was related to a 7% lower risk for all cancer mortality (RR = 0.93, 95% CI = 0.91-0.95). In conclusion, the present meta-analysis provides evidence of an inverse association between pre-diagnosis PA and all cancer mortality among the general population. High-quality epidemiological studies that employ standardized PA assessments and unified definitions of PA levels should be developed in future.

  20. 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

  1. Characterizing dose-responses of catalase to nitrofurazone exposure in model ciliated protozoan Euplotes vannus for ecotoxicity assessment: enzyme activity and mRNA expression.

    PubMed

    Li, Jiqiu; Zhou, Liang; Lin, Xiaofeng; Yi, Zhenzhen; Al-Rasheid, Khaled A S

    2014-02-01

    In environmental studies, some biological responses, known as biomarkers, have been used as a powerful bioassay tool for more than four decades. Disparity between enzyme activity and mRNA abundance leads to correlation equivocality, which makes the application of biomarkers for environmental risk assessment more complicated. This study investigates this disparity in the case of catalase when used as a biomarker for detecting ecotoxicity induced by antibiotics in aquatic ecosystems. In particular, dose-responses for catalase activity and mRNA expression abundance were investigated in Euplotes vannus which were exposed to graded doses of nitrofurazone for several discrete durations, and dose-response models were developed to characterize the dose-response dynamics. Significant differences were found in both catalase activity and mRNA expression abundance among the E. vannus treated with nitrofurazone. Catalase activity showed a hormetic-like effect in terms of dose-response, characterized by a biphasic relationship which was more clearly evident after a longer exposure period, while mRNA expression abundance increased linearly with the exposure duration. Additionally, the correlation between catalase activity and mRNA expression abundance reversed along with the duration of exposure to nitrofurazone. Taken together, our results demonstrate that catalase mRNA expression offers a more straightforward dose-response model than enzyme activity. Our findings suggest that both catalase enzyme activity and mRNA expression abundance can be used jointly as bioassay tools for detecting ecotoxicity induced by nitrofurazone in aquatic ecosystems.

  2. Recognizing the importance of exposure-dose-response dynamics for ecotoxicity assessment: nitrofurazone-induced antioxidase activity and mRNA expression in model protozoan Euplotes vannus.

    PubMed

    Hong, Yazhen; Liu, Shuxing; Lin, Xiaofeng; Li, Jiqiu; Yi, Zhenzhen; Al-Rasheid, Khaled A S

    2015-06-01

    The equivocality of dose-response relationships has, in practice, hampered the application of biomarkers as a means to evaluate environmental risk, yet this important issue has not yet been fully recognized or explored. This paper evaluates the potential of antioxidant enzymes in the ciliated protozoan Euplotes vannus for use as biomarkers. Dose-response dynamics, together with both the enzyme activity and the gene expression of the antioxidant enzymes, superoxide dismutase, and glutathione peroxidase, were investigated when E. vannus were exposed to graded doses of nitrofurazone for several discrete durations. Mathematical models were explored to characterize the dose-response profiles and, specifically, to identify any equivocality in terms of endpoint. Significant differences were found in both enzyme activity and messenger RNA (mRNA) expression in the E. vannus treated with nitrofurazone, and the interactions between exposure dosage and duration were significant. Correlations between enzyme activity, mRNA expression, and nitrofurazone dose varied with exposure duration. Particularly, the dose-responses showed different dynamics depending on either endpoint or exposure duration. Our findings suggest that both the enzyme activity and the gene expression of the tested antioxidant enzymes can be used as biomarkers for ecotoxicological assessment on the premise of ascertaining appropriate dosage scope, exposure duration, endpoint, etc., which can be achieved by using dose-response dynamics.

  3. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  4. [Adrenergic beta-agonist intoxication].

    PubMed

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency.

  5. 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.

  6. 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

  7. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  8. Quantitative Measure of Receptor Agonist and Modulator Equi-Response and Equi-Occupancy Selectivity

    PubMed Central

    Zhang, Rumin; Kavana, Michael

    2016-01-01

    G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR agonism and allosterism data permits the determination of all affinity and efficacy parameters based on a general operational model. We report here a quantitative and panoramic measure of receptor agonist and modulator equi-response and equi-occupancy selectivity calculated from these parameters. The selectivity values help to differentiate not only one agonist or modulator from another, but on-target from off-target receptor or functional pathway as well. Furthermore, in conjunction with target site free drug concentrations and endogenous agonist tones, the allosterism parameters and selectivity values may be used to predict in vivo efficacy and safety margins. PMID:27116909

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

    PubMed

    Wang, Wei-Ling; Xu, Hui; Li, Ying; Ma, Zhi-Zhong; Sun, Xiao-Dong; Hu, Yun-Tao

    2016-07-01

    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 (Mn(2+))-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. PMID:27630707

  10. A quantitative structure activity/dose response relationship for contact allergic potential of alkyl group transfer agents.

    PubMed

    Roberts, D W; Basketter, D A

    1990-11-01

    As part of the investigation of structure activity relationships in contact allergy, it has been shown that methyl transfer agents are capable of acting as skin sensitizers. This work has now been extended to a more general examination of alkyl transfer reactions. The modified single injection adjuvant test has been used to investigate the sensitization potential of C12, C16 and unsaturated C18 alkyl transfer agents. Dose responses to challenge and the patterns of cross-reactivity between these materials and methyl transfer agents have been studied. All alkyl transfer agents examined were potent sensitizers in the guinea pig. There was evidence of mutual cross-reactivity between all alkyl transfer agents examined (including methyl transfer agents). Analysis of the data in terms of a modified relative alkylation index showed evidence of an overload effect. The sensitization data has been accurately modelled using a mathematical equation. These results emphasize the possibilities for relating physicochemical parameters and skin sensitization potential. Further studies with alkyl transfer agents are in progress of amplify the observations and conclusions presented in this report. No in vitro model is available for the prediction of skin sensitization potential. Therefore an approach based on a model using physicochemical criteria is the most likely route to a reduced requirement for animal testing. PMID:1965716

  11. 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

    2015-08-25

    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.

  12. QMRA for Drinking Water: 1. Revisiting the Mathematical Structure of Single-Hit Dose-Response Models.

    PubMed

    Nilsen, Vegard; Wyller, John

    2016-01-01

    Dose-response models are essential to quantitative microbial risk assessment (QMRA), providing a link between levels of human exposure to pathogens and the probability of negative health outcomes. In drinking water studies, the class of semi-mechanistic models known as single-hit models, such as the exponential and the exact beta-Poisson, has seen widespread use. In this work, an attempt is made to carefully develop the general mathematical single-hit framework while explicitly accounting for variation in (1) host susceptibility and (2) pathogen infectivity. This allows a precise interpretation of the so-called single-hit probability and precise identification of a set of statistical independence assumptions that are sufficient to arrive at single-hit models. Further analysis of the model framework is facilitated by formulating the single-hit models compactly using probability generating and moment generating functions. Among the more practically relevant conclusions drawn are: (1) for any dose distribution, variation in host susceptibility always reduces the single-hit risk compared to a constant host susceptibility (assuming equal mean susceptibilities), (2) the model-consistent representation of complete host immunity is formally demonstrated to be a simple scaling of the response, (3) the model-consistent expression for the total risk from repeated exposures deviates (gives lower risk) from the conventional expression used in applications, and (4) a model-consistent expression for the mean per-exposure dose that produces the correct total risk from repeated exposures is developed.

  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. Advancing Dose-Response Assessment Methods for Environmental Regulatory Impact Analysis: A Bayesian Belief Network Approach Applied to Inorganic Arsenic

    PubMed Central

    Zabinski, Joseph W.; Garcia-Vargas, Gonzalo; Rubio-Andrade, Marisela; Fry, Rebecca C.; Gibson, Jacqueline MacDonald

    2016-01-01

    Dose-response functions used in regulatory risk assessment are based on studies of whole organisms and fail to incorporate genetic and metabolomic data. Bayesian belief networks (BBNs) could provide a powerful framework for incorporating such data, but no prior research has examined this possibility. To address this gap, we develop a BBN-based model predicting birthweight at gestational age from arsenic exposure via drinking water and maternal metabolic indicators using a cohort of 200 pregnant women from an arsenic-endemic region of Mexico. We compare BBN predictions to those of prevailing slope-factor and reference-dose approaches. The BBN outperforms prevailing approaches in balancing false-positive and false-negative rates. Whereas the slope-factor approach had 2% sensitivity and 99% specificity and the reference-dose approach had 100% sensitivity and 0% specificity, the BBN's sensitivity and specificity were 71% and 30%, respectively. BBNs offer a promising opportunity to advance health risk assessment by incorporating modern genetic and metabolomic data.

  15. Specific accumulation of orally administered redox nanotherapeutics in the inflamed colon reducing inflammation with dose-response efficacy.

    PubMed

    Vong, Long Binh; Mo, John; Abrahamsson, Bertil; Nagasaki, Yukio

    2015-07-28

    Although current medications for ulcerative colitis (UC) are effective to some extent, there are still some limitation of their use due to the non-specific distribution, drug metabolism in the gastrointestinal tract, and severe adverse effects. In our previous studies, we developed oral redox nanoparticles (RNP(O)) that specifically accumulated and scavenged overproduced reactive oxygen species (ROS) in an inflamed colon. However, the mechanism leading to specific accumulation of RNP(O) in an inflamed colon is still unclear. In this study, we investigated the cellular uptake of RNP(O) into ROS-treated epithelial colonic cells in vitro, and compared to the untreated cells, found a significantly increased uptake in ROS-treated cells. In vivo, we discovered that orally administered RNP(O) were not internalized into the cells of a normal colon. A significant amount of disintegrated RNP(O) was detected in the cells of an inflamed colon of dextran sodium sulfate (DSS)-induced colitis mice, resulting in scavenging of ROS and suppression of inflammation with low adverse effects. Furthermore, we confirmed a significant reduction of disease activity and a robust dose response efficacy following RNP(O) treatment in acute DSS-induced colitis mice, outperforming the positive control 5-aminosalicylic acid. Oral administration of RNP(O) is a promising approach to develop a new therapy for UC disease. PMID:25998050

  16. Dose-response relationship between total cadmium intake and prevalence of renal dysfunction using general linear models.

    PubMed

    Hochi, Y; Kido, T; Nogawa, K; Kito, H; Shaikh, Z A

    1995-01-01

    To determine the maximum allowable intake limits for chronic dietary exposure to cadmium (Cd), the dose-response relationship between total Cd intake and prevalence of renal dysfunction was examined using general linear models considering the effect of age as a confounder. The target population comprised 1850 Cd-exposed and 294 non-exposed inhabitants of Ishikawa, Japan. They were divided into 96 subgroups by sex, age (four categories) cadmium concentrations in rice (three categories) and length of residence (four categories). As indicators of the cadmium-induced renal dysfunction, glucose, total protein, amino nitrogen, beta 2-microglobulin and metallothionein in urine were employed. General linear models were fitted statistically to the relationship among prevalence of renal dysfunction, sex, age and total Cd intake. Prevalence of abnormal urinary findings other than glucosuria had significant associations with total Cd intake. When total Cd intake corresponding to the mean prevalence of each abnormal urinary finding in the non-exposed subjects was calculated using general linear models, total Cd intakes corresponding to glucosuria, proteinuria, aminoaciduria (men only) and proteinuria with glucosuria were determined to be ca. 2.2-3.8 g and those corresponding to prevalence of metallothioneinuria were calculated as ca. 1.5-2.6 g. The low-molecular-weight protein in urine was confirmed to be a more sensitive indicator of renal dysfunction, and these total Cd intake values were close to those calculated previously by simple regression analysis, suggesting them to be reasonable values as the maximum allowable intake of Cd.

  17. 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

  18. 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.

  19. 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. PMID:27630707

  20. 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.

  1. 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.

  2. EMS in Viracept--initial ('traditional') assessment of risk to patients based on linear dose response relations.

    PubMed

    Gocke, Elmar; Müller, Lutz; Pfister, Thomas

    2009-11-12

    Prior to having performed in depth toxicological, genotoxicological and DMPK studies on ethyl methanesulfonate (EMS) providing solid evidence for a thresholded dose response relationship, we had prepared and shared with regulatory authorities a preliminary risk estimate based on standard linear dose-effect projections. We estimated that maximal lifetime cancer risk was in the order of 10(-3) (for lifetime ingestion of the maximally contaminated tablets) or 10(-4) for the exposure lasting for 3 months. This estimate was based on a lifetime cancer study with methyl methanesulfonate (MMS; as insufficient data were available for EMS) in rodents and default linear back extrapolation. Analogous estimates were made specifically for breast cancer based on short term tumorigenicity studies with EMS in rats, for the induction of heritable mutations based on specific locus and dominant lethal tests in mice and for the induction of birth defects based on teratogenicity studies in mice. We concluded that even under worst case assumptions of linear dose relations the chance of experiencing these adverse effects would be very small, comprising at most a minute additional burden among the background incidence of the patients.

  3. 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

  4. Dose-response efficacy and long-term effect of the hypocholesterolemic effect of octadecylpectinamide in rats.

    PubMed

    Marounek, Milan; Volek, Zdeněk; Dušková, Dagmar; Tůma, Jan; Taubner, Tomáš

    2013-09-12

    The dose-response efficiency and long-term effect of the hypocholesterolemic effect of octadecylpectinamide was examined in female rats fed diets containing cholesterol at 10 g/kg. In our first experiment, amidated pectin supplied at 20 g/kg, 40 g/kg and 60 g/kg significantly decreased serum cholesterol from 3.32 μmol/ml (control) to 1.23 μmol/ml in a dose-dependent manner. In a second experiment, the hypocholesterolemic effect of amidated pectin supplied at 20 g/kg persisted after 3 months of feeding. In both experiments, the amidated pectin significantly decreased the concentrations of cholesterol in hepatic tissue and triacylglycerols in serum. The serum concentration of aspartate aminotransferase significantly increased in rats fed amidated pectin at 60 g/kg for 4 weeks, and at 20 g/kg for 3 months. In conclusion, amidated pectin at a low dose and used for a period shorter than 3 months might be considered as an effective hypocholesterolemic and lipid-lowering agent that may substitute typical antilipidemic drugs.

  5. QMRA for Drinking Water: 1. Revisiting the Mathematical Structure of Single-Hit Dose-Response Models.

    PubMed

    Nilsen, Vegard; Wyller, John

    2016-01-01

    Dose-response models are essential to quantitative microbial risk assessment (QMRA), providing a link between levels of human exposure to pathogens and the probability of negative health outcomes. In drinking water studies, the class of semi-mechanistic models known as single-hit models, such as the exponential and the exact beta-Poisson, has seen widespread use. In this work, an attempt is made to carefully develop the general mathematical single-hit framework while explicitly accounting for variation in (1) host susceptibility and (2) pathogen infectivity. This allows a precise interpretation of the so-called single-hit probability and precise identification of a set of statistical independence assumptions that are sufficient to arrive at single-hit models. Further analysis of the model framework is facilitated by formulating the single-hit models compactly using probability generating and moment generating functions. Among the more practically relevant conclusions drawn are: (1) for any dose distribution, variation in host susceptibility always reduces the single-hit risk compared to a constant host susceptibility (assuming equal mean susceptibilities), (2) the model-consistent representation of complete host immunity is formally demonstrated to be a simple scaling of the response, (3) the model-consistent expression for the total risk from repeated exposures deviates (gives lower risk) from the conventional expression used in applications, and (4) a model-consistent expression for the mean per-exposure dose that produces the correct total risk from repeated exposures is developed. PMID:26812257

  6. 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.

  7. Dose response of benzo(a)pyrene-induced mutagenesis using the BigBlue{reg_sign} transgenic mouse assay

    SciTech Connect

    Kotturi, G.; Holcroft, J.; Boer, J. de

    1997-10-01

    To investigate the dose response of benzo(a)pyrene-induced mutagenesis, groups of five BigBlue{reg_sign} transgenic mice were injected with a single intra-peritoneal dose were injected with corn oil containing benzo(a)pyrene to achieve the following concentrations: 0, 62.5, 125, 250, 500 mg/kg. Tissues were harvested after a 14 day expression time and analysed for mutational events. DNA adducts were measured in the liver of mice that were sacrificed 1 day after injection. The mutant frequency in the mouse liver linearly increased from 5.2 to 53.5 x 10{sup -5} in a dose-specific manner from 0 to 500 mg/kg benzo(a)pyrene. Mutants were sequenced to give an estimate of the number of clonal events as a function of benzo(a) pyrene with a total of 20 exposed animals (4 doses and five animals/dose), we established frequently mutated sites or `mutational hotspots` as well as a full mutational spectrum. Various other factors associated with the BigBlue{reg_sign} assay were analysed such as the effect of plating density on the purity of mutant plaques during the phage purification step.

  8. The evolution of beta2-agonists.

    PubMed

    Sears, M R

    2001-08-01

    Beta-agonists have been widely used in the treatment of asthma for many years Although concerns have been expressed over their safety based largely upon epidemics of increased mortality in asthmatics associated with high doses of isoprenaline in the 1960s and fenoterol in the 1970s and 1980s, the specific beta2-agonists are vital drugs in asthma management. The short-acting beta2-agonists have an important prophylactic role in the prevention of exercise-induced bronchoconstriction, and are essential in the emergency treatment of severe asthma. However, little if any benefit seems to be derived from regular use of short-acting beta2-agonists and regular or frequent use can increase the severity of the condition. The development of beta2-agonists with long-acting properties, such as salmeterol and formoterol, has provided advantages over short-acting beta-agonists, such as prolonged bronchodilation, reduced day- and night-time symptoms and improved quality of sleep, and has reduced the requirement for short-acting beta2-agonists as relief medication. Both drugs are well tolerated and, when added to inhaled corticosteroids, produce greater mprovement in lung function than increased steroid dose alone. Because of its rapid onset of action, formoterol also has the potential to be used for as-needed bronchodilator therapy in asthma.

  9. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  10. Interactions of dopaminergic agonists and antagonists with dopaminergic D3 binding sites in rat striatum. Evidence that (/sup 3/H)dopamine can label a high affinity agonist-binding state of the D1 dopamine receptor

    SciTech Connect

    Leff, S.E.; Creese, I.

    1985-02-01

    The interactions of dopaminergic agonists and antagonists with /sup 3/H-agonist labeled D3 dopaminergic binding sites of rat striatum have been characterized by radioligand-binding techniques. When the binding of (/sup 3/H)dopamine and (/sup 3/H)apomorphine to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone, these ligands appear to label selectively the previously termed D3 binding site. Antagonist/(/sup 3/H)dopamine competition curves are of uniformly steep slope (nH . 1.0), suggesting the presence of a single D3 binding site. The relative potencies of antagonists to inhibit D3 specific (/sup 3/H)dopamine binding are significantly correlated with their potencies to block D1 dopamine receptors as measured by the inhibition of both dopamine-stimulated adenylate cyclase and (/sup 3/H)flupentixol-binding activities. The affinities of agonists to inhibit D3 specific (/sup 3/H)dopamine binding are also correlated with estimates of these agonists affinities for the high affinity binding component of agonist/(/sup 3/H)flupentixol competition curves. Both D3 specific (/sup 3/H) dopamine binding and the high affinity agonist-binding component of dopamine/(/sup 3/H)flupentixol competition curves show a similar sensitivity to guanine nucleotides. Taken together, these data strongly suggest that the D3 binding site is related to a high affinity agonist-binding state of the D1 dopamine receptor.

  11. 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...

  12. 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, ...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells

    DOE PAGES

    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

  18. Automated quantitative dose-response modeling and point of departure determination for large toxicogenomic and high-throughput screening data sets.

    PubMed

    Burgoon, Lyle D; Zacharewski, Timothy R

    2008-08-01

    Regulatory and homeland security agencies undertake safety and risk assessments to assess the potential hazards of radiation, chemical, biological, and pharmaceutical agents. By law, these assessments must be science-based to ensure public safety and environmental quality. These agencies use dose-response modeling and benchmark dose methods to identify points of departure across single end points elicited by the agent. Regulatory agencies have also begun to examine toxicogenomic data to identify novel biomarkers of exposure and assess potential toxicity. The ToxResponse Modeler streamlines analyses and point of departure (POD) calculations across hundreds of responses (e.g., differential gene expression, changes in metabolite levels) through an automated process capable of large-scale modeling and model selection. The application identifies the best-fit dose-response model utilizing particle swarm optimization and calculates the probabilistic POD. The application analyzed a publicly available 2,3,7,8-tetrachlorodibenzo-p-dioxin dose-response data set of hepatic gene expression data in C57BL/6 mice to identify putative biomarkers. The Gene Ontology mapped these responses to specific functions to differentiate adaptive effects from toxic responses. In principle, safety and risk assessors could use the automated ToxResponse Modeler to analyze any large dose-response data set including outputs from high-throughput screening assays to assist with the ranking and prioritization of compounds that warrant further investigation or development.

  19. The Skipping Rope Curve

    ERIC Educational Resources Information Center

    Nordmark, Arne; Essen, Hanno

    2007-01-01

    The equilibrium of a flexible inextensible string, or chain, in the centrifugal force field of a rotating reference frame is investigated. It is assumed that the end points are fixed on the rotation axis. The shape of the curve, the skipping rope curve or "troposkien", is given by the Jacobi elliptic function sn. (Contains 3 figures.)

  20. Anodic Polarization Curves Revisited

    ERIC Educational Resources Information Center

    Liu, Yue; Drew, Michael G. B.; Liu, Ying; Liu, Lin

    2013-01-01

    An experiment published in this "Journal" has been revisited and it is found that the curve pattern of the anodic polarization curve for iron repeats itself successively when the potential scan is repeated. It is surprising that this observation has not been reported previously in the literature because it immediately brings into…

  1. Agonist self-inhibition at the nicotinic acetylcholine receptor a nonspecific action

    SciTech Connect

    Forman, S.A.; Firestone, L.L.; Miller, K.W.

    1987-05-19

    Agonist concentration-response relationships at nicotinic postsynaptic receptors were established by measuring /sup 86/Rb/sup +/ efflux from acetylcholine receptor rich native Torpedo membrane vesicles under three different conditions: (1) integrated net ion efflux (in 10 s) from untreated vesicles, (2) integrated net efflux from vesicles in which most acetylcholine sites were irreversibly blocked with ..cap alpha..-bungarotoxin, and (3) initial rates of efflux (5-100 ms) from vesicles that were partially blocked with ..cap alpha..-bungarotoxin. Exposure to acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, or (-)-nicotine over 10/sup 8/-fold concentration ranges results in bell-shaped ion flux response curves due to stimulation of acetylcholine receptor channel opening at low concentrations and inhibition of channel function at 60-2000 times higher concentrations. Concentrations of agonists that inhibit their own maximum /sup 86/Rb/sup +/ efflux by 50% (K/sub B/ values) are 110, 211, 3.0, 39, and 8.9 mM, respectively, for the agonists listed above. For acetylcholine and carbamylcholine, K/sub B/ values determined from both 10-s and 15-ms efflux measurements are the same, indicating that the rate of agonist-induced desensitization increases to maximum at concentrations lower than those causing self-inhibition. For all partial and full agonists studied, Hill coefficients for self-inhibition are close to 1.0. Concentrations of agonists up to 8 times K/sub B/ did not change the order parameter reported by a spin-labeled fatty acid incorporated in Torpedo membranes. The authors conclude that agonist self-inhibition cannot be attributed to a general nonspecific membrane perturbation. Instead, these results are consistent with a saturable site of action either at the lipid-protein interface or on the acetylcholine receptor protein itself.

  2. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  3. 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

  4. 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.

  5. 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.

  6. Dose response effects of dermally applied diethanolamine on neurogenesis in fetal mouse hippocampus and potential exposure of humans.

    PubMed

    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.

  7. Dose-response of chronic ultraviolet exposure on epidermal forward scattering-absorption in SK-1 hairless mouse skin.

    PubMed

    Menter, J M; Agin, P P; Sayre, R M; Willis, I

    1992-05-01

    This work provides a dose-response model of UV-induced epidermal-stratum corneum thickening induced by irradiation at wavelength lambda. This model assumes that photobiochemical reaction(s) can give rise to hyperplasia in a manner which is predictable from a simple photochemical kinetic scheme. In this work, we derive an equation which predicts an approximately linear relationship between the logarithm of the increase in optical skin thickening measured at 320 nm (delta OD320) and total cumulative dose (DT) seen by the target cells in or near the basal layer. For each excitation wavelength lambda, the slope R(lambda) of the log delta OD320 vs DT plot is proportional to epsilon(lambda) phi rx, where epsilon(lambda) is the extinction coefficient for the target chromophore at excitation wavelength, and phi rx is the quantum yield for the photochemical reaction(s) leading to hyperplasia. Our data previously obtained from irradiation of SK-1 hairless mice with "monochromatic" UV wavebands at 280, 290, 300, 307 and 313 nm (Menter et al., 1988, Photochem. Photobiol. 47, 225-260.) and data from Sterenborg and van der Leun at 254 and 313 nm (1988, Photodermatology 5, 71-82) are in good agreement with this model, except for 254 and 280 nm excitation, which are greatly attenuated by epidermis-stratum corneum. For excitation at the latter wavelengths, "dark" regressive processes successfully compete with the "light" reaction(s) which lead to (pre)cancerous lesion. This difficulty notwithstanding, the "intrinsic" action spectrum for hyperplasia derived from these measurements indicates that the target chromophore preferentially absorbs in the UV-C region.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Dose-response and time course relationships for vitellogenin induction in male western fence lizards (Sceloporus occidentalis) exposed to ethinylestradiol.

    PubMed

    Brasfield, Sandra M; Weber, Lynn P; Talent, Larry G; Janz, David M

    2002-07-01

    The long-term goal of this research is to develop and validate an in vivo reptile model for endocrine-mediated toxicity using fence lizards (Sceloporus spp.). One of the best defined estrogenic responses in oviparous vertebrates is induction of the yolk precursor protein, vitellogenin (Vtg). In this study, dose-response and time course relationships for Vtg induction were determined in male western fence lizards (Sceloporus occidentalis) given intraperitoneal injections of 17alpha-ethinylestradiol (EE2). Plasma Vtg was quantified directly with an antibody-capture enzyme-linked immunosorbent assay (ELISA) and indirectly using plasma alkaline-labile phosphate (ALP) in order to compare these two methods. Both ELISA and ALP predicted similar median effective dose (ED50 [dose causing a 50% maximal response]) values for plasma Vtg induction (0.167 mg/kg for ELISA and 0.095 mg/kg for ALP). In addition, both ELISA and ALP detected significant Vtg induction at a dose of 0.0003 mg/kg of EE2, which was the lowest dose used in our study. A decrease in body weight at the highest dose (10 mg/kg) and an increase in hepatosomatic index at the four highest doses were observed. Serial dilutions of plasma from an EE2-exposed male revealed a high correlation between plasma Vtg and ALP determinations in this species. In conclusion, our data show that plasma ALP may be a suitable alternative for measuring plasma Vtg compared with developing a Vtg ELISA in fence lizards exposed to estrogenic compounds. PMID:12109741

  9. 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.

  10. Dose-response of 1, 3, and 5 sets of resistance exercise on strength, local muscular endurance, and hypertrophy.

    PubMed

    Radaelli, Regis; Fleck, Steven J; Leite, Thalita; Leite, Richard D; Pinto, Ronei S; Fernandes, Liliam; Simão, Roberto

    2015-05-01

    The study's purpose was to compare the response of performing 1, 3, and 5 sets on measures of performance and muscle hypertrophy. Forty-eight men, with no weight training experience, were randomly assigned to one of the 3 training groups, 1 SET, 3 SETS, 5 SETS, or control group. All training groups performed 3 resistance training sessions per week for 6 months. The 5 repetition maximum (RM) for all training groups increased in the bench press (BP), front lat pull down (LPD), shoulder press (SP), and leg press (LP) (p ≤ 0.05), with the 5 RM increases in the BP and LPD being significantly greater for 5 SETS compared with the other training groups (p ≤ 0.05). Bench press 20 RM in the 3-SET and 5-SET groups significantly increased with the increase being significantly greater than the 1-SET group and the 5-SET group increase being significantly greater than the 3-SET group (p ≤ 0.05). LP 20 RM increased in all training groups (p ≤ 0.05), with the 5-SETS group showing a significantly greater increase than the 1-SET group (p ≤ 0.05). The 3-SET and 5-SET groups significantly increased elbow flexor muscle thickness (MT) with the 5-SET increase being significantly greater than the other 2 training groups (p ≤ 0.05). The 5-SET group significantly increased elbow extensor MT with the increase being significantly greater than the other training groups (p ≤ 0.05). All training groups decreased percent body fat, increased fat-free mass, and vertical jump ability (p ≤ 0.05), with no differences between groups. The results demonstrate a dose-response for the number of sets per exercise and a superiority of multiple sets compared with a single set per exercise for strength gains, muscle endurance, and upper arm muscle hypertrophy.

  11. 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.

  12. Dietary fiber intake and risk of type 2 diabetes: a dose-response analysis of prospective studies.

    PubMed

    Yao, Baodong; Fang, Hong; Xu, Wanghong; Yan, Yujie; Xu, Huilin; Liu, Yinan; Mo, Miao; Zhang, Hua; Zhao, Yanping

    2014-02-01

    Observational studies suggest an association between dietary fiber intake and risk of type 2 diabetes, but the results are inconclusive. We conducted a meta-analysis of prospective studies evaluating the associations of dietary fiber intake and risk of type 2 diabetes. Relevant studies were identified by searching EMBASE (from 1974 to April 2013) and PubMed (from 1966 to April 2013). The fixed or random-effect model was selected based on the homogeneity test among studies. In addition, a 2-stage random-effects dose-response meta-analysis was performed. We identified 17 prospective cohort studies of dietary fiber intake and risk of type 2 diabetes involving 19,033 cases and 488,293 participants. The combined RR (95 % CI) of type 2 diabetes for intake of total dietary fiber, cereal fiber, fruit fiber and insoluble fiber was 0.81 (0.73-0.90), 0.77 (0.69-0.85), 0.94 (0.88-0.99) and 0.75 (0.63-0.89), respectively. A nonlinear relationship was found of total dietary fiber intake with risk of type 2 diabetes (P for nonlinearity < 0.01), and the RRs (95 % CI) of type 2 diabetes were 0.98 (0.90-1.06), 0.97 (0.87-1.07), 0.89 (0.80-0.99), 0.76 (0.65-0.88), and 0.66 (0.53-0.82) for 15, 20, 25, 30, and 35 g/day. The departure from nonlinear relationship was not significant (P for nonlinearity = 0.72), and the risk of type 2 diabetes decreased by 6 % (RR 0.94, 95 % CI 0.93-0.96) for 2 g/day increment in cereal fiber intake. Findings from this meta-analysis indicate that the intakes of dietary fiber may be inversely associated with risk of type 2 diabetes.

  13. Dairy foods intake and risk of Parkinson's disease: a dose-response meta-analysis of prospective cohort studies.

    PubMed

    Jiang, Wenjie; Ju, Chuanxia; Jiang, Hong; Zhang, Dongfeng

    2014-09-01

    Dairy foods have been linked to Parkinson's disease (PD), and a meta-analysis of prospective cohort studies on dairy foods intake and PD risk was conducted. Eligible studies were identified in a literature search of EMBASE and PubMed up to April 2014. Seven results from prospective studies were included, including 1,083 PD cases among 304,193 subjects. The combined risk of PD for highest vs. lowest level of dairy foods intake was 1.40 (1.20-1.63) overall, 1.66 (1.29-2.14) for men and 1.15 (0.85-1.56) for women. For highest vs. lowest level, the PD risk was 1.45 (1.23-1.73) for milk, 1.26 (0.99-1.60) for cheese, 0.95 (0.76-1.20) for yogurt and 0.76 (0.51-1.13) for butter. The linear dose-response relationship showed that PD risk increased by 17% [1.17 (1.06-1.30)] for every 200 g/day increment in milk intake (Pfor non-linearity = 0.22), and 13% [1.13 (0.91-1.40)] for every 10 g/day increment in cheese intake (Pfor non-linearity = 0.39). The absolute risk differences were estimated to be 2-4 PD cases per 100,000 person-years for every 200 g/day increment in milk intake, and 1-3 PD cases per 100,000 person-years for every 10 g/day increment in cheese intake. Dairy foods (milk, cheese) might be positively associated with increased risk of PD, especially for men. PMID:24894826

  14. Dose response evaluation of gene expression profiles in the skin of K6/ODC mice exposed to sodium arsenite

    SciTech Connect

    Ahlborn, Gene J.; Nelson, Gail M.; Ward, William O.; Knapp, Geremy; Allen, James W.; Ouyang Ming; Roop, Barbara C.; Chen Yan; O'Brien, Thomas; Kitchin, Kirk T.; Delker, Don A.

    2008-03-15

    Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, we characterized gene expression profiles from analysis of K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Following exposure, total RNA was isolated from mouse skin and processed to biotin-labeled cRNA for microarray analyses. Skin gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 GeneChips (registered) , and pathway analysis was conducted with DAVID (NIH), Ingenuity (registered) Systems and MetaCore's GeneGo. Differential expression of several key genes was verified through qPCR. Only the highest dose (10 ppm) resulted in significantly altered KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, including MAPK, regulation of actin cytoskeleton, Wnt, Jak-Stat, Tight junction, Toll-like, phosphatidylinositol and insulin signaling pathways. Approximately 20 genes exhibited a dose response, including several genes known to be associated with carcinogenesis or tumor progression including cyclin D1, CLIC4, Ephrin A1, STAT3 and DNA methyltransferase 3a. Although transcription changes in all identified genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other systems suggests that these genes may play a role in the early stages of arsenic-induced skin carcinogenesis and can be considered potential biomarkers.

  15. 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.

  16. 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 d